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"A new way of thinking about illness . . a igi pr spetiveon the persistence of human vulnerabilitWy.-Peter D. Kramer, author of Listening PtoPza

The New Science of

Darwinian Medicine

Acclaim for

Randolph M. Nesse and George C. Williams's

WHY WE GET SICK

"This is the most important book written about issues in biomedi-

cine in the last fifty years. When the world's leading evolutionary

biologist (Williams) teams up with a thoughtful physician

(Nesse), the product is a gripping exploration of why our bodies

respond the way they do to injury and disease."

-Michael S. Gazzaniga, Ph.D.,

director, Center for Neuroscience,

University of California at Davis

"Darwinian medicine . . . holds that there are evolutionary expla-

nations for human disease and physical frailties, just as for

everything else in biology, and that these insights can inspire

better treatments.... In Why We Qet Sick ... two proponents

of Darwinian medicine lay out the ambitious reach of the

adventurous new discipline."

-The New York Times Magazine

"Every so often, a book comes along that has the power to

change the way we live and die. This splendid book is one, and

it could well revolutionize the way physicians are taught, the

way they practice, and even the way parents watch over their

child with a fever or a cough."

-Professor Robert Ornstein,

author of The Psychology of Consciousness

"Would you accept that eating certain kinds of red meat couldhelp ward off heart attacks? That taking aspirin when you aresick could make things worse? That mothers should sleep rightnext to their infants to prevent sudden infant death? You mightafter hearing how your prehistoric ancestors lived, according toa small but growing tribe of 'Darwinian medicine' thinkers.They argue that for too long physicians have ignored the forcesthat shaped us over evolutionary eons.... Such ideas are ...controversial, but that's the point."

-Wall Street Journal

"Why We Qet Sick is certain to be recognized as one of the mostimportant books of the decade, and what's more, it's beautifullywritten."

-Roger Lewin,author of Human Evolution, 3rd Edition

"Why We Qet Sick offers both a provocative challenge to medi-cine and a thoughtful discussion of how evolutionary theoryapplies to people."

-Business Week

Randolph M. Nesse, M.D.George C. Williams, Ph.D.

WHY WE GET SICK

Randolph M. Nesse, M.D., is a practicing physician andprofessor and associate chair for education and academicaffairs in the Department of Psychiatry at the Universityof Michigan Medical School.

George C. Williams, Ph.D., is a professor emeritus ofecology and evolution at the State University at StonyBrook and editor of The Quarterly Review of Biology.

WHY WE GET SICKThe New Science

of Darwinian Medicine

Randolph M. Nesse, M.D.

George C. Williams, Ph.D.

VINTAGE BOOKS

A Division of Random House, Inc.

New York

FIRST VINTAGE BOOKS EDITION, JANUARY 1996

a division of Random House, Inc., New York, and simultaneously in Canadaby Random House of Canada Limited, Toronto. Originally published

in hardcover by Times Books, a division of Random House, Inc.,New York, in 1995.

Grateful acknowledgment is made to the following for permissionto reprint previously published material:

Lawrence M. Crapo and James F. Fries, M.D.: Two charts from Vitalityand Aging by Lawrence M. Crapo and James F. Fries, M.D.

(W. H. Freeman & Company, San Francisco, 1981).Reprinted by permission.

Harcourt Brace & Company: Chart 12-1 from Life: An Introductionto Biology by George C. Simpson, Colin S. Pittendrigh,

and Lewis H. Tiffany. Copyright C 1957 by George C. Simpson,Colin S. Pittendrigh, and Lewis H. Tiffany. Copyright renewed 1985

by Anne R. Simpson, Joan Simpson Burns, Ralph Tiffany,Helen Vishniac, and Elizabeth Leonie S. Wurr.

Reprinted by permission of Harcourt Brace & Company.

The Library of Congress has catalogedthe Times Books edition as follows:

Nesse, Randolph M.Why we get sick: the new science of Darwinian medicine

Randolph M. Nesse and George C. Williams.-1st ed.p. cm.

Includes bibliographical references and index.ISBN 0-8129-2224-7

1. Medicine-Philosophy. 2. Human evolution.3. Human biology. 4. Adaptation (Physiology)

I. Williams, George C. (George Christopher), 1926- II. Title.R723.N387 1995

610'.1-dc2O 94-27651Vintage ISBN: 0-679-74674-9

Illustrations by Jared M. Brown

Manufactured in the United States of America10 9 8 7

ACKNOWLEDGMENTS

Q - ur work has benefited enormously from commentsmade by many colleagues and friends who know morethan we do about certain aspects of medicine and evolu-tion. We have not always had the sense to take their

advice, so don't blame them for our mistakes. Among those whohave offered comments or other suggestions on the manuscript are:James Abelson, M.D., Ph.D., Laura Betzig, Ph.D., Helena Cronin,Ph.D., Lyubica Dabich, M.D., Wayne Davis, Ph.D., William Ens-minger, M.D., Paul Ewald, Ph.D., Joseph Fantone, M.D., RosalindFantone, R.N., Robert Fekety, M.D., Linda Garfield, M.D., RobertGreen, M.D., Daniel Hrdy, M.D., Sarah Hrdy, Ph.D., Matt Kluger,Ph.D., Isaac Marks, M.D., Steven Myers, M.D., James Neel, M.D.,Ph.D., Margie Profet, M.A., Robert Smuts, M.A., William Solo-man, M.D., Paul Turke, Ph.D., Alan Weder, M.D., Brant Wenegrat,M.D., and Elizabeth Young, M.D. For help in finding references weespecially thank Doris Williams, Jeanette Underhill, M.D., andJoann Tobin. A sabbatical provided by The University of Michiganwith support from John Greden, M.D., and George Curtis, M.D.,made it possible for Randolph Nesse to work on the manuscript atStanford University, where Brant Wenegrat, M.D., and AnneO'Reilly offered hospitality beyond measure. Barbara Polcyn's loyaland effective secretarial support was wonderful. We are grateful toour agent, John Brockman, for convincing us that we could presentserious new science in a book for a general audience and for handlingnegotiations and publishing details with great effectiveness, and toBarbara Williams for persuading us to take John Brockman seri-ously. The style and structure of the book are much improved thanksto detailed editing by Margaret Nesse and by our editor at TimesBooks, Elizabeth Rapoport.

ACKNOWLEDGMENTS

Our greatest debt is to those who made us realize that we had areason to write this book. They are the pioneers and visionarieswhose ideas and investigations form the heart of the now flourishingfield of Darwinian medicine. Some, like Paul Ewald and MargieProfet, figure prominently in several places in our text. Others arementioned more briefly or merely have their publications listed inour endnotes. We are confident that, over the next few years, theywill all be getting growing shares of the recognition they richlydeserve.

CONTENTS

Acknowledgments vPreface ix

1. The Mystery of Disease 32. Evolution by Natural Selection 133. Signs and Symptoms of Infectious Disease 264. An Arms Race Without End 495. Injury 666. Toxins: New, Old, and Everywhere 777. Genes and Disease: Defects, Quirks,

and Compromises 918. Aging as the Fountain of Youth 1079. Legacies of Evolutionary History 123

10. Diseases of Civilization 14311. Allergy 15812. Cancer 17113. Sex and Reproduction 18214. Are Mental Disorders Diseases? 20715. The Evolution of Medicine 234

Notes 251Index 273

vii

PREFACE

W xe first met and discovered our shared interests in1985 at a meeting of a group that later developedinto the Human Behavior and Evolution Society.One of us (Nesse) was a physician in the Department

of Psychiatry at the University of Michigan Medical School. Frustra-tion with psychiatry's lack of theoretical foundation and fascinationwith the extraordinary progress that evolutionary ideas had broughtto the field of animal behavior had led to his association with theUniversity of Michigan Evolution and Human Behavior Program.Colleagues in that interdisciplinary group, on hearing about his long-term interest in the evolutionary origins of aging, suggested a 1957paper by a biologist named George Williams. The paper was a reve-lation. Aging had an evolutionary explanation. Why not anxietydisorders or schizophrenia? Thanks to subsequent years of conversa-tions with evolutionists, especially Williams, and with medicalschool residents and faculty, he has found that an evolutionary per-spective on patients' disorders has become steadily more natural anduseful.

The other author (Williams) has divided his career betweenmarine ecological research and theoretical studies on evolution. Hisinterest in medical applications of evolutionary ideas was aroused byreading a 1980 article by Paul Ewald in The Journal of Theoretical Biol-ogy, "Evolutionary Biology and the Treatment of the Signs andSymptoms of Infectious Disease." Ewald's work suggested that evo-lutionary ideas might well have significance for many medical prob-lems, not just those that arise from infection. Williams' generalknowledge of evolutionary genetics included many principles withobvious implications for genetic diseases, and his early work on theevolution of the aging process suggested a basic relevance of evolu-tion to gerontology.

PREFACE

We convinced each other, shortly after we met, that the potentialcontribution of evolutionary biology to medical progress was impor-tant enough to justify a real effort to bring this idea to others. Wedecided to put our reasoning and some obvious examples into printas a way of stimulating other workers to explore many other possi-bilities. After our jointly written article, "The Dawn of DarwinianMedicine," published in The Quarterly Review of Biology in March1991, drew a favorable reception from the press as well as colleaguesin both medicine and evolutionary biology, we decided that it couldeasily be expanded into a book that would interest a wide range ofreaders.

Charles Darwin's theory of natural selection as the explanationfor the functional design of organisms is the foundation of almosteverything in this book. The discussion centers on the concept ofadaptation by natural selection: adaptations by which we combatpathogens, adaptations of pathogens that counter our adaptations,maladaptive but necessary costs of our adaptations, maladaptativemismatches between our body's design and our current environ-ments, and so on.

As we wrote, we kept discovering new ways in which Darwinismcan aid the progress of medicine. We gradually realized that Darwin-ian medicine is not just a few ideas, but a whole new field, with excit-ing new developments arising at an ever-increasing rate. However, wemust emphasize that Darwinian medicine is still in its infancy. Theexamples of Darwinian thinking applied to medical problems shouldnot be taken as authoritative conclusions or medical advice. They aredesigned only to illustrate the use of evolutionary thinking in medi-cine, not to instruct people on how to protect their health or treattheir diseases. This is not to say that we believe Darwinian medicineis merely a theoretical endeavor. Far from it! We have every expecta-tion that the pursuit of evolutionary questions will demonstrablyimprove human health. That will require effort, money, and time. Inthe meanwhile, we hope this book will stimulate people to thinkabout their illnesses in a different way, to ask questions of their doc-tors, perhaps even argue with them, but certainly not to ignore theirinstructions.

Having made that disclaimer, we will also make a few others. Thisbook does not arise from a disapproval of current medical research orpractice in Western industrialized nations. It is based on the convic-tion that medical research and practice would be even better if ques-

PREFACE

tions of adaptation and historical causation were routinely consideredalong with those of immediate physical and chemical causation. Weare urging not an alternative to modern medical practice but rather anadditional perspective from a well-established body of scientificknowledge that has been largely neglected by the medical profession.We would be very much against Darwinian medicine being viewed asa kind of alternative cult opposed to some supposed orthodoxy. It islikewise not our purpose to make political recommendations,although we believe that some of our reasoning might prove impor-tant to those who formulate health care or environmental policies.

In addition to trying to make this book interesting and informa-tive to a wide audience, we have tried to make it a preliminary but sci-entifically valid guide for physicians and researchers who are askingevolutionary questions in their own areas of expertise. We well real-ize that many medical professionals have already been asking suchquestions. Often, however, they have done so apologetically, treatingtheir own ideas not as serious hypotheses but as mere speculationsundeserving of serious inquiry. We challenge this attitude as stronglyas possible and hope that the examples in this book will make manyscientists realize that their evolutionary hypotheses are legitimate anddeserve scientific testing, in ways that may be easier and more deci-sive than they suspect. This book does not offer formal instructionon how to test evolutionary hypotheses, but it does give many exam-ples of such testing.

We hope readers will realize that this meager book can provideonly a brief glimpse of a few current evolutionary ideas in relation toa select list of medical examples. Medicine is now such a huge fieldthat no one can master more than a small part of it. Even specialtiessuch as internal medicine are quickly splitting into subspecialties,such as cardiology, and into subsubspecialties. Neither of us claimsto have mastered more than a small fraction of the knowledge encom-passed by modern medicine. We are well aware that any discussionof such a wide range of topics as is found in this book must of neces-sity be superficial and oversimplified. We hope that this will not seri-ously mislead anyone and that specialists will forgive us for anyminor inaccuracies they may find. These risks seem worth it becauseof the potential utility of a broad overview of Darwinian medicineand because we believe that readers will derive real pleasure from anevolutionary understanding of their bodies' functioning, and occa-sional malfunctioning.

WHY WE GET SICK

THEMYSTERY OF

DISEASE

hy, in a body of such exquisite design, are there aW /thousand flaws and frailties that make us vulnerableto disease? If evolution by natural selection canshape sophisticated mechanisms such as the eye,

heart, and brain, why hasn't it shaped ways to prevent nearsighted-ness, heart attacks, and Alzheimer's disease? If our immune systemcan recognize and attack a million foreign proteins, why do we stillget pneumonia? If a coil of DNA can reliably encode plans for anadult organism with ten trillion specialized cells, each in its properplace, why can't we grow a replacement for a damaged finger? If wecan live a hundred years, why not two hundred?

We know more and more about why individuals get specific dis-eases but still understand little about why diseases exist at all. Weknow that a high-at diet causes heart disease and sun exposure causesskin cancer, but why do we crave fat and sunshine despite their dan-gers? Why can't our bodies repair clogged arteries and sun-damagedskin? Why does sunburn hurt? Why does anything hurt? And whyare we, after millions of years, still prone to streptococcal infection?

The great mystery of medicine is the presence, in a machine ofexquisite design, of what seem to be flaws, frailties, and makeshiftmechanisms that give rise to most disease. An evolutionary approach

WHY WE GET SICK

transforms this mystery into a series of answerable questions: Whyhasn't the Darwinian process of natural selection steadily eliminatedthe genes that make us susceptible to disease? Why hasn't it selectedfor genes that would perfect our ability to resist damage and enhancerepairs so as to eliminate aging? The common answer-that naturalselection just isn't powerful enough-is usually wrong. Instead, as wewill see, the body is a bundle of careful compromises.

The body's simplest structures reveal exquisite designs unmatchedby any human creations. Take bones. Their tubular form maximizesstrength and flexibility while minimizing weight. Pound for pound,they are stronger than solid steel bars. Specific bones are masterfullyshaped to serve their functions-thick at the vulnerable ends, stud-ded with surface protrusions where they increase muscle leverage,and grooved to provide safe pathways for delicate nerves and arteries.The thickness of individual bones increases wherever strength isneeded. Wherever they bend, more bone is deposited. Even the hol-low space inside the bones is useful: it provides a safe nursery for newblood cells.

Physiology is still more impressive. Consider the artificial kidneymachine, bulky as a refrigerator yet still a poor substitute that per-forms only a few of the functions of its natural counterpart. Or takethe best man-made heart valves. They last only a few years and crushsome red blood cells with each closure, while natural valves gentlyopen and close two and a half billion times over a lifetime. Or con-sider our brains, with their capacity to encode the smallest details oflife that, decades later, can be recalled in a fraction of a second. Nocomputer can come close.

The body's regulatory systems are equally admirable. Take, forinstance, the scores of hormones that coordinate every aspect of life,from appetite to childbirth. Controlled by level upon level of feed-back loops, they are far more complex than any man-made chemicalfactory. Or consider the intricate wiring of the sensorimotor system.An image falls onto the retina; each cell transmits its signal via theoptic nerve to a brain center that decodes shape, color, and move-ment, then to other brain centers that link with memory banks todetermine that the image is that of a snake, then to fear centers anddecision centers that motivate and initiate action, then to motornerves that contract exactly the right muscles to jerk the hand away-all this in a fraction of a second.

THE MYSTERY OF DISEASE

Bones, physiology, the nervous system-the body has thousands ofconsummate designs that elicit our wonder and admiration. By con-trast, however, many aspects of the body seem amazingly crude. Forinstance, the tube that carries food to the stomach crosses the tube thatcarries air to the lungs, so that every time we swallow, the airway mustbe closed off lest we choke. Or consider nearsightedness. If you are oneof the unlucky 25 percent who have the genes for it, you are almost cer-tain to become nearsighted and thus unlikely to recognize a tiger untilyou are nearly its dinner. Why haven't these genes been eliminated? Ortake atherosclerosis. An intricate network of arteries carries just theright amount of blood to every part of the body. Yet many of usdevelop cholesterol deposits on the walls of our arteries, and the result-ing blockage in blood flow causes heart attacks and strokes. It is as if aMercedes-Benz designer specified a plastic soda straw for the fuel line!

Dozens of other bodily designs seem equally inept. Each may beconsidered a medical mystery. Why do so many of us have allergies?The immune system is useful, of course, but why can't it leave pollenalone? For that matter, why does the immune system sometimesattack our own tissues to cause multiple sclerosis, rheumatic fever,arthritis, diabetes, and lupus erythematosus? And then there is nau-sea in pregnancy. How incomprehensible that nausea and vomitingshould so often plague future mothers at the very time when they areassuming the burden of nourishing their developing babies! And howare we to understand aging, the ultimate example of a universaloccurrence that seems functionally incomprehensible?

Even our behavior and emotions seem to have been shaped by aprankster. Why do we crave the very foods that are bad for us buthave less desire for pure grains and vegetables? Why do we keep eating when we know we are too fat? And why is our willpower so weakin its attempts to restrain our desires? Why are male and female sex-ual responses so uncoordinated, instead of being shaped for maxi-mum mutual satisfaction? Why are so many of us constantly anxious,spending our lives, as Mark Twain said, "suffering from tragediesthat never occur"? Finally, why do we find happiness so elusive, withthe achievement of each long-pursued goal yielding not contentment,but only a new desire for something still less attainable? The design ofour bodies is simultaneously extraordinarily precise and unbeliev-ably slipshod. It is as if the best engineers in the universe took everyseventh day off and turned the work over to bumbling amateurs.

WHY WE GET SICK

Two KINDS OF CAUSES

T w o resolve this paradox, we must discover the evolutionarycauses for each disease. By now it is obvious that these evo-lutionary causes of disease are different from the causesmost people think of. Consider heart attacks. Eating fatty

foods and having genes that predispose to atherosclerosis are majorcauses of heart attacks. These are what biologists call proximate("near") causes. We are more interested here in the evolutionarycauses, those that reach further back to why we are designed the waywe are. In studying heart attacks, the evolutionist wants to know whynatural selection hasn't eliminated the genes that promote fat cravingand cholesterol deposition. Proximate explanations address how thebody works and why some people get a disease and others don't.Evolutionary explanations show why humans, in general, are suscep-tible to some diseases and not to others. We want to know why someparts of the human body are so prone to failure, why we get some dis-eases and not others.

When proximate and evolutionary explanations are carefully dis-tinguished, many questions in biology make more sense. A proxi-mate explanation describes a trait-its anatomy, physiology, andbiochemistry, as well as its development from the genetic instruc-tions provided by a bit of DNA in the fertilized egg to the adult indi-vidual. An evolutionary explanation is about why the DNA specifiesthe trait in the first place and why we have DNA that encodes for onekind of structure and not some other. Proximate and evolutionaryexplanations are not alternatives-both are needed to understandevery trait. A proximate explanation for the external ear wouldinclude information about how it focuses sound, the tissues it ismade of, its arteries and nerves, and how it develops from theembryo to the adult form. Even if we know all this, however, we stillneed an evolutionary explanation of how its structure gives creatureswith ears an advantage, why those that lack the structure are at a dis-advantage, and what ancestral structures were gradually shaped bynatural selection to give the ear its current form. To take anotherexample, a proximate explanation of taste buds describes their struc-ture and chemistry, how they detect salt, sweet, sour, and bitter, andhow they transform this information into impulses that travel via

THE MYSTERY OF DISEASE

neurons to the brain. An evolutionary explanation of taste budsshows why they detect saltiness, acidity, sweetness, and bitternessinstead of other chemical characteristics, and how the capacities todetect these characteristics help the bearer to cope with life.

Proximate explanations answer "what?" and "how?" questionsabout structure and mechanism; evolutionary explanations answer"why?" questions about origins and functions. Most medical researchseeks proximate explanations about how some part of the body worksor how a disease disrupts this function. The other half of biology, thehalf that tries to explain what things are for and how they got there, hasbeen neglected in medicine. Not entirely, of course. A primary task ofphysiology is to find out what each organ normally does; the wholefield of biochemistry is devoted to understanding how metabolic mech-anisms work and what they are for. But in clinical medicine, the searchfor evolutionary explanations of disease has been halfhearted at best.Since disease is often assumed to be necessarily abnormal, the study ofits evolution may seem preposterous. But an evolutionary approach todisease studies not the evolution of the disease but the design charac-teristics that make us susceptible to the disease. The apparent flaws inthe body's design, like everything else in nature, can be fully under-stood only with evolutionary as well as proximate explanations.

Are evolutionary explanations mere speculations, of intellectualinterest only? Not at all. For instance, consider morning sickness. If,as Seattle researcher Margie Profet has suggested, the nausea, vomit-ing, and food aversions that often accompany early pregnancyevolved to protect the developing fetus from toxins, then the symp-toms should begin when fetal-tissue differentiation begins, shoulddecrease as the fetus becomes less vulnerable, and should lead toavoidance of foods that contain the substances most likely to inter-fere with fetal development. As we will see, substantial evidencematches these predictions.

Evolutionary hypotheses thus predict what to expect in proximatemechanisms. For instance, if we hypothesize that the low iron levelsassociated with infection are not a cause of the infection but a part ofthe body's defenses, we can predict that giving a patient iron mayworsen the infection-as indeed it can. Trying to determine the evolu-tionary origins of disease is much more than a fascinating intellectualpursuit; it is also a vital yet underused tool in our quest to understand,prevent, and treat disease.

WHY WE GET SICK

THE CAUSES OF DISEASEE -xperts on various diseases often ask themselves why a par,ticular disease exists at all, and they often have some goodideas. In many cases, however, they confuse evolutionarywith proximate explanations, or do not know how to go

about testing their ideas, or are simply reluctant to propose explana-tions that seem outside the mainstream. These difficulties can per-haps be reduced with the help of a formal framework for Darwinianmedicine. To this end, we propose six categories of evolutionaryexplanations of disease. Each of these will be described at length inlater chapters, but this brief overview illustrates the logic of the enter-prise and provides an overview of the terrain ahead.

1. Defenses

D efenses are not actually explanations of disease, but becauseThey are so often confused with other manifestations of diseasewe list them here. A fair-skinned person with severe pneumonia maytake on a dusky hue and have a deep cough. These two signs of pneu-monia represent entirely different categories, one a manifestation ofa defect, the other a defense. The skin is blue because hemoglobin isdarker in color when it lacks oxygen. This manifestation of pneumo-nia is like a clank in a car's transmission. It isn't a preprogrammedresponse to the problem, it is just a happenstance result with no par-ticular utility. A cough, on the other hand, is a defense. It resultsfrom a complex mechanism designed specifically to expel foreignmaterial in the respiratory tract. When we cough, a coordinated pat-tern of movements involving the diaphragm, chest muscles, andvoice box propels mucus and foreign matter up the trachea and intothe back of the throat, where it can be expelled or swallowed to thestomach, where acid destroys most bacteria. Cough is not a happen-stance response to a bodily defect; it is a coordinated defense shapedby natural selection and activated when specialized sensors detectcues that indicate the presence of a specific threat. It is, like the lighton a car's dashboard that turns on automatically when the gas tank isnearly empty, not a problem itself but a protective response to aproblem.

THE MYSTERY OF DISEASE

This distinction between defenses and defects is not merely of aca-demic interest. For someone who is sick it can be crucial. Correctinga defect is almost always a good thing. If you can do something tomake the clanking in the transmission stop or the pneumonia patient'sskin turn warm pink, it is almost always beneficial. But eliminating adefense by blocking it can be catastrophic. Cut the wire to the lightthat indicates a low fuel supply, and you are more likely to run out ofgas. Block your cough excessively, and you may die of pneumonia.

2. Infection

G iven that some bacteria and viruses treat us mainly as meals, weGcan think of them as enemies. Unfortunately, they are not justsimple pests put here to bedevil us but sophisticated opponents. Wehave evolved defenses to counter their threats. They have evolvedways to overcome our defenses or even to use them to their own ben-efit. This endlessly escalating arms race explains why we cannot erad-icate all infections and also explains some autoimmune diseases. Weexpand greatly on these topics in the next two chapters.

3. Novel Environments

O ur bodies were designed over the course of millions of years forOlives spent in small groups hunting and gathering on the plainsof Africa. Natural selection has not had time to revise our bodies forcoping with fatty diets, automobiles, drugs, artificial lights, and cen-tral heating. From this mismatch between our design and our envi-ronment arises much, perhaps most, preventable modern disease.The current epidemics of heart disease and breast cancer are tragicexamples.

4. Genes

S ome of our genes are perpetuated despite the fact that they causedisease. Some of their effects are "quirks" that were harmless

when we lived in a more natural environment. For instance, most ofthe genes that predispose to heart disease were harmless until webegan overindulging on fatty diets. The genes that cause nearsighted-ness cause problems only in cultures where children do close work

WHY WE GET SICK

early in life. Some of the genes that cause aging were subject to littleselection when average life spans were shorter.

Many other genes that cause disease have actually been selectedfor because they provide benefits, either to the bearer or to otherindividuals with the gene in other combinations. For instance, thegene that causes sickle-cell disease also prevents malaria. In additionto this well-known example, many others are discussed in later chap-ters, including sexually antagonistic genes that benefit fathers at theexpense of mothers or vice versa.

Our genetic code is constantly being disrupted by mutations. Onvery rare occasions these changes in DNA are beneficial, but muchmore commonly they create disease. Such damaged genes are con-stantly being eliminated or kept to a minimum by natural selection.For this reason defective genes with no compensating benefit are nota common cause of disease.

Finally, there are "outlaw" genes that facilitate their own trans-mission at the expense of the individual and thus bluntly demon-strate that selection acts ultimately to benefit genes, not individualsor species. Because selection among individuals is a potent evolu-tionary force, outlaw genes are also an uncommon cause of disease.

5. Design Compromises

Just as there are costs associated with many genes that offer an over-Jall benefit, there are costs associated with every major structuralchange preserved by natural selection. Walking upright gives us theability to carry food and babies, but it predisposes us to back prob-lems. Many of the body's apparent design flaws aren't mistakes, justcompromises. To better understand disease, we need to understandthe hidden benefits of apparent mistakes in design.

6. Evolutionary Legacies

E volution is an incremental process. It can't make huge jumps,Only small changes, each of which must be immediately beneficial.Major changes are difficult to accomplish even for human engineers.Fires occurred when a popular line of pickup truck was struck fromthe side because the gasoline tanks were located outside the frame. Butto locate the tanks within the frame would require a major redesign of

THE MYSTERY OF DISEASE

everything now there, which could cause new problems and requirenew compromises. Even human engineers can be constrained by his-torical legacies. Similarly, our food passes through a tube in front ofthe windpipe, and must cross it to get to the stomach, thus exposingus to the danger of choking. It would be more sensible to relocate thenostrils to somewhere on the neck, but that will never happen, as weexplain in Chapter 9.

WHAT WE ARE NOT SAYINGB -efore we discuss the details of the above causes of disease,we would like to try to forestall several potentially danger-ous misunderstandings. First of all, our enterprise has noth-ing to do with eugenics or Social Darwinism. We are not

interested here in whether the human gene pool is getting better orworse, and we are emphatically not advocating actions to improvethe species. We are not even particularly interested in most geneticdifferences between people, but much more in the genetic materialthat we all have in common.

An evolutionary perspective on disease does not change theancient goals of medicine carved on a statue honoring physician E. L.Trudeau's work at Saranac Lake: "To cure, sometimes, To help,often, To console, always." The goal of medicine has always been(and, in our belief, always should be) to help the sick, not the species.Confusion regarding this point has justified much mischief. At thebeginning of the century, Social Darwinist ideology helped to justifywithholding medical care from the poor and letting capitalist giantsbattle irrespective of effects on individuals. These beliefs were inti-mately linked to those of the eugenicists, who advocated sterilizationof certain groups in order to improve the species (or race!). Such ide-ology has long ago earned a well-deserved ill repute. It mademetaphorical use of some of the terminology of Darwinism but nouse of the theory as biologists understand it. We are by no meansadvocating that medicine should assist natural selection, nor do wesuggest that biology can guide moral decisions. We would neverargue that any disease is good, even though we will offer many exam-ples in which pathology is associated with some unappreciated bene-

WHY WE GET SICK

fit. Darwinism gives no moral guidelines about how we should live orhow doctors should practice medicine. A Darwinian perspective onmedicine can, however, help us to understand the evolutionary ori-gins of disease, and this knowledge will prove profoundly useful inachieving the legitimate goals of medicine.

EVOLUTION BYNATURAL SELECTION

Now, as each of the parts of the body, like everyother instrument, is for the sake of some purpose,viz. some action, it is evident that the body as awhole must exist for the sake of some complexaction.

-Aristotle

he solutions to the mysteries discussed in Chapter 1 are tobe found in the workings of natural selection. The processis fundamentally very simple: natural selection occurswhenever genetically influenced variation among individu-

als affects their survival and reproduction. If a gene codes for charac-teristics that result in fewer viable offspring in future generations,that gene is gradually eliminated. For instance, genetic mutations thatincrease vulnerability to infection, or cause foolish risk taking or lackof interest in sex, will never become common. On the other hand,genes that cause resistance to infection, appropriate risk taking, andsuccess in choosing fertile mates are likely to spread in the gene pool,even if they have substantial costs.

A classic example is the spread of a gene for dark wing color in aBritish moth population living downwind from major sources of airpollution. Pale moths were conspicuous on smoke-darkened treesand easily caught by birds, while a rare mutant form of moth whosecolor more closely matched that of the bark escaped the predators'

WHY WE GET SICK

beaks. As the tree trunks became darker, the mutant gene spreadrapidly and largely displaced the gene for pale wing color. That is allthere is to it. Natural selection involves no plan, no goal, and nodirection-just genes increasing and decreasing in frequency depend-ing on whether individuals with those genes have, relative to otherindividuals, greater or lesser reproductive success.

The simplicity of natural selection has been obscured by manymisconceptions. For instance, Herbert Spencer's nineteenth-centurycatch phrase "survival of the fittest" is widely thought to summarizethe process, but it actually promotes several misunderstandings. Firstof all, survival is of no consequence in and of itself. This is why nat-ural selection has created some organisms, such as salmon and annualplants, that reproduce only once, then die. Survival increases fitnessonly insofar as it increases later reproduction. Genes that increaselifetime reproduction will be selected for even if they result inreduced longevity. Conversely, a gene that decreases total lifetimereproduction will obviously be eliminated by selection even if itincreases an individual's survival.

Further confusion arises from the ambiguous meaning of "fittest."The fittest individual, in the biological sense, is not necessarily thehealthiest, strongest, or fastest. In today's world, and many of thoseof the past, individuals of outstanding athletic accomplishment neednot be the ones who produce the most grandchildren, a measure thatshould be roughly correlated with fitness. To someone who under-stands natural selection, it is no surprise that parents are so con-cerned about their children's reproduction.

A gene or an individual cannot be called "fit" in isolation but onlywith reference to a particular species in a particular environment.Even in a single environment, every gene involves compromises. Con-sider a gene that makes rabbits more fearful and thereby helps to keepthem from the jaws of foxes. Imagine that half of the rabbits in a fieldhave this gene. Because they do more hiding and less eating, thesetimid rabbits might be, on average, a bit less well fed than their boldercompanions. If, hunkered down in the March snow waiting forspring, two thirds of them starve to death while this is the fate of onlyone third of the rabbits who lack the gene for fearfulness, then, comespring, only a third of the rabbits will have the gene for fearfulness. Ithas been selected against. It might be nearly eliminated by a few harshwinters. Milder winters or an increased number of foxes could havethe opposite effect. It all depends on the current environment.

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NATURAL SELECTION BENEFITSGENES, NOT GROUPS

M [any people have seen the nature film in which drovesof starving lemmings jump eagerly to a watery death

as a resonant voice explains that when food becomesscarce, some lemmings sacrifice themselves so that

there will be enough food for at least some of the group to survive. Afew decades ago, such "group selection" explanations were takenseriously by professional biologists, but not now. To see why, com-pare two imaginary lemmings. One is a noble fellow who, upon sens-ing that the population is about to outrun its food supply, quicklyjumps to his death in the nearest stream. The other is a selfish loutwho waits for the noble ones to do away with themselves and theneats as much food as he can get, mates as often as possible, and has asmany offspring as possible. What would happen to the genes thatcode for the behavior of sacrificing oneself for the benefit of thegroup? No matter how beneficial they might be for the species, theywould be eliminated.

So how can we explain the observations of apparently suicidallemmings? When food becomes scarce in late winter, lemmingsmigrate, rushing along in large groups that do not always stop whenthey encounter waters created by early snowmelt. Drownings are,however, rather uncommon. To get the footage they wanted, themakers of the film apparently had to use brooms to surreptitiouslyherd the lemmings into the water, a dramatic example of the humanpreference for altering reality rather than theory when the two con-flict! There are special circumstances in which selection at the grouplevel can outweigh the usually stronger force of selection at the levelof the individual, but they do not apply very often.

As British biologist Richard Dawkins, author of The Selfish Gene,has emphasized, individuals may be viewed as vessels created bygenes for the replication of genes, to be discarded when the genes arethrough with them. This perspective mightily shakes the commonview that evolution tends toward a world of health, harmony, andstability. It does not create such a world. We would like to imaginethat life is naturally happy and healthy, but natural selection caresnot a whit for our happiness, and it promotes health only when it is

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in the interests of our genes. If tendencies to anxiety, heart failure,nearsightedness, gout, and cancer are somehow associated withincreased reproductive success, they will be selected for and we willsuffer even as we "succeed," in the purely evolutionary sense.

KIN SELECTIONW e have implied that reproduction is the essence ofthe fitness maximized by natural selection, and inour discussion of lemmings we indicated that evo-lution does not favor individuals who act to help

others at their own expense. These generalizations tell only part ofthe story. Ultimately, it is the genetic representation in future gener-ations that counts, whether that is accomplished by having childrenor by doing things that increase the reproduction of your close rela-tives, many of whose genes are identical to yours.

Half of the genes in a child are identical to those in the mother, andhalf are identical to those in the father. Full siblings, on average, alsoshare half of each other's genes. One fourth of the genes in a grandpar-ent are identical to those in the grandchild. Cousins share one eighth oftheir genes. This means that, from the perspective of your genes, yoursister's survival and reproduction are half as important as your ownand your cousin's one eighth as important. For this reason, selectionfavors extending help to relatives if, all else being equal (e.g., age andhealth), the cost to oneself of extending the help is less than the benefitto the relative times the degree of relationship. In a classic anecdote,British biologist J. B. S. Haldane was asked if he would sacrifice his lifefor his brother. "No," he said, "not for one brother. But I would fortwo brothers. Or eight cousins." Formal recognition of this principleand its importance in explaining cooperation awaited the landmark1964 paper by British biologist William Hamilton, winner of the 1993Crafoord Prize, created to honor scientists whose work is in fields notcovered by the Nobel Prize. Another great British biologist, John May-nard Smith, christened the phenomenon kin selection.

Another apparent exception to the nice-guys-finish-last principlein evolution is the result of reciprocal exchanges of favors betweenindividuals who need not be relatives. If Elsa is an expert maker ofshoes and Fritz is a skillful hunter of animals that supply excellent

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leather, trading resources will benefit them both. It pays me to benice to you, and vice versa. Ever since Robert Trivers's classic 1971paper on reciprocity theory, biologists have routinely interpretedcooperative relations among organisms in nature as resulting fromeither reciprocal exchanges or kin selection. The biology of social lifehas grown thanks to the efforts of pioneers such as E. 0. Wilson,author of Sociobiology, and Richard Alexander, author of Darwinismand Human Affairs. Early controversies and misunderstandings havebeen largely supplanted by growing work in this new field of science.

How DOES NATURALSELECTION OPERATE?T w here is a widespread misconception that evolution proceeds

according to some plan or direction, but it has neither, andthe role of chance ensures that its future course will beunpredictable. Random variations in individual organisms

create tiny differences in their Darwinian fitness. Some individualshave more offspring than others, and the characteristics that increasedtheir fitness thereby become more prevalent in future generations.Once upon a time (at least) a mutation occurred in a human populationin tropical Africa that changed the hemoglobin molecule in a way thatprovided resistance to malaria. This enormous advantage caused thenew gene to spread, with the unfortunate consequence that sickle-cellanemia came to exist, as will be discussed in later chapters.

Chance can influence the outcome at each stage: first in the cre-ation of a genetic mutation; second in whether the bearer lives longenough to show its effects; third in chance events that influence theindividual's actual reproductive success; fourth in whether a gene,even if favored in one generation, is, by happenstance, eliminated inthe next; and finally in the many unpredictable environmentalchanges that will undoubtedly occur in the history of any group oforganisms. As Harvard biologist Stephen Jay Gould has so vividlyexpressed it, if one could rewind the tape of biological history andstart the process over again, the outcome would surely be different.Not only might there not be humans, there might not even be any-thing like mammals.

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We will often emphasize the elegance of traits shaped by naturalselection, but the common idea that nature creates perfection needsto be analyzed carefully. The extent to which evolution achieves per-fection depends on exactly what you mean. If you mean "Does nat-ural selection always take the best path for the long-term welfare of aspecies?" the answer is no. That would require adaptation by groupselection, and this is, as noted above, unlikely. If you mean "Doesnatural selection create every adaptation that would be valuable?" theanswer again is no. For instance, some kinds of South Americanmonkeys can grasp branches with their tails. This trick would surelyalso be useful to some African species, but, simply because of badluck, none have it. Some combination of circumstances started someancestral South American monkeys using their tails in ways that ulti-mately led to an ability to grab onto branches, while no such devel-opment took place in Africa. Mere usefulness of a trait does notnecessarily mean that it will evolve.

There is a sense, however, in which natural selection does regu-larly come close to perfection, and that is in optimizing some quanti-tative features. If a trait serves a specific function, selection amongminor modifications over many generations tends to make its quan-titative aspects closely approach the functional ideal. For instance, abird's wings must be long enough to give good lift but short enoughto allow the bird to maintain control. Measurements on birds foundkilled after a major storm showed more than expected numbers ofunusually long or unusually short wings. The survivors showed abias toward intermediate (more nearly optimal) wing lengths.

In human physiology, there are hundreds of similar examples inwhich traits have been shaped to nearly optimal values: the sizes andshapes of bones, blood pressure, glucose level, pulse rate, age at onsetof puberty, stomach acidity-the list could go on and on. Theobserved values may never be exactly perfect, but they usually comeclose. When we think that natural selection has erred, it is morelikely that we have missed some important consideration. Forinstance, stomach acid aggravates ulcers, yet people who takeantacids can still digest their food. So is there too much acid? Proba-bly not, given the importance of stomach acid in digestion and inkilling bacteria, including those that cause tuberculosis. To identifythe imperfections of the body, one must first understand its perfec-tions and the compromises on which many of them are based.

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Like any engineer, evolution must constantly compromise. Anauto designer could increase the thickness of the fuel tank in order todecrease the risk of fire, but at some point increased cost anddecreased mileage and acceleration require a compromise. Thus, fueltanks do rupture in some collisions, and this compromise costs somelives each year. While natural selection cannot achieve perfection inevery character simultaneously, its compromises are not random butare accurately shaped to give the greatest net benefit.

An apocryphal story tells of Henry Ford looking at a junkyardfilled with Model Ts. "Is there anything that never goes wrong withany of these cars?" he asked. Yes, he was told, the steering columnnever fails. "Well then," he said, turning to his chief engineer,"redesign it. If it never breaks, we must be spending too much on it."Natural selection similarly avoids overdesign. If something workswell enough that its deficiencies do not constitute a selective force,there is no way natural selection can improve it. Thus, while everypart of the body has some reserve capacity to deal with occasionallyencountered extreme circumstances, every part is also vulnerablewhen its reserve capacity is exceeded. There is nothing in the bodythat never goes wrong.

Moderate increments of a resource often have enormous value,while higher amounts may have less benefit. If you are making a stew,two onions may be better than one, but ten onions would be muchmore expensive yet offer little, if any, extra benefit. Such cost-benefitanalyses are routine procedures in economics, but they are useful inbiology and medicine as well. Consider the use of an antibiotic forpneumonia. A tiny dose will probably have no detectable benefit, amoderate dose will cost more but offer much greater benefits, whilea high dose will have still higher costs with no additional benefits andperhaps significant danger.

Just as there are costs as well as benefits involved in every engi-neering or medical decision, there are costs associated with everybeneficial genetic change preserved in evolution. Natural selectionisn't weak or capricious; it just selects for genes that give an overallfitness advantage, even if those same genes increase vulnerability tosome disease. Is there any way, for instance, for anxiety to be a func-tionally desirable trait? Consider what would happen to those rabbitswe discussed if they had no anxiety in a year when foxes were espe-cially abundant. Even some genes that cause aging are not necessarily

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maladaptive. They may give benefits during the early years of life,when selection is the strongest, benefits that are more important tofitness than the later costs of aging and inevitable death. To under-stand disease better, we need to understand the hidden benefits ofapparent mistakes in design.

TESTING EVOLUTIONARY HYPOTHESEST w his chapter started with a quotation from Aristotle for aserious reason. We can think of him as the originator ofthe general procedure for functional analysis that has beenparticularly fruitful in many kinds of biological research

and that we expect to be similarly rewarding in medicine. There is, ofcourse, a big difference between Aristotle's outlook and that of mod-ern biologists. He had almost no grasp of the physical and chemicalprinciples that underlie the workings of any organism. He didn'tthink experiments were necessary. He had no notion of the principleof natural selection and certainly did not realize that organisms weredesigned entirely to maximize their success in reproduction.Whether applied to the human hand or brain or immune system,Aristotle's powerful question, "What is it for?" now has a very spe-cific scientific meaning: "How has this trait contributed to reproduc-tive success?" His conviction that the body as a whole exists for thesake of some complex action is correct. Only in the past few decadeshas it become clear that that complex action is reproduction.

Many people have the notion that questions about the function ofa trait are not scientific, that they are "teleological" or "speculative"and therefore not appropriate objects of scientific inquiry. This ideais incorrect, as many examples in this book will demonstrate. Ques-tions about the adaptive function of a biological trait are just asamenable to scientific inquiry as are questions about anatomy andphysiology. It makes sense to ask about the adaptive significance ofbiological traits such as eyes, ears, and the cough reflex because theyare products of historical processes that have gradually modifiedthem in ways that improve their capacity to serve special functions.

Yet when we ask these "why" questions, we must guard againsttoo readily believing fanciful stories. Why do we have prominentnoses? It must be to hold up eyeglasses. Why do babies cry for no

EVOLUTION BY NATURAL SELECTION

apparent reason? It must be to exercise their lungs. Why do we nearlyall die by age 100? It must be to make room for new individuals.Almost anything can be the subject of such speculation, but if this isas far as it goes it is not science. The problem is not in the questionsbut in a lack of adequate investigation and critical thinking about sug-gested answers.

The above absurd examples demonstrate how easily some expla-nations can be tested and proven false. Noses could not have evolvedto hold up glasses, since we had noses long before we had eyeglasses.Crying cannot be to develop the lungs, since lung health in adulthooddoes not require crying in infancy. Aging cannot have evolved tomake room for new individuals, because natural selection cannotfavor such benefits to the group and the details of aging simply do notconform to the expectations for such a function.

Other functional hypotheses are so easily supported that they areof little interest. Anyone thoroughly familiar with the heart's struc-ture and operation can see that it pumps blood. One can also see thatcoughing expels foreign material from the respiratory tract and thatshivering increases body heat. You don't need to be an evolutionaryscientist to figure out that teeth allow us to chew food. The interest-ing hypotheses are those that are plausible and important but not soobviously right or wrong. Such functional hypotheses can lead tonew discoveries, including many of medical importance.

THE ADAPTATIONIST PROGRAMS tudies of the functional reasons for human attributes arebased on a method of investigation recently named the adap-tationist program. By suggesting the functional significance ofsome known aspect of human biology, you may logically be

able to predict some other, unknown aspects. An appropriate inves-tigation can then confirm that these characteristics are either there ornot. If they are there, they may be of medical significance. If they'renot, we can eliminate our hypothesis and go back to the drawingboard.

We will give three examples here of interesting discoveries made byconsidering questions on how various features might contribute to fit-ness. They relate to beavers and birds but not to medical questions, for

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which we will give many examples in the chapters to come. To variousdegrees these examples show that intuitive ideas about fitness, even theintuitions of professional biologists, may not always be adequate. Seri-ous, often mathematical, theorizing is needed to provide the logicalanswers that can then be tested by investigating real organisms.

Beavers harvest trees in or near their ponds for their food andshelter. They use their teeth to chop through the trunks near theground, drag the trees to the water if they are not already in it, andtow them to their lodges. How do beavers decide which trees to chopdown? They do so adaptively, was the hypothesis considered byMichigan biologist Gary Belovsky. This implies an economicallyrational decision based on a tree's likely value to a beaver, the diffi-culty expected in chopping it down and moving it, and how far it isfrom home. Belovsky's calculations showed that an efficient beaverought to be increasingly discriminating as the distance from the pondincreases. Small trees may be rejected for not being worth the time totransport them, large ones for not being worth the labor of fellingand transporting them, especially dragging them or pieces of themthrough the woods to where they can be floated in the pond.Belovsky predicted that the range of sizes of trees harvested bybeavers would steadily decrease as the distance from the pondincreased. At some point, only trees of an ideal size would be har-vested; beyond that, none at all. Observation of stumps of beaver-felled trees near their ponds confirmed the prediction. The next timeyou see a beaver pond, admire not only the beaver's legendary indus-try but also its cleverness at setting priorities.

Now imagine a woodland songbird about to lay a clutch of eggsthat she and her mate will incubate. Her reproductive success for thisbreeding season will depend entirely on those eggs. How manyshould she lay? Remember, she is not trying to assure the survival ofthe species, she is trying to maximize her own lifetime reproductivesuccess. Laying too few eggs would obviously be foolish, but layingtoo many can also decrease her total lifetime reproduction if there isnot enough food and some of the chicks die, or if she exhausts herenergy reserves in caring for her brood and thus jeopardizes herchances of living until the next breeding season. These considerationsapply equally to every individual in the woodland, but different birdsreach different decisions on how many eggs to lay. If the average fora species is four eggs per pair, some pairs may have five and someonly three. Do we conclude that all are trying for four but some can't

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count? Or do we perhaps conclude that egg numbers are not subjectto optimization by natural selection?

An adaptationist forgoes such explanations until after consideringthe possibility that the birds deserve more credit. Could it be that, asa general rule, three eggs is best for those that lay only three, four forthose that lay four, and so on? A simple sort of experiment providesthe answer. If there are thirty nests with four eggs, leave ten randomlyselected nests alone. From ten other nests remove an egg (the ownersare now down to three) and add them to the ten remaining nests(four-egg birds now have five eggs). Now measure the average successof the three groups of birds: those allowed to choose their own eggnumber and those with one more or one less than they originally laid.

If all relevant factors are carefully considered, the results of suchstudies usually vindicate the conclusion reached fifty years ago byOxford ornithologist David Lack: birds adjust the number of eggsthey lay to maximize their individual reproductive success. To dothis requires an accurate assessment of their own individual healthand capabilities and experience. Having to provide food for fournestlings is more difficult and hazardous than providing for onlythree. Nestlings in more crowded nests may weigh less at fledging andbe less likely to survive the following winter. Conditions vary unpre-dictably from year to year, and worse-than-normal years are espe-cially dangerous for the more crowded broods. Surely suchknowledge enhances a naturalist's pleasure in watching a pair of wildbirds feed their young. Those birds are doing it right-not just rightin general or on average, but right for them as unique individuals.

In this discussion of clutch size we considered the optimal numberof offspring. We ignored the fact that there are two kinds of offspring,male and female. Should our birds ideally produce one or the other orboth in some ideal proportion? In the natural selection of sex ratio oneoverwhelmingly important strategy maximizes fitness: producing off-spring of whichever sex is in short supply. Any frequenter of singlesbars knows that the minority sex has a mating advantage. In nature,individuals that produce male offspring when females are scarce willbe selected against because many of those males will never have off-spring. If males are scarce, individuals that produce females will nothave as many grand-offspring as individuals who produce males. Theoperation of this process of selection explains why there are equalnumbers of males and females. This simple, elegant evolutionaryexplanation was first recognized by the great evolutionary geneticist

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R. A. Fisher in 1930. If you are thinking that an equal sex ratio arisesbecause an individual has an equal chance of getting an X or a Y chro-mosome from its father, you are right, but this is a proximate expla-nation. The insufficiency of a proximate explanation is demonstratedby the many special cases such as ants and fig wasps, which are toocomplex to describe here but in which grossly unequal sex ratios turnout to match the more complex predictions.

Does natural selection in fact produce populations with exactlythe same number of males and females? No, it does not, as would beexpected by detailed reflection on factors such as the two sexes reach-ing maturity at different ages, differing death rates, differing costs tomale and female parents, and other factors. Careful calculations sup-port the conclusion that, for organisms with sex-determination andreproductive processes like ours, the sex ratio will stabilize when theparents collectively spend equal resources on rearing sons and rear-ing daughters. The demography of human and many other popula-tions conforms closely to these expectations.

We hope to convince you in the coming chapters that the moderntheory of natural selection can be just as helpful in making medicallyimportant discoveries as it is for predicting the foraging patterns ofbeavers, the effects of altered clutch sizes of birds, and the sex ratiosof mammals. The reasoning will always start with some prior infor-mation about health or disease and a question about evolved adapta-tion: Is this feature of the human body a part of some adaptivemachinery? If so, what must the rest of the machinery be like? Howcan we test our predictions for unknown aspects of the machinery? Ifany feature of human biology seems functionally undesirable, howcan natural selection have permitted it to arise? Is an undesirable traitthe price of a positive feature? Could it be a trait that was adaptive inthe Stone Age but that now causes disease? What are the medical con-sequences of natural selection acting to improve adaptation in ourpathogens and parasites? These are just a few of the sorts of questionsnow routinely asked by evolutionary biologists, and efforts atanswering them have been enormously fruitful.

We must temper our enthusiasm with a note of caution. A ques-tion about function can have more than one right answer. Forinstance, the tongue is important both for chewing and for speech;the eyebrows, both for keeping the sweat out of the eyes and for com-munication. Second, the evolutionary history of a species or a diseaseis like any other kind of history. There is no experiment, in the usual

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sense, that we can do now to decide how long ago our ancestors firststarted to use fires for cooking or other purposes and what subse-quent evolutionary effects that change may have had. History can beinvestigated only by examining the records it has left. Charred bonesor even carbon deposits from an ancient campfire can be informativedocuments to people who know how to read them. Likewise, thechemical structure of proteins and DNA may be read to reveal rela-tionships among now strikingly different organisms. Until a timemachine is invented, we will not be able to go back and watch theevolution of major traits, but we can nonetheless reconstruct prehis-toric events by the records they left in fossils, carbon traces, struc-tures, and behavioral tendencies, as well as protein and DNAstructures. Even when we cannot reconstruct the history of a trait, wecan often still be confident that it was shaped by natural selection.This can be supported by evidence for its function in other speciesand by the match between the trait's characteristics and its functions.

So hypotheses about the evolutionary origins and functions of atrait, just like hypotheses about proximate aspects of a trait, needtesting and are often testable. Special difficulties attend the testing ofevolutionary hypotheses, but these are no reason to give up-theyjust make the work more challenging and interesting. Do we claim totest evolutionary hypotheses in this book? Not really. While we willtry to separate speculation from fact, and will cite evidence for mostof our examples, hardly any of them can be considered proven by theevidence we present. Some of the examples are based on many stud-ies, each with different data bearing on a different aspect of the prob-lem, but even this is often insufficient.

Our goal is not to prove any specific hypothesis but to show thatevolutionary questions are interesting, important, and testable. Wewant people to start asking new questions. So, without apology, weask questions about the possible evolutionary significance of diverseaspects of disease and offer answers that are often speculative. Somepeople will, despite our warnings, insist on taking these speculationsas facts. Perhaps in a few years Darwinian medicine will have enoughconfirmed findings to fill a book. For now, our goal is not to exhaus-tively test a few hypotheses but to encourage patients, doctors, andresearchers to ask new questions about why disease -exists. AsGertrude Stein said on her deathbed, "The answer, the answer, theanswer. What is the answer? ... In that case, what is the question?"

SIGNS ANDSYMPTOMS OF

INFECTIOUS DISEASE

oppose you are on the side of the mice in cat-mouse con-flicts. The mice say they hate the smell of a cat. It makesthem jittery and unable to concentrate on important mat-ters, such as food and courtship and babies. You know of a

drug that will dull the sense of smell so that the mice will no longer bebothered by the odor of cats. Do you prescribe the drug? Probablynot. The ability to detect cat odor, however unpleasant it may be, is avaluable asset for mice. The presence of the cat's smell may signal theimminent arrival of its claws and teeth, and avoiding these is far moreimportant than the stress of an unpleasant odor.

More realistically, suppose you are a pediatrician treating childrenwith colds. Colds bring many symptoms that children dislike-runny nose, headache, fever, and malaise. Acetaminophen (e.g.,Tylenol) can reduce or eliminate some of these symptoms. Do youtell the parents of cold-stricken children to give them aceta-minophen? If you are a traditional physician or are in the habit ofusing acetaminophen yourself to relieve similar symptoms, youprobably do. Is this wise? Consider the analogy between aceta-minophen and the drug we were considering for the mice. Like thesmell of a cat, fever is unpleasant but useful. It is an adaptationshaped by natural selection specifically to fight infection.

SIGNS AND SYMPTOMS OF INFECTIOUS DISEASE

FEVER AS DEFENSE AGAINST INFECTIONM[ att Kluger, a physiologist at the Lovelace Institute,believes that "there is overwhelming evidence infavor of fever being an adaptive host response toinfection that has persisted throughout the animal

kingdom for hundreds of millions of years." He believes that usingdrugs to suppress fever may sometimes make people sicker-andeven kill them. Some of the best evidence comes from his laboratory.In one experiment, he showed that even cold-blooded lizards benefitfrom fever. When infected, they seek out a place warm enough toraise their body temperature about two degrees Celsius. If they can-not move to a warm place, they are more likely to die. Baby rabbitsalso cannot generate a fever, so when they are sick they too seek outa warm place to raise their body temperature. Adult rabbits do getfever when infected, but if the fever is blocked with a fever-loweringdrug, they are more likely to die.

Fever results not from any mistake in temperature regulation butfrom the activation of a sophisticated evolved mechanism. If you puta rat with a two-degree fever into a very hot room, the rat activates itscooling mechanisms to keep its body temperature two degrees abovenormal. If you put it into a cooler room, it activates heat-conservationmechanisms to maintain that two-degree fever. Body temperature iscarefully regulated even during fever; the thermostat is just set a bithigher.

Perhaps the most dramatic human evidence for the value of fevercomes from studies by Julius Wagner-Jauregg in the early decades ofthis century. After noting that some syphilis patients improved aftergetting malaria and that syphilis was rare in areas where malaria wascommon, he intentionally infected thousands of syphilis patientswith malaria. In an era when fewer than one in a hundred syphilispatients recovered, this treatment achieved remission rates of 30 per-cent, an advance that made Wagner-Jauregg worthy of his 1927Nobel Prize in Physiology or Medicine. At that time, the value offever was much more widely recognized than it is now.

Doctors still say, as the joke goes, "Take two aspirin and call mein the morning." This isn't so surprising, given that only a few humanstudies have tried to evaluate fever as an adaptation to combat infec-tion. In one study, children with chicken pox who were given aceta-

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minophen took on average about a day longer to recover than thosewho took a placebo (sugar pill). In another study, fifty-six volunteersgot colds on purpose, from an infectious nasal spray. Some then tookaspirin or acetaminophen, others a placebo. The placebo group had asignificantly higher antibody response and less nasal stuffiness. Theyalso had a slightly shorter period of infectious dispersal of viruses.The paucity of detailed studies of this sort, given that so many drugsare used to relieve the symptoms of so many infectious diseases in somany patients, shows the reluctance to study the adaptive aspects ofunpleasant symptoms.

This may be about to change. Dr. Dennis Stevens, professor ofmedicine at the University of Washington, cites "evidence that treat-ing a fever in certain circumstances actually may make it more likelythe patient will develop septic shock." Medications that block feverapparently interfere with the normal mechanisms that regulate thebody's response to infection, with results that may be fatal.

Before going on to other defenses, we should emphasize that agiven expression of a defense need not be adaptive, and that evenwhen it is, it may not be essential. We would not dream of recom-mending that people never take drugs to reduce fever. Even if manystudies were to establish decisively that fever is usually important forcombating infection, that would not justify an unbending policy ofencouraging fever or even of routinely letting it rise to its naturallevel. An evolutionary perspective draws attention to the costs aswell as the benefits of an adaptation like fever. If there were no com-pensating disadvantage in having the human body operate at 400 C.(1030 F.), it ought to stay at that temperature all the time, so as to pre-vent infections from ever getting started. But even this moderatefever has costs; it depletes nutrient reserves 20 percent faster andcauses temporary male sterility. Still higher fevers can cause deliriumand perhaps seizures and lasting tissue damage. It should also be real-ized that no regulation mechanism can perfectly anticipate all situa-tions. We would expect temperature to rise, on average, to a levelclose to an optimum to fight infection, but because regulatory preci-sion is limited, fever will sometimes rise too much and at other timesnot enough.

Even if we knew that it would prolong an infection, we would stillsometimes want to block fever. Maintaining and improving healthare, after all, not the only goals of medicine. If she is about to singNanetta in a Metropolitan Opera performance of Falstaff, soprano

SIGNS AND SYMPTOMS OF INFECTIOUS DISEASE

Barbara Bonney might well decide to take a medication to relieve atouch of laryngitis, even if she knew it might delay her completerecovery. The rest of us may choose to take drugs just to feel betterduring a cold, even though our recovery might be slower.

The important point, with respect to the adaptive significance offever, is that we need to know what we are doing before we interferewith it. At present we don't. If discomfort were the whole story, wecould always choose to reduce or eliminate it. But if reducing feverwill often delay recovery or increase the likelihood of secondary infec-tion, we should interfere only when the expected gain is worth therisk. We hope that medical research will soon produce the evidence tohelp doctors and patients decide when fever is and is not useful.

IRON WITHHOLDINGQ~- ur bodies have a related defense mechanism, of whichmost people are unaware and which physicians some-times unwittingly attempt to frustrate. Here are someclues about how it works. A patient with chronic tuber-

culosis is found to have a low level of iron in his blood. A physicianconcludes that correcting the anemia may increase the patient's resis-tance, so she gives him an iron supplement. The patient's infectiongets worse. Another clue: Zulu men often drink beer made in ironpots and often get serious liver infections caused by an amoeba. Incontrast, less than 10 percent of Masai tribesmen have amoebic infec-tions. They are herdsmen and drink large amounts of milk. When agroup of Masai were given iron supplements, 88 percent soon got anamoebic infection. In another study, well-meaning investigators gaveiron to supplement the low levels found in Somali nomads. At theend of one month, 38 percent had infections versus 8 percent ofthose who had not taken the supplements.

Yet another clue: eggs are a rich source of nutrients, but theirporous shells can be readily penetrated by bacteria. So how can eggsstay fresh so long? They contain lots of iron, but it is all in the yolk,none in the surrounding white. Egg white protein is 12 percent conal-bumin, a molecule whose structure tightly binds iron and therebywithholds it from any bacteria that might get in. Prior to the antibi-otic era, egg whites were used to treat infections.

WHY WE GET SICK

The protein in human milk is 20 percent lactoferrin, another mol-ecule designed to bind iron. Cow's milk has only about 2 percentlactoferrin, and breast-fed babies consequently have fewer infectionsthan those fed from bottles. Lactoferrin is also concentrated in tearsand saliva and especially at wounds, where an elevated acidity makesit especially efficient in binding iron. The researchers who discoveredconalbumin predicted that there should be a similar molecule to bindiron within the body. This led to the discovery of transferrin, anotherprotein that binds iron tightly. Transferrin releases iron only to cellsthat carry special recognition markers. Bacteria lack the needed codeand can't get the iron. People suffering from protein deprivation mayhave levels of transferrin less than 10 percent of normal. If theyreceive iron supplements before the body has time to rebuild its sup-ply of transferrin, free iron in the blood makes fatal infectionslikely-as has been a tragic outcome of some attempts to relieve vic-tims of famine.

By now the nature of this defense is surely obvious. Iron is a cru-cial and scarce resource for bacteria, and their hosts have evolved awide variety of mechanisms to keep them from getting it. In the pres-ence of infection, the body releases a chemical called leukocyte endoge-nous mediator (LEM), which both raises body temperature and greatlydecreases the availability of iron in the blood. Iron absorption by thegut is also decreased during infection. Even our food preferenceschange. In the midst of a bout of influenza, such iron-rich foods asham and eggs suddenly seem disgusting; we prefer tea and toast. Thisis just the ticket for keeping iron away from pathogens. We tend nowto think of bloodletting as an example of early medical ignorance, butperhaps, as Kluger has suggested, it did help some patients by lower-ing their iron levels.

It became clear in the 1970s that low iron levels associated withdisease could be helpful, not harmful, but even now, Kluger and hisassociates find that only 11 percent of physicians and 6 percent ofpharmacists know that iron supplementation may harm patientswho have infections. Although the sample was small, the studyillustrates the difficulty of making clinicians aware of some estab-lished scientific findings. Even top researchers may neglect to men-tion this adaptive mechanism. A recent study in The New EnglandJournal of Medicine showed that children with cerebral malaria weremore likely to recover if they were treated with a chemical that

SIGNS AND SYMPTOMS OF INFECTIOUS DISEASE

binds iron, but the article did not describe the body's natural sys-tem for binding iron during infection. The evolved mechanism thatregulates iron binding is but one specific illustration of the broaderprinciple that we should be careful to distinguish defenses fromother manifestations of infection, slow to conclude that a bodilyresponse is maladaptive, and cautious about overriding defensiveresponses. In short, we should respect the evolved wisdom of thebody.

STRATEGIES AND COUNTERSTRATEGIESM medical researchers are not the only ones who deal withconflicts between organisms. Ecologists and animal-behavior specialists routinely deal with predator-prey relationships, struggles between males for mating

opportunities, and many other sorts of conflict. They recognize theevolutionary significance of the phenomena they observe and usesuch terms as strategy and tactic, winner and loser, and other indicationsof commitment to the adaptationist program. This approach has beenrichly rewarding for ecologists and others who are steeped in Darwin-ism. A similar approach to phenomena such as fever ought to be sim-ilarly rewarding in a field of such vital interest to all of us.

The contest between parasites and their hosts is a war, and everysign and symptom of infection can be understood in relation to theunderlying strategies of one or the other belligerent. Some, likefever and iron withholding, benefit the host (defenses); others ben-efit the pathogen; and a few are incidental effects of the war betweenthem. The strategies are not, of course, products of consciousthought, but they are strategies nonetheless. Bacteria that sneakinto the body by pretending to be harmless are rather like Greeksoldiers hiding in a wooden horse. When the manifestations ofinfection are related to conflicting interests, they fit neatly into cat-egories based on their functional importance. Table 3-1 gives anoverview of these categories and a guide to the organization of thischapter.

WHY WE GET SICK

TABLE 3-1 A CLASSIFICATION OF PHENOMENA

ASSOCIATED WITH INFECTIOUS DISEASE

OBSERVATION EXAMPLES BENEFICIARY

Hygienic measures Killing mosquitoes, Hosttaken by host avoiding sick neighbors,

avoiding excrement

Host defenses Fever, iron withholding, Hostsneezing, vomiting,immune response

Repair of damage Regeneration of tissues Hostby host

Compensation for Chewing on other side to Hostdamage by host avoid tooth pain

Damage to host tissues Tooth decay, harm to Neitherby pathogen liver in hepatitis

Impairment of host Ineffective chewing, Neitherby pathogen decreased detoxification

Evasion of host defenses Molecular mimicry, Pathogenby pathogen change in antigens

Attack on host defenses Destruction of white Pathogenby pathogen blood cells

Uptake and use of Growth and proliferation Pathogennutrients by pathogen of trypanosomes

Dispersal of pathogen Transfer of blood parasite Pathogento new host by mosquito

Manipulation of host Exaggerated sneezing or Pathogenby pathogen diarrhea, behavioral changes

How can a host guard against infection? First, it can avoid expo-sure to pathogens. Second, it can erect barriers to keep them out ofthe body and act quickly to defend and repair any breaches in thedefenses. If pathogens do get beyond the outer ramparts, it can flagany cells that lack proof of identity and expel them from their entryportal. If they have breached this defense line, it can poke holes inthem, poison them, starve them, do whatever is necessary to killthem. And if all this does not work, it can wall them off so that theycannot reproduce and spread. If they have done damage, it can repairit. If the damage can't be repaired immediately, it can compensate for

SIGNS AND SYMPTOMS OF INFECTIOUS DISEASE

it in some way. Some of this damage and the resulting impairmentbenefit neither the host nor the pathogen. They are, like the agingbomb craters on the coast of France, just incidental relics of an oldbattle.

The pathogens will not, of course, give up readily. Our bodies are,after all, their homes and dinners. We understandably tend to seebacteria and viruses as evils, but how anthropocentric this is! Our

defenses attempt to prevent the poor streptococcus from getting evena microgram of our body tissues, but if it cannot find a way aroundour defenses, it will die. So, for each of our defenses, pathogens haveevolved counterdefenses. They find ways to get transmitted to us andways to breach our walls. Once inside, they hide from our sentries,attack our defenses, use our nutrients to make copies of themselves,and find ways to get those copies out of the body and to new victims,often by turning our own defenses to their own advantage. Beforedescribing the clever stratagems used by pathogens to elude ourdefenses, we will discuss the defenses in more detail.

HYGIENE

T he best defense is avoidance of danger; proper hygiene canprevent a pathogen from gaining that first toehold. Instinc-tively slapping at a mosquito is not just an attempt to spareoneself the minor annoyance of a mosquito bite. It may

also prevent a long list of serious insect-borne diseases, of whichmalaria is the best known. Is the itch of a mosquito bite just part ofthe insect's nastiness? It may be merely an accidental result of thechemicals the mosquito uses to ensure that our blood flows freely,but it may also be our adaptation for avoiding future bites. Imaginewhat would happen to a person who did not mind being bitten bymosquitoes. And imagine how successful a mosquito could be if itsbiting were not noticeable!

Our tendencies to avoid contact with people who may be infec-tious may have the same significance. Likewise, an instinctive disgustmotivates us to avoid feces, vomit, and other sources of contagion.Our tendency to defecate away from others may prevent the infec-tion of close associates, and social pressures to conform to such prac-tices may protect us from infection by others. The best defense

WHY WE GET SICK

against infection is avoidance of pathogens, and natural selection hasshaped many mechanisms to help us keep our distance.

THE SKINO ur skin is like the wall around an ancient city, a formi-dable protective barrier. It not only prevents the entryof parasites but also protects against injury by mechani-cal, thermal, and chemical forces. Unlike induced

defenses such as fever, which are aroused only when a particular dan-ger threatens, the skin is constantly present, always on guard. It istough and much more resistant to puncture and abrasion than theinternal tissues it protects. Minor infections here and there are harm-less because the skin is constantly being sloughed off the top andrenewed from below. An ink stain on the fingers will be gone in a fewdays, not because the ink has been absorbed or chemically altered butbecause the stained cells are replaced by others rising from below.Fungal growths or other potential pathogens in surface cells are con-stantly cast off by this rapid replacement of the epidermis.Sycamores and shagbark hickory trees seem to use the same strategy.

Not only is the skin a good defensive armor in general, it is alsogood in particular. Those parts of the body that are most in need ofarmor, such as the soles of the feet, have thicker and tougher skinright from birth. Any particular patch of skin that is subjected torepeated friction, like that at the top edge of a shoe or the tip of a cel-list's finger, grows the thicker skin we call a callus. This adaptivegrowth, an induced defense, not only minimizes mechanical injury, italso prevents breaks in the skin that could provide entrances forpathogens.

Some of our most useful hygienic behaviors help maintain theskin's barrier. The most obvious are behaviors that keep nasty thingsoff the skin. Scratching and other grooming maneuvers remove exter-nal parasites, important sources of discomfort and disease transmis-sion for most people during most of human history and stillproblems in less fortunate societies. Benjamin Hart, a veterinarianfrom the University of California at Davis, has shown just how cru-cial grooming is to preventing illness in animals. An animal that can-not groom is quickly infested with fleas, ticks, lice and mites, and will

SIGNS AND SYMPTOMS OF INFECTIOUS DISEASE

lose weight and fall ill. The mutual grooming of monkeys is not just aritual, it is preventive health care.

PAIN AND MALAISEJ ust as an itch can motivate defensive scratching, pain is an adap-tation that can lead to escape and avoidance. The skin, sensiblyenough, is highly sensitive to pain. If it is being damaged, some-thing is clearly wrong, and all other activities should be droppeduntil the damage is stopped and repair can begin. Other kinds of

pain can also be helpful. While an abstract realization that chewing isimpaired because of an abscessed tooth might possibly lead to morechewing with other, unimpaired teeth, the tormenting pain of atoothache far more effectively prevents the pressure on the tooth thatwould delay healing and spread bacteria. Continued pain from infec-tion or injury is adaptive because continued use of damaged tissuemay compromise the effectiveness of other adaptations, such as tis-sue reconstruction and antibody attacks on bacteria. Pain motivatesus to escape quickly when our bodies are being damaged, and thememory of the pain teaches us to avoid the same situation in thefuture.

The simplest way to determine the function of an organ like thethyroid gland is to take it out and then see how the organism mal-functions. The capacity for pain cannot be removed, but very occa-sionally someone is born without it. Such a pain-free life might seemfortunate, but it is not. People who cannot feel pain don't experiencediscomfort from staying in the same position for long periods, andthe resulting lack of fidgeting impairs the blood supply to the joints,which then deteriorate by adolescence. People who cannot feel painare nearly all dead by age thirty.

Generalized aches and pains, or merely feeling out of sorts(malaise, in medical terminology), are also adaptive. They encouragea general inactivity, not just disuse of damaged parts. That this isadaptive is widely recognized in the belief that it is wise to stay in bedwhen you are sick. Inactivity also likely favors the effectiveness ofimmunological defenses, repair of damaged tissues, and other hostadaptations. Medication that merely makes a sick person feel lesssick will interfere with these benefits. This is fine when patients are

WHY WE GET SICK

well informed about the risks and realize that they are sicker thanthey feel and should make a special effort to take it easy. Otherwise,a drug-induced feeling of well-being may lead to activity levels thatinterfere with defensive adaptations or repairs.

DEFENSES BASED ON EXPULSION

he body must have openings for breathing, for the intakeT of nutrients and expulsion of wastes, and for reproduc-tion. Each of these openings offers pathogens an invasionroute, and each is endowed with special defense mecha-

nisms. The constant washing of the mouth with saliva kills somepathogens and dislodges others so they can be destroyed by the acidand enzymes in the stomach. The eyes are washed by tears laden withdefensive chemicals and the respiratory system by antibody andenzyme-rich secretions that are steadily propelled up to the throat,where they can be swallowed so the invaders can be killed and theprotein in the mucus recycled. The ears secrete an antibacterial wax.Projections inside the nose, called turbinates, provide a large surfacethat warms, moistens, and filters pathogens from the incoming air.Mouth-breathers don't get the full benefit of this defense and aremore subject to infection. The nose and ears have hairs strategicallyarrayed to keep out insects.

The defenses at each body opening can be quickly increased ifdanger threatens. Irritation of the nose by a viral infection provokesthe discharge of such copious mucus that one can go through a wholebox of tissues in a day. Millions of people use nasal sprays each yearto block this useful response, but there are remarkably few studiesthat have investigated whether the use of such devices delays recov-ery from a cold. If they do not demonstrably delay recovery, as seemsto be the case from the limited data, it would be evidence that a runnynose is not a defense but an example of a pathogen manipulating thehost's physiology in order to spread itself. Sneezing is obviously adefensive adaptation, but not every sneeze need be adaptive for thesneezer. Some sneezing may possibly be an adaptation that virusesuse to disperse themselves.

Irritation deeper in the respiratory tract induces coughing. Cough-ing is made possible by an elaborate mechanism that involves detect-

SIGNS AND SYMPTOMS OF INFECTIOUS DISEASE

ing foreign matter, processing this information in the brain, stimulat-ing a cough center at the base of the brain, and then coordinatingmuscle contractions in the chest, the diaphragm, and the tubes in therespiratory tract. All along the lining of these tubes tiny hairs calledcilia beat in a steady rhythm, sweeping pathogen-trapping mucusupward. In the urinary tract, periodic flushing washes pathogensaway along with the cells on the surface of the urethral lining, whichare systematically shed like those on the skin. When the bladder orurethra becomes infected, urination understandably becomes morefrequent.

The digestive system has its own special defenses. Bacterialdecomposition and fungal growths produce repulsive odors, therepulsiveness being our adaptation to be disinclined to put bad-smelling things into our mouths. If something already in the mouthtastes bad, we spit it out. Taste receptors detect bitter substances thatare likely to be poisonous. After we swallow something, there arereceptors in the stomach to detect poisons, especially those made bybacteria that multiply in the gastrointestinal tract. When absorbedtoxins enter the circulation, they pass by a special group of cells in thebrain, the only brain cells directly exposed to the blood. When thesecells detect toxins, they stimulate the brain's chemoreceptor triggerzone to respond first with nausea and then with vomiting. This is whyso many drugs are so nauseating, especially the toxic ones used forcancer chemotherapy.

Circulating toxins almost always originate in the stomach, so it iseasy to see how vomiting is useful: it ejects the toxin before more isabsorbed. What about nausea? The distress of nausea discourages usfrom eating more of the noxious substance, and its memory discour-ages future sampling of whatever food seemed to cause it. Just a singleexperience of nausea and vomiting after eating a novel food will causerats to avoid it for months; people may avoid it for years. Thisremarkably strong onetime learning was named the "sauce bearnaisesyndrome" by Martin Seligman, a psychologist who recognized its sig-nificance after contemplating the untimely loss of his gourmet dinner.Why is the body capable of such a strong association after a singleexposure to a food that produces illness? Imagine, for a moment, whatwould happen to the person who ate poisonous foods repeatedly.

The other end of the intestinal tract has its own defense, diar-rhea. People understandably want to stop diarrhea, but if reliefcomes from merely blocking the defense, there is likely to be some

WHY WE GET SICK

penalty. Indeed, H. L. DuPont and Richard Hornick, infectious dis-ease experts at the University of Texas, found just this. Theyinfected twenty-five volunteers with Shigella, a bacterium thatinduces severe diarrhea. Those who were treated with drugs to stopthe diarrhea stayed feverish and toxic twice as long as those who didnot. Five out of six who received the antidiarrheal drug Lomotilcontinued to have Shigella in their stools, compared to two out ofsix who did not receive the drug. The researchers concluded,"Lomotil may be contraindicated in shigellosis. Diarrhea may rep-resent a defense mechanism." Consumers will no doubt want toknow when they should and should not take such medications formore commonplace diarrhea, but the needed research has not beendone. There are dozens of studies of side effects, of safety, and ofthe effectiveness of medications that block diarrhea, but few con-sider the consequences of the main effect of blocking a normaldefense.

Our reproductive machinery requires yet another opening, whichin males is the same as that of the urinary tract, whose defenses therebydo double duty. Women have a separate opening that poses a specialproblem for defense against infection. While the female reproductivetract uses many defenses, such as cervical mucus and its antibacterialproperties, one largely unappreciated defense is the normal outwardmovement of secretions that makes it difficult for bacteria and virusesto gain access. These secretions move steadily from the abdominal cav-ity through the fallopian tubes, uterus, cervix, and vagina to the out-side. There is one noteworthy exception to this constant downstreammovement. Sperm cells swim upstream, from the vagina through theuterus into the fallopian tubes and the pelvic cavity. Unusually smallfor human cells, sperm are still large compared to bacteria. Potentialpathogens can stick to sperm cells and be transported from the outsideto deep within a woman's reproductive system.

Only recently has the threat of sperm-borne pathogens been rec-ognized. Biologist Margie Profet notes that menstruation has sub-stantial costs and argues that it must therefore give somecompensating benefit. After a consideration of the evidence, she con-cluded that many aspects of menstruation seem designed as an effec-tive defense against uterine infection. The same anti-infectionbenefits that come from sloughing off skin cells are achieved by theperiodic extrusion of the lining of the uterus. This is supported byevidence that menstrual blood differs from circulating blood in ways

SIGNS AND SYMPTOMS OF INFECTIOUS DISEASE

that make it more effective in destroying pathogens while minimizinglosses of nutrients. Studies of menstruation in other mammals sug-gest that each species menstruates to just the extent appropriate forits vulnerability to sperm-borne pathogens. The threat is small forspecies that restrict their sexual behavior to widely separated fertileperiods, but women's continuous sexual attractiveness and receptiv-ity are largely unrelated to the ovulatory cycle. This extraordinaryamount of human sexual activity may have its benefits, as we will dis-cuss in Chapter 13, but it substantially increases the risk of infection.This risk may be responsible for the unusually profuse human men-strual discharge, as compared to other mammals'.

We have mentioned several times that evolutionary hypothesesneed to be and can be tested. Beverly Strassmann has mounted a chal-lenge to the hypothesis that menstruation protects against infection.She maintains that the pathogen load in the reproductive tract is thesame before and after menstruation, that menstruation does notincrease when there is infection, and that there is no consistent rela-tionship between the amount of sperm females in a particular speciesare exposed to and the amount of menstrual flow. As an alternativeexplanation, Strassmann proposes that the degree of shedding orreabsorption of the uterine lining depends on the metabolic costs ofmaintaining it or shedding it, a hypothesis that she supports withcomparisons between species and the relationship between menstru-ation and the body weight of the female and her neonate. Obviously,we have not heard the last word on this issue.

MECHANISMS TO ATTACK INVADERSV vertebrates in general, and mammals in particular, haveamazingly effective immunological defenses that are inessence a system of carefully targeted chemical warfare.Cells called macrophages constantly wander the body

searching for any foreign protein, whether from a bacterium, a bit ofdirt in the skin, or a cancer cell. When they find such an intruder, themacrophages transfer it to a helper T cell, which then finds and stim-ulates whichever white blood cells can make a protein (called an anti-body) that binds specifically to that particular foreign protein (anantigen). Antibodies bind to antigens on the surfaces of bacteria,

WHY WE GET SICK

thereby impairing the bacteria and also labeling them for attack byspecialized larger cells. If the antigens persist, say during a continuingbacterial infection, they stimulate the production of ever more of thecells that make that specific antibody, so that the bacteria aredestroyed at an ever-increasing rate. Whatever is recognized as aproperly functioning part of the body is permitted to remain. Allelse-disease organisms, cancerous tissue, organs transplanted fromother individuals-is attacked.

How does the body recognize cells as its own? Each cell has a mo-lecular pattern on its surface, called the major histocompatibility com-plex (MHC), which is like a photo ID card. Cells that have a validMHC are left alone, but those that have a foreign or missing MHCare attacked. Interestingly, when cells are infected, they transportprotein from the invader to the MHC, where it is bound. Like indi-viduals with obviously fake ID cards, such cells are priority targetsfor the killer cells of the immune system. The adenovirus, a commoncause of sore throats, has found a way to get around this defense. Itmakes a protein that blocks the ability of the cell to move foreignproteins to the MHC. In essence, it prevents the infected cell fromsignaling that it has been invaded.

The operation of the MHC system is a vivid example of altruismin its biological sense. An infected cell "volunteers" for destructionfor the good of the rest of the body. This is like a soldier with plagueasking his comrades to destroy him before he infects them. The anal-ogy, however, is false in one crucial respect. The cell's comrades aregenetically identical, and its only chance for passing on its genes liesin the success of the whole organism. Soldiers, however, seldomshare foxholes with identical twins and are understandably less likelyto volunteer for elimination.

The weapons of the immune system are truly fearsome. Theyinclude general inflammation, several kinds of antibodies-each spe-cialized for a different group of opponents and a series of chemicals(the complement system), five of which attack the targeted cells, boringholes in their membranes and digesting them. Despite these weapons,some invaders can nonetheless persist. When a clump of bacteria canbe neither expelled nor destroyed, it may be walled off by a membranethat keeps it away from vulnerable tissues. The tubercles from whichtuberculosis gets its name are the best-known example, but analogousimprisonment of roundworms and other multicellular parasites hasalso been important throughout most of human evolution.

SIGNS AND SYMPTOMS OF INFECTIOUS DISEASE

DAMAGE AND REPAIRI n the contest with their host, pathogens must rob the host tosecure their own nourishment. Various bacteria and the proto-zoa that causes amoebic dysentery secrete enzymes that digestnearby host tissues and then absorb the products of digestion.

Others literally eat through host tissues, for example, filaria worms,which live in the anterior part of the eye, or the larvae of anotherspecies of worm, Angiostrongylus cantonensis, which burrow throughthe brain. Both of these defend themselves with secretions thatinhibit inflammation. Still others, such as the trypanosomes, a groupof protozoans that cause diseases such as African sleeping sickness,live in the bloodstream and absorb nutrients directly from theplasma. Whatever the means, parasites secure their resources fromthe host and then use them for their own maintenance, growth, andreproduction.

These activities of pathogens incidentally damage the host, butthis damage is not a pathogen adaptation. It does not do a tapewormany good to have its host malnourished. It does not do the malarialparasite any good to destroy its host's blood cells (unless, perhaps,this frees up iron for use by the parasite). Most often, the oppositemust be true. The survival and well-being of the parasite depend onthe host's continued survival and ability to provide it with nourish-ment and shelter. Such incidental damage must therefore be consid-ered a cost to both host and pathogen.

The cost may be a general reduction in host resources or an obvi-ously localized destruction. Bacteria that attack bone where a tooth isrooted cause structural damage and perhaps the loss of the tooth.The bacteria that cause gonorrhea may erode the connective tissueand cartilage of joints, causing functional impairment. Hepatitisviruses may destroy substantial portions of the liver, so that all liverfunctions, such as the clearing of toxins from the blood, become lesseffective. Such functional impairments are simply incidental conse-quences of pathogen adaptations. It does not do bacteria any good tomake the host's chewing less effective or its running less rapid.

It's important to keep damage conceptually separate from anyresulting functional impairment. The damage causes the impairment,which can then itself be a cause for another host adaptation, whichwe call compensatory adjustment. There are many examples, some

WHY WE GET SICK

much more subtle than chewing on the left side of your mouth if ithurts to chew on the right. For instance, when disease-damaged lungs

become less effective at oxygenating the blood, this may be partlycompensated for by an increase in blood hemoglobin concentration.The body has a mechanism that monitors the oxygen level in theblood. If there is too little, whether from living at a high altitude orfrom lung damage, the body makes more erythropoietin, a hormonethat stimulates the production of more red blood cells.

Another obvious host adaptation is repair of damage. Naturalselection has adjusted the ability to regenerate various tissues accord-ing to how useful it would normally be to do so. The skin, which isoften damaged, is a first line of defense against pathogens andinjuries. As might be expected, it quickly regenerates and rapidlyrecovers its protective capabilities. Other structures that regeneratequickly are the lining of the gut and organs such as the liver, whichare in open communication with the gut and therefore with the out-side world and its infectious agents. By contrast, the heart and espe-cially the brain are less accessible to most pathogens. If pathogens dogain access and cause serious damage, it is ordinarily fatal, so regen-erative capabilities would rarely be of benefit.

PATHOGEN EVASION OF HOST DEFENSESSo far we have mentioned only one kind of pathogen adapta-tion, the ability to nourish itself in the body of the host. Wecan also expect it to have evolved ways of shielding itselffrom the host's efforts to destroy, expel, or sequester it. We

will now turn to one such mechanism, evasion of host defenses.The first trick for many parasites, once inside the body, is to gain

entrance to cells. Invaders may accomplish this just as door-to-doorpeddlers do, by appearing to offer something else. The rabies virusbinds to acetylcholine receptors as if it were a useful neurotransmit-ter; the cowpox virus to epidermal growth-factor receptors as if itwere a hormone; and the Epstein-Barr virus (which causes mononu-cleosis) to a C4 receptor. Rhinovirus, a common cause of colds,binds to the intercellular adhesion molecule (ICAM) on the surfaceof the lymphocytes that line the respiratory tract. This is extremelyclever, since attacking lymphocytes releases chemicals that greatly

SIGNS AND SYMPTOMS OF INFECTIOUS DISEASE

increase the number of ICAM binding sites, thus providing manymore openings by which the virus can enter cells.

Another trick is to evade the immune system. The trypanosomethat causes African sleeping sickness does this by rapidly changing itsdisguises. It takes the body about ten days to make enough antibod-ies to control the trypanosome, but on about the ninth day, the try-panosome changes its disguise by exposing an entirely new surfacelayer of proteins, thus escaping attack by the antibodies. The try-panosome has genes for more than a thousand different antigeniccoats and so can live on for years in the human host, always one stepahead of the immune system. Two other common bacteria use simi-lar strategies. Hemophilus influenza, a common cause of meningitisand ear infections, and Neisseria gonorrhoeae, the cause of gonorrhea,both have what seem to be flaws in the genetic mechanisms that maketheir surface proteins. The seeming errors are useful, however,because the resulting variation makes it hard for our immune systemsto keep up with the random changes.

Malarial parasites have special surface proteins that allow them tobind to the walls of blood vessels so that they are not swept to thespleen, where they would be filtered out and killed. The genes thatcode for these binding proteins in malarial parasites mutate at a rateof 2 percent per generation, just enough so that the immune systemcannot lock in on the organism. The pneumococcal bacteria thatcause pneumonia use a different trick to circumvent the immune sys-tem. They have "slippery" polysaccharides on their surface thatwhite blood cells can't get a grip on. The body copes with this bymaking chemicals called opsonins, which bind to the microbe likehandles that the antibodies can grab.

Another common evasion is a chemical analog of a disguise a spymight use behind enemy lines. The external chemistry of some bacte-ria and some worms is so similar to that of human cells that the hostmay have difficulty in recognizing them as foreign. (Thus antibodiessometimes attack both invader and host cells.) The streptococcusbacterium, a longtime associate of humans, is especially adept at thistrick. The antibodies to some strains cause rheumatic fever, in whicha person's antibodies attack his or her own joints and heart. Similarantibody attack on nerve cells in the basal ganglia of the braincan cause Sydenham's chorea, with its characteristic uncontrollablemuscle twitches. Interestingly, many patients who have obsessive-compulsive disorder, a psychiatric illness characterized by excessive

WHY WE GET SICK

hand washing and fear of accidentally harming others, had Syden-ham's chorea in childhood. There is now growing evidence that thebrain areas involved in obsessive-compulsive disorder are very close tothose damaged by Sydenham's chorea. Thus, some cases of obsessive-compulsive disorder may result from the arms race between thestreptococcus and the immune system.

Chlamydia, today's most common cause of venereal disease, doesthe equivalent of hiding in the police station. It enters white bloodcells and then builds a wall to prevent itself from being digested.Schistosomes of the mansoni type go a step further and essentiallysteal police uniforms. These parasites, a serious cause of liver diseasein Asia, pick up blood-group antigens so that they may look to theimmune system like our own normal blood cells.

ATTACK ON HOST DEFENSES

athogens not only attempt to shield themselves from theweaponry of the host, they also have destructive weaponryof their own. The bacterium that causes most simple skininfections, Staphylococcus aureus, secretes a neuropeptide

that blocks the action of Hageman's factor, a crucial first step in use-ful inflammation. Bacteria that cannot secrete this peptide do notcause infection. Even the common streptococcal bacteria that causeso many sore throats make streptolysin-O, which kills white bloodcells. Vaccinia, the virus that causes cowpox, makes a protein thatinhibits the complement system, an important host defense, as notedpreviously. Why doesn't the complement system attack our owncells? In part because our cells have a layer of sialic acid, a chemicalthat protects them from attack by the complement system. Sureenough, certain bacteria, in this case the KI strain of the common E.coli that live in our guts, are able to cover themselves in sialic acid andthus gain protection from the complement system.

One of the great dangers of serious infection with certain kinds ofbacteria is shock, a decrease in blood pressure that can be rapidlyfatal. Shock is caused by chemical lipopolysaccharide (LPS) formedby the bacteria. Superficially, it would seem that LPS is a toxin madeby bacteria to harm us, but, as researcher Edmund LeGrand hasnoted, this is unlikely, because LPS is a necessary component of the

SIGNS AND SYMPTOMS OF INFECTIOUS DISEASE

cell wall of this whole group of bacteria. Hosts recognize this reliablecue to the presence of dangerous infection and react strongly-some-times too strongly. Here is an example of a defensive weapon that canturn on its bearer.

The human immunodeficiency virus (HIV), the virus that causesAIDS, hides in the helper T cells that bring antigens to the attentionof the immune system. These cells have a protein in their outer mem-brane called CD-4, to which the HIV binds to gain entrance to cells.This protein on HIV would make it vulnerable to the immune sys-tem, except that it is hidden in deep crevices in the viral wall. As HIVkills helper T cells, it incidentally causes the victim to be ever morevulnerable to other infections and cancer, the problems that eventu-ally kill a person who has AIDS.

OTHER PATHOGEN ADAPTATIONST w here remain two related categories of parasite adaptation.No matter how well a pathogen survives and proliferates ina host, it must have a dispersal mechanism so that it can getitself or its descendants into other hosts. For external par-

asites this can be rather easy. Lice and the fungus that causes ring-worm, for example, are readily spread by personal contact. Internalparasites face greater problems. Those that can regularly get onto theskin have the possibility of contact with other susceptible individu-als. Cold viruses and intestinal bacteria may get onto hands or othersurfaces and be spread by handshakes or more intimate contact.

Microorganisms in the bloodstream are not likely to be spread inthis way. Many can be transmitted only with the help of biting insectsor other transport agents (vectors). Malaria is a well-known example.If there are about ten malarial parasites in the dispersal stage (calledgametocytes) in each milligram of blood and a mosquito sucks upthree milligrams, it will be taking in about thirty gametocytes. Thenext item on the mosquito's agenda is to convert this rich blood mealinto eggs and get them fertilized and laid in an environment suitablefor development. Meanwhile, the sexually produced offspring of themalarial plasmodia have migrated to the mosquito's salivary glands,where they transform into an infectious stage in the fluid that will beused to inhibit clotting when the mosquito sucks up its next blood

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meal. The mosquito then unwittingly injects the plasmodia into thenext victim. An enormous variety of insects and other organisms canserve as vectors of human diseases.

Another kind of parasitic adaptation is technically termed hostmanipulation. By subtle chemical influence a parasite may gain somecontrol over the machinery of the host's body and cause that machin-ery to serve the interests of parasite rather than host. Many curiousexamples are known from many groups of organisms. The tobaccomosaic virus causes its host to enlarge the pores between adjacenttobacco cells enough to allow the virus particles to pass through andinfect other cells. One kind of parasitic worm alternates its life stagesbetween ants and sheep, just as malarial parasites must alternatebetween vertebrate hosts and mosquitoes. The worm is effectivelytransmitted from an ant to a sheep because it enters certain sites inthe ant's nervous system where it causes the ant to climb to the top ofa blade of grass and hang on, unable to let go. This greatly increasesthe likelihood that the ant will be eaten by a sheep. Another kind ofworm alternates between snails and gulls. It causes the snail, which isordinarily hard to find in the tangled growths of shallow coastalwaters, to crawl up to a high level of bare rock or sand and stay there.It is then easily seen and eaten by a gull.

The rabies virus offers a particularly remarkable and gruesomeexample of how a pathogen can manipulate a host's behavior. Aftergaining entrance to the body, usually via the bite of an infected indi-vidual, the rabies virus moves along nerve fibers to the brain, where itconcentrates in regions that regulate aggression. It can then make thehost attack and bite, thereby infecting other individuals. It also para-lyzes the victim's swallowing muscles, thus causing virus-laden salivato build up in the mouth, increasing the likelihood of transmissionand incidentally causing the victim to have the terror of choking onfluids that originally gave the disease the name hydrophobia.

Perhaps the most important human examples of manipulation bypathogens are the sneezing, coughing, vomiting, and diarrhea trig-gered by bacteria and viruses. At some stage in the history of an infec-tion, this expulsion will serve the interests of both host and microbe.The host is benefited by having fewer pathogens attacking its tissues,the microbe by an increased chance of finding other hosts. The losersin this game are currently healthy but vulnerable individuals. Achemical released by cholera bacteria reduces absorption of liquidfrom the bowel, causing profuse diarrhea that, in a society without

SIGNS AND SYMPTOMS OF INFECTIOUS DISEASE

well-developed public hygiene, can effectively spread an epidemic.Sometimes we are successfully manipulated by our parasites, at

other times we successfully resist manipulation, and in still other sit-uations there is some intermediate resolution. Any given example ofsuch a conflict is likely to be at an evolutionary equilibrium and havea consistent outcome. Conflicts are often decided in favor of theantagonist that has the most to gain from winning. If someone issneezing twice as often as would be ideal for the control of a coldvirus, that is not likely to be a great burden of lost time or energy, butit may nearly double the rate at which the virus reaches new hosts.This is just the sort of contest we would expect the virus to win. Howfrequently are expulsion mechanisms exaggerated by pathogensbeyond what would be optimal to a human host? The paucity of evi-dence on this issue shows the habitual neglect of such evolutionaryquestions.

A FUNCTIONAL APPROACH TO DISEASEW e end this chapter by making three remarks aboutTable 3.1 (page 32), which classifies the signs andsymptoms of infectious disease according to theirfunctions. First, a functional classification of the

signs and symptoms of disease is important and useful. In order tochoose appropriate treatment, we need to know if the cough, orother symptom, benefits the patient or the pathogen. We also needto know if the pathogen is manipulating the host or attacking itsdefenses. Instead of just relieving symptoms and trying, perhaps inef-fectively, to kill the pathogen, we can analyze its strategies, try tooppose each of them, and try to assist the host in its efforts to over-come the pathogen and repair the damage. The second point is thatthe classification is really rather simple and obvious.

Now for the third point: When and by whom do you think theideas in this chapter were first proposed? Was it by some nineteenth-century medical researcher building on the ideas of Pasteur and Dar-win as well as the rapidly expanding body of knowledge of parasitelife histories? No. The classification scheme used in our table andthroughout this chapter was first proposed at the University ofMichigan in 1980 by Paul Ewald, an ornithologist and evolutionary

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biologist now at Amherst College. And when did the ideas in thischapter first become standard elements in the thinking of physiciansand medical researchers? The answer to this question is a simple anddiscouraging not yet. We do not mean that physicians never intu-itively think in the categories formalized by Ewald. We merely meanthat they have not been explicitly taught to use them and that defi-ciencies of training make it easy to neglect these essential ideas inthinking about infectious disease. There is hope, which is especiallyevident in the proceedings from several recent conferences that haveemphasized the benefits of interchange between evolutionists andinfectious disease experts. But it will still be years before this sort ofmaterial becomes part of the regular medical curriculum.

Why has the medical profession not taken advantage of the helpavailable from evolutionary biology, a well-developed branch of sci-ence with great potential for providing medical insights? One reasonis surely the pervasive neglect of this branch of science at all educa-tional levels. Religious and other sorts of opposition have minimizedthe impact in general education of Darwin's contributions to ourunderstanding of ourselves and the world we live in. There has alsobeen a peculiar neglect of evolution in the training of physicians andmedical researchers, a matter discussed further in Chapter 15.

Still another reason is that many of the evolutionary ideas of great-est bearing on medicine have only been formulated in recent years.These ideas are often simple and not very different from commonsense-once they are pointed out. Yet their recognition and theappreciation of their importance have come only in the past fewyears, far behind the development and application of many reallycomplex and subtle branches of physical science and molecular biol-ogy. Exactly why the application of evolutionary biology to medicineand other aspects of human life has advanced so slowly after its mag-nificent inception in 1859 is a question that ought to be getting majorattention from historians of science.

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E ^very time a nation or a tribe designs a new weapon, a com-peting nation or tribe will soon devise a counterweapon.Thus spears and swords gave rise to shields and bodyarmor, and radar defenses to the Stealth Bomber. Likewise,

the evolutionary origin of a predator's improved hunting techniquecan be countered by the prey's improved armor, evasive tactics, orother defensive adaptation, which is then met by countermeasuresfrom its predators. If foxes start running faster, rabbits are selected torun even faster so that foxes must run faster still. If foxes' eyesightimproves, this selects for rabbits that blend better with the back-ground, which may select for foxes that can locate rabbits by smell,which in turn may select for rabbits that tend to move downwindfrom foxes. Thus predator and prey coevolve in an escalating cycle ofcomplexity. Biologists have named this idea the Red Queen Principleafter Lewis Carroll's Red Queen, who explained to Alice, "Now,here, you see, it takes all the running you can do, just to keep in the

same place."Like contests between predators and prey, wars between hosts

and parasites initiate escalating arms races that require extravagant,harmful expenditures and create extraordinarily complex weaponsand defenses. Just as political powers sometimes put more and moreof their energies into weaponry and defense to keep from being

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dominated by opponents, hosts and parasites must both evolve asfast as they can to maintain their current levels of adaptation. Therecomes a point where the expense of an arms race is so great that theorganism, political or biological, is hard put to meet other basicneeds, but the cost of losing it is so great that enormous expensesmay nonetheless be maintained. We are in a relentless all-out strug-gle with our pathogens, and no agreeable accommodation can everbe reached.

The relationships between hosts and parasites are so competitive,wasteful, and ruthlessly destructive that arms-race terminologyoffers an entirely appropriate framework for describing them. Therest of this chapter explains this point of view, but for an introduc-tion, just try to imagine the magnitude of the personal tragedy thatinfectious agents have caused throughout human history, until just afew decades ago. The mother of one of the authors (Williams) wasorphaned at age nine by meningitis. He has a sister whose best frienddied suddenly of acute appendicitis in fourth grade. Our micro-scopic enemies take no account of individual merit or importance.Shortly before Calvin Coolidge succeeded to the presidency of theUnited States, his sixteen-year-old son got a blister on his foot whileplaying tennis but bravely went on playing. The blister broke openand became infected, and in two weeks the boy was dead. As aresult, the president of the United States was an ineffective emo-tional cripple (as even his admirers concede) throughout the ensuingcampaign and his one term in office.

The analogy between international arms races and host-parasitecoevolution is not exact. The Pentagon can plan new weapons on thedrawing board and then try out models and prototypes. It has thebenefit of rational planning, fresh starts, and trial-and-error tinker-ing. In evolution, there are no think tanks systematically devisingways of putting scientific knowledge to new destructive or defensiveuses. No plans contribute to evolution, and there can be no freshstarts. Evolution consists entirely of trial-and-error tinkering. The slightlydifferent variants of every generation compete in the game of life.Some achieve a higher reproductive output than others, and the pop-ulation averages shift slightly in their direction. The process is slowand unguided-in some ways misguided-but there is no limit to theprecision and complexity of adaptation that the Darwinian processcan generate.

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PAST VERSUS CURRENT EVOLUTIONM [any microbiologists incorrectly assume that hostsand their pathogens are usually in a state of slow evo-lutionary change toward some optimal future state,usually of active cooperation. This is a grossly unreal-

istic idea. Both pathogens and hosts must normally maintain close-to-stable equilibria by making trade-offs between competing values,such as growth rates and defensive activities. At equilibrium, a unitof improvement of one adaptation would require more than one unitof loss of another. A leaner rabbit might run faster, but at some pointthe benefit of still greater speed would not be worth the added risk ofstarvation. Likewise, our fever response is presumably optimized, atleast for historically normal conditions. Higher and more frequentfever would make us less vulnerable to pathogens but would be morethan counterbalanced by the costs of tissue damage and nutrientdepletion. This will be true as long as the environment stays constant.If circumstances change, some of the optima for both host andpathogen will likely change. If bacterial pathogens are artificially keptin check for many generations, this may select for a decreased feverresponse, but if our technology fails and we become vulnerable again,we might recover a heightened fever response.

In all of this book's other chapters we deal mainly with features ofhuman biology established by long-term historical processes. In thepresent chapter we will discuss evolutionary changes that can occurwithin the next year, or perhaps maybe even next week. Becausepathogens reproduce so rapidly, they also evolve rapidly.

Some of our defenses against disease, such as sickle cell hemoglo-bin, have evolved markedly in the last ten thousand years, duringwhich we have had perhaps three hundred generations. The speciesas a whole has evolved significantly higher resistance to a few epi-demic diseases such as smallpox and tuberculosis in the last few cen-turies, perhaps a dozen generations. Compare this to a bacterium'sthree hundred generations in a week or two and the even faster repro-duction of a virus. Bacteria can evolve as much in a day as we can ina thousand years, and this gives us a grossly unfair handicap in thearms race. We cannot evolve fast enough to escape from microor-ganisms. Instead, an individual must counter a pathogen's evolution-

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ary changes by altering the ratios of its various kinds of antibody-producing cells. Fortunately, the number and diversity of thesechemical weapons factories are enormous and at least partly com-pensate for our pathogens' great evolutionary advantage.

From an immunological perspective, an epidemic may change ahuman population dramatically. Those individuals who have con-tracted a disease and recovered will likely be immune to reinfectionbecause they harbor vastly increased concentrations of the lympho-cytes that make the antibodies that are most destructive of that partic-ular pathogen. Adult immunity to childhood diseases such as mumpsdepends not on changing human gene pools but on changing the con-centrations of different kinds of antibodies within each individual.

Small size gives our pathogens another advantage: their enormousnumbers. Each of us carries around (mostly in our digestive and res-piratory systems) more bacterial cells than there are people on Earth.These enormous numbers mean that even improbable sorts of muta-tions will occur with appreciable frequency and that any mutant bac-terial strain with even the most minute advantage over the others willsoon prevail numerically. We can expect our pathogens' quantitativecharacteristics to evolve rapidly to whatever values are optimal forpresent circumstances.

In some catastrophic epidemics, a human population can evolvea higher level of resistance to an infectious disease in mere months.When Europeans first arrived in the New World, for example, someEuropean diseases quickly killed as much as 90 percent of a NativeAmerican community in a short time. If the Native Americans' vul-nerability had had any genetic basis, the genes of the lucky few whosurvived the epidemic would have become proportionately morefrequent, and we could say that the population, in this limited sense,evolved a higher resistance. This is an extreme example. More often,a human gene pool will be little changed by an epidemic, while thepathogen's features may evolve dramatically.

BACTERIAL RESISTANCE TO ANTIBIOTICSp perhaps the greatest medical advance of this century, and oneof the greatest of all time, was the discovery that toxins pro-duced by fungi could kill the bacteria that cause human dis-ease. While arsenic compounds had been used for syphilis

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since Paul Ehrlich introduced them in 1910, the antibiotic era did notreally begin until Alexander Fleming noted one day in 1929 that bac-teria in his petri dishes would not grow properly in the vicinity ofcontaminating colonies of the mold Penicillium. Why should thishave been? Why did the most effective antibiotics come from molds?Antibiotics are chemical warfare agents that evolved in fungi and bac-teria to protect them from.pathogens and competitors. They wereshaped by millions of years of trial-and-error selection to exploit thespecial vulnerabilities of bacteria but to be nontoxic to the fungi.

A wide variety of fungal and bacterial products that are safe formost people can devastate the bacteria that cause tuberculosis, pneu-monia, and many other infections. For several decades now, theseantibiotics have given economically advanced societies a golden ageof relief from bacterial disease. A combination of public health mea-sures and antibiotics made the death rates from infectious diseasefall so rapidly that in 1969 the Surgeon General of the United Statesfelt justified in announcing that it was "time to close the book oninfectious disease."

Like other golden ages, this one may be short-lived. Dangerousbacteria, most notably those that cause tuberculosis and gonorrhea,are now more difficult to control with antibiotics than they were tenor twenty years ago. Bacteria have been evolving defenses againstantibiotics just as surely as they have been evolving defenses againstour natural weaponry and that of fungi throughout their evolution-ary history. As Mitchell Cohen of the Centers for Disease Controland Prevention put it recently, "Such issues have raised the concernthat we may be approaching the post-antimicrobial era."

Indeed we may. Consider staphylococcal bacteria, the most com-mon cause of wound infection. In 1941, all such bacteria were vul-nerable to penicillin. By 1944, some strains had already evolved tomake enzymes that could break down penicillin. Today, 95 percentof staphylococcus strains show some resistance to penicillin. In the1950s, an artificial penicillin, methicillin, was developed that couldkill these organisms, but the bacteria soon evolved ways around thisas well, and still new drugs needed to be produced. The drugciprofloxacin raised great hopes when it was introduced in the mid-1980s, but 80 percent of staphylococcus strains in New York City arenow resistant to it. In an Oregon Veterans' Administration hospital,the rate of resistance went from less than 5 percent to over 80 percentin a single year.

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In the 1960s, most cases of gonorrhea were easy to control withpenicillin, and even the resistant strains responded to ampicillin.Now 75 percent of gonococcal strains make enzymes that inactivateampicillin. Some of these changes were apparently a result of stan-dard chromosomal mutation and selection, but bacteria have anotherevolutionary trick. They are themselves infected by tiny rings ofDNA called plasmids, which occasionally leave a part of their DNAbehind as a new part of the bacterial genome. In 1976, it was discov-ered that the bacteria that cause gonorrhea had gotten the genes thatcode for penicillin-destroying enzymes via plasmids from Escherichiacoli, bacteria that normally live in the human gut, so that now 90 per-cent of the gonorrheal bacteria in Thailand and the Philippines havebecome resistant. Similarly, the gene that caused antibiotic resistancein a strain of Salmonella flexneri that caused a 1983 outbreak of severediarrhea on a Hopi Indian reservation was traced back to a womanwho had been taking long-term antibiotics to suppress an E. coli uri-nary tract infection.

The list of threats we face from antibiotic-resistant bacteria is longand frightening. A plasmid-mediated ability to prevent binding oferythromycin has made over 20 percent of pneumococcal bacteriaresistant to treatment with that drug in France. Some strains of thecholera now threatening thousands in South America are resistant toall five previously effective drugs. Amoxicillin is no longer effectiveagainst 30 to 50 percent of pathogenic E. coli. It appears that we areindeed running, together with the Red Queen, as fast as we can just tostay in the same place.

Perhaps most frightening of all, one third of all cases of tuberculosisin New York City are caused by tuberculosis bacilli resistant to oneantibiotic, while 3 percent of new cases and 7 percent of recurrent casesare resistant to two or more antibiotics. People with tuberculosis resis-tant to multiple drugs have about a 50 percent chance of survival. Thisis about the same as before antibiotics were invented! Tuberculosis isstill the most common cause of death from infection in developingcountries, causing 26 percent of avoidable adult deaths and 6.7 percentof all deaths. TB rates in the United States fell steadily until 1985 buthave increased 18 percent since then. About half of these cases resultedfrom impaired immune function in people with AIDS, the rest fromincreased opportunity for contagion and drug-resistant pathogens.

Increasing tolerance to antibiotics is the most widely known andappreciated kind of pathogen evolution. Since their discovery in the

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1950s, an enormous number of studies have established many med-ically important conclusions:

1. Bacterial resistance to antibiotics arises not by thegradual development of tolerance by individualbacteria but by rare gene mutations or new genesintroduced by plasmids.

2. Gene mutations can be transmitted by plasmidinfection or other processes to different species ofbacteria.

3. The presence of an antibiotic causes the initiallyrare mutant strain to increase and graduallyreplace the ancestral type.

4. If the antibiotic is removed, ancestral strainsslowly replace the resistant forms.

5. Mutations within a resistant strain can confer stillgreater resistance, so that increasing the dose of anantibiotic may be effective only temporarily.

6. Low concentrations of an antibiotic, which mayretard bacterial growth only slightly, will eventuallyselect for strains that resist the slight retardation.

7. Mutations that confer still higher levels of resis-tance arise in such partially adapted strains moreoften than in the original nonresistant strain.

8. Resistance to one antibiotic may confer resistance toanother, especially if the two are chemically related.

9. Finally, the disadvantage of resistant strains in theabsence of an antibiotic is gradually lost by furtherevolutionary changes, so that resistance can pre-vail even where no antibiotics have been used for along time.

The implications of these findings for medical practice are nowwidely appreciated. If one antibiotic doesn't alleviate your disease, itmay be better to try another, instead of increasing the dose of thefirst. Avoid long-term exposure to antibiotics; taking a daily peni-cillin pill to ward off infection is accepted therapy for some condi-tions, such as infection of vulnerable heart valves, but has theincidental effect of selecting for resistant strains. Unfortunately, wemay often be exposed to this side effect without knowing it, by con-

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suing meat or eggs or milk from animals routinely dosed withantibiotics. This is a hazard that has recently provoked conflictbetween food producers and public health activists. The problem ofantibiotic use in farm animals needs to be more widely recognizedand carefully evaluated in relation to whatever economic gains maybe claimed. As Harold Neu, professor of medicine at Columbia Uni-versity, says in concluding his 1992 article "The Crisis in AntibioticResistance," "The responsibility of reducing resistance lies with thephysician who uses antimicrobial agents and with patients whodemand antibiotics when the illness is viral and when antibiotics arenot indicated. It is also critical for the pharmaceutical industry not topromote inappropriate use of antibiotics for humans or for animalsbecause this selective pressure has been what has brought us to thiscrisis." Such advice is unlikely to be heeded. As Matt Ridley andBobbi Low point out in a recent article in The Atlantic Monthly,moral exhortations for the good of the many are often welcomed butrarely acted upon. To get people to cooperate for the good of thewhole requires sanctions that make lack of cooperation expensive.

Viruses don't have the same kind of metabolic machinery as bac-teria and are not controllable by fungal antibiotics, but there aredrugs that can combat them. An important recent example is zidovu-dine (AZT), used to delay the onset of AIDS in HIV-infected individ-uals. Unfortunately, AZT, like antibiotics, is not as reliable as it oncewas because some HIV strains are now (no surprise) resistant to AZT.HIV is a retrovirus, a really minimal sort of organism with speciallimitations and special strengths. It has no DNA of its own. Itsminute RNA code acts by slowly subverting the DNA-replicatingmachinery of the host to make copies of itself. The cells it exploitsinclude those of the immune system. The virus can hide inside thesecells, where it is largely invulnerable to the host's antibodies.

A retrovirus's lack of self-contained proliferation machinery isboth its weakness and its strength. It reproduces and evolves moreslowly than DNA viruses or bacteria. Another weakness is its lowlevel of reproductive precision, which means that it produces anappreciable number of defective copies of itself. This functionalweakness can be an evolutionary strength, however, because some ofthe defective copies may be better at evading the host's immune sys-tem or antiviral drugs. Another strength of retroviruses is their lackof any easily exploited Achilles' heel in their simple makeup.

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It takes months or years for HIV to evolve resistance to AZT, inmarked contrast to the few weeks it takes bacteria to evolve signifi-cant levels of resistance to some antibiotics. Unfortunately, HIV hasa long time to evolve in any given host. A single infection, after yearsof replication, mutation, and selection, can result in a diverse mix-ture of competing strains of the virus within a single host. The pre-dominant strains will be those best able to compete with whateverdifficulties must be overcome (e.g., AZT or other drug). They will bethe ones that most rapidly divert host resources to their own use-inother words, the most virulent.

SHORT-TERM EVOLUTION OF VIRULENCE

he evolution of virulence is a widely misunderstoodprocess. Conventional wisdom has it that parasites shouldalways be evolving toward reduced virulence. The reason-ing assumes, correctly, that the longer the host lives, the

longer the parasites can live and the longer they can disperse off-spring to new hosts. Any damage to the host on which they dependwill ultimately damage all dependent parasites, and the most success-ful parasites should be those that help the host in some way. Theexpected evolutionary sequence starts with a virulent parasite thatbecomes steadily more benign until finally it may become an impor-tant aid to the host's survival.

There are several things wrong with this seemingly reasonableargument. For example, it ignores a pathogen's ultimate requirementof dispersing offspring to new hosts. This dispersal, as noted in theprevious chapter, frequently makes use of host defenses, such ascoughing and sneezing, that are activated only as a result of apprecia-ble virulence. A rhinovirus that does not stimulate the host to defenditself with abundant secretion of mucus and sneezing is unlikely toreach new hosts.

Another error in the traditional view is the assumption that evo-lution is a slow process not only on a time scale of generations, butalso in absolute time. Such a belief arises from a failure to appreciatethe capacity for rapid evolution of any parasite that will go throughhundreds or thousands of generations in one host's lifetime. If the

(Video) How to Write a Summary

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virulence of the amoeba that causes dysentery is too low or too highfor maximizing its fitness, the virulence can be expected to evolvequickly toward whatever level is currently ideal. We should notexpect the present virulence of any pathogen to be in transit from onelevel to another unless conditions have changed recently. By"recently," we mean last week or last month, not the last ice age,which is what an evolutionary biologist often means by "recently."

Yet another flaw in the conventional wisdom is its neglect of selec-tion among different parasites within hosts, as we just implied in ourdiscussion of HIV. What good would it do a liver fluke to restrainitself so as not to harm the host if that host is about to die of shigel-losis? The fluke and the Shigella are competing for the same pool ofresources within the host, and the one that most ruthlessly exploitsthat pool will be the winner. Likewise, if there is more than oneShigella strain, the one that most effectively converts the host'sresources to its own use will disperse the most progeny before thehost dies. As a rule, all else being equal, such within-host selectionfavors increased virulence, while between-host selection acts to decreaseit. A recent comparative study of eleven species of fig wasps and theirparasites confirmed that increased opportunities for parasite trans-mission are associated with increased parasite virulence.

As with many other applications of evolutionary theory, carefulquantitative reasoning is needed to understand the balance betweennatural selection within and between hosts. The graph on the nextpage is a naive representation of what we have in mind.

An adequate theory of the evolution of virulence must take intoaccount the rate of establishment, in a given host, of new infections;the extent to which these competing pathogens differ in virulence; therate of origin of new strains by mutation within a host; and the extentto which these new strains differ in virulence. From such considera-tions it should be possible to infer the expected levels of virulence fora given pathogen, assuming that conditions stay the same, which theynever really do. The most important changes would be those that alterthe means by which a pathogen reaches new hosts. If dispersaldepends not only on a host's survival but also on its mobility, anydamage to the host is especially harmful to the pathogen. If you are sosick from a cold that you stay home in bed, you are unlikely to comeinto contact with many people that your virus might infect. If you feelwell enough to be up and about, you may be able to disperse it far andwide. It is very much in a cold virus's interest to avoid making you

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FIGURE 4-1. SELECTION WITHIN AND BETWEEN HOSTS.A shows the effects of an extremely virulent pathogen, which would be

favored by natural selection within a host. It exploits its host to maximizethe current rate of dispersal of new individuals to new hosts. It may kill the

host quickly, but while the host lives it does better than any competingpathogen. B shows the effects of a pathogen that is favored by selectionbetween pathogen communities of different hosts. It maximizes its long-term total productivity (rate of reproduction times duration, graphicallythe area under the production curve). Host death in B is most likely from

something other than the pathogen.

A. Selection Within Hosts B. Selection Between Hosts

Lethal damage to host Lethal damage to host

Infe

.- -- . - - -- - - . - . -- - -- -

Pathogen productivity

/ Harm to host

- - --

Time

Infection Host death

really sick. By contrast, the malaria agent Plasmodium gets no benefitfrom the host's feeling well. In fact, as shown by experiments with rab-bits and mice, a prostrate host is more vulnerable to mosquitoes. Peo-ple in the throes of a malarial attack are not likely to expend mucheffort warding off insects. Mosquitoes can feast on them at leisure andspread the disease far and wide.

This evolutionary perspective suggests that diseases spread by per-sonal contact should generally be less virulent than those conveyedby insects or other vectors. Do the facts fit this expectation? They doindeed. Among Paul Ewald's important discoveries is the truth ofthis generalization and its importance for public health. He hasshown that diseases from vector-borne pathogens tend to be moresevere than those spread by personal contact and that mosquito-borne infections are generally mild in the mosquito and severe in ver-tebrate hosts. This is to be expected because any harm to the

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mosquito would make it less likely to bite another vertebrate. Forgastrointestinal pathogens, the death rate is lower for direct, as com-pared to waterborne, transmission, as long as really sick hosts caneffectively contaminate the water supply. As pure water became thenorm in the United States early in this century, the deadly Shigelladysenteriae was displaced by the less virulent Shigella flexneri. Aswater was purified in South Asia during the middle of the century,the lethal form of cholera was steadily displaced by a more benignform, and the transition took place earliest at the places where waterwas first purified.

An unsanitary water supply is only one example of what Ewaldcalls cultural vectors. The history of medicine shows repeatedly thatthe best place to acquire a fatal disease is not a brothel or a crowdedsweatshop but a hospital. In hospitals, large numbers of patients maybe admitted with infectious diseases normally transmitted by per-sonal contact. People who are acutely ill do not move around much,but hospital personnel and equipment move rapidly from such peo-ple to others not yet infected. Inadequately cleaned hands, ther-mometers, or eating utensils can be quite effective cultural vectors,and the transmitted diseases may rapidly become more virulent.

Take, for instance, the streptococci that can cause uterine infectionin women after childbirth. Most nineteenth-century women knew thatthey risked their lives by having their babies in the hospital, but somestill did so. Viennese physician Ignaz Semmelweis noted in 1847 thatwomen in a clinic staffed by medical personnel contracted childbedfever three times as frequently as those in a clinic staffed by midwives.On investigating, he found that doctors came directly from doingautopsies on women who had died from childbed fever to do pelvicexaminations on women in labor. Semmelweis proposed that theywere transmitting the causative agent and showed that infections wereless frequent when examiners washed their hands in a bleach solution.Was he thanked for his wonderful discovery? No. He was dismissedfrom his post for suggesting that doctors were causing the deaths ofpatients. He became more and more frantic in his efforts to save thethousands of women who were dying unnecessarily, but he wasignored, and finally, at age forty-seven, he died in an insane asylum.Nowadays, we all accept the need for hygiene in hospitals, but when-ever it becomes lax, conditions are perfect for selecting for increasedvirulence, as in the virulent hospital-acquired (versus community-acquired) infantile diarrhea studied by Paul Ewald.

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It is widely believed that HIV is a new pathogen, perhaps origi-nating from a monkey infected with simian immunodeficiency virus(SIV). However, evidence now suggests that monkeys might haveacquired SIV from people with HIV. While HIV may have beenpresent in some humans for many generations, AIDS is apparently anew disease, resulting from the evolutionary origin in recent decadesof highly virulent HIV strains. AIDS may have arisen because ofchanged sexual behavior resulting from the socioeconomic disrup-tion of some traditional societies. Large numbers of prostitutes serv-ing hundreds of men per year were so effective at spreading infectionthat host survival became much less important to virus survival.Those strains that most rapidly exploited their hosts came to prevailwithin the hosts, and even the highly virulent strains had plenty ofopportunity to disperse to new hosts before the old ones died.

In Western countries, AIDS appeared initially as a disease mainlyof male homosexuals because their large numbers of sex partnersgreatly accelerated sexual transmission, and of intravenous drugusers because the drug users' needles were effective vectors. As inAfrica, the most virulent HIV strains prevailed over the less virulentbecause between-host selection for lower virulence was greatly weak-ened. Even highly virulent viruses had abundant opportunities toreach new hosts before the original host died. Conversely, the use ofclean needles and condoms can not only curtail the transmission ofthe virus, it can also cause the evolution of lower virulence.

COSTS AND BENEFITS OFTHE IMMUNE RESPONSE

A s described in the previous chapter, natural selection hasgiven us a fiendishly effective system of chemical war-

/,A fare. For every invading pathogen there will be a worst-case scenario as to what kind of molecules it might

encounter. Our immune systems have been shaped over a hundredmillion years to make the pathogen's worst nightmares come true.Unfortunately, every effective weapon can sometimes be dangerousto the one who wields it.

WHY WE GET SICK

The immune system can make two kinds of mistakes: failing toattack when it should and attacking something when it shouldn't. Thefirst kind of mistake results from inadequate response, so that a diseasethat should have been nipped in the bud becomes serious. The secondkind of mistake results from mounting too aggressive a response tominute chemical differences. Autoimmune diseases such as lupus ery-thematosus and rheumatoid arthritis could be the result. The averageperson's degree of sensitivity and responsiveness is presumably closeto what has historically been the optimum: enough to counterpathogens but not so great as to attack the body's own structure.

Given that we have this chemical superweapon-immunity-howcan we possibly remain vulnerable to infectious diseases? Once again,it is because the infectious agents can evolve rapidly and become bet-ter adapted by natural selection. Those variants that are least vulner-able to immunological attack will be those whose genes are bestrepresented in future generations. So the pathogens may evolve oneor another kind of defensive superweapon. Molecular mimicry, men-tioned in the last chapter, is one such weapon.

ESCALATING DECEPTION

S scientists first developed the concept of mimicry to describethe patterns on butterflies' wings. For instance, the viceroybutterfly looks almost exactly like the monarch butterfly,which birds do not attack because they want to avoid the

toxins the monarch caterpillar gets from eating milkweed leaves. Theviceroy has no such toxins, but birds mistake it for its bitter look-alike and likewise shun it. Examples are now also known in manyother animal groups. Any edible species that by chance resembles atoxic species will have an advantage, and selection will make thismimic species look increasingly like the toxic model. This is bad forthe model because predators that eat the edible mimic learn to goafter the model as well. This sets up an arms race between the mimic,which evolves an ever closer resemblance to the model, and themodel, which evolves to be as different as possible from its edibleneighbors. Some environmental circumstances favor the mimic tosuch an extent that really detailed resemblances between unrelatedspecies may evolve. We notice such mimicry easily because we per-

AN ARMS RACE WITHOUT END

ceive so much of the world visually. Detection of chemical mimicryrequires more subtle techniques, but there is no reason to think itless common than visual examples.

The molecular mimicry shown by pathogens turns out to be atleast as subtle, complicated, and full of surprises as the visual mim-icry shown by butterflies and other animals. Deceptive resemblancesto human proteins are shown by the surfaces of various parasiticworms, protozoa, and bacteria. If there is any deficiency in the mim-icry of human tissues by a bacterium, we can expect it to evolve animprovement rapidly. Pathogen surfaces may have a complex sculp-turing of convexities and concavities, and the molecular forms mostreadily recognized by antibodies are hidden in crevices. As noted inthe last chapter, some pathogens alter their exposed molecular struc-tures so rapidly that the host has difficulty producing newly neededantibodies fast enough. This is rapid change without evolution,because the same pathogen genotype codes for a variety of molecularstructures.

Mimicry may not only permit pathogens to escape from immuno-logical attack but also make active use of hosts' cellular processes.For instance, streptococcal bacteria make molecules similar to hosthormones that have receptor sites on cell membranes. In effect, thebacterium has a key to the lock on the door that normally admits ahormone. Once inside the cell, the bacterium is shielded fromimmunological and other host defenses. The host has an endosome-lysosome complex that can attack pathogens within its cells, butmolecular mimicry and other countermeasures protect the pathogenthere too.

NOVEL ENVIRONMENTAL FACTORSB -efore leaving infectious disease, we will anticipate a themeof Chapter 10 by noting the large proportion of epidemicsthat have resulted from novel environmental circum-stances. We have already mentioned how changed social

conditions may have initiated the AIDS epidemic, but the same istrue for many other plagues. Richard Krause, of the National Insti-tutes of Health, reports that early measles and smallpox epidemicsspread along caravan routes in the second and third centuries and

WHY WE GET SICK

killed a third of the people in some communities. Bubonic plague,the black death, had long festered in Asia, but became epidemic onlywhen Mongol invaders brought it to unexposed populations inEurope who lived with large populations of flea-infested rats. Whilewe like to imagine that such events are in the past, AIDS continues tospread alarmingly, and the causes of other sudden outbreaks of infec-tion are unknown. The Ebola virus ravaged parts of Africa in the1980s, killing half of those who became ill, including most of the doc-tors and nurses who cared for the patients. It stopped as suddenly asit started, for reasons that remain unclear.

Some infectious diseases stem directly from modern technology.Legionnaires' disease arose from an organism that was able to growand be dispersed from the water in a hotel air-conditioning system.Toxic shock syndrome arose when a new superabsorbent tamponmaterial allowed enough surface area and oxygen for the growth ofunusually large concentrations of toxic staphylococcal bacteria. Lymedisease became a problem only when deer populations multipliedadjacent to new suburbs. Influenza has become a major threat sincemass worldwide transportation began spreading new strains that con-tain new genes. It is often called the Asian flu because new strains sooften originate on Asian farms, where people, ducks, and pigs (somestrains are called swine flu) live in such close proximity that genes fromone influenza strain can easily be passed from one to another.

Tuberculosis became epidemic in Europe with the rise of large,crowded cities. Unsanitary practices and poverty are always cited ascauses, but we wonder if the disease didn't become epidemic simplybecause large numbers of people began spending large amounts oftime together indoors. Air exhausted from a TB ward reliably pro-duces infection in guinea pigs but no longer causes infection if it isbriefly exposed to ultraviolet light. A single sneeze can produce a mil-lion droplets, which settle to the ground at a rate of only about onecentimeter per minute in still air. In the open air they would be dis-persed or killed by sunlight, but indoors they might last for weeks, asthey no doubt did in 1651, when tuberculosis caused 20 percent of alldeaths in London.

Finally, we note that epidemics can result from the best of inten-tions. Polio was not an epidemic disease that caused paralysis untilthe early twentieth century. Before that time, most children got thedisease in the first years of life, when it usually produces only mildeffects. By midcentury, improving sanitation delayed the infection

AN ARMS RACE WITHOUT END

until late childhood, when it can be much more severe. Mononucle-osis is also less severe at earlier ages. In each of these examples, a dis-ease became a serious problem only when its mode of transmissionwas changed by novel environments. We will return in Chapter 10 toother novel environmental factors and their role in disease.

INJURY

W hen Huck Finn's drunken "Pap" fell over a tub ofsalt pork and barked both shins, he

fetched the tub a rattling kick. But it warn't goodjudgment because that was the boot that had a coupleof his toes leaking out the front end . . . and thecussing he done then laid over everything he had everdone previous.

Pap acted as if the tub wanted to hurt him, as if kicking and curs-ing it could deter future harm to his shins. But the kicking andcussing were wasted effort. The tub was not a rival trying to stealPap's mate, a predator trying to catch him, or even a microorganismstealthily trying to devour his tissues. It was merely inanimate wood.

In discussing such things as tubs of salt pork as sources of injury,we leave behind the conflicting interests, strategies, and arms racesthat complicate contests between living opponents. The problemsassociated with injuries are conceptually simpler than those of infec-tious diseases, but there is complexity aplenty. Some dangers, likebeing struck by a meteorite, have always been so rare and unpre-dictable that we have no evolved defenses and can repair the damage

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only by using general-purpose mechanisms. Others, like exposure tohigh levels of gamma rays, are so new that we have not had time toevolve adequate defenses. But some dangers, like drowning or attackby predators, have happened often enough in evolutionary historythat we have evolved ways to avoid them. This chapter is about theways we avoid, escape, and repair damage from sources of injury suchas mechanical trauma, radiation, burning, and freezing. It is also aboutwhy these adaptations do not always work as well as we might wish.

AVOIDANCE OF INJURY

ooled by milk, the coffee needed to be warmed up just aC bit. The microwave oven sounded its three pleasant beeps,and, as one of the authors opened the door, the air filledwith the aroma of steaming cafe au lait. As he grabbed the

handle of the ceramic mug, searing pain struck in a fraction of a sec-ond, too soon, too intense even to get the hot-handled mug to thecounter. It crashed to the floor, splattering hot coffee for yards. Afterhe got his painful hand under cold water, the victim realized that thismug must be different from others, which stay cool to the touch aftermicrowaving. In fact, its handle must have had a metal core. The painprevented the worse damage that would have resulted from more pro-longed contact. The fearful memory of the pain, months later, stillmakes him shy away from using that particular mug.

Pain and fear are useful, and people who lack them are seriouslyhandicapped. As noted already, the rare individuals who are bornwithout the sense of pain are almost all dead by age thirty. If there arepeople born without the capacity for fear, you might well look forthem in the emergency room or the morgue. We need our pains andour fears. They are normal defenses that warn us of danger. Pain isthe signal that tissue is being damaged. It has to be aversive to moti-vate us to set aside other activities to do whatever is necessary to stopthe damage. Fear is a signal that a situation may be dangerous, thatsome kind of loss or damage is likely, that escape is desirable.

Here we come to a distressing insight. Pain and fear, the sources ofso much human suffering, the targets of much medical intervention,are not themselves diseases or impairments but instead are normalcomponents of the body's defenses. Blocking pain and fear in any

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way other than eliminating the cause may make the damage worse.For instance, people with syringomyelia, a degeneration of the cen-tral part of the spinal cord where the pain nerves are located, experi-ence no pain in their hands. A person with syringomyelia would havepicked up that hot cup of coffee and drunk it calmly as the flesh cur-dled on his fingers. If he smokes, his fingers are likely to be charred.Pain is useful, and its link to fear is no accident. When the body isdamaged, pain motivates rapid escape and fear prevents recurrence.

But our adaptations for avoiding injury are more subtle than themere avoidance of pain and its portents. Avoidance can be conditionedmore easily to some cues than to others, depending on what kind ofharm occurs. Psychologist John Garcia easily conditioned dogs toavoid a peppermint smell associated with gastrointestinal illness butfound it much more difficult to use such sickness to condition avoid-ance of a tone. Dogs also readily learned to avoid an electric shock thatwas preceded by a tone but had much more difficulty when the cue wasan odor. This makes eminent evolutionary sense. Auditory stimuli aremore likely than odors to be good cues to the danger of impendinginjury, while odors are far more reliable indicators of toxic food. Likeso many good ideas, Garcia's was difficult to get published, wasridiculed shortly thereafter, and has been praised ever since.

Some cues-for instance, snakes, spiders, and heights-readilyelicit fear in ourselves and other primates. It should not surprise us todiscover that we instinctively avoid certain cues that have long beenassociated with such dangers as falling and dangerous animals. Afterall, a rabbit that learned a fear of foxes only by being bitten wouldpass on few of its genes. Rabbit brains are preprogrammed to avoidfoxes, and it should not be surprising to find that our brains havesome similar capacities. But the price of innate behavior is its inflexi-bility. Better than a fixed innate response would be a more flexiblesystem that induced fear only to stimuli shown to pose a threat. Anewborn fawn will stand and stare at an approaching wolf until it seesits mother flee. Then it too flees, and the flight pattern is set for therest of its life, ready to pass on to the next generation by imitation.Our fears of snakes, spiders, and heights are prepared but not hard-wired. They are partly learned and can be unlearned.

Psychologist Susan Mineka carried out an ingenious series of exper-iments at the University of Wisconsin Primate Center to demonstratethe development of such fears. Monkeys raised in the laboratory haveno fear of snakes and will reach over a snake to get a banana. After

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watching a single video that shows another monkey reacting with alarmto a snake, however, the monkeys develop a lasting phobia of snakes.They will no longer even approach the side of a cage closest to a snake,much less reach across it. By contrast, if the video shows another mon-key apparently recoiling in fear from a flower, no phobia to flowers iscreated, even though the response the monkey sees is otherwise identi-cal. Monkeys readily learn fear of snakes, but not fear of flowers.

GENERALIZED LEARNINGAND UNDERSTANDINGI n addition to the simple conditioning discussed above, we humans

have more subtle adaptations: our capacities for communication,memory, and reasoning. Drivers can imagine that speeding downan icy mountain road is dangerous, even if they have never actually

seen it cause an accident. Even those who haven't personally knownanyone killed by a fire can understand that a burning building is a seri-ous hazard that a smoke detector can reduce. People can even avoid dan-gerous things they cannot perceive, such as radon gas, dioxins, anddietary lead, thanks to learning and reasoning. Our capacity to createand manipulate mental representations has many benefits, and the abil-ity to foresee new dangers is clearly one of them. This capacity also helpsus to avoid repetitions of actual experiences of danger or injury withoutcreating unnecessary phobias. If we see someone get a shock while wear-ing suspenders and working carelessly with household wiring, we canreason that the wiring, not the suspenders, caused the misfortune.

REPAIR OF INJURYI njury cannot always be avoided. Whether at the tenth or the tenthousandth stroke, the hammer eventually comes down on thethumb. The resulting injury brings a whole battery of repairmechanisms into play. Blood platelets secrete clotting factors that

soon stem the bleeding, whether external or internal (in the form of abruise). Other cells secrete a complex variety of substances that causeinflammation, thus raising the temperature of the tissue and making itharder for any invading bacteria to grow. They also keep the thumb

WHY WE GET SICK

painful, thus protecting it from minor stresses that might disrupt thehealing process. Simultaneously, the immune system rushes special-ized infection fighters to the site. They either attack any bacteria thatthe injury might have introduced or take them to lymph nodes, wherethey can be more easily destroyed. Fibrin strands link the tissuestogether, and, as healing proceeds, they slowly shrink and pull the sidesof the wound together. Eventually nerves and blood vessels grow anewinto the damaged tissue, and the hammering can proceed as before,albeit more cautiously. These repair processes show a precise, complexcoordination that a symphony orchestra might well envy.

Unfortunately, no one has yet written the score for the healing sym-phony. Many individual parts are described at great length by pathol-ogy books, and some attention has even been paid to coordinationamong the parts, especially the different roles of several groups ofimmune cells. What we lack is an adaptationist story for the over-all process. Such an account would have a plot-the effort to achievethe best possible repairs in as short a time as possible-to which all thedetails could be related. It would be a tale of optimal trade-offs in theallocation of scarce resources such as time and materials, and betweensuch conflicting values as continued effective use of the damaged partand its protection from stresses that could slow the healing. It woulddeal with the optimal timing of events, with no job being started untilthose that must be finished first are completed. It would recognize theneed for cooperation and effective communication, not only withinsuch systems such as the immune but also in the participating hor-monal, enzymatic, and structural adaptations. It would deal not onlywith events at the site of injury but with hormonal and other adjust-ments of emotion and behavior and of physiological processesthroughout the body. We hope the score of this well-crafted sym-phony will be written in the not-too-distant future.

BURNS AND FROSTBITEE -ven instantaneous pain was not quick enough to save the tensof thousands of skin cells burned by the hot handle of thatcoffee mug. Two small regions on the thumb and index fingerturned white in seconds. Curdled like an egg white dropped

into boiling water, the skin cells formed a mass of denatured protein, akind of injury more difficult to repair than a minor cut. This is, no

INJURY

doubt, why heat so quickly causes intense pain. Skin with a minorburn heals readily because the mechanism that replaces epidermal cellsremains ready to work, but deeper burns pose more difficult prob-lems. If a burn destroys the cells that replace the epidermis, specialmechanisms are required to protect the site from infection, clear awaythe dead tissue, and infuse the region with new skin cells that can growand gradually resurface the site of the bum. We can do it, but onlywith time and risk of infection. Far better to avoid the burn.

We have used and abused fire for a hundred thousand years ormore. Even before people learned to make fire, they took burningmaterials from natural sources and maintained fires for cooking andother uses. Has this long association sharpened our reactions to fire'sdangers? It would be interesting to learn if we are better defendedagainst hot objects than closely related species are, perhaps by beingmore sensitive to hot objects or by more rapid healing of burns.

Heat is not the only cause of thermal damage. Freezing can leavecells just as curdled and dead, a condition known as frostbite.Although this was not a routine danger during most of human evolu-tion, it may have shaped our avoidance of extended exposure to coldair and especially to cold water, which is hundreds of times as effec-tive a heat conductor as still air. Liquid nitrogen and dry ice are noveldangers that were entirely absent in the Stone Age. They can be asharmful as fire, but we have not evolved reactions to make us recoilinstinctively from liquid nitrogen or dry ice as we do from hot coals.

RADIATIONT he most important radiation damage has always been fromthe sun. Dark-skinned races are fully equipped with theprimary defense against the sun's rays, the pigmentmelanin in the outer skin, which protects the underlying

tissues simply by shading them. A few thousand generations of free-dom from sunshine, as may happen to animal populations living incaves, results in a loss of the ability to make pigment. The continuouspresence of pigmentation in dark-skinned races shows the benefits ofits protection against sunshine.

People of European descent pose a special evolutionary problem.Their pale skins show that protection from sunshine has not been

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such a consistently important factor in their history, and they areespecially vulnerable to sunburn. The first warm, sunny days ofspring tempt some of them to bare their skins for many hours.Maybe they know from painful experience that this is not wise, but itfeels so good after the winter chill. If fear of repeating the previousyear'.; sunburn does not deter them, the pain of this year's will noteither, because it comes too late. Only hours after exposure does thesunburned area become sore, red, and feverish. For several days,sheets of dead skin peel off. Recovery can be complete in a week ortwo, but this may not be the end of the story, because getting even afew serious sunburns greatly increases the risk of skin cancer years ordecades later.

Gradually increasing one's exposure to the sun is less harmful,because all but the most fair-skinned individuals can develop a suffi-ciently protective layer of melanin. Suntan is a fine example of aninducible defense that is developed only when needed. The fact thatfair-skinned people are not heavily pigmented all the time suggeststhat for their ancestors pigment production had important costs tofitness. In Chapter 9 we will explore the possibility that pallor may beadaptive in shady and cloudy environments.

Everyone knows that it is an excess of solar ultraviolet that causessunburn, but ordinary visible light, while far less destructive, is alsophotochemically active and potentially harmful. It does not normallyharm us, because natural selection has provided almost everyonewith enough melanin and enough enzymes that counter photochemi-cal alterations. Organisms that do not ordinarily live with bright illu-mination are much more sensitive to sunshine or even to someartificial light sources. For instance, when fluorescent lighting firstreplaced incandescent light in trout hatcheries, it caused massivemortality in trout eggs. Hatchery biologists knew that in nature sucheggs develop under a shady layer of streambed gravel. They hypothe-sized that the mortality resulted from the greater brightness andshorter (blue) wavelengths of fluorescent light. Experiments showedthat this explanation was right: when the trout eggs were shieldedfrom the harmful rays, they did just fine.

Sunlight kills skin cells not by thermal damage but by photo-chemical alteration of essential substances. The resulting abnormalcompounds and dead cells invite attack by the immune system. Tosome extent this is desirable. It is wasteful to devote resources tosupporting dead or inevitably dying cells that ought to be efficiently

INJURY

cleared away. It is equally important not to eliminate cells that canadequately repair themselves. Distinguishing between these cate-gories may not be easy. For an injury that doesn't involve pathogeninvasion, such as sunburn or perhaps a simple fracture, it may be bestto suppress some aspects of the immune response so as not to inter-fere with healing.

The immune cells themselves, like any others, can be damaged byradiation. At the moment it is not at all clear which of the ultraviolet-induced changes in the immune system are adaptive adjustments andwhich are impairments. The Langerhans cells in the epidermis, whichtake up foreign substances and present them to the immune system,react to the ultraviolet wavelengths from 290 to 320 nanometers(UV-B) in complex ways. These cells are intimately associated withnerves that secrete a hormone that blocks their action. UV-B radia-tion depletes the skin of these cells, thus blocking its ability to reactto contact with foreign proteins. Such a lack of sensitivity is charac-teristic of almost all people who get skin cancer. But UV-B is not theonly culprit. There is some evidence that some commercially avail-able sunscreen lotions block UV-B and prevent sunburn but stillallow the passage of the longer-wave UV-A, which may damage theskin's immune cells. People who get a rash from being in the sun areoften advised to use sunscreens, but sunscreens might in fact makethe problem worse by encouraging more exposure to UV-A thanthey could otherwise tolerate.

An alarming increase in the occurrence of melanoma, a potentiallyfatal skin cancer, is causing a justified fear of excessive exposure tothe sun. The rates in Scotland have doubled in the past decade, andthe rates among fair-skinned people are increasing at a rate of 7 per-cent a year in many countries. Explanations for the increase rangefrom the new cultural desire to be tan to the thinning of the ozoneshield, which has always blocked much ultraviolet light. While bothof these factors need to be considered, an evolutionary view suggestsother explanations too. We do spend more time at beaches, but wespend far less walking in the sun without clothes on. The loss of ultra-violet blocking resulting from ozone depletion is more than counter-balanced in most areas by the local air pollution. What is new isnot sun exposure or ozone inadequacy but our pattern of sun expo-sure. People now spend most of their time indoors and then go out-side on weekends for intense bouts of unaccustomed exposure.People who are outdoors for hours every day adapt to their amount

WHY WE GET SICK

of usual exposure and are unlikely to get sunburnt. The risk ofmelanoma is related more closely to the number of sunburns than tothe total amount of time spent in the sun.

Another novel environmental factor is the use of chemically com-plex sun lotions. Blocking ultraviolet radiation does curtail the devel-opment of cancerous lesions. A recent controlled study of 588Australians found that those who used an active sunscreen developedsignificantly fewer precancerous skin lesions than those who used acream that did not block much ultraviolet light. But might the chem-icals in sunscreens also cause problems? They don't just sit on thesurface of the skin but are absorbed into it. What effects do they haveon skin cells, and how might they be transformed after binding to tis-sue proteins and being bombarded by strong light? The answers arevery much in doubt. How ironic it would be if we were to discoverthat skin cancer can be caused, directly or indirectly, by suntanlotions! Attention should also be given to the products used toinhibit the inflammatory process of sunburn. Such inhibition mightprevent cancer by preventing unnecessary damage from autoimmunereactions, but it might also protect damaged and potentially cancer-ous cells from being naturally destroyed by the immune system.

We emphasize that these are not facts but mere speculations thatarise from our lack of understanding. Why do we understand so lit-tle about sunburn despite the abundance of available information?Understanding that provides a reliable basis for protection and ther-apy will be reached when researchers well versed in evolutionary rea-soning and with a detailed knowledge of the cellular and molecularevents of sunburn put together an explanation that: (1) distinguishesUV impairment of skin function from its adaptive responses to UVstress; (2) distinguishes UV impairment of the immune functionfrom the adaptive immune response; (3) distinguishes impairment ofLangerhans cell function from adaptive responses; (4) delineates thespecial components of the repair processes and their coordination;and (5) shows the positive and negative effects of protective lotionsapplied before exposure and anti-inflammatory medications usedafterward.

Sun damage also appears to contribute to cataracts, a clouding ofthe lens in the eye. While most sunglasses now block ultraviolet light,older models often did not. Instead they reduced the total amount ofvisible light, so that the pupil actually opened more widely and admit-ted more ultraviolet light. Worse yet, many of the cheap sunglasses

INJURY

that children are likely to wear still transmit large proportions of theultraviolet. We wonder whether some of today's cataract patientsmight owe their misfortune to sunglasses they wore decades ago.

REGENERATION OF BODY PARTSC hildren often ask the most intelligent questions. "Why,"asks an inquisitive child, "can't Uncle Bob grow a new leglike a starfish does?" Why not indeed? If lizards regrowlost tails, starfish lost arms, and fish lost fins, why can we

not even regenerate a lost finger? It is remarkable that this questionseldom bothers adults, even biologists. The answer, in general evolu-tionary terms, is that natural selection will not maintain capacitiesthat are unlikely to be useful or that have costs that would exceed theexpected benefits. Thus, as noted in Chapter 3, serious damage to thebrain or heart was uniformly fatal before the era of modern medicine,and the ability to regenerate these tissues could not be selected for.An individual who lost an arm in a Stone Age accident could bleed todeath in a few minutes. If the bleeding were somehow controlled, thevictim would likely soon die of tetanus, gangrene, or other infection.Any process that might have allowed our remote ancestors' arms toregenerate has gradually been lost by the accumulation of mutationsthat have not been selected against.

But what about the loss of a finger? This would not be as likely tocause death as the loss of a whole arm, and such injuries often do healunder Stone Age conditions. Why not regenerate the finger insteadof merely healing the wound? The explanation given in the previousparagraph will not suffice here. We suggest instead two other factors.The first is merely that this regenerative ability would not be usedvery often and would not produce a major benefit. Most people donot lose fingers, and if they do, the long-term impairment need not beserious. A nine-fingered Neanderthal might live to the ripe old age offifty. Another reason, which we have already repeatedly emphasized,is that every adaptation has costs. The capacity to regenerate dam-aged tissue demands not only the cost of maintaining the machineryto make this possible but also the cost of a decreased ability to con-trol harmful growths. A mechanism that allows cell replicationincreases the risk of cancer. It is dangerous to let mature, specialized

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tissues have more than the minimum needed capability to repairlikely injuries, as we will discuss in the chapter on cancer.

A different kind of explanation is often offered for our inability toregenerate a missing finger. Regeneration would require growth hor-mones, control of cell movement, and many other processes, andthey are simply not there. This is another way of saying that, after anearly stage of fetal development, the machinery needed for producinga finger is missing. This is the sort of proximate explanation, basedon the details of the mechanism, that most medical researchers wouldthink of first. But we also need an evolutionary explanation of whythe needed machinery is missing, whatever that machinery might be.Such an evolutionary explanation is more likely to satisfy a child'scuriosity, and it can lead researchers to fruitful ideas on what sort ofrepair machinery we might expect to be activated by the loss of a fin-ger. We suggest that the machinery will conform to an optimal trade-off between the advantages of rapid and reliable repair, the costs ofthe needed machinery, and the dangers of cancer.

TOXINS:NEW, OLD,

AND EVERYWHERE

ss^it nat," says Don Birnharn (Ray Milland) to his bartender inThe Lost Weekend, "You don't approve of drinking.Shrinks my liver, doesn't it? It pickles my kidneys. Yes,but what does it do to my mind?" We will consider the

effects on his mind in later chapters. Here we will merely mentionsome effects prior to those on his liver and kidneys.

Don's rye whisky rewards him with a gentle burning sensation asit passes through his esophagus and on to his stomach. His nerves aresignaling the deaths of millions of cells as alcohol diffuses rapidlythrough the usually protective barrier of mucus and enters thosecells. If a cell gets more than a critical concentration of alcohol, itdies. Dead cells, or even those with damaged membranes, releasewound hormones and growth factors, which diffuse to other cells held inreserve for just such an emergency. These reserve cells, deep in theprotected crypts of the stomach lining, react to the chemical messagesby migrating to the site of injury and dividing to produce new cells ofthe kind needed there. The most exposed layer of stomach cells canbe replaced in mere minutes-but does Don allow them enough timebefore quaffing again?

WHY WE GET SICK

NATURAL AND UNNATURAL TOXINSH righ-proof alcohol is only one of the many novel hazardsto which we are exposed. Agricultural pests are con-trolled mainly by insecticides that did not exist before1940. Silos are perfused with poisonous vapors to pro-

tect grain from insects and rodents. Demonstrably toxic chemicalssuch as nitrates are used to extend the shelf life of our foods. Manyworkers inhale toxic dust or fumes, and suburbanites spray insecti-cides such as lindane into their trees, often with little regard to the pos-sible effects on themselves or their neighbors. There are heavy metalsin our water, pollutants in our air, and radon gas rising from our base-ments. Obviously our modern age is especially hazardous, with respectto poisons in the food we eat and the air we breathe. Right?

Wrong. While we are now exposed to many toxins that did notexist in even the recent past, our exposure to many natural toxins hasgreatly decreased since the Stone Age and early agricultural times.Recall from the chapters on infectious disease that the contest betweenconsumer and consumed can generate an evolutionary arms race.Plants can't protect themselves by running away, so they use chemicalwarfare instead. People have always known that some plants are toxic.Gardening books routinely list plants known to have caused illness ordeath from being eaten. These lists merely deal with the worst offend-ers. Most plants contain toxins that would be harmful if eaten in morethan a minimal amount. Scientists have only recently realized that thetoxic substances are not by-products that just happen to be toxic tocertain potential consumers; they are the plants' essential defensesagainst animals that want to eat them (herbivores), and they play a keyrole in the ecology of natural communities. People who live in the east-ern United States needn't look far for an example. Most lawns thereare of tall fescue, a grass species popular because it grows fast andresists pests. The fantasy of getting rid of our lawn mowers and lettinghorses graze our lawns once a week is appealing, but the horses wouldsoon get sick. Most tall fescue is infected at its base with a fungus thatmakes potent toxins. The grass protects itself by transporting thesetoxins to the tips of the blades of grass, the perfect location for dis-couraging herbivores. Tall fescue and its fungus help each other.

Only very recently have a few pioneers, such as Timothy Johnsand Bruce Ames and his collaborators, made us aware of the enor-

TOXINS: NEW, OLD, AND EVERYWHERE

mous medical importance of the plant-herbivore arms race. We canheartily recommend Johns's book With Bitter Herbs Thou Shalt Eat Itfor an introduction to the role of plant toxins in human history.

Here we are again dealing with an arms race, this time between ani-mals such as ourselves, who eat plants, and the plants, which need toprotect themselves from being eaten. When Stone Age inhabitants ofcentral Europe died of starvation late one winter instead of happilyfilling up on oak buds and acorns, they were losers in the contest withoak trees. Oak buds and acorns are loaded with nutrients, but, unfor-tunately for potential consumers, they are also loaded with tannins,alkaloids, and other defensive toxins. Early Europeans who filled upon unprocessed oak tissues died even sooner than their starving com-panions did.

Animals that eat other animals may have to deal with venoms orother harmful materials manufactured by their prey, and they willcertainly have to deal with at least traces of the plant toxins eaten bythe prey. The monarch butterfly caterpillar, mentioned earlier, feedson milkweed not only because it has machinery that makes it invul-nerable to the milkweed's deadly cardiac glycosides but also becauseit becomes poisonous itself by consuming the plant and is thereforeavoided by potential predators. Many insects and arthropods protectthemselves with venoms and poisons. Many amphibians are poison-ous, especially the bright-colored frogs that Amazonian peoples useto poison their arrowheads. The vivid colors and patterns of suchpoisonous animals protect them from predators, who have learnedfrom bitter experience that such prey are not pleasant food items. Ifyou are starving in a rain forest, eat the camouflaged frog that is hid-ing in the vegetation, not the bright one sitting resplendent on anearby branch.

How do plant toxins work? They do whatever will keep herbi-vores from eating the plants. Why are there so many different toxins?Herbivores would quickly find a way around any one defense, so thearms race creates many different ones. The list of different toxins andtheir diverse actions is impressive. Some plants make precursors ofcyanide, which is released either by enzymes in the plant or by theintestinal bacteria of the consumer. The bitter almond is noteworthyin this regard, but apple and apricot seeds use the same strategy, as docassava roots, which are used for food in many cultures.

All adaptations, however, have costs, and plants' defensive chem-icals have theirs. Toxin manufacture requires materials and energy,

WHY WE GET SICK

and the toxins may be dangerous to the plant that produces them. Ingeneral, a plant can have high toxin levels or rapid growth, but notboth. To put it from the herbivore's point of view, rapidly growingplant tissues are usually better food than stable or slowly growingstructures. This is why leaves are more vulnerable than bark and whythe first leaves of spring are especially vulnerable to caterpillars andother pests.

Seeds are often especially poisonous, because their destructionwould thwart the plant's reproductive strategy. Fruits, however, arebright, aromatic packets of sugars and other nutrients specificallydesigned to be attractive food for animals that can disperse the seedscontained in them. The seeds within the fruit are designed either tobe discarded intact (like peach pits) or to pass safely through anintestinal tract (like raspberry seeds) to be deposited at some distantplace surrounded by natural fertilizer. If the fruit is eaten before theseeds are ready, the whole investment is wasted, so many plants makepotent poisons to discourage consumption of immature fruits, thusthe proverbial stomachache caused by green apples. Nectar is like-wise designed to be eaten, but only by whatever pollinators are bestfor the plant that makes it. Nectar is an elaborate cocktail of sugarand dilute poisons. The recipe has evolved as an optimal trade-offbetween the need to repel the wrong visitors and not discourage theright ones.

Nuts represent a still different strategy. Their hard shells protectthem from many animals, and some, like acorns, are also protectedby high levels of tannin and other toxins. Though many acorns areeaten, some are trampled into the ground, while others are buried bysquirrels and thus have a chance to sprout into new trees. It takessuch elaborate processing to turn acorns into human food that wewonder if the tannin may be too much even for squirrels. Perhaps itleaches out when acorns are buried in moist soil. If so, the squirrelsare processing as well as hiding their food, a neat ploy in their armsrace with the oak. If you find yourself starving in an unknown wilder-ness, seek your nourishment in soft sweet fruits, the nuts with thehardest shells, and perhaps some inaccessible tubers. Avoid seem-ingly unprotected fleshy plant materials like leaves; they are muchmore likely to be poisonous, as they must be to protect them fromyour own or any other hungry mouth.

Plants' escalations of the arms race are numerous and varied.Some plants make little defensive toxin until they are mechanically

TOXINS: NEW, OLD, AND EVERYWHERE

damaged, after which toxin rapidly accumulates in or near theinjured part. Damage to a tomato or potato leaf induces productionof toxins (proteinase inhibitors) not only at the site of the wound butthroughout the plant. A plant has no nervous system, but it doeshave electrical signaling and a hormone system that can keep all itsparts informed about what takes place in a small region. Some aspentrees have even more impressive communication. When a leaf isdamaged, a volatile compound (methyl jasmonate) evaporating fromthe wound can turn on the proteinase response in nearby leaves, eventhose on other trees. The usual result of such defenses is that insectsare discouraged after feeding even briefly. Some particularly adeptinsects, however, begin their meal by cutting the main supply vein toa leaf so the plant cannot deliver more toxins. And so the arms racegoes on.

DEFENSES AGAINST NATURAL TOXINSTr he best defenses are, of course, the sorts of avoidance andexpulsion already discussed in relation to infectious dis-eases. We avoid eating moldy bread or rotten meat, whichsmell and taste bad, because we react with an adaptive dis-

gust to the toxins produced by fungi and bacteria. We rapidly expeltoxic substances by spitting or vomiting or diarrhea. We quicklylearn to avoid whatever gives us nausea or diarrhea.

Many swallowed toxins can be denatured by stomach acid anddigestive enzymes. The stomach lining is covered with a mucous layerthat protects it from ingested toxins and stomach acid. If some cellsbecome contaminated, the effect is temporary since stomach andintestinal cells, like those of the skin, are shed regularly. If toxins areabsorbed by the stomach or intestine, they are taken by the portalvein directly to the liver, our most important detoxification organ.There, enzymes alter some toxic molecules to render them harmlessand bind others to molecules excreted in the bile back into the intes-tine. Toxin molecules in sufficiently low concentration will bequickly taken up by receptors on cells in the liver and rapidlyprocessed by the liver's detoxification enzymes.

For instance, our protection against cyanide depends on an enzymecalled rhodanase, which adds a sulfur atom to cyanide to form a chem-

WHY WE GET SICK

ical called thiocyanate. Although thiocyanate is far less toxic thancyanide, it still prevents the normal uptake of iodine into thyroid tissueand thus can cause the overworked thyroid gland to enlarge-a condi-tion called goiter. Plants from the genus Brassica (including broccoli,Brussels sprouts, cauliflower, and cabbage) get their strong taste fromallylisothiocyanate. The ability to taste a related compound, phenyl-thiocarbamate (PTC) varies greatly, as is well known by generations ofstudents who have tasted a bit of PTC-impregnated filter paper as partof an experiment to demonstrate genetic variation. While some peoplecan't taste PTC, those with a different gene experience it as bitter. Theymay have an advantage in avoiding natural compounds that cause goi-ter. About 70 percent of individuals in most populations can tastePTC, but in the Andes, where such compounds are especially likely inthe diet, 93 percent of the native people can taste it.

Oxalate is another common plant defense. Found in especiallyhigh concentrations in rhubarb leaves, it binds metals, especially cal-cium. The majority of kidney stones are composed of calcium oxa-late, and doctors have for years recommended that such patientskeep their diets low in calcium. However, a study of 45,619 men,published in 1992, showed a higher risk of kidney stones for thosewho had low calcium intakes. How is this possible? Dietary calciumbinds oxalate in the gut so that it cannot be absorbed. If dietary levelsof calcium are too low, some oxalate is left free to enter the body. If,as researchers S. B. Eaton and D. A. Nelson have argued, the amountof calcium in the average diet is now less than half of what it was inthe Stone Age, our current susceptibility to kidney stones may resultfrom this abnormal aspect of our modern environment, which makesus especially vulnerable to oxalate.

There are dozens of other classes of toxins, each with its own wayof interfering with bodily function. Plants in the foxglove and milk-weed family make glycosides (e.g., digitalis), which interfere with thetransmission of electrical impulses needed for maintaining normalheart rhythm. Lectins cause blood cells to clump and block capillar-ies. Many plants make substances that interfere with the nervous sys-tem-opioids in poppies, caffeine in coffee beans, cocaine in the cocaleaf. Are such medically useful substances really toxins? The dose ofcaffeine contained in a few coffee beans may give us a pleasant buzz,but imagine the effect of the same dose on a mouse! Potatoes containdiazepam (Valium), but in amounts too small even to cause relax-ation in humans. Other plants have toxins that cause cancer or

TOXINS: NEW, OLD, AND EVERYWHERE

genetic damage, sun sensitivity, liver damage-you name it. Theplant-herbivore arms race has created weapons and defenses of enor-mous power and diversity.

What happens if we overload our bodies with so many toxin mol-ecules that all the processing sites in the liver are occupied? Unlikethe orderly queues of shoppers in the supermarket, these moleculesdo not just wait their turn to be processed. The excess toxins circu-late through the body, doing damage wherever they can. While ourbodies cannot instantly make additional detoxification enzymes,many toxins stimulate increased enzyme production in preparationfor the next challenge. When medications induce these enzymes, thismay hasten the destruction of other medications in the body, thusnecessitating dose adjustments. Timothy Johns's book notes theinteresting possibility that inadequate exposure to everyday toxinsmay leave our enzyme systems unprepared to handle a normal toxicload when one occurs. Perhaps with toxins, as with sun exposure,our bodies can adapt to chronic threats but not to occasional ones.

Grazers and browsers limit their consumption of certain plants toavoid overloading any one kind of detoxification machinery. Thisdietary diversification also helps to provide adequate supplies of vit-amins and other trace nutrients. Left to our own devices in a naturalenvironment, we do the same. If your favorite vegetable is broccoliand you were given an unlimited supply of it and nothing else, youwould not eat as much as you would if given both broccoli andcucumbers. Many weight-loss diets are based on the principle that weeat less if given only a few foods than we would if we had access to awell-stocked cafeteria. We minimize the damage caused by dietarytoxins by this instinctive diversification, as well as with our own spe-cial array of detoxification enzymes. These enzymes are not as potentor diverse as those of a goat or a deer, but they are more formidablethan those of a dog or cat. We would be seriously poisoned if we atea deer's diet of leaves and acorns, just as a dog or cat would quicklysicken on what we might regard as a wholesome salad.

We can also, more than any other species, protect ourselves frombeing poisoned by learning about how to avoid it. Only we can readabout the dangerous plants in our gardens and woodlands, and we arethe species whose diets are most shaped by social learning. A foodour mothers fed us can usually be accepted as safe and nourishing.What our friends eat without apparent harm is at least worth a try.What they avoid we would be wise to treat cautiously.

WHY WE GET SICK

More broadly, there is great wisdom in our innate tendency to fol-low the seemingly arbitrary dictates of culture. The rituals of manysocieties require that corn be processed with alkali before it is eaten.Can't you just imagine prehistoric Olmec teenagers ridiculing theirelders for going to all the bother? But those teenagers who ate onlyunprocessed corn would have developed the skin and neurologicalabnormalities characteristic of pellagra. Neither rebels nor elderscould have known that boiling corn with alkali balances the aminoacid composition and frees the vitamin niacin, which prevents pella-gra, but the cultural practice accomplished what was needed, despitethe lack of scientific understanding.

Or consider the prehistoric residents of California, whose mainsustenance came from acorns. The abundant tannins in acorns areastringent and combine strongly with proteins, properties that makethem especially useful as leather-tanning agents. As noted above, theyare highly toxic as they come from the tree. Whether the tanninsevolved to protect the acorn against large animals or against insectsand fungi is uncertain, but dietary concentrations of over 8 percentare fatal to rats. The tannin concentrations in acorns can reach 9 per-cent, and this explains why we cannot eat acorns raw. The Pomo Indi-ans of California mixed unprocessed acorn meal with a certain kindof red clay to make bread. The clay bound enough of the tannin tomake the bread palatable. Other groups boiled the acorns to extractthe tannin. Our enzyme systems can apparently cope with low con-centrations of tannin, and many of us like its taste in tea and redwine. Small amounts of tannin may even be helpful by stimulatingproduction of the digestive enzyme trypsin.

Human diets expanded after fire was domesticated. Because heatdetoxifies many of the most potent plant poisons, cooking makes itpossible for us to eat foods that would otherwise poison us. Thecyanogenetic glycosides in arum leaves and roots are destroyed byheat, so that arum could be cooked and eaten by early Europeans.Unfortunately, some toxins are stable at high temperatures, whileother new toxins are actually produced by cooking. That tasty charon barbecued chicken contains enough toxic nitrosamines for severalauthorities to recommend restricting our intake of grilled meat toprevent stomach cancer. Have we been cooking meat long enough tohave developed specific defenses against the char toxins? Cookingmay have been invented hundreds of thousands of years ago, and it

TOXINS: NEW, OLD, AND EVERYWHERE

must have started with barbecues on open fires. It would be interest-ing to know if we are more resistant to heat-produced toxins than ourclosest primate relatives are.

Since the invention of agriculture we have been selectively breed-ing plants to overcome their evolved defenses. Berry bushes were bredfor reduced spininess and the berries for reduced toxin concentra-tions. The history of potato domestication, as described in Johns'sbook, is especially instructive. Most wild species of potato are highlytoxic, as you might expect, given that they are an otherwise unpro-tected, concentrated source of nourishment. Potatoes are from thesame plant family as deadly nightshade and contain harmful amountsof the highly toxic chemicals solanidine and tomatidine. Up to 15 per-cent of their protein is designed to block enzymes that digest proteins.Still, a few wild species can be eaten in limited quantity, and edibilitycan be increased by freezing, leaching out the toxins, and cooking. Weenjoy thoroughly edible potatoes today thanks mainly to many cen-turies of selective breeding by native farmers in the Andes.

Concerns about pesticides have recently spurred programs tobreed plants that are naturally resistant to insects. This protection isprovided, of course, by increased levels of natural toxins. A new vari-ety of disease-resistant potato was recently introduced that did notneed pesticide protection, but it had to be withdrawn from the mar-ket when it was found to make people ill. Sure enough, the symp-toms were caused by the same natural toxins the Andean farmers hadspent centuries breeding out. An evolutionary view suggests that newbreeds of disease-resistant plants should be treated as cautiously asartificial pesticides are.

NOVEL TOXINSO ne reason to stress the prevalence of toxins in our nat-ural environment, and our evolutionary adaptation tothem, is to provide a perspective on the medical signifi-cance of novel toxins. Novel toxins are a special prob-

lem not because artificial pesticides such as DDT are intrinsicallymore harmful than natural ones but because some of them areextremely different chemically from those with which we are adapted

WHY WE GET SICK

to cope. We have no enzymatic machinery designed to deal withPCBs or organic mercury complexes. Our livers are ready and wait-ing for many plant toxins, but they don't know what to do with somenovel substances. Furthermore, we have no natural inclination toavoid some novel toxins. Evolution equipped us with the ability tosmell or taste common natural toxins and the motivation to avoidsuch smells and tastes. In psychological jargon, the natural toxinstend to be aversive stimuli. But we have no such machinery to protectus from many artificial toxins, like DDT, that are odorless and taste-less. The same is true of potentially mutagenic or carcinogenicradioisotopes. Sugar synthesized from radioactive hydrogen or car-bon tastes as sweet as that made with ordinary stable isotopes, but wehave no way of detecting its dangers.

It is not always easy to tell what the effects of a novel environ-mental factor may be. For instance, the debate about the possibledangers of mercury in dental fillings has gone back and forth, butAnne Summers and her colleagues at the University of Georgia haverecently found that mercury fillings increase the number of gut bac-teria that are resistant to common antibiotics, apparently because themercury acts as a selective factor for bacterial genes that protectagainst mercury and some of these same genes confer resistance toantibiotics. The clinical significance of this finding is uncertain, but itnicely illustrates the unexpected means by which novel toxins canaffect our health.

Since we can no longer, in our modern chemical environment,rely on our natural reactions to tell us which substances are harmfuland which are not, we often rely on public agencies to assess the dan-gers and take measures to protect us from them. It is important toavoid unrealistic expectations of such agencies. Tests on rats are oflimited reliability as models for human capabilities, and there aremany political difficulties that can frustrate public action on envi-ronmental hazards. Scientifically illiterate legislatures can pass lawssaying that no amount of any chemical that causes cancer can beallowed in food, even though many such chemicals are already pres-ent naturally in many foods. Conversely, political pressures can leadto inadequate controls on known toxins, from nicotine to dioxins.There is no such thing as a diet without toxins. The diets of all ourancestors, like those of today, were compromises between costs andbenefits. This is one of the less welcome conclusions that arise froman evolutionary view of medicine.

TOXINS: NEW, OLD, AND EVERYWHERE

MUTAGENS AND TERATOGENSM [utagens are chemicals that cause mutations, which maycause cancer or damage genes and thus lead to healthproblems for many generations. Teratogens are chemi-cals that interfere with normal tissue development and

cause birth defects. Mutagens and teratogens are not sharply separatefrom each other or from toxins with short-range effects. Ionizing radi-ation and mutagens such as formaldehyde and nitrosamines can allcause distress immediately or cancer or birth defects years later.

While it is important to learn which poisons harm everyone, peo-ple vary in their susceptibility to many substances, such that oneman's meat may be another's poison. We will deal with special aspectsof individual variability in the chapter on allergy. Vulnerability variesby age and sex. It seems particularly unlikely that detoxification capa-bility is the same in both adults and the very young, especially duringembryonic and fetal development. There are abundant theoretical rea-sons, as well as data from many experimental studies, that show thatactively metabolizing tissues are more vulnerable to toxins than dor-mant ones, cells that divide rapidly more than quiescent ones, andcells that differentiate into specialized types more than those thatmerely reproduce more of the same.

All these perspectives suggest that embryonic and fetal tissues maybe harmed by lower concentrations of toxins than adult tissues are.We regard Figure 6-1 as a likely picture of vulnerability throughhuman prenatal development. Vulnerability rises rapidly from thelevel characteristic of a quiescent egg in an ovary to a peak in the crit-ical stages of organ formation and tissue differentiation, then slowlydeclines to closer to the adult level of tolerance at full term.

We will return to this graph in a moment, but first let's look at aclassic mystery of traditional medicine. So-called morning sickness isoften the first reliable sign of pregnancy, especially for women whorecognize it from prior experience. This nausea and its associatedlethargy and food aversions are so common as to be considered a nor-mal part of pregnancy, although they are quite variable in intensity.For some women they mean many weeks of misery, while othersaren't bothered much. We may even think of morning sickness asone of the symptoms of pregnancy, as if pregnancy were a disease.The current clinical approach seems to be: pregnancy sickness makes

WHY WE GET SICK

Vulnerabilityto Toxins

0 3 6 9Time (months) (Birth)

FIGURE 6-1. Toxin vulnerability at different prenatal ages.

women distressed, so let's find a way to alleviate the symptoms andmake them feel better. Unfortunately, making people feel better doesnot always improve their health or secure other long-term interests.As pointed out in Chapters 1 and 2, natural selection has no mandateto make people happy, and our long-range interests are often wellserved by aversive experiences. Before we block the expression of asymptom, we should first try to understand its origin and possiblefunctions.

Fortunately, a biologist thoroughly committed to the adaptation-ist program has recently wondered at the mystery of morning sick-ness and devised an explanation. Margie Profet, an independentscholar and biologist in Seattle, argues that a condition as commonand spontaneous as pregnancy sickness is unlikely to be pathological.Note on the graph how fetal vulnerability corresponds almost exactlyto the course of pregnancy sickness. This concordance providedProfet with a crucial clue. Nausea and food aversions during preg-nancy evolved, she argues, to impose dietary restrictions on themother and thereby minimize fetal exposure to toxins. The fetus is aminor nutritional burden on the mother in the early weeks of preg-nancy, and a healthy, well-nourished woman can often afford to eatless. The food she is inclined to eat is usually bland and without thestrong odors and flavors provided by toxic compounds. She avoidsnot only spicy plant toxins but also those produced by fungal and

TOXINS: NEW, OLD, AND EVERYWHERE

bacterial decomposition. A lamb chop that smells fine to a man maysmell putrid and repulsive to his pregnant wife.

Profet amassed diverse evidence in support of her theory. Oneexample is the correlation between toxin concentrations and thetastes and odors that cause revulsion. Another is the observation thatwomen who have no pregnancy nausea are more likely to miscarry orto bear children with birth defects. Much more evidence needs to begathered on the evolutionary and related medical questions. Wethink it unlikely, for instance, that the phenomenon is uniquelyhuman. Is it found in mammals in general, especially herbivores? Donewly pregnant rabbits eat less and choose their food more carefullythan either before pregnancy or later on? Studies of wild animalswould be the best way to answer these evolutionary questions. Themedically more important research can be carried out on laboratoryanimals. An essential premise to be tested is that some toxins of triv-ial importance for normal adults have seriously deleterious effects onfetal development. We also need to know the common environmen-tal toxins that are most likely to harm a fetus. We also need to lookfor associations between diet during pregnancy and the more fre-quent kinds of birth defects, as well as at individual variations indetoxification enzymes.

Some practical applications of this theory are illustrated by thehistory of the antinausea medication Bendectin. Pregnant women,understandably, often ask their physicians to do something abouttheir nausea. Recognizing the dangers of drug administration duringpregnancy, physicians were generally cautious, but the drug Ben-dectin was thought to be safe and was widely prescribed. After thethalidomide tragedy, there were many studies on the possible harm-ful effects of Bendectin, and the equivocal evidence has even been thetopic of Supreme Court deliberations. Unfortunately, none of thestudies has ever considered the possible functions of morning sick-ness. Perhaps anything that suppresses morning sickness may causebirth defects indirectly by encouraging harmful dietary choices.

If Profet's theory is correct, it means that pregnant women shouldbe extremely wary of all drugs, both therapeutic and recreational.Fetal alcohol syndrome is perhaps the biggest current problem,affecting thousands of babies every year. Cigarettes can also causeproblems, and coffee, spices, and strong-tasting foods may well bestbe avoided. Certainly, it would be wise to avoid taking any medica-tions if possible. Studies can determine which medications cause

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major birth defects, but because others may have more subtle effects,it is better to be safe than sorry.

Other than avoiding toxins, what should a pregnant woman doabout her nausea? The easy and obvious answer is "Respect it. Yourreactions to food are probably adaptive for your baby. Do not succumbto the urgings of others to eat what you are inclined to avoid. Better tooffend the host at the party than to risk imposing a long-term impair-ment on your child." But what about your own suffering? It would beeasy enough for two male authors to say, "Accept your nausea; it con-tributes to your long-term desire for a healthy family." We realize thatthis is not a satisfactory recommendation. Relief of unpleasant symp-toms is desirable as long as side effects are acceptable. We would hopethat obstetricians someday will be able to provide their patients with alist of all the substances they ought to avoid. Armed with this knowl-edge, women could safely use a medication to prevent nausea if it is pos-sible to find one that is effective and to have confidence that it is safe.

People in many cultures, especially pregnant women, eat certainkinds of clay. Although this clay has often been regarded as a mineralsupplement, it can relieve gastrointestinal distress and for this reasonis used in some modern antidiarrheal medications. Certain kinds ofclay, as mentioned in the discussion about acorns, tightly bind solu-ble organic molecules, including many toxins. In other words, theymay relieve symptoms in the best possible way-by removing theharmful cause. Unfortunately, we doubt that it is possible to patentclay. Our present system of drug marketing makes it unlikely thatany company would invest the millions needed to test such a productand bring it to market if it could not control an exclusive patent. Reg-ulatory agencies protect us, but they also constrain us.

As fetuses grow older, they become children who tend to hate veg-etables. They especially dislike strong-flavored vegetables such asonions and broccoli, the very ones that contain high levels of planttoxins. The developmental course of these dislikes offers a clue totheir explanation. Even finicky children often begin to experimentwith new foods just as they mature into teenagers and their growthnears completion. The evolutionary explanation for this sensitivitymay be the benefits, during the Stone Age, of avoiding the most toxicplants during childhood. Modern-day children and adults wouldboth benefit from eating more of our modern low-toxin vegetables,but there may be a good evolutionary explanation for why childrensteadfastly resist eating their vegetables.

GENES AND DISEASE:DEFECTS, QUIRKS,

AND COMPROMISES

The medical school lecture hall was surprisingly full for aMonday at eight A.M. The lecture dealt with nearsighted-ness. As the room darkened, the overhead spotlights glintedoff the eyeglasses worn by nearly half the students. "So

that's why so many showed up," murmured the professor."The facts are clear," he summarized an hour later. "Myopia is

caused by excessive growth of the eye. When it gets too long fromlens to retina, the focal point remains above the surface of the retina,so that the image is blurred. Refractive lenses, in the form of glassesor contact lenses, can refocus the image a bit further back so we cansee clearly, overcoming nature's inexactitude."

Some hands began to wave. "But what causes the eye to grow toolong?" asked one student.

"Genes," he said. "It's as simple as that. Some of us were justunlucky enough to get bad genes. If your identical twin is nearsighted,you will almost certainly be also. If your sibling is nearsighted, the like-lihood is high, but not as high. Pulling all the figures together, myopiaseems to be a genetic disease with a heritability of over eighty percent."

"But how could such genes survive before glasses were invented?"asked another student. "Without my glasses, I wouldn't last a day onthe African plains." The class laughed uneasily.

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"Well, the genes might be recent mutations," said the professor."Or perhaps Stone Age myopic people worked in camp sewing andweaving. In any case, the facts make it clear that myopia is a geneticdisorder."

"But how could that be?" the student persisted. "The force ofselection against it would be enormous. If such a severe defect canpersist, then why aren't our bodies riddled with defects?"

"In fact, our bodies don't work very well," the professor saidpointedly. "As you have been learning, we are bundles of geneticflaws. The body is a fragile, jury-rigged device. Our job as physiciansis to fix Mother Nature's oversights."

The medical students grumbled a bit more among themselves butdid not persist further.

WHAT GENES Do

he instructions for making a human body are contained inmolecules of DNA, twisted into our twenty-three pairs ofchromosomes. We are still learning the details, wonderfulalmost beyond belief, of how DNA stores and uses infor-

mation to build a body. Each DNA molecule is like a ladder, withsides made up of alternating units of phosphate and a sugar calleddeoxyribose. The information is in the rungs, which are composed ofpairs of four molecular components with names abbreviated A, C, Q,and T. It is hard to comprehend the amount of information in thegenetic code. The DNA in a single cell contains a sequence of twelvebillion of the A-C-G-T symbols, the amount of information in a smalllibrary. If the DNA in a single human cell were untwisted and themolecules put end to end, it would stretch about two meters. If thiswere multiplied by the ten trillion cells in the body, it would stretchtwenty billion kilometers, about the distance to the planet Pluto!

About 95 percent of human DNA is never translated into pro-teins. The rest can be divided into somewhere in the neighborhood ofone hundred thousand functional subunits called genes. Each genecodes for a single protein. How this DNA chain of As, Cs, Gs, and Tsis translated into a protein is the realm of molecular biology, the fast-growing field that may make more changes in our lives than even thediscovery of electricity. There are lonely voices crying for attention

GENES AND DISEASE: DEFECTS, QUIRKS, AND COMPROMISES

to the ethical and political implications of these changes, but the mes-sage has not yet gotten through to the general public. Soon it will.Already we have drugs made by DNA cloning. Food plants contain-ing bacterial genes are in production. Pioneering experiments arenow relieving previously hopeless diseases by inserting replacementgenes into human cells. A less welcome possibility is that an insur-ance company might, as part of a routine blood test, read samples ofDNA and thus learn a client's risks for a variety of diseases. Screen-ing for some genetic disorders in the early stages of pregnancy isalready routine, giving a mother of an abnormal fetus the option ofterminating the pregnancy.

It is 2010, and Mary, a woman who was in elementary school in1995, has just found out she is pregnant. "Well, you are pregnant, allright, Mary. Congratulations! The nurse will be here in a minute toexplain the normal procedures, but I do need to find out if you wantthe standard gene screen. I presume so."

"Well, what does it involve?""The risks are nonexistent these days, but it is expensive unless

you have executive-level health benefits.""We do have the high-benefits package, but what will the tests

tell me?""The basic screen identifies forty serious genetic diseases, and

then you can get the supplement to look for things like nearsighted-ness and attention deficit disorder and susceptibility to alcoholism.Most people think it's worth it."

"But what if it shows a problem?""Yes . . . well . .. then we will have to talk about what to do.

Probably you wouldn't want to terminate just for an increased likeli-hood of alcoholism or something like that, but it is better to knowearly. At any rate, it is better to find out now rather than after theproblem arises, don't you think?"

"Well, I suppose so, but what am I supposed to do if, say, mybaby is going to be nearsighted?"

"Well . ..I t will be a few years before the comprehensive testing imaginedabove is available, but we already know the chromosomal loca-tions of many genes and the code sequences of some. The goalof the controversial Human Genome Project is to unravel the

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entire code, to find the order of As, Cs, Gs, and Ts that make up thehundred thousand or so genes. When we have the code in hand, wewill be able to compare the genes of any individual to those in thestandard sequence, thus making it much easier to find abnormalgenes.

But is there a "normal" human genetic makeup, as our term stan-dard sequence might imply? We are not, of course, all identical. About7 percent of human genes can differ from individual to individual.For most proteins the variation is low, about 2 percent, while for cer-tain groups of enzymes and blood proteins, 28 percent of genes mayhave multiple versions. Often, as far as we can tell, different versionsof the gene function identically. In other cases, one version (oneallele) is normal, while the other is defective. In many cases the defec-tive allele is recessive, meaning that it has no noticeable effect if pairedwith the normal allele. If the defective allele is dominant, however,even one copy will cause disease.

The problem for an evolutionist is to explain why there is geneticdisease at all. Was the professor who gave the myopia lecture right?Are our bodies "bundles of genetic flaws" with legions of disease-causing genes that have not been eliminated by natural selection? Notexactly. There are many genetic defects that are so rare that naturalselection has not been able to eliminate them, but they cause rela.tively little disease compared to more common genes that are, para-doxically, selected for even though they cause disease. We will soonexplain how genes that cause disease can be selected for, but first weneed to consider how genes work and the rare genetic abnormalities.

All it takes is a single error in the DNA of a sperm or an egg, a Cinstead of an A, or perhaps a single missing T, to cause a fatal geneticdisease. Such errors arise from copying mistakes, from chemicaldamage, or from ionizing radiation. The wonder is that such errorsare not more common. It is estimated that the likelihood of any givengene being altered is one in a million per generation. This means that,on average, about 5 percent of us start life with at least one brand-newmutation found in neither parent. In most cases such mutations haveno detectable effects; in others they cause minor effects; in a few theyare fatal.

As the individual develops from a single cell to an adult withabout ten trillion cells, many more mistakes will creep in. Those thatoccur after most of the cells in the body have formed are likely to

GENES AND DISEASE: DEFECTS, QUIRKS, AND COMPROMISES

have little effect. Many mutations code for a protein that worksabout as well as the original or for a protein that is not even expressedin the kind of cell that has the mutation. If the mutation is fatal to thecell, even that will likely be of no consequence since there are usuallyplenty of other cells available to do the same job. A mutation in a sin-gle cell can, however, cause major problems if it knocks out somecrucial part of the machinery that regulates cell growth and division.It takes only a single cell multiplying out of control to create a tumorthat jeopardizes the whole organism. This hazard is countered by themultiple mechanisms discussed in Chapter 12.

Apart from the difficulties arising from an occasional mutation,how can even an enormously long sequence of only four chemicalsymbols manage to code for a complete human being? We knowquite a bit about how DNA reproduces itself, how it produces RNA,how RNA produces protein molecules, and how these moleculescombine to produce microscopic chains or two-dimensional sheets.Beyond that is a vast sea of ignorance in which there are scatteredislands of understanding. For instance, we know about some cause-effect relationships and even some details of the machinery of hor-monal regulation of tissue development. These isolated points ofenlightenment, however, are only the beginnings of a general under-standing of animal and plant development.

Even though developmental genetics is still largely mysterious,patterns of genetic transmission are well worked out. At conception,each of us got a copy of each gene at each locus on each chromosomefrom each parent. A single complete complement of genes (collec-tively a genome) is a random sample of a gene from each locus of thetwo complete genomes of each parent. So each of us, having two par-ents, must have two copies of each gene, two complete genomes thattogether constitute the genotype. What we observe in organisms is thephenotype, the expression of the genotype as influenced in the courseof individual development by many subtle environmental factors.Sexual reproduction is a random shuffling of the genotypes of par-ents to provide the unique genotype of each offspring. If the shuf-fling, at a particular locus, gives identical copies of the same genefrom both parents, the offspring is homozygous at that locus. If it getsa different contribution from each parent, it is heterozygous.

A gene will have some average effect over the large number of indi-viduals in which it finds itself over the course of generations, but its

WHY WE GET SICK

effect in any given individual may be quite different from the average.Genes interact with one another and with the environment in deter-mining the features of a phenotype. So a sexually produced individ-ual is unique in many ways and may differ strikingly from eitherparent. The development of one fertilized egg into two offspring(identical twins) is an asexual reproductive process that produces twoindividuals with the same genotype.

RARE GENES THAT CAUSE DISEASEO f the thousands of serious genetic diseases, the vastmajority are rare, affecting fewer than one in ten thou-sand people. Most of these diseases result from reces-sives, genes that don't cause any trouble except in

individuals unlucky enough to get two copies, so there is no normalallele at that locus. This misfortune becomes more likely if you marrya relative, who will have more genes identical to yours than a non-relative will. This is why marriages between close relatives are morelikely to produce abnormal babies.

It is hard for natural selection to eliminate a deleterious recessivegene. If, as is likely, people heterozygous for a rare recessive have nodisadvantage, the rate of adverse selection may be so small that nat-ural selection cannot depress the gene frequency further. If a gene ispresent in one in a thousand individuals and people normally marrynonrelatives, then on average only one in a million will be homozy-gous. Even if all of these unfortunate people die early in life, theeffect of selection is weak. In this situation, new mutations can oftencreate the defective gene as fast as natural selection eliminates it,because as the gene frequency decreases, the prevalence of homozy-gous individuals decreases even faster. A lethal recessive gene that iscreated by mutation in one out of a million pregnancies will stabilizein frequency at about one in a thousand individuals. This is indeed asituation in which the power of natural selection is limited.

Dominant genes are another matter. If you have even one copy ofa dominant gene that causes a disease, you get the disease and, onaverage, so will half your children. One of the best known such genescauses Huntington's disease. Most people with this disease have no

GENES AND DISEASE: DEFECTS, QUIRKS, AND COMPROMISES

symptoms until their forties, when their memory fades and theirmuscles begin to twitch. Some of their nerve cells steadily degenerateuntil these people cannot walk, remember their own names, or carefor themselves. This disease is a particularly vivid example because ofits devastating effects and because all known cases can be traced to asmall number of European families in the 1600s. One of the menmigrated to Nova Scotia. The gene and the disease have been passedon to hundreds of his descendants, including the folk singer WoodyGuthrie. In the 1860s a Spanish sailor from Germany, Antonio JustoDoria, settled on the western shores of Lake Maracaibo inVenezuela. His descendants now form the greatest concentration ofpeople with Huntington's disease. Steady detective work and fabu-lous luck have enabled geneticists to pinpoint the Huntington's geneon the short arm of chromosome 4.

This brings us back to the mystery: Why hasn't this devastatinggene been eliminated? The answer is that it usually causes little harmbefore age forty and thus cannot substantially decrease the number ofchildren born to someone who later develops Huntington's disease.In fact, some studies have suggested that women who later developHuntington's disease may have more than the average number ofchildren. The reproductive rate of men is somewhat decreased, butnet selection against the gene in modern societies must be very slight.Studies estimate that one out of twenty thousand people in theUnited States have the gene for Huntington's disease.

This disease again illustrates a principle emphasized in Chapter 2:natural selection does not select for health, but only for reproductivesuccess. If a gene does not reduce the average number of survivingoffspring, it may remain common even if it also causes a devastatingillness. There are genes that cause disease but may possibly increasereproductive success (at least in modern societies)-notably the genesthat cause manic-depressive illness. During mania some patientsbecome sexually aggressive, while others accomplish feats that makethem successful and thus attractive. If a gene increases the rate of suc-cessful reproduction-by whatever mechanism-it will spread.

Table 7-1 offers a classification, based on the beneficiary, of genesthat cause disease. While there are many diseases that result frommutation and the limitations of natural selection, they account forrelatively little sickness. In most cases the story is more complicatedand interesting.

WHY WE GET SICK

TABLE 7-1 BENEFICIARIES OF GENES THAT CAUSE DISEASE

The individual with the gene:* Costs and benefits at different stages of the life cycle (Chapter 8); DR3

gene causes diabetes but gives an advantage in utero* Benefits only in certain environments (e.g., G6PD deficiency is benefi-

cial in areas with malaria; certain HLA haplotypes increase susceptibil-ity to some diseases but protect against others)

* Quirks: Benefits (or at least no costs) in the ancestral environment,costs only in a modern environment (this chapter)

Other individuals:* Heterozygote advantage to individuals with one copy of a gene, costs

to individuals with two copies or none (e.g., the sickle-cell gene)* The fetus at the expense of the mother (e.g., hPL, see Chapter 13)* The father at the expense of the mother (or vice versa) (e.g., IGF-Il,

IGF-I receptor; see Chapter 13)* Sexually antagonistic selection (e.g., hemochromatosis)

The gene at the expense of the individual:

* Outlaw genes that are perpetuated by meiotic drive (e.g. T-locus in mice)

No one:

* Mutations that occur at a rate equal to the selection rate (equilibrium)

* Some genes are especially vulnerable to mutation because they arevery large (e.g., muscular dystrophy). Recessive genes are especiallydifficult to eliminate because as the frequency of the gene decreases,the force of selection decreases even faster

* Genes present in spite of adverse selection (genetic drift or foundereffects)

COMMON GENES THAT CAUSE DISEASES ickle-cell anemia is the classic example of a disease caused bya gene that is also useful. The gene that causes sickle-cell dis-ease occurs mostly in people from parts of Africa where

malaria has been prevalent. A person who is heterozygousfor this gene gets substantial protection from malaria because the

gene changes the hemoglobin structure in a way that speeds the

removal of infected cells from the circulation. Homozygotes, how-

GENES AND DISEASE: DEFECTS, QUIRKS, AND COMPROMISES

ever, get sickle-cell disease. Their red blood cells twist into a crescentor sickle shape that cannot circulate normally, thus causing bleeding,shortness of breath, and pain in bones, muscles, and the abdomen.People with this disease suffer terribly in childhood, and untilrecently all of them died before reproducing. An individual homozy-gous for the normal allele has perfectly good red blood corpusclesbut lacks the special resistance to malaria. The sickle-cell gene thusillustrates heterozygote advantage. Because of their resistance tomalaria, heterozygotes are favored over both kinds of homozygotes:Homozygotes for the sickle-cell allele have low fitness resulting fromsickle-cell disease, while homozygotes for the normal allele have lowfitness resulting from their vulnerability to malaria. The relativestrength of these two selective forces determines the allelic frequen-cies. Thus, a gene that causes a lethal childhood illness and a gene thatmakes one susceptible to malaria can both be maintained at high fre-quencies in the population.

While the sickle-cell allele is the most frequently cited example ofa gene that is selected for even though it causes disease, it is unusualfor three reasons. First, it is not widely distributed, being originallyfound almost exclusively in people of tropical African descent. Sec-ond, the hemoglobin alteration is a simple sort of adaptation. Mostadaptations, such as color vision or the capacity for fever, are com-plex, closely regulated systems whose assembly requires many genes.By contrast, the sickle-cell allele differs from that for normal hemo-globin only by a single T substituted for a single A. When this geneticcode is translated into the protein hemoglobin, the amino acid valineends up where glutamic acid should be. It is this molecular changethat gives the blood cell its abnormal shape and other properties.Third, there is extraordinarily strong selection acting on one genelocus. It may well be that heterozygote advantage is common inhuman populations, but when selection against homozygotes isweak, the effect is hard to demonstrate.

In areas where malaria is rare, you would expect the sickle-cellallele to decrease in frequency. Indeed, African Americans, many ofwhom have lived in malaria-free regions for ten generations, show alower sickle-cell frequency than Africans, lower than any admixturewith Caucasian genes would explain. It appears that selection hasbeen decreasing the frequency of the sickle-cell gene in regionswhere malaria is unimportant, as would be expected from evolu-tionary theory.

WHY WE GET SICK

Several other inherited blood abnormalities also protect againstmalaria, the most dramatic being a deficiency of the enzyme glucose-6-phosphate-dehydrogenase (G6PD). Patients with this abnormalityget very sick when exposed to oxidizing medications such as quinine,the original and still effective antimalarial drug. When a malarial par-asite uses oxygen in a red blood cell, a lack of G6PD causes the cell toburst, thus interfering with the reproduction of the malarial organ-ism. The ability of some malarial parasites to make their own G6PDillustrates the prevalence of the host-parasite arms race.

One in twenty-five northern Europeans has a copy of the recessivegene that causes cystic fibrosis, and 70 percent of cases are accountedfor by a single mutant allele (AF508). According to Francis Collins,director of the Human Genome Project, this "suggests that there mayhave been some heterozygote selection or a very strong foundereffect for this particular mutation in the northern European popula-tion." Exactly what benefits might maintain the frequency for thegene for cystic fibrosis remain unknown, but decreased death fromdiarrhea has been suggested.

Tay-Sachs disease kills all homozygote individuals before theyreproduce but the gene is present in 3 to 11 percent of AshkenazicJews. Maintenance of this high a frequency would require an overallreproductive advantage of 6 percent for heterozygotes compared tohomozygotes for the normal gene. Data on infection rates and popu-lation distributions suggest that the benefit to heterozygotes mayhave been protection against tuberculosis, historically a major selec-tive force in Ashkenazic Jews. Fragile-X syndrome is still anothercommon genetic disease, which causes mental retardation in aboutone out of every two thousand males born. For this syndrome thereis direct evidence of increased reproductive success of heterozygouswomen.

University of California physiologist Jared Diamond recentlyemphasized another mechanism that can explain the unexpectedlyhigh frequency of some genes that cause disease. He says that as manyas eight out of ten conceptions end in early abortion or later miscar-riage. The majority are never noticed because they occur before orjust after implantation of the embryo. If a gene were to decrease thechances of miscarriage even slightly, it could be selected for even if italso increased the risk of developing a disease. Diamond gives theexample of childhood-onset diabetes, which can be caused by a genecalled DR3. If one parent is heterozygous and the other is homo-

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zygous for the normal allele, 50 percent of the babies would beexpected to have the DR3 gene, but the observed rate is 66 percent! Itseems that the presence of the DR3 gene in a fetus greatly decreasesthe miscarriage rate and thus it perpetuates itself, despite causing dia-betes.

Phenylketonuria (PKU) may be another example of disease causedby a gene maintained by frustrating the mother's uterine selectivity.When homozygous it causes mental retardation because the bodycannot handle normal levels of phenylalanine, an amino acid foundin many foods. The retardation can be prevented if the child is givena diet free of this common component. PKU is a fine example of adisease that is completely genetic yet whose effects are completelypreventable by environmental manipulation. It is so common (oneperson in a hundred has the gene) that most states require screeningat birth. Why is it so common? Like the diabetes-risk gene, the PKUgene seems to reduce the likelihood of miscarriage and thus to per-petuate itself despite causing disease.

OUTLAW GENES

xford biologist Richard Dawkins has viewed the body asQ Mthe gene's way of making more genes. Genes cooperateto form cells, organs, and individuals only because thatis the best way of making more copies of themselves.

The body's cells are factories, each with specialized functions, thatmust cooperate in order for the individual to survive and reproduce.There isn't any way for genes to get into the next generation except bydoing their part for the whole organism. Or is there? Given thestakes, one would expect that any gambit that would get a gene intothe next generation would be used, even if it decreased the viability ofthe individual. Does this occur?

Certain genes do compete to get into a sperm or egg, even to thedetriment of their carriers. There are several examples, the bestknown being the T-locus gene in mice. Two copies of the abnormalallele are lethal in males, but males with only one copy transmit it tomore than 90 percent of their offspring, instead of the usual 50 per-cent. This is a fine example of an outlaw gene whose actions benefititself but harm both the individual and the species. We know about

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it because it produces a striking effect and because we can do care-fully controlled experiments on mice. Might there not be minorhuman defects that owe their existence to a biased transmission ofgenes from parent to offspring that balances the decrement of fitnessfrom the defect?

One possibility is polycystic ovaries. This disorder, whichaccounts for 21 percent of all visits to infertility clinics, is character-ized by menstrual irregularity, obesity, and signs of masculinization.A recent study found that 80.5 percent of sisters of women with poly-cystic ovaries were also affected, a number far too high to beexplained by an autosomal dominant or an X-linked gene. ResearcherWilliam Hague and his colleagues in Adelaide, Australia, have con-sidered the possibilities that the condition results from transmissionof DNA in the cytoplasm of the ovum or from genes that distort theprocess of meiosis in ways that increase their own chances of gettinginto an egg, a phenomenon called meiotic drive.

GENETIC QUIRKS:MYOPIA AND MANY OTHERS

he above diseases result from the specific effects of onegene, but susceptibility to many diseases is determined bythe complex effects of many genes. Hardly a week goes bywithout a newspaper report on the genetics of heart dis-

ease, breast cancer, or drug abuse. In most of these polygenic diseaseswe don't know how many genes are responsible or what chromo-somes they are on. We know only that the risk increases if close rel-atives have the disease. Such associations become especiallyconvincing when people who were adopted as infants show closerresemblances to their biological families than to those in which theygrew up, thus reducing the likelihood that the similarity is due toenvironmental factors.

Susceptibility to coronary artery disease is a good example. Therisk of having a heart attack depends considerably on genes. A manwhose father had a heart attack before the age of fifty-five has a riskof early death from heart attack five times that of other men. Twins

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GENES AND DISEASE: DEFECTS, QUIRKS, AND COMPROMISES

with identical genes have heart-attack rates more similar than those ofnonidentical twins, even when all the twin pairs share the same envi-ronment. Does this mean that heart attacks are caused by a geneticdefect? In some cases, yes. Several abnormalities of cholesterolmetabolism have been discovered, one of which is an early candidatefor treatment by genetic engineering in which a new gene is insertedinto the cells of blood vessel walls. But we also know that heart dis-ease results from eating a high-fat diet. Japanese immigrants to theUnited States who adopt the high-fat diets of this country have heartattacks more than twice as often as their relatives back home. Therate of premature death from heart disease is high enough that nat-ural selection must be steadily weeding out any genes that contributeto the risk. People often want to know what proportion of heart dis-ease results from genes and what proportion from the environment,but this is not the way the question should be asked. To find outwhy, let's return to the mystery of myopia.

As the professor said, myopia is a genetic disease. If one identicaltwin has myopia, the other will almost certainly have it. We have alsoargued that such a harmful genetic defect would not be expected topersist. Yet about 25 percent of Americans have myopia, often sosevere that they would have a hard time in a hunter-gatherer society.How well could they avoid predators, fight in a battle, or recognize aface at fifty paces? Recall poor Piggy, the castaway in Lord of the Flies,who without his glasses was trapped "behind the luminous wall ofhis myopia." Given the disadvantage, it is perhaps no surprise thatpresent-day hunter-gatherer populations have a low incidence ofmyopia. So why is it so common in modem populations?

When we look carefully at the transition from hunter-gatherer toindustrial societies, we see that myopia does not result from a newgene. Native people in the Arctic were seldom nearsighted when theywere first contacted by Europeans, but when their children beganattending school, 25 percent of them became myopic. It would seemthat learning to read and prolonged confinement to classrooms maypermanently impair the vision of a substantial proportion of chil-dren. Why should this be?

Imagine, for a moment, the difficulty of accurately growing an eye.The cornea and the lens have to focus an image exactly on the retina,even as the eyeball grows steadily during childhood. How exact doesthe length of the eyeball have to be? The leeway is 1 percent of the

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length of the eyeball, about the thickness of a fingernail. Is it possibleto program the growth of the cornea, the lens, and the eyeball so thatthe image stays exactly in focus? Unlikely. Yet somehow, even as itgrows, the eye keeps images in focus. How?

In a series of experiments, scientists at several laboratories are try-ing to work out the mechanisms that lead to nearsightedness. First,they noted that an eye with a clouded view grows longer than a nor-mal eye, whether the clouding results from inherited disease, frominjury, or from wearing foggy glasses. This is the case for chickens,rabbits, some monkeys, and some other animals, as well as humans.Next, they cut the nerve that carries information from the eye to thebrain and found that in some species this stopped the excessivegrowth of the eye. They began to suspect that whenever a blurredimage falls onto the retina, the brain sends back a message, in theform of a growth factor, that induces expansion of the eyeball. Theclincher: when only one part of the visual field is blurry, only thatpart of the eye grows. This kind of asymmetrical growth results inastigmatism.

This mechanism is as necessary as it is elegant. In order to ensurecoordinated development of the parts of the eye, the brain processesa signal from the retina, detects blurring, and sends back a signal toincrease growth at the particular spot where it is needed. Whengrowth is sufficient, the stimulus stops, and growth does too exceptin some people. For 25 percent of us, there is something about read-ing or other close work that causes the eye to keep growing. Perhapsit is the blurred edges of letters or the plane of focus on a book heldclose with distant objects all around. It seems possible that printingchildren's books with especially large, sharply defined letters onoversized pages could prevent some nearsightedness.

Myopia is a classic illustration of a disease whose cause is simulta-neously strongly genetic and strongly environmental. To becomemyopic, a person must have both the myopia genotype and exposureto early reading or other close work. Many other diseases also resultfrom complex gene-environment interactions. For instance, somepeople eat all the fat they want and never get heart disease, while oth-ers eat the same amount of fat and drop dead at age forty. Similarly,some people go through all kinds of losses and never become seri-ously depressed. For others, the loss of a pet can set off a severeepisode of melancholia. Remember also the gene-environment inter-

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action in PKU. For such diseases, it is a mistake to ask what propor-tion of the cause is genetic and what proportion is environmental.They are both completely genetic and completely environmental.

Can conditions such as myopia and clogged arteries be blamed ondefective genes? In our current environment the genes that causethese conditions can certainly create a disadvantage, but in the ances-tral human environment many of them might have caused no troubleat all or might even have conferred some real benefits. Perhapshunter-gatherers with the myopia gene have better vision duringchildhood. A craving for fatty foods might have been thoroughlyadaptive in an environment where such foods were scarce. For thisreason we prefer to call such genes not defects, but quirks. They haveno deleterious effects except in people who are exposed to novelenvironmental influences. Dyslexia may be another example, diffi-culty in reading not being a problem for hunter-gatherers.

Susceptibility to drug or alcohol addiction likewise depends onhistorically abnormal conditions. There are strong genetic influenceson susceptibility to alcoholism, but they were a relatively modestproblem before the reliable availability of beverages with at least sev-eral percent alcohol. Before the rise of agriculture and the vintners'and brewers' development of yeast strains tolerant of high alcoholconcentrations, these genes probably were no problem at all. It mayprove fruitless to search for a "gene for alcoholism." There may bemany such genes on different chromosomes that can make a personsusceptible to alcoholism. Many of these genes probably have somepositive effects-for instance, a tendency to continue pursuingsources of reward despite difficulties, or a tendency to experiencestrong reinforcement in response to stimulation of certain brainareas. While it may be tempting to postulate genetic defects in peoplewho abuse drugs, we think it is more likely that the genetic factorsthat influence drug use will turn out to be a diversity of geneticquirks.

Is there even such a thing as a normal human genome? Certainlyno one string of DNA code is ideal, with all deviations to be stigma-tized as abnormal. While we humans have much in common, ourgenes are diverse. There is no one ideal type but only the many variedphenotypes that express the diversity of human genes, all competingin varying environments to get copies of themselves into the next gen-eration.

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DON'T LET GENES SCARE YOUT w here are widespread but totally unjustified fears and pes-simism about genetic influences on human disease andbehavior. There is an associated pervasive distrust of sci-entists who recognize and study these influences. To some

extent these anti-gene sentiments reflect a more general antagonismto biological and especially evolutionary explanations among socialscientists, the general public, and even some medical professionals.Many people suppose that human behavior and any aspects ofhuman disease that arise from human nature are matters to be dealtwith entirely by religion or sociopolitical action, not by seeking bio-logical causes and remedies. When they get cancer or heart disease,however, most people become less concerned about such abstrac-tions.

Is it pointless to try to alter biologically inherited conditions? Forsome reason, this seems to be a widespread assumption. A recent dis-cussion of myopia contrasted a "use-abuse theory," said to implythat the condition was preventable, with a "genetically determined"theory, said to imply the impossibility of prevention. Fortunately,the subsequent discussion supported the idea expressed in this chap-ter that myopia is indeed genetically determined and also undoubt-edly preventable. In fact, the finding that a medical condition isinherited should generally be considered good news. Genetically pro-grammed development is very much a material process and suscepti-ble to material manipulation. It was the study of the genetic cause ofPKU that led to the discovery that its effects could be prevented by adiet free of phenylalanine. Studies of the actions of genes, and of theiroccasional failure to act, are already preventing and curing many dis-eases. As Melvin Konner observed in 1983, "The discovery of agenetic determination for a disorder may provide the best hope foran environmental treatment of it." Many others have since made thesame point.

Studies of the genetic bases of disease deserve every encourage-ment, and clinical medicine makes good use of information providedby such studies. When a gene acts against the interests of the patient,the physician should act against the gene. As Oxford biologistRichard Dawkins puts it, we should "rebel against the tyranny of theselfish replicators."

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YOUTH

Let's not have a sniffle,Let's have a bloody good cry.And always remember the longer you live,The sooner you'll bloody well die!

-From an old Irish ballad

r he plane sat on the Minneapolis runway in the hot Junesun of 1970, the air inside stuffy to the point of apprehen-sion. A white-haired woman, about seventy, turned to theyoung man in the seat to her left.

"Are you a student?" she asked."Well, I just graduated from college. Now I'm about to start med

school.""How wonderful, to have the opportunity to save lives, you must

look forward to it.""Well, uh, yes."The plane lifted off, fresh air blew from the nozzles above, and

a typical airplane conversation ensued-hometowns, commonacquaintances, the weather. Then the woman paused, turned to theyoung man, and spoke plaintively.

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"Do you know that there is one disease that we really, really needa cure for, one disease worse than all others, one we all get? Do youknow what it is?"

"Uh, no. What?""What we really need, what I hope you will look for, is a cure for

the worst disease, for old age. It is so terrible, it makes me feel sohelpless, and no one has found a cure. Please, please, try to find acure." Then, she turned away, silent, to gaze out the window.

THE MYSTERY OF AGINGO- f the many burdens of consciousness, the fact of death isthe heaviest. The possibility of untimely death is fright-ening, but the inevitability of aging and dying casts thelongest shadow on human life. Even apart from reli-

gious doctrine, humankind's efforts to overcome aging have beenimpressively persistent. From Ponce de Le6n searching the wilds ofFlorida for the fountain of youth to Life magazine reporters searchingout native Georgians in the former Soviet Union who claim to be 150years old, human hope lives forever. We, however, do not. By age 80,half of us will die; by age 100, 99 percent; and by about age 115, everyone of us will be dead, medical breakthroughs and hopeful news sto-ries notwithstanding.

During the past few hundred years, the average length of life (lifeexpectancy) in modern societies has steadily increased, but the maxi-mum duration of life (life span) has not. Centuries ago a few peoplemay have lived to 115; today this maximum remains about the same.All the wonders of medicine, all the advances in public health havenot demonstrably increased the maximum duration of life. If aging isa disease, it seems to be incurable.

Technically, we are not really talking about aging, the process ofgrowing older from birth onward, but senescence, the process of bod-ily deterioration that occurs at older ages. Senescence is not a singleprocess but is manifested in an increased susceptibility to many dis-eases and a decreasing ability to repair damage. Death rates in theUnited States are very low at age 10 to 12, about 0.2 per 1000 childrenper year. The death rate increases slowly to 1.35 per 1000 at age 30,

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AGING AS THE FOUNTAIN OF YOUTH

then increases exponentially, doubling every 8 years. As Figure 8-1shows, by age 90, the death rate is 169 per 1000. A person age 100 hasonly a one-in-three chance of living another year. Every year the mor-tality curve becomes steeper, until eventually we all are gone.

Imagine a world in which all causes of premature death have beeneliminated, so that all deaths result from the effects of aging. Wewould live hearty, healthy lives, until, in a sharp peak of a few yearscentered at age 85, we would nearly all die. Conversely, imagine aworld in which senescence is eliminated, so that death rates do notincrease with age but remain throughout life at the level for eighteen-yeat olds, that is, about one per thousand per year. Some peoplewould still die at all ages, but half the population would live to age693, and more than 13 percent would live to age 2000! (See Figure8-2.) Even if death rates were much higher, say the 10 per 1000 esti-mates for young adults in India in 1900, eliminating the effects ofsenescence would still give a substantial advantage, with some peopleliving to age 300. From an evolutionist's point of view, an individualwho did not senesce would have, to put it mildly, a substantial repro-ductive advantage.

This brings us to the mystery. If senescence so devastates our fit-ness, why hasn't natural selection eliminated it? This possibilityseems preposterous only because senescence is such an inescapablepart of our experience. Consider, however, the miracle of develop-ment: from a single cell with forty-six strands of nucleic acid, a bodygradually forms, with each of ten trillion cells in the right place, mak-ing tissues and organs that function together for the good of thewhole. Certainly it should be easier to maintain this body than toform it!

Furthermore, our bodies have remarkable maintenance capacities.Skin and blood cells are replaced every few weeks. Our teeth getreplaced once-but why not six times, like those of elephants? Dam-aged liver tissue can be rapidly replaced. Most wounds heal quickly.Broken bones grow back together. We can replace missing bits ofskin and bone and liver, but some tissues, like heart and brain, do notregenerate. There are revealing differences between species in thisregard. In some species of lizards, when the tail is cut off, a new oneimmediately starts growing. Our bodies do have some capacity torepair damage and replace worn-out parts; it is just that this capacityis limited. The body can't maintain itself indefinitely. Why not?

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Deaths/1000/Year

Age (years)

FIGURE 8-1.The number of deaths per year per 1000 individuals

entering each age is shown at each age for theUnited States in the years 1910 and 1970.

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. AA

AGING AS THE FOUNTAIN OF YOUTH

WHAT IS SENESCENCE?

or most of us, there is a moment in the mid-forties when wesuddenly realize that we can no longer read a book except atF arm's length. Yes, some of our hair has fallen out or turnedarm'white, and our faces sport some wrinkles, but these changes

can be denied far more easily than the weight of a book held on out-stretched arms. Fiftieth-birthday parties usually are sickly affairs,where new devotees of mineral water tell nervous jokes about mem-ory loss, hot flashes, and impotence. We know all too well what is tocome, but few realize that aging has had a long running start. Senes-cence starts not at forty or fifty but with far more subtle changesshortly after puberty.

In sports, you don't have to be very old to be past your prime.Look at Figure 8-3, which shows the best times for each age group inrunning a marathon. The curve looks remarkably like the mortalitycurves in Figure 8-1. Performance is best in early adult life and there-after worsens with increasing rapidity. These declines are a sign ofsenescence. Yes, many people can still run fast at forty, but not as fastas they could at thirty. They would be at a bit of a disadvantagewhether chasing an impala or escaping a tiger, and it is the relative dis-advantage that counts. There is a joke about two men who are run-ning away from a tiger. One stops to put on a pair of running shoes.

"What are you doing that for?" the other asks. "Even with run-ning shoes you can't outrun a tiger."

"No," he says, "but I can outrun you."

THE ONE-HOSS SHAYT 1he "one-hoss shay" in the poem by Oliver Wendell Holmesis the classic metaphor for the remarkable apparent coordi-nation of the effects of senescence. That one-horsecarriage ...

Went to pieces all at once,All at once and nothing first,Just as bubbles do when they burst.

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1 00 0 -K , Actual reproductive years900800700

t 600500

) 400300200100

-A n It WI r- x 0E

Age (years)

FIGURE 8-2.Reproductive advantage, if there were no senescence.

Our organ systems also all seem to wear out at about the samerate, on average. Researchers Strehler and Mildvan have measuredthe reserve capacity of heart, lungs, kidneys, neurons, and otherbody systems at different ages and found that these diverse bodilysystems deteriorate at remarkably similar rates. By the time a personreaches age 100, every system has lost almost all its capacity for meet-ing increased demands, so that even the tiniest challenge to any sys-tem causes a fatal failure. Senescence itself is not a disease but theresult of every bodily capacity steadily declining so that we growsteadily more vulnerable to a myriad of diseases, not only cancer andstroke but also infections, autoimmune diseases, and even accidents.

WHY Do WE AGE?

enescence is a first-class evolutionary mystery. Any explana-tion must account for the phenomena we've just described.Some clues come from other species. One warm summerevening one of us walked with a group of friends to a picnic

on the western shore of Beaver Island in the northern reaches of LakeMichigan. As we mounted the dune overlooking the lake, the last

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rays of golden sun broke through fiery clouds. We stopped short,breathless at the sight of millions of iridescent wings, flashing in thedying sun. The mayflies formed a golden cloud hovering over thebreaking surf, waiting for a chance to mate, lay eggs, and then die onthe same day they matured. It seems so wasteful. Yet other speciesshare the mayflies' fate. In the fall, salmon rush up nearby streams,lay their eggs, and die, their rotting bodies washing back to the biglake. This is senescence with a vengeance. How can we understand it?

Many people have thought that senescence must benefit thespecies. When one of us (Nesse) first became fascinated by senes-cence as a college sophomore, he investigated every explanation hecould find and concluded that senescence was necessary to makeroom for new individuals so that evolution could keep a speciesabreast of ecological changes. This was just a step away from the posi-tion of the nineteenth-century Darwinian August Weismann, whowrote, in 1881, "Worn-out individuals are not only valueless to thespecies, but they are even harmful, for they take the place of thosewhich are sound. Hence, by the operation of natural selection, thelife of our hypothetically immortal individual, will be shortened bythe amount which was useless to the species."

Nagging misgivings about this theory grew after he learned thatnatural selection acts not for the benefit of the species but normallyfor the benefit of individuals. There had to be another explanation.When he revealed this preoccupation with the evolutionary explana-tion of senescence to colleagues in the Evolution and Human Behav-ior Program at the University of Michigan, they laughed and askedhow anyone could possibly not know about the 1957 paper on senes-cence by a biologist named George Williams.

Williams's paper draws on insights by biologists J. B. S. Haldaneand Peter Medawar to show how natural selection can actually selectfor genes that cause senescence. In 1942, Haldane realized that therewould be no selection against genes whose harmful effects occurredonly after the oldest age of reproduction. This was a major advancebut did not explain why reproduction should cease. In 1946,Medawar went further and showed that the force of selectiondecreases late in life, when many individuals have been killed byforces other than senescence:

It is by no means difficult to imagine a genetic endow-ment which can favor young animals only at the

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expense of their elders; or rather at their own expensewhen they, themselves, grow old. A gene or combina-tion of genes that promotes this state of affairs will,under certain numerically definable conditions,spread throughout a population simply because theyounger animals it favors have, as a group, a relativelylarge contribution to make to the ancestry of thefuture population.

Williams expanded these ideas into the pleiotropic theory of senes-cence. (Genes are called pleiotropic if they have more than one kind ofeffect.) Imagine that there is a gene that changes calcium metabolismso that bone heals faster, but the same gene also causes slow andsteady calcium deposition in the arteries. Such a gene might well beselected for, because many individuals will benefit from its advantagesin youth, while few will live long enough to experience the disadvan-tage of arterial disease in old age. Even if the gene caused everyone todie by age 100, it would still spread if it offered even minor benefits inyouth. This argument does not depend on the prior existence of senes-cence. Other causes of death-accidents, pneumonia, and all therest-are sufficient to reduce the population at older ages. Nor doesthe theory depend, like Haldane's, on cessation of reproduction.

The existence of menopause is a related mystery. Why hasn't itbeen eliminated by natural selection? Menopause is unlikely to be sim-ply a result of senescence because most species continue to have repro-ductive cycles even into old age and because human menstrual cyclesconsistently stop within a few years of age fifty instead of graduallytapering off in parallel with other decreases in organ functions. In his1957 article, Williams offered a possible explanation of menopause. Awoman makes a substantial investment in each child, and this invest-ment will pay off genetically only if the child survives to healthy adult-hood. If the mother has more babies (with the associated dangers) evenas the ravages of age become severe, she is having children she may notbe able to care for, and she is risking the future success of her existingchildren. If, instead, she stops having additional children and devotesher effort to helping those she already has, she may have more total off-spring who grow up to reproduce themselves. Recent papers byanthropologists Kim Hill and Alan Rogers challenge this explanationof menopause, but the hypothesis nonetheless offers a fine example ofhow kin selection might explain apparently useless traits.

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Not all genes that cause senescence necessarily have early benefits.Some were simply never exposed to selection because too few peoplelived long enough in the ancestral environment for the gene to causea disadvantage. This explanation was thought sufficient by AlexComfort, the distinguished biologist who is equally well known, insomewhat overlapping circles, for his classic texts The Biology ofSenescence and The Joy of Sex. If Comfort is right, senescence shouldalmost never cause the death of wild animals. He observed thatdecrepit animals are rarely found in nature and concluded that senes-cence is not a factor in the mortality of wild populations. But don'tforget the sports records. If aging animals run just a little bit slower,they will be caught by predators sooner than their younger competi-tors are and will thus die from the effects of senescence long beforewe would notice any decrepitude.

One way to look into this situation is to calculate the force of selec-tion acting on wild populations by comparing the survival curve for theactual population to a curve for an imaginary population that is identi-cal except that its mortality rate does not increase with age. The ratio ofthe areas under the curves gives an estimate of how much senescencedecreases fitness (Figure 8-2 gives an example). In many wild mammals,senescence is a major negative selective force, and most genes thatcause senescence are thus within the reach of natural selection. Theirprevalence is probably explained by benefits early in life.

A ent;3u -

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(hours)3:00-

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Age (years)

FIGURE 8-3. World record marathon times for men, ages 10 to 79.(Data from Runner's World, 1980.)

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The astute reader will now want to see some examples of suchsenescence genes with early benefits. Many genes that have multipleeffects are known: for instance, the gene that causes PKU causes fairhair in addition to mental retardation. Here, however, we are inter-ested in genes that have one effect that gives a benefit in youth andanother effect that imposes a cost with age. In a 1988 article, Univer-sity of Michigan physician Roger Albin cited several diseases thatmay result from such genes. One candidate is hemochromatosis, adisease that causes excess absorption of iron and death in middle age,when the resulting iron deposits destroy the liver. Earlier in life theability to absorb extra iron may give people with this disorder anadvantage (avoiding iron-deficiency anemia) that outweighs the laterdisadvantage. Albin notes that the prevalence of this gene (about 10percent of the population has it) can also be explained by heterozy-gote advantage. Or this may be a gene that is maintained by sexuallyantagonistic selection. It may benefit women, who need the iron toreplace what they lose during menstruation, but harm middle-agedmen, who simply accumulate excess iron.

In another example, Albin notes that some people have a gene thatresults in excess production of a gastric hormone called pepsinogen I.These people are more likely than others to get peptic ulcers and, asthey grow older, to die from these ulcers. Throughout life, however,these people have high levels of stomach acid, which may provideextra protection against infection. Insofar as we are aware, no one hascarried out the test Albin suggested, of looking to see if high levels ofpepsinogen I protect people against gastrointestinal infections such astuberculosis and cholera.

Paul Turke, an evolutionary anthropologist and senescenceresearcher who has gone to medical school to become a Darwinianphysician, reminds us that the whole immune system is age biased. Itreleases damaging chemicals that protect us from infection, but thesesame chemicals inevitably damage tissues and may ultimately lead tosenescence and cancer.

The genes that predispose to Alzheimer's disease may also havebeen selected for because of earlier benefits. The most common causeof devastating mental deterioration, it affects 5 percent of people byage sixty-five and 20 percent by age eighty. It has long been known tobe influenced by genetic factors, as shown by many familial cases andby its high frequency in people with three copies of chromosome 21.

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In 1993, scientists from the Department of Neurology at Duke Uni-versity discovered that a gene on chromosome 19 that makes a pro-tein called apolipoprotein E4 is especially common in people whodevelop Alzheimer's disease. People who are heterozygous for thegene have a 40 percent chance of developing the disease by age eighty.So far as we know, no one has looked for possible benefits early inlife in those people who later develop Alzheimer's disease. Now thatthis gene has been discovered, it should be possible to address thequestion. S. I. Rapoport at the National Institute on Aging has sug-gested a related explanation. He notes that Alzheimer's disease ischaracterized by abnormalities in more recently evolved regions ofthe brain and that it does not occur in other primates. This led him tosuggest that the genetic changes that led to the very rapid increasein human brain size over the past four million years either causeAlzheimer's in some people or produce side effects that have not yetbeen mediated by other genetic changes. It would be very interestingto see if intelligence early in life is higher, or brain size larger, in peo-ple who have the gene that predisposes to Alzheimer's disease.

Considerable laboratory evidence demonstrates that genes withearly benefits contribute to senescence. Population biologist RobertSokal bred flour beetles, those common kitchen pests, and selectedfor those that reproduced early in their life cycles. After forty gener-ations, the beetles selected for early reproduction produced consid-erably more offspring sooner in life, but they also aged and diedearlier, possibly an effect of genes selected because of their benefitsearly in the life span despite their costs later in life. Biologists MichaelRose and Brian Charlesworth went the other way, breeding fruit fliesthat reproduced late in their life cycle. These fruit flies not only hadmore offspring later in life, they also lived longer and had fewer totaloffspring, exactly what would be expected if the artificial selectionhad eliminated genes with early benefits and later costs.

Growing evidence suggests that such genes contribute to senes-cence in wild animals. For years, gerontologists accepted Alex Com-fort's erroneous conclusion that senescence does not occur in wildanimals. In a classic example of seeing what they expected to see,many scientists who studied wild populations didn't even bother tocheck to see if the oldest animals showed increased mortality rates,they just assumed that mortality rates remained constant throughoutlife. Now that gerontologists have begun looking, however, the evi-

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dence is everywhere. For many species, senescence decreases repro-ductive success more than do all other forces of selection combined.This does not prove the role of pleiotropic genes in senescence, but itcertainly challenges the theory that natural selection simply has nothad a chance to eliminate the genes that cause senescence.

While evidence for senescence in wild animals supports our trade-off theory of senescence, it has been challenged by evidence that thelife span can be readily extended. Severely restricting the diets of ratsand mice increases their life span by 30 percent or more. This seemsmysterious, because a major increase in life span resulting fromsomething as simple as caloric restriction is inconsistent with ourbelief that senescence results from many genes acting in concert. Sowhy don't mice and rats eat less and live longer? The first possibilityis that they are normally overfed in the laboratory and thus age pre-maturely. Perhaps their bodies are designed for less lavish diets, sothat the starvation experiments were not extending the life span butsimply reducing the adverse effects of excess food. This does notseem to be correct. Rats and mice who can eat all they want to are notmuch heavier than their wild relatives, and poorly nourished rats liveeven longer than wild animals that are protected from predators andpoisons.

Harvard biologist Steven Austad reviewed hundreds of studies ofdietary restriction and found the key in a crucial fact mentioned inonly a few studies. The food-deprived rats may live longer, but theydon't have offspring. In fact, they don't even mate! They seem toremain at a prereproductive state of development, waiting for an ade-quate food supply. The mechanisms that explain diet-inducedlongevity remain of great interest, but to an evolutionist, dietaryrestriction that eliminates reproductive success is no boon butalmost as bad as early death.

MECHANISMS OF SENESCENCEW Ahat proximate mechanisms are responsible forI I 7 / senescence and limited longevity? Recent researchhas found several. Free radicals, for instance, arereactive molecules that damage whatever tissue they

contact. Our bodies have developed a number of defenses, especially

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a compound called superoxide dismutase (SOD), that neutralizes freeradicals before they can cause much damage. Lack of normal SODmay cause amyotrophic lateral sclerosis (also known as Lou Gehrig'sdisease), a fatal disease of muscle wasting. The levels of SOD in vari-ous species are directly related to their life spans. On the one hand,this shows that damage by free radicals is indeed a proximate cause ofsenescence, but on the other it demonstrates how natural selectionadjusts a defense to whatever level is needed.

Blood levels of uric acid, another antioxidant, are also correlatedclosely with a species' life span. We humans have lost the ability, pos-sessed by most other mammals, to break down uric acid. Becauseuric acid crystals precipitate in the joint fluid and cause gout, this lossis often cited in medical books as a deficiency in human biochem-istry, but, as noted in this extract from a biochemistry text, it mayalso be an advantage that facilitates our long life:

What is the selective advantage of a urate level sohigh that it teeters on the brink of gout in many peo-ple? It turns out that urate has a markedly beneficialaction. Urate is a very efficient scavenger of highlyreactive and harmful oxygen species-namelyhydroxyl radical, superoxide anion, singlet oxygen,and oxygenated heme intermediates in high Fevalence states (+4 and +5). Indeed urate is about aseffective as ascorbate as an antioxidant. The increasedlevel of urate in humans compared with prosimiansand other lower primates may contribute signifi-cantly to the longer life span of humans and to thelower incidence of human cancer.

The flaming painful gouty toe is a cost of a gene that may havebeen selected because it helps to delay senescence. This gene haseffects that are the opposite of those already described, in that thegene gives benefits late in life by slowing aging while exacting its coststhroughout adult life. It would be most interesting to see if aging isslower in people with gout.

The levels of an enzyme that repairs abnormal DNA are alsohigher in longer-lived species. This demonstrates that damage toDNA is a force of selection, and, as with SOD and uric acid, it alsodemonstrates that nature has found a solution to the problem. If one

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sees natural selection as a weak force, one sees free radicals and DNAdamage as causes of senescence. Appreciation of the strength of nat-ural selection, however, makes one much more inclined to expectthat damage from oxygen radicals and defective DNA is limited byevolved mechanisms that are as effective as they need to be to maxi-mize reproductive success.

As Austad points out, the mechanisms of senescence are likely todiffer from species to species. Rats and mice, the subjects of mostsenescence research, are distant from humans, not only phylogeneti-cally but also in their patterns of senescence. Austad therefore pro-posed extensive cross-species studies of senescence to uncovercommon patterns. He began his research on an island off the coast ofGeorgia where opossums had been living without predators for severalthousand years and predicted that they would have evolved longer lifespans. The fieldwork-catching opossums on both the island and themainland and determining their ages-took several years. (The taskwas much easier with the island opossums, because they sleep on theground in plain view, having lost the defense, essential on the main-land, of hiding all day in deep burrows.) The results of the study? Notonly do the island opossums live longer than their landlocked distantcousins, they also age more slowly on a variety of indicators. The costof these changes, however, is smaller litters at all ages and delayed ageat first reproduction. It is clear that the rate of senescence, like otherlife-history characteristics, is shaped by natural selection.

SEX DIFFERENCES INRATES OF SENESCENCE

ack to humans. Boys born in the United States in 1985 areexpected to live seven years less, on average, than girls, andcomparable differences have been found in other countriesand in earlier times. Why do women have this advantage

over men? The most important evidence for why males age sooner inso many species comes from a cross-species comparison. Males thatmust compete for mates have shorter lives than females. Part of theincreased mortality results from males fighting over females, buteven males living alone in cages die sooner than females.

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Why are males the vulnerable sex? Male reproductive success is sodependent on competitive ability that male physiology is devotedmore to this competition and proportionately less to preservation ofthe body. Their game of life is played for higher stakes. If unusuallyfit males can sire large numbers of offspring while mediocre malesusually have none, heavy sacrifices must be made in the effort toreach high fitness. Among the processes sacrificed may be those thatcontribute to longevity.

MEDICAL IMPLICATIONS

esearch on senescence seems to be discovering the valueof an evolutionary point of view. Gerontologists are real-izing that the mechanisms that cause senescence may notbe mistakes but compromises carefully wrought by nat-

ural selection. An evolutionary view suggests that more than a fewgenes are involved in senescence and that some of them have func-tions crucial to life. These genes express their various effects in aseemingly coordinated cluster of escalating signs, because any genewhose deleterious effects occur earlier than those of other genes willbe selected against the most strongly. Selection will act on it andother genes to delay its effects until they are in synchrony with thoseof other genes that cause senescence. This process explains the one-hoss shay effect, the concordance of many signs of senescence eventhough there is no internal clock that coordinates senescence.

This view discourages the hopes of that lady on the plane, thehope that senescence is a disease that may someday be cured. Hope-ful talk about a life-extending research breakthrough is just hopefultalk. What gerontological research does offer, and what justifies con-siderable investment in studying the mechanisms of senescence, isthe likelihood that many diseases of senescence can be postponed orprevented so we can live more fully and vigorously throughout adultlife. Despite our pessimism about substantially extending the lifespan, we concede that the history of science is full of confident theo-reticians proving something impossible just a few years before it isaccomplished. And we are well aware that natural selection hasgreatly increased our life span in just a few million years. So we ask

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not that gerontologists give up their efforts to extend the life span,only that they conduct them in the light of evolution.

We should also note that pessimistic assessments of what sciencecan accomplish often have substantial utility. They provide whatphilosopher E. T. Whittaker called postulates of impotence. Because ofsuch pessimism, engineers no longer try to design perpetual-motionmachines and chemists no longer try to turn lead into gold. If geron-tologists stop trying to find the fountain of youth in some single, con-trollable cause of senescence, their efforts may prove more fruitfulfor human well-being.

The clinician has more immediate concerns. The proportion ofpeople over the age of eighty-five is growing six times faster than thepopulation as a whole. In just the past three decades, the average lifeexpectancy in the United States has gone from 69.7 to 75.2 years.More than a quarter of every health care dollar is now spent onpatients in the last year of life, and the need for nursing home beds isexpected to quadruple in the next twenty years. Medicine haschanged its focus from acute diseases of children and younger adultsto chronic diseases of the elderly. Doctors who imagined spendingtheir careers giving antibiotics to stop pneumonia and doing heroiccurative surgery now find themselves monitoring high blood pres-sure, evaluating memory problems, and relieving the symptoms ofchronic heart disease. Many of these physicians and their patientsstill think of senescence as a disease. We expect that knowledgeabout the evolutionary origins of senescence will have profoundeffects that are difficult to predict.

This perspective may also change how we see our own lives. Somemay find it a consolation to know that senescence is the price we payfor vigor in youth. There is also relief as well as disappointment inknowing that no medical advance is ever likely to extend our lives toany dramatic extent. The search for some pill or exercise or diet thatcan save us from senescence may be replaced by an appreciation oflife as it is, of vigorous function at whatever age. The preoccupationwith living forever is likely to be supplanted by a desire to live as fullyas possible, while it is possible.

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HISTORY

(Video) Watch This If You Are Student | Assignment Hack Part 2 #shorts

The past! the past! the past!The past-the dark unfathom'd retrospect!The teeming gulf-the sleepers and the shadows!The past-the infinite greatness of the past!For what is the present after all but a growth out ofthe past?

-"Passage to India" by Walt Whitman

hil, the unfortunate television weatherman who lives oneday over and over again in the movie Groundhog Day, entersa restaurant just as a diner begins to choke on a bite of food.Phil, having observed this scene many times before, calmly

steps behind the gasping man, wraps his arms around the man'supper abdomen, and suddenly squeezes hard. The food is expelledfrom the diner's windpipe and he can breathe again, his life saved byPhil and the Heimlich maneuver.

About one person in a hundred thousand chokes to death eachyear. While this death rate is small compared to that from automo-bile accidents, choking has been a persistent cause of death not onlythroughout human evolution but throughout vertebrate evolutionbecause all vertebrates share the same design flaw: our mouth is

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below and in front of our nose, but our food-conveying esophagus isbehind the air-conveying trachea in our chest, so the tubes mustcross in the throat. If food blocks this intersection, air cannot reachour lungs. When we swallow, reflex mechanisms seal off the open-ing to the trachea so that food does not enter it. Unfortunately, noreal-life machinery is perfect. Sometimes the reflex falters and"something goes down the wrong pipe." For this contingency wehave a defense, the choking reflex, a precisely coordinated pattern ofmuscular contractions and tracheal constriction that creates a burstof exhaled air to forcibly expel misdirected food. If this backupmechanism fails and an obstruction blocking the trachea is not dis-lodged, we die-unless, that is, Phil or someone like him happens tobe nearby.

But why do we need the protective mechanisms of traffic controland a backup choking reflex? It would be so much safer and easier ifour air and food pathways were completely separate. What functionalreason is there for this crisscross? The answer is simple-none at all.The explanation is historical, not functional. Vertebrates from fish tomammals are all saddled with an intersection of the two passages.Other animal groups, such as insects and mollusks, have the more sen-sible arrangement of complete separation of respiratory and digestivesystems.

Our air-food traffic problem got started by a remote ancestor, aminute wormlike animal that fed on microorganisms strained fromthe water through a sievelike region just behind the mouth. The ani-mal was too small to need a respiratory system. Passive diffusion ofdissolved gases between its innermost parts and the surroundingwater easily supplied its respiratory needs. Later, as it evolved a largersize, passive diffusion was ever less adequate, and a respiratory sys-tem evolved.

If evolution proceeded by implementing sensible plans, the newrespiratory system would have been just that, a new system designedfrom scratch, but evolution does no sensible planning. It always pro-ceeds by just slightly modifying what it already has. The food sieve atthe forward end of the digestive system already exposed a large sur-face area to a flowing current. With no special modifications, it wasalready serving as a set of gills by providing a large proportion of theneeded gaseous exchanges between internal tissues and environment.Additional respiratory capacity was created by slow modifications of

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this food sieve. Rare minor mutations that made it slightly moreeffective in respiration were gradually accumulated over evolution-ary time. Part of our digestive system was thereby coopted to serve anew function-respiration-and there was no way to anticipate thatthis would later cause great distress in a Pennsylvania restaurant onGroundhog Day. Today, the food-sieving worm stage in our evolu-tion is still found in the closest invertebrate relatives of modern ver-tebrates, which have combined respiratory and digestive passages, asshown in Figure 9-1.

Much later, the evolution of air breathing caused some otherevolutionary changes that we now have cause to regret. When partof the respiratory region was modified to form a lung, it branchedoff the lower side of the esophagus that led to the stomach. Acces-sory openings for air breathing at the surface of the water evolved,understandably, from the already available olfactory organs (nos-trils) on the upper surface of the snout, not on the chin or throat.So the air passage opened above the mouth opening and led into theforward part of the digestive tract. Air then passed back throughthe mouth and larynx to where the trachea branched off and wentthrough this passage to the lungs. This is the lungfish stage (see Fig-ure 9-2).

Subsequent evolution moved the connection from the nostrilsback into the throat so that the air passage was as completely sepa-rate from the digestive system as it could become without redesign-ing the structure of the head and throat. Thus a long dual-functionpassage was gradually shortened until only the crisscross remained,but we and all higher vertebrates are still stuck with it. Vertebrateshave the unenviable capacity to be asphyxiated by their food. Dar-win pointed out, in 1859, how difficult it is, from a purely functionalperspective, to

understand the strange fact that every particle of foodand drink which we swallow has to pass over the ori-fice of the trachea, with some risk of falling into thelungs, notwithstanding the beautiful contrivance bywhich the glottis is closed.

We are actually worse off than other mammals because trafficcontrol in our throat is further compromised by modifications to

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Water flow

Mouth Gut

Branchial sieve

FIGURE 9-1.Diagram of respiratory and digestive passages of a larval tunicate, and of

the extinct ancestor of all vertebrates, as seen in a horizontal sectionthrough the forward end of the body.

FIGURE 9-2.The lungfish stage of the evolution of respiratory and digestive systems ofhigher vertebrates, as seen in a vertical section to one side of the midline.

The dotted lines show the later shift of the nostril connection to the cross-ing in the throat, as is found in mammals.

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facilitate speech. Did you ever watch a horse drinking? It keeps itsmouth in the water and drinks without interrupting its breathing. Itcan do this because the opening from its nasal region can be preciselylined up with the opening into the trachea. The respiratory passageforms a sort of bridge across the digestive passage, so that when thehorse swallows, it can make use of space to the left and right of thebridge. Unfortunately for us, our tracheal opening has slipped fur-ther back in the throat, so that the bridge connection can no longerbe made. At least not for adults; babies, for the first few months oflife, can swallow liquids and breathe simultaneously, like many othermammals. Once they start making the babbling that is the precursorof human speech, however, they can no longer drink like horses. Thehuman capacity for choking represents an ancient maladaptive legacyaggravated by a much later compromise.

OTHER MALFUNCTIONALDESIGN FEATURES

M [any other serious design flaws make us susceptible tomedical problems. Perhaps the most often recognizedis the inside-out retina. Vertebrate eyes started aslight-sensitive cells under the skin of a minute trans-

parent ancestor. The blood vessels and nerves that served these light-sensitive cells came from the outside, as good a direction as any, for atransparent animal. Now, hundreds of millions of years later, lightstill must pass through these nerves and blood vessels on the surfaceof the retina before it reaches the rods and cones that react to thelight. The nerve fibers of the retina gather into a bundle, the opticnerve, which must exit the eye to get to the brain. At the hole wherethe optic nerve exits the retina, there can be no rods and cones. Thiscauses the eye's blind spot. To demonstrate it, close your left eye andfocus your right eye straight ahead at the eraser end of a pencil. Movethe pencil to the right without letting the eye follow it. The eraser willdisappear at a spot about twenty degrees from the forward line ofvision. The left eye is similarly blind twenty degrees to the left of itsmidline.

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AOpticnerve B nerve

FIGURE 9-3.A. The human eye as it ought to be, with a squid-like retinal orientation.

B. The human eye as it really is, with nerves and vessels traversing theinside of the retina.

The blood vessels on the retina create another problem. Theycast shadows that create a network of blind spots on the retina. Toovercome this, our eyes move constantly in tiny twitches so thatthey scan slightly different areas every fraction of a second. Thismass of information is processed in the brain, which compiles it intoa coherent image. We are deceived into thinking we see somethingcontinuously with both eyes when we may only be seeing it inter-mittently with one. Nevertheless, the shadows, like the blind spot,are always there. To demonstrate this useful self-deception, go intoa dark room, press the light end of a penlight against the side of yourclosed eyelid, turn it on, and gently wiggle it around. When thelineup is exactly right, you will see the shadow of the intricatelybranching system of parallel veinlets and arterioles that supply theretina.

The inversion of the retina is a universal defect in vertebratesthat makes no functional sense. As with the unfortunate intersec-tion between the passages for food and air, the explanation is his-torical, and it applies only to the vertebrates. The functionallyanalogous eye of a squid has a more sensibly oriented retina withthe nerves and blood vessels coming from behind the retina. Thesquid eye does not need secondary contrivances to minimize the

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effect of the design flaw that plagues vertebrates, any more than itneed worry about eating interfering with breathing. The squid andother mollusks have their own suites of malfunctional historicallegacies.

Our inverted retina is responsible not only for slight visualimpairment but also for some special medical problems. Any bleed-ing or minor obstruction of blood flow in the retina casts a shadowthat may seriously impair the visual image. Still more serious is theease with which the light-gathering surface (rods and cones) can liftloose from the underlying interior of the eyeball. Once this conditionof detached retina gets started, it is a dire emergency that, if untreated,can lead to blindness. The more sensibly designed squid eye, by con-trast, has its retina anchored securely from below by numerous nervefibers so that it cannot become detached.

In addition to those flaws, which affect all vertebrates or all mam-mals, there are some that affect only humans, or only humans andour closest primate relatives. The appendix is an example. Peoplewho recover from appendectomies seem to suffer no disadvantagefrom not having this part of the human body. The only functionalsignificance of the appendix, as far as we know for sure, is to enableus to have appendicitis. The appendix is the vestige of part of the cae-cum, a digestive organ in our early mammalian ancestors that helpedto process plant foods of low nutritional value. For rabbits and manyother mammals, the caecum still serves this function. The shift to adiet of foods with more concentrated nutrition, such as fruit andinsects, caused the caecum to degenerate in the course of primateevolution because there was no selection to maintain it. Unfortu-nately, it has not yet entirely disappeared, and the vestige now makesus vulnerable to appendicitis.

So why does the appendix persist at all? It does make a minor-but by no means important-contribution to the immune system.We also wonder if it might, paradoxically, be maintained by appen-dicitis. The long, thin shape of the appendix makes it vulnerablewhen inflammation causes swelling that squeezes the artery to theappendix and cuts off its only blood supply. When filled with bacte-ria, an appendix without a blood supply cannot defend itself. Bacte-ria grow rapidly and eventually burst the appendix, spreadinginfection and toxins throughout the abdominal cavity. A bit ofinflammation and swelling is less likely to disrupt the blood supply ofa large appendix than that of a long, thin one. Natural selection grad-

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ually reduces the size of the useless appendix, but any appendix nar-rower than a certain diameter becomes more vulnerable to appen-dicitis. Thus, deaths from appendicitis may paradoxically select for aslightly larger appendix, maintaining this less-than-useless trait.Selection is also almost certainly very slowly making the appendixshorter, but in the meantime the appendix may be maintained by theshortsightedness of natural selection. We wonder if other vestigialtraits might also be maintained because further diminishing themincreases vulnerability to a disease.

Many primates and most other mammals can make their own vit-amin C, but we humans cannot. Our ancestral shift to a high-fruitdiet, rich in vitamin C, had the incidental consequence about fortymillion years ago of allowing the degeneration of the biochemicalmachinery for making this vitamin. Our frugivorous close relativesshare our requirement for dietary vitamin C. All animals need par-ticular organic substances (vitamins) in their food, but differentgroups have different requirements.

Some of our vulnerability to mechanical damage can also beblamed on various past evolutionary developments. A sharp blow tothe side of the human head may fracture the skull, damage the brain,and cause death or permanent impairment. The same blow to an apehead may result merely in a bruised temporalis muscle and tempo-rary impairment of chewing. The difference arises from the increasedsize of the human brain case and shrinkage of the jaw musculature,which incidentally rob the skull of its earlier cushioning. The hardhats construction workers and cyclists wear are a technological fixfor a biological deficiency. If workers and cyclists go on being care-less about wearing their hard hats, perhaps in another million yearswe will again have a thick padding of tissue under our scalps toreduce brain injuries.

The same increased skull size has resulted in a fetal head that fitsthrough a human pelvis only with difficulty. A woman's pelvic struc-ture is slightly different from a man's, so as to provide a large birthpassage and, as childbirth approaches, the pubic joint loosens to fur-ther facilitate the passage of the infant. Yet childbirth is still more dif-ficult than it would be if the vagina could open outside the massivering of pelvic bone, perhaps above the pubis on the lower abdomen.The passage of the vagina through the pelvis is a severe historical con-straint on the evolution of any further increase in fetal head size. This

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constraint, of having to fit an oversize head through the pelvic ring ofbone, explains why human babies have to be born at such an earlyand vulnerable stage of development, compared to, for example, apebabies.

The prevalence of maladaptive human design features has beenrecognized for a long time. A 1941 book by George Estabrooks,Man, The Mechanical Misfit, describes many of the structural defectsand compromises in human anatomy, especially those that resultfrom turning a horizontal fourfooted animal into an upright two-footed one. The weight of the top part of the body greatly com-presses the vertebrae in the lower spine, and standing uprightrequires more muscular effort than a horizontal posture would. Thepelvis was originally designed to resist a back-to-belly force of grav-ity, not the fore-to-aft force that ours must resist as long as we remainupright, either standing or sitting. Elaine Morgan's recent book TheScars of Evolution gives a readable account of these maladaptivelegacies.

A long list of medical problems, ranging from minor annoyancesto serious disabilities, results from the mechanical inadequacies ofour adaptations for an upright posture and two-footed locomotion.Perhaps the most important is the episodic lower back pain experi-enced by so many people. Our knees, ankles, and feet are also extra-ordinarily vulnerable. How often do we hear of athletes missinggames because of knee and ankle injuries? One of the authors onceleaped high in a volleyball game, and when he came down only hisleft foot was on the court. The right landed on the foot of a team-mate and turned sharply inward, seriously straining the vulnerablelateral ligament, which is usually the part that fails when an ankle issprained. The author met his classes on crutches for the next weekand was glad he was not part of a band roving over the Paleolithicsavannah. He also regretted that the human ankle is not betterdesigned.

The abdominal viscera of a mammal are enclosed in sheets of tis-sue designed to hang from the upper wall of the abdominal cavity.This is fine for a mammal on all four legs, but in an upright mammalthe sheets of tissue may be said to hang from a vertical pole, a grosslyineffective arrangement that causes such diverse problems as diges-tive system blockages, visceral adhesions, hemorrhoids, and inguinalhernia. The mammalian circulatory system is also compromised by

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upright posture. It works fine for a dog or a sheep, but our uprightposture increases the hydrostatic pressure in the lower extremitiesand can cause varicose veins and swollen ankles. The opposite effect,deficient blood pressure in the brain, can result in dizziness ormomentary partial blackout when we suddenly stand up from arecumbent position.

Sometimes the body's responses to problems are just the oppositeof what would be adaptive. When the heart muscle is too weak topump all the blood it receives, the blood backs up into the lungs andfeet and causes shortness of breath, swollen ankles, and other symp-toms of congestive heart failure. You might expect that this wouldcause excretion of excess fluid, but patients with heart failure retainsalt and fluid, and this excess blood volume makes the problem evenworse. This response is maladaptive in patients with heart disease,but, as internal medicine physician Jennifer Weil points out, thebody's response is designed for a different problem. In a natural envi-ronment, most instances of deficient blood pumping would resultfrom bleeding or dehydration, in which the fluid retention mecha-nism would be useful indeed! Heart failure occurs mainly in old ageand mechanisms to conserve body fluid can be useful throughoutlife, so this system is a fine example of a cause of senescence which ismaintained because of its benefits in youth.

We have been discussing defects in the basic plan of the humanbody. These should not be confused with mere inadequacies of exe-cution and random departures from optimal values. As a generalrule for any readily measured physical feature, it pays to be in themiddle of the pack, as we illustrated previously with the birds withlonger- or shorter-than-average wings, which were especially likelyto be killed in a storm. Unusually tall or short people tend not tolive as long or as healthily as those of average height. Babies of aver-age birth weight are usually better off than those who are muchheavier or lighter. Everyone knows that high or low blood pressureis not as good as normal blood pressure. A high level of adaptiveperformance usually requires that many quantitative characteristicsclosely approach optimal values. While no individual is perfect, thevarious parameters sometimes combine to yield remarkable excel-lence. Yet even in near perfection there is substantial variation-asis well known to those basketball stars who played against MichaelJordan.

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Many design features, while not maladaptive, are functionallyarbitrary and explicable only as historical legacies. In mammals, theright side of the heart circulates the blood to the lungs, the left side tothe rest of the body. In birds it is the other way around, for no betterreason than that birds and mammals came from different reptilianancestors that took arbitrarily different routes to cardiac specializa-tion. Either way works equally well. Some arbitrary features can beadvantageously exploited. Many people who are alive today wouldbe dead except for the happenstance of everyone having two kidneys.When one fails or is donated, the other is able to do double service.By the same logic, many people die of having only one heart. The rea.son we have two kidneys and one heart is simply that, right fromtheir origins, all vertebrates had two kidneys and one heart. This ispure historical legacy and has nothing to do with the advantage ofhaving two of one organ or the disadvantage of having only one ofanother.

We have belabored what is wrong or arbitrary with the humanbody because the design flaws can cause many medical problems, butwe hope that our readers will also realize that much about it is justright. Our oversize brains may be vulnerable to injury and mayimpede childbirth, but they make us the unchallenged leaders of theanimal kingdom in cognitive capability and in all the social and tech-nological advances that this makes possible. No other species in thehistory of our planet has ever controlled its environment to theextent that we have since the invention of agriculture. Similarly, ourlongevity is impressive in relation to that of any other mammal,except a few, such as elephants, that are far larger than we are. We canlive about half again as long as any other primate.

Moreover, many of our other adaptations are equal or superior tothose in other mammals. Our immune system is superb. Also,despite conspicuous design flaws and individual imperfections, oureyes and related brain structures incorporate layer upon layer ofinformation-processing marvels that extract the maximum amount ofusefulness from visual stimuli. If hawks, for example, have visualacuity that is in some ways superior to ours, this one kind of superi-ority must be purchased with some kind of trade-off. Animals thatcan see better than we can in the dark cannot see as well in the light.Normal human vision approaches a theoretical maximum of sensitiv-ity and discrimination over a wide range of conditions. We are only

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beginning to understand how it is that a face, seen from one angle ata certain distance, may later, from another angle and distance, beinstantly recognized. No current computer can approach such feats.Our hearing is so sensitive to some frequencies that if it were moresensitive we would not hear as well. Informative sounds would belost in the noise of random air molecules colliding with oureardrums.

THE FINISHING TOUCH

e have been discussing mainly attributes thatW Y humans share with other vertebrates, other mam-mals, or other primates. Our discussions of ourproblems with upright stature also apply to extinct

members of our genus, Homo. We now turn to more explicitlyhuman legacies, with an emphasis on the evolutionary adjustmentsmade in the period from about one hundred thousand to about tenthousand years ago. While natural selection has been changing us inmany small ways in the last ten thousand years, this is but a momenton the scale of evolutionary time. Our ancestors of ten thousand orperhaps even fifty thousand years ago looked and acted fully human.If we could magically transport babies from that time and rear themin modern families, we could expect them to grow up into perfectlymodern lawyers or farmers or athletes or cocaine addicts.

The point of the rest of this chapter, and the following one, is thatwe are specifically adapted to Stone Age conditions. These condi-tions ended a few thousand years ago, but evolution has not had timesince then to adapt us to a world of dense populations, modernsocioeconomic conditions, low levels of physical activity, and themany other novel aspects of modern environments. We are not refer-ring merely to the world of offices, classrooms, and fast-food restau-rants. Life on any primitive farm or in any third-world village mayalso be thoroughly abnormal for people whose bodies were designedfor the world of the Stone Age hunter-gatherer.

Even more specifically, we seem to be adapted to the ecologicaland socioeconomic conditions experienced by tribal societies livingin the semiarid habitat characteristic of sub-Saharan Africa. This is

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most likely where our species originated and lived for tens of thou-sands of years and where we spent perhaps 90 percent of our historyafter becoming fully human and recognizable as the species we aretoday. Prior to that was a far longer period of evolution in Africa inwhich our ancestors' skeletal features lead scientists to give themother names, such as Homo erectus and Homo habilis. Yet even thesemore remote ancestors walked erect and used their hands for mak-ing and using tools. We can only guess at many aspects of their biol-ogy. Speech capabilities and social organizations are not apparent instone artifacts and fossil remains, but there is no reason to doubtthat their ways of life were rather similar to those of more recenthunter-gatherers.

Technological advances later allowed our ancestors to invadeother habitats and regions, such as deserts, jungles, and forests.Beginning about one hundred thousand years ago, our ancestorsbegan to disperse from Africa to parts of Eurasia, including season-ally frigid regions made habitable by advances in clothing, habitation,and food acquisition and storage. Yet despite the geographic and cli-matic diversity, people still lived in small tribal groups with hunter-gatherer economies. Grainfield agriculture, with its revolutionaryalteration of human diet and socioeconomic systems, was practicedfirst in southwest Asia about eight thousand years ago and shortlythereafter in Egypt, India, and China. It took another thousand yearsor more to spread to central and western Europe and tropical Africaand to begin independently in Latin America. Most of our ancestorsof a few thousand years ago still lived in bands of hunter-gatherers.We are, in the words of some distinguished American anthropolo-gists, "Stone Agers in the fast lane."

DEATH IN THE STONE AGEI magine what it must have been like in that idyllic era. You wereborn into a nomadic band of forty to a hundred people. What-ever its size, it was a stable social group. You grew up in the careof various close relatives. Even if your local band consisted of a

hundred or more people, many of them were distant cousins. Youknew them all and knew their genetic and marital connections to

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yourself. Some you loved deeply and they loved you in return. Ifthere were those you did not love, at least you knew what to expectfrom them, and you knew what everyone expected of you. If youoccasionally saw strangers, it was probably at a trading site, and youknew what to expect of them too. In a sparsely peopled world thenecessities of life-plant and animal foods uncontaminated by pesti-cides-were there for the taking. You breathed the pure air anddrank the pure water of a preindustrial Eden.

Having asked you to imagine an idyllic past, we now urge thatyou be more realistic. Like other Golden Age legends, such as theage of chivalry or that delightful antebellum world into which Scar-lett O'Hara was born, it is a fabricated myth. Enjoy it in fantasy orfiction, but do not let it mislead serious thought on medicine orhuman evolution. The unpleasant fact is that our hunter-gathererancestors lived with enormous difficulty and hardship. Simplearithmetic on the rates of death and reproduction makes this con-clusion inescapable. Death always balanced reproduction, eventhough people reproduced at something approaching the maximumfeasible rate.

In most primitive social systems, women start bearing children assoon as they are able to do so, which, because of nutritional limita-tions, is often delayed until about age nineteen. Pregnancy and child-birth are followed by two or three years of lactation, which inhibitsovulation. Then the mother is soon pregnant again, whether this ismedically advisable or not. In the unlikely event that she remainsfully fertile and survives to menopause, she will probably produceabout five babies. Having more children would require shortened lac-tation periods, and this is unlikely given the limited foods availablefor babies in preagricultural societies.

But even if hunter-gatherer women averaged only four childrenbefore succumbing to sterility or death, only half their babies couldhave survived to maturity. Otherwise the human population wouldhave steadily increased, and this obviously did not happen. Even anincrease of 1 percent per century would cause a population tobecome a thousand times as numerous in less than seventy thou-sand years, but populations remained extremely sparse until theinvention of agriculture. The conclusion is thus quantitativelyinescapable that deaths almost precisely kept up with births fornearly all of human history. The extraordinarily low death rates ofthe last few centuries, and especially in the last few decades in West-

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ern societies, show that we live in times of unprecedented safetyand prosperity. It is no doubt difficult for most readers of this bookto appreciate the harshness and insecurity of human life under nat-ural conditions.

Mortality rates in the Stone Age, like those of today, were highestin infancy and declined throughout childhood. Many early deaths insome groups were from infanticide, motivated by parents' economichardship or imposed by patriarchs. While fictional accounts of StoneAge conditions probably exaggerate the ravages of predation andother wild-animal attack, lions, hyenas, and venomous snakes wereever-present hazards and took a steady toll, with children especiallyvulnerable. Death rates from poisoning and accidents were far higherthan they are now.

The infectious diseases, which were probably the most importantsource of mortality for all age groups, were not the same bacterialand viral diseases that afflict us today. Most of today's infectionsdepend on rates of personal contact only possible in abnormallydense populations. Back then, vector-borne protozoa and wormswere common causes of prolonged sickness and ultimate death.Many of these diseases are not merely lethal but most unpleasantlyso. Some readers will know how unpleasant malaria can be, frompersonal experience or from knowing someone who has had the dis-ease. It is a lark compared to other protozoan diseases such as kala-azar, which slowly destroys the liver and other viscera; parasitessuch as lungworms, which cause death by suffocation; hookworms,which are seldom fatal but can make children grow into physicallyand mentally defective adults; and filaria, which among other thingscause elephantiasis. The name comes from the swelling of the limbsand scrotum to elephantine proportions because the parasites blockthe lymphatic vessels.

Food was often abundant for hunter-gatherers, but memories ofbounteous fruit harvests or an occasional big kill must have been apoor solace during the regularly recurring famines. Climatic varia-tions induce fluctuation in resources. Even in the most stableclimates, food abundance varies because of plant and animal dis-eases. Prior to the invention of reliable preservation techniques,temporarily abundant food could not be saved for leaner times.Even foods preserved by drying or smoking could be attacked bypests that could frustrate the most careful planning for future emer-gencies.

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Shortages of vital necessities were not only directly stressful, theyalso encouraged strife. Imagine that people from a hill tribe were suf-fering from a protein shortage, while people in the valley were feast-ing on the abundant fish from their lake. The people from the hillswould no doubt insist that their leaders take them to that lake, nomatter how loudly the valley people asserted their exclusive fishingrights. If catching the fish means killing the fishermen and appropri-ating their fishing gear, that is what the hill people might decide to do.Even in the absence of economic necessity, human nature often findsexcuses for armed robbery and attendant taking of life. Fortunatelyfor early tribal societies, they lacked the technology of transport andcommunication that permitted banditry on the scale practiced byGenghis Khan or Alexander of Macedon.

Human nature has, of course, its nobler aspects. There are suchthings as love and charity and honesty. Unfortunately, the evolution-ary origins of such qualities are rooted in their utility in parochialtribal settings. Natural selection clearly favors being kind to close rel-atives because of their shared genes. It also favors being known tokeep one's promises and not cheating members of one's local groupor habitual trading partners in other groups. There was, however,never any individual advantage from altruism beyond these localassociations. Global human rights is a new idea never favored by evo-lution during the Stone Age. When Plato urged that one ought to beconsiderate of all Greeks, not merely all Athenians, it was a contro-versial idea. Today, humanistic sentiments still face formidableopposition from parochialism and bigotry. In fact, these destructivetendencies are aggravated by what we just now called the "nobler"aspects of human nature. As Michigan biologist Richard Alexanderso neatly put it, today's central ethical problem is "within-groupamity serving between-group enmity."

LIFE IN THE STONE AGEH ' uman nature was formed in what anthropologists haverecently termed (following a 1966 suggestion by psychia-trist John Bowlby) the environment of evolutionary adapt-edness, or EEA. Despite their frequent reference to the

EEA, anthropologists differ widely about what it was like. They can-

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not directly observe the ways of our ancestors of tens of thousands ofyears ago or the effects of environmental conditions on the humangenetic makeup. They must base their conclusions on indirect evi-dence: skeletal remains, stone tools, cave paintings, and informationabout modem groups with seemingly primitive economies and socialconditions.

The shortage of information is serious. What are the historicallynormal conditions of human childbirth? This is just one of manybasic questions for which there is no assured answer. We suspect thatthe correct answer to many such questions is, it was highly variable.Attitudes toward childbirth differ enormously among different cul-tures today, and there is no reason to believe they were any less vari-able a hundred thousand years ago. They must also have been quitevariable within social groups. The solicitude offered to a chief's wifeno doubt differed from that proffered a concubine captured from ahostile tribe. Giving birth during times of plenty in a settled campmight have been rather different from giving birth in leaner times orduring travel to a new location.

We also suggest that the correct answer to other important ques-tions is, it varied. What sorts of rewards went to gifted poets, artists,or others of high intellectual attainment, compared to those whowere good hunters or warriors? How stratified, by family connec-tions or merit, were the socioeconomic conditions? Was inheritancematrilineal or patrilineal? What were the child-rearing customs?What were the religious doctrines and constraints, and how strong afactor was religion? These questions would have vastly differentanswers in different societies in the EEA. There is no one "natural"way of human life.

Despite great variation in the human adaptations to a variety ofEEA conditions, the available evidence does support some general-izations. Social systems were constrained by economics and demog-raphy. No elaborately stratified societies with hereditary classstructures were possible in the Stone Age, because groups that had togather their food from within walking distance necessarily remainedsmall. Likewise, no chief of a nomadic band can have dozens of wiveswhen the band only includes a few dozen people. Prior to the devel-opment of agriculture, no chief could control enough land, wealth,and people to build cathedrals or pyramids.

Social systems were also constrained by the physiological andstructural differences between the sexes. The physiological costs of

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reproduction involved in pregnancy and lactation are borne entirelyby women. By what rules were the economic costs of reproductionapportioned? Again, we suggest, they varied. On the basis of what weknow about current human groups, husbands no doubt contributedsignificantly in most cultures, but in others a mother's brothers andother relatives made a greater contribution. Likewise, the gross phys-ical differences between the sexes imply behavioral differences. Thegreater size and strength of men suggest that these attributes providedimportant competitive advantages, especially in the competition formates. We discuss this and related matters in Chapter 13.

Economic necessity often demanded that adults and older chil-dren of both sexes spend much of their time searching for andpreparing food. It is usually assumed that men did the hunting andwomen the gathering in hunter-gatherer societies, although the antiq-uity and importance of big-game hunting have been exaggerated infictional accounts of Stone Age life. Archery and other weaponseffective against such animals as deer were in fact not invented untillate in the Stone Age. Dogs, which can play crucial roles in manyhunting techniques, were not common human associates beforeabout fifteen thousand years ago. Meat or hides from large animalsmay often have been procured not by hunting but by scavenging orstealing from other predators.

The mainstay foods in the Stone Age would seem to us inedible ortoo demanding of time and effort. We would find most of the gamestrong-tasting and extremely tough. Most of us have little apprecia-tion of the tedious skinning and butchering it takes to turn a wild ani-mal carcass into a serving of meat. Many wild fruits, even when fullyripe, are sour to our tastes, and other plant products are bitter orhave strong odors. We find them unpleasant thanks to our adapta-tions that make us avoid toxins, as discussed in Chapter 6. Most nat-ural human foods require a far greater labor of preparation andchewing than the foods we eat now. Domesticated animals and plantshave been artificially selected to be tender, nontoxic, and easilyprocessed.

Despite the abundance of foods available in the EEA much of thetime, the village elders would have been able to remember times ofsevere famine. Actual starvation may have been rare, but deaths fromthe combined stresses of disease, malnutrition, and poisoning by theexcessive consumption of marginally edible plants were probably

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common. These same stresses also would have caused abortion offetuses, curtailment of lactation, reduced fertility, and actions such asinfanticide and the abandonment of the old or impaired.

In addition to xenophobic conflict with other groups, socialstrife within groups, famines, and toxic diets, there were manyother environmental stresses. Our ability to tolerate the atmos-pheric pollution of modern cities may owe much to our many thou-sands of years of exposure to smoke toxins from woods and otherfuels. Imagine living in a hut with a fire on the floor and only a smallhole in the roof. Atmospheric pollution was different in the EEA,but it was substantial and real. We would find the odors of a StoneAge settlement most unpleasant. There were no soaps or deodor-ants, no flush toilets, or readily cleanable chamber pots, or anyinstallations worthy of the term latrine. Wastes of various kindswere taken away to some customary distance and no further. Otherwastes simply accumulated where they were produced. The averageStone Ager lived in a dump and moved away when conditions gotreally bad.

Children grew up, and adults lived out their lives, in the con-stant awareness, and sooner or later the personal experience, ofwoeful illness, painful injury, physical handicaps, debilitation, anddeath. There were no antibiotics, tetanus shots, or anesthetics, noplaster casts, corrective lenses, or prosthetic devices, no sterilesurgery or false teeth. Our remote ancestors had few cavities, butthey had many other dental problems. Teeth could be injured orlost in accidents, and they could literally wear out before what wecall middle age. Abrasive plant products can wear molars down togum level, as seen in some fossil skulls and even in some contem-porary groups.

Lest it seem that our account of the EEA is merely a selection ofitems for a catalog of horrors, we should emphasize that we are dis-cussing our fully human ancestors, with a fully human capacity forpleasure as well as pain and a fully human intellect. The bonds of kin-ship and friendship could be strong and a source of great pleasureand security. In seasons of plenty there would be abundant time forplay: games, music and dancing, storytelling and poetry recitals, intel-lectual and theological disputes, and the creation of ornamental art-work. The cave paintings at Lascaux, France, created perhaps 25,000years ago, have been described by anthropologist Melvin Konnor as

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"a Paleolithic Sistine Chapel" that impresses a sensitive observer"whether religious or not-whether expert or not-with a strongsense of the holy." And our ancestors also had the ability to look onthe bright side in times of adversity and to find reasons for laughter.Mark Twain's hero Sir Boss in A Connecticut Yankee in King Arthur'sCourt lamented having to listen, at a sixth-century campfire, to thesame jokes he had already found tiresome in the nineteenth. We sus-pect that if he had gone back to the Stone Age he would have groanedat many of the same jokes.

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Y You have now spent several hours reading this book. Doyou realize how much thoroughly abnormal use of youreyes this feat required? Was the light source the sun, withits normal spectrum? Probably not, at least not entirely.

How much muscular exertion did you expend during those hours ofreading? How could you be so inactive for that much time withoutjeopardizing your well-being, perhaps your life, by having spent inad-equate time and effort in vigilance against enemies and in foraging forfood? But you are in fact well fed? How long did it take to pick or digor hunt or fish for your last meal? How much shelling and grindingand butchering? If the food was cooked, how long did it take you togather the fuel and kindle the fire? How much sweating and shiveringhave you done in the last twenty-four hours? What's that about ther-mostatically controlled heating and air conditioning? How bizarre!And what are the long-term consequences of such meager challengeto your body's built-in temperature controls?

As the last chapter (we hope) made clear, only the grossly unin-formed or irrationally romantic would think we were ever better offthan we are now. Rousseau's noble savage and the Flintstones' merrycapers are delightful in escapist fiction, but the reality was painfuland sad compared to our lives today or even to when farming firstreplaced nomadic scrounging. Agriculture led to urban civilization,with its durable architecture and associated fine arts, and the nauticaland other technological advances that permitted exploration of dis-

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tant lands. The domestication of hoofed animals enabled one workerto do jobs that would previously have required several. It also con,tributed to revolutionary advances in transportation. Continuingtechnological advances have led to ever greater freedom from wantand freedom of movement for ever larger numbers of people.

The long-term consequences of the soft and gratifying lives we nowenjoy are mostly beneficial or harmless, but many of the advantageswe enjoy today are mixed blessings. Benefits have costs, and even themost worthwhile benefits can be costly to our health. For a goodexample we need look no further than the effects of lower mortalityrates in early life. Because fewer people die young from smallpox,appendicitis, childbirth complications, and hunting accidents, thedeath rates from old-age afflictions like cancer and heart failure aremuch higher now than they were a couple of generations ago. This islargely because a higher proportion of people live to the ages at whichthe body becomes especially vulnerable to these illnesses. The price ofnot being eaten by a lion at age ten or thirty may be a heart attack ateighty. Modern practices of food production, medicine, publichealth, and industrial and household safety have drastically improvedthe prospects of surviving to old age. Unfortunately, the increasedeffects of aging are not the only bad aspects of the good life.

Novel environments often interact with previously invisiblegenetic quirks to cause more variation in phenotypes, some of it out-side the normal range. As described already in the chapter on genet-ics, these abnormalities arise only when a vulnerable genotypeencounters an environmental novelty. Novel physical, chemical, bio-logical, and social influences will cause problems for some peopleand not others or will have different effects on different individualsdepending on their specific genetic makeup. We have already dis-cussed some human examples; for instance, the genetic quirks thatcause myopia impose problems in literate societies, but they causedno difficulties for our ancestors.

Our ways of getting food changed the environment in ways thatcreated new problems. Thousands of years ago some of our ancestorshunted wild goats or cattle. Hunters followed herds for hours in thehope of killing one of the animals for food, hide, and other resources.Sometimes they may have found, early in the morning, the same herdthey had been following the day before. If animals can be followedfor two days, why not three, or a week, or a month? How long wouldthis go on before the hunters would start thinking of the herd as their

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own, driving off wolves or rival groups of hunters or other predatorsand chasing strays back into the group to maintain a large herd? Thisprocess gradually converted hunters into nomadic herdsmen.

Other ancestors were more vegetarian and found that some plantscould produce a lot more food if they were intentionally planted forlater harvest. Plowing, weeding, fertilizing, and selecting variants withthe highest yields soon became standard practice and resulted insteadily greater and more reliable food production. It has been sup-posed that local increases in population may have encouraged theinvention of agriculture or its adoption from neighboring peoples.Whether this is true or not, agriculture permitted the maintenance ofmuch denser and more sedentary populations than could be sup-ported by hunter-gatherer economies. Increased population densitythen became a source of other problems, some of which will be dis-cussed in this, others in the next four chapters.

MODERN DIETARY INADEQUACIESParadoxically, the increased food production made possibleby herding and agriculture resulted in nutritional shortages.There are more calories and protein in a bushel of wheatthan in a handful of wild berries, but there is more vitamin C

in the berries. If wheat provides most of the calories and protein fora farming community, deficiencies of vitamins and other trace nutri-ents are much more likely to arise than they would be with the morediversified diets of hunter-gatherers. If the wheat or other agricul-tural produce is also used as feed for the domestic animals that pro-vide meat or eggs or milk, the farmers' meals are much improved, butshortages, especially of vitamin C, remain a threat.

Iceland is a good example, with a vitamin C problem that lastedwell into this century. Icelandic farmers raised mainly sheep, whichgrazed the wild grasses of the countryside. The more successful fami-lies might have had a dairy cow, but mutton provided a large part ofthe diet, and wool was the chief commercial export, sold mostly toDanish colonials. The money so earned allowed the farmers toimport flour and such luxuries as coffee and sugar. Nothing in the listso far contains vitamin C, which was provided mainly by blueberriesand other wild plant foods. Unfortunately, the supply of these com-

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modities was strictly seasonal. During winter and spring, when dietswere notably lacking in vitamin C, many a seemingly robust andhealthy Icelandic farmer would start bleeding from the gums and feel-ing lethargic and depressed, the usual symptoms of scurvy. Somemembers of a family would sicken and others not, with the severityof scurvy varying greatly.

For those who survived the winter sick with scurvy, folk wisdomcame to the rescue. As soon as the marshes thawed, people could digangelica roots, which are a fair source of vitamin C. The so-called"scurvy grass" might be sprouting at the same time and could beeaten as an alternative. The observation that such wild produce couldcure scurvy antedated the use of citrus fruits for preventing the dis-ease among long-distance sailors. Scurvy is a disease of civilization.Before people relied heavily on domestic plants and animals, theynever had such abnormal diets as those of Icelandic farmers in thewinter or sailors at sea for months at a time.

Long before there were any ocean voyages such as those of theoriginal limeys or those that took the first settlers to Iceland, peoplesuffered from other dietary deficiencies resulting from agriculture.About fifteen hundred years ago, some native tribes of the south cen-tral United States abandoned their hunter-gatherer lifestyles andstarted growing corn and beans. The change is clearly recorded intheir skeletal remains. Compared with earlier skeletons, those of thefarmers are on average less robust, and they often show effects ofnutritional deficiencies of the B vitamins and perhaps protein.Despite these deficiencies, such farmers may have been less likely todie of starvation than their ancestors. They may even have been morefertile, because cornmeal and beans can facilitate earlier weaning.Nonetheless, in important respects, they were not as healthy.

These diseases of civilization thus existed fifteen hundred yearsago in what would become Tennessee and Alabama, and long beforethat in earlier agricultural regions of other continents. The same sortsof nutritional deficiencies afflict the impoverished people of manythird-world countries today. Our Stone Age ancestors no doubtfaced frequent shortages of food, but if they were getting enoughcalories they were probably getting enough vitamins and other tracenutrients. Shortages of specific vitamins and minerals arose in justthe past ten thousand years or so.

We are now aware of the need for vitamins and minerals, and weget more of them from a modern diversified diet than many early

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agriculturalists did. Contrary to pharmaceutical sales pitches, fewmodern people need vitamin supplements. If we eat a diverse array offruits and vegetables, some of them preferably uncooked, and espe-cially if we also get abundant protein from grains, legumes, and ani-mal products, we are getting all the vitamins, minerals, and othernutrients we need. The current danger for most of us is not the depri-vation suffered by our ancestors but an excess of nutrition.

MODERN NUTRITIONAL EXCESSES

A wise man once observed that it makes little sense to worryabout excessive eating in the festive week from Christmas

l to New Year's Day. It makes much more sense to worryabout what we eat between New Year's Day and Christ-

mas. Of course, it is possible to overeat in a week. We can evenovereat at one sitting, but this was also a danger in the Stone Age, andwe are equipped with instincts to avoid doing so. There comes a pointat which we feel stuffed and no longer hungry, even for that honey-cured Christmas ham. This normally puts an end to the meal andkeeps us, as it did our ancestors, from overburdening the machineryof digestion, detoxification, and assimilation. Modem overnourish-ment is mainly the result of steady long-term overeating.

In the Stone Age it was adaptive to pick the sweetest fruit avail-able. What happens when you take people with this adaptation andput them in a world full of marshmallows and chocolate eclairs?Many will choose these modern delicacies over an equally availablepeach, itself sweeter than any fruit available in the Stone Age. Marsh-mallows and chocolate eclairs exemplify the supernormal stimulidescribed by students of animal behavior. The classic example camefrom observations on geese. If an egg rolls out of a nest, a broodinggoose will reach out and roll it back with her chin. Her adaptive pro-gramming is "If a conspicuously egglike object is nearby, I must rollit into the nest." What happens if you put both an egg and a tennisball near her nest? She prefers the tennis ball. To her it looks moreegglike than an egg. There can be supernormal stimuli in any sensorymode, for instance, taste. Next time you find yourself reaching for aslice of apple pie instead of an apple, think of that goose who seemsto think she should incubate a tennis ball.

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Our dietary problems arise from a mismatch between the tastesevolved for Stone Age conditions and their likely effects today. Fat,sugar, and salt were in short supply through nearly all of our evolu-tionary history. Almost everyone, most of the time, would have beenbetter off with more of these substances, and it was consistentlyadaptive to want more and to try to get it. Today most of us canafford to eat more fat, sugar, and salt than is biologically adaptive,more than would ever have been available to our ancestors of a fewthousand years ago. Figure 10-1 shows a plausible relationshipbetween intake and benefit of these substances and proposes a con-trast in the foraging capabilities of a Stone Age tribesman and of ahigh-salaried diner in a gourmet restaurant.

An overwhelming amount of preventable disease in modern soci-eties results from the devastating effects of a high-fat diet. Strokesand heart attacks, the greatest causes of early death in some socialgroups, result from arteries clogged with atherosclerotic lesions.

Good

Health

Poor

Fat Intake

FIGURE 10-1.Our view of the dependence of health and fitness on resource availability,

such as dietary fat intake per month. We propose that fat availability in theStone Age would seldom exceed the levels indicated. Today an originally

adaptive craving for fatty foods may lead to intakes far out on the negativeslope to the right.

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Cancer rates are increased substantially by high-fat diets. Much dia-betes results from the obesity caused by excess fat consumption.Forty percent of the calories in the average American diet come fromfat, while the figure for the average hunter-gatherer is less than 20 per-cent. Some of our ancestors ate lots of meat, but the fat content ofwild game is only about 15 percent. The single thing most people cando to most improve their health is to cut the fat content of their diets.

One of us once met with three others early one morning to travelto a hearing on claims that agricultural uses of pesticides were endan-gering the health of nearby suburban residents. A stop at a diner forbreakfast yielded a vivid memory. One of the eaters lamented thelikelihood that the wheat and eggs in his pancakes were no doubtcontaminated with unnatural pesticides and antibiotics that mightgive him cancer ten or twenty years later. Perhaps so, but these toxinswere a minor danger to his future health compared to the grosslyunnatural fat content of his sausage and buttery pancakes, and theenormous caloric value of the syrup in which everything was bathed.The cumulative effect of that kind of eating is surely more likely tocause future health problems than are the traces of exotic chemicals.

Some people are more prone to this sort of overdosing than oth-ers. This is indicated by observable variation across the spectrumfrom underweight to overweight. Overweight people are more likelyto suffer the cardiovascular problems associated with excess nutri-tion and to have higher rates of various cancers. This commonimpression is supported by recent studies. University of Michigangeneticist James Neel and his associates have noted that efforts torelieve the chronic malnutrition of the Pima Indians of Arizona inad-vertently caused an epidemic of obesity and diabetes. He proposedthat the affected individuals had what he called "thrifty genotypes," agenetically based ability to get and store food energy with unusualefficiency. With what seem like normal diets many Pimas steadilyincrease their stores of body fat. This could well be adaptive in aworld that threatens frequent famine. Those who have built up copi-ous fat stores might survive a prolonged food shortage while theirless efficient associates perish. Thrifty genotypes are not adaptive ina world in which food shortages never occur. The most famine-adapted individuals may just get fatter and fatter until medical prob-lems or other difficulties intervene.

Excess nourishment is not an easily corrected health hazard, andmany common solutions may do more harm than good. Voluntary

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restrictions on food intake may be interpreted by the body's regula-tory machinery as a food shortage. The result may be a resetting of

the basal metabolism so that calories are used even more efficientlyand further fat reserves are amassed. Another consequence of foodrestriction is intensified hunger, with consequent eating binges. Stud-ies of artificial sweeteners fail to show that they help people to loseweight, a finding that might have been expected. Sweetness in themouth, throughout human evolution, has reliably predicted sugar inthe stomach and shortly thereafter in the bloodstream. It is not sur-prising that the sweet taste quickly resets metabolic processes so as tocurtail the conversion of fat and carbohydrate reserves into bloodsugar. This would be adaptive only if, in fact, the stomach contentsquickly compensate for the change. If the sugar signal is a lie, therecould soon be deficient blood sugar and increased hunger, especiallyfor quick-energy sources like candy. There has been little recognitionof such effects of artificial sweeteners. A similar hazard may be antic-ipated for nonnutritive fat substitutes. There are now desserts thatlook and taste like ice cream but are not only low in sugar but free offat. What kind of signals do these send to the metabolic regulatorymechanisms?

Dental cavities are rare in preagricultural societies. If dental work-ers had been conscious of Stone Age fitness requirements, theywould have realized long ago that the twentieth-century epidemic ofdental caries must have been due to some environmental novelty,which we now know to be the frequent and prolonged exposure ofthe teeth to sugar. It nourishes bacteria on the teeth that generateacid, which in turn erodes the dental enamel. Here likewise there isprehistoric evidence for the harmful effects of dietary sugar. Skeletalremains more than a thousand years old from coastal areas in what isnow Georgia (USA) show few dental cavities. They became commonwith the introduction of maize-based agriculture, and perhaps cornsyrup, at about that time. They became still more common with theintroduction of other forms of sugar by European settlers.

Cavities are technically not a nutritional problem, but they are adietary problem and very much a disease of civilization. The goodnews is that they are of steadily decreasing concern. They were a seri-ous scourge for adolescents and young adults born in the UnitedStates before 1940. Advances in preventive dentistry, such as fluo-ride treatment, have helped to overcome the difficulty, but before

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these advances could be made it was crucial to realize that sugar is theculprit.

Simple rules and illustrative devices such as Figure 10-1 are alwaysbased on conceptual simplifications and all-else-equal assumptions.A diet that is too high in calories and fat for one person may be idealfor another. Much depends on age, size, sex, reproductive processes,genetic factors, and especially activity levels. Early subsistence farm-ers maintained what might be considered, from an evolutionary per-spective, a normal activity level. Except for professional athletes,dancers, cowboys, and a few other groups, most people in modernindustrial societies have abnormally low energy expenditures. Work-ers sitting in swivel chairs or in drivers' seats of cars or even pushingvacuum cleaners or electrically powered lawn mowers are beingsedentary, and their leisure hours may be even more so.

During almost all of human evolution, it was adaptive to con-serve energy by being as lazy as circumstances permitted. Energywas a vitally needed resource and could not be wasted. Today thistake-it-easy adaptation may lead us to watch tennis on televisionwhen we would be better off playing it. This can only aggravate theeffects of excess nutrition. The average office worker would bemuch more healthy if he or she spent the day digging clams or har-vesting fruit in scattered tall trees. What would an ancestor of a fewthousand years ago have thought of the expensive and complicatedexercise machine in the office worker's basement-especially if itwere actually used?

ADDICTIONSH Historical and anthropological records show that opiumand other psychotropic drugs have been availablethroughout human history, with almost every inhabitedregion supplying one or more substances with the poten-

tial for abuse. Most addicting substances are elaborated by plants asa way of discouraging insect pests and grazers. Many act on the ner-vous system, and a few just happen to induce pleasure in humans.Alcohol is present in very ripe fruit, and storage of fruit juices yieldsa beverage with an alcohol content of up to several percent.

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Substance abuse today is a greater problem than it was in prein-dustrial societies because of the technological innovations of thepast few centuries or millennia. When every household had tomake its own wine or other fermented beverage in small vesselsand with primitive equipment, it was unlikely that anyone wouldhave enough for heavy daily consumption. Urban civilizations,with their professional vintners and brewers, were more likely toprovide the quantities of alcoholic beverages that would permitthe wealthier classes to get all they wanted. Improved methodsof storage and transportation, which allowed British tribesmen toget drunk on Roman wines, were another factor in the advance ofalcoholism.

Another contribution to this advance was the invention of distil-lation. The readily available beverages containing a few percent alco-hol could then be distilled into ones with high alcohol concentration.It may be easier to succumb to alcoholism by drinking gin than bydrinking wine or beer. More recent innovations facilitated the pro-duction of heroin from opium and crack from cocaine, concentratesthat are more rapidly addictive than the natural substances. Theinvention of hypodermic syringes is part of the same story. Similarly,the mass production of cigarettes from newly developed tobaccosthat caused relatively little throat irritation greatly increased the inci-dence of nicotine addiction. Despite the great antiquity of addictivepossibilities, the modern scourge of substance abuse is largely a prod-uct of our abnormal environment.

Of course, as every reader of the headlines knows, addiction is aninherited disorder. We are not sure what the average writer or readerof headlines might understand by this, but what we understand iswhat we discussed in Chapter 7 as genetic quirks. Some people canhave frequent evening cocktails, wine or beer with meals, and occa-sional weekend binges and never show a sign of alcohol addiction. Aperson with the relevant genetic quirk will, with the same alcoholintake, show a steady increase in drinking until he or she is spendingprodigiously to support an ever-worsening addiction and is ever lessable to work and maintain normal social relationships. The conse-quences of this genetic quirk would have been minimal until aftersuch civilizing inventions as stills and six-packs. Alcoholism andmuch other substance abuse can justifiably be considered diseases ofcivilization.

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DEVELOPMENTAL PROBLEMSFROM MODERN ENVIRONMENTS

L ack of adequate exercise may be expected to cause problemsother than those associated with overweight and fattyfoods. It makes no evolutionary sense, for example, for thehuman developmental process to cause a large proportion

of the population to grow incisors in malfunctional positions and tosuffer so many problems with wisdom teeth. If a large proportion ofmodern children need orthodontia and then later some requireexpensive and painful surgery on wisdom teeth, it implies that thereis something wrong with their environment.

One possibility is a deficient demand for jaw exercise. No StoneAge ten-year-old would have been living on foods of anything like thetenderness and fragility of modem potato chips, hamburgers, andpasta. Their meals would have required far more prolonged and vig-orous chewing than is ever demanded of a modem child. We wonderif deficient use of jaw muscles in the early years of life may result intheir underdevelopment and indirectly in weaker and smaller associ-ated bone structure. The growth of human teeth is more autonomous,but it assumes a jaw structure of a certain size and shape, one thatmight not be produced if usage during development is inadequate.Crowded and misplaced incisors and imperfectly erupted wisdomteeth may be diseases of civilization. Perhaps many dental problemswould be prevented if prolonged vigorous biting were considered aprestigious athletic attainment for children. Perhaps chewing gumshould be encouraged in schools!

Other abnormal behaviors during childhood might cause abnor-mal physical development. Sitting for hours at a time on chairs orbenches in classrooms is unnatural, and nothing of the sort was everdemanded of Stone Age children. When they were sedentary, theywould have been squatting, not sitting. Stone Agers must also havebeen able to shift from squatting to kneeling to walking or running orother sorts of activity. Might it not be that many of today's sufferersfrom lower back pain owe their distress to the hours of abnormalposture imposed day after day during childhood? Maybe the laterproblems could be avoided by having children do more squatting and

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less sitting and giving them more exercise breaks or walks betweenclasses.

University of Michigan physician Alan Weder and his colleagueNicholas Schork have tried to understand high blood pressure as adisease of civilization. Instead of emphasizing the high levels of salt inour diets, however, they note that blood pressure must be higher tosupply the needs of larger bodies and that there is a mechanism thatincreases the pressure during adolescent growth spurts. In the ances-tral environment, they argue, this mechanism would have madeadjustments within a range of small body sizes. Today, our nutrition-ally rich environment yields fast growth and large body sizes thatwere rare in the past. The blood-pressure-regulating mechanism,pushed to adjust the system outside the range for which it wasdesigned, often overshoots, causing high blood pressure.

Myopia is not the only ocular abnormality that may arise fromnovel environmental conditions early in life. Medical science hasonly recently become aware of ways in which eye usage in the firstweeks and months after birth may be critical to the normal develop-ment of vision. Preferential use of one eye rather than the other, fromwhatever cause, may lead to changes in the allocation of brain regionsto ocular functions so that a child may later prove incapable of usingbinocular cues for depth perception. Twenty-four-hour bright lights,sometimes used to treat neonatal jaundice, can cause color-visiondefects not likely to be detected until much later. Would it be sur-prising to discover that constant exposure to loud noises, especiallythe unchanging sounds of modern machinery, can cause defectivehearing development in some babies?

OTHER DISEASES RESULTING FROMMODERN ENVIRONMENTS

C old weather can be considered a novel environmental fac-tor. The spread of human populations to seasonally coldenvironments was facilitated by technological innova-tions, such as clothing and fire, which we achieved only a

few tens of thousands of years ago. We still need these artificialities,or their modern equivalents, to survive the winter over much of the

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currently inhabited surface of the earth. Technology compensates forhuman biological inadequacies in dealing with such novel environ-mental threats as frostbite and hypothermia.

But low temperature is not the only stress imposed by high lati-tudes. Clothing and shelter that enable us to survive in places likeMontreal and Moscow impose their own health problems. Our syn-thesis of vitamin D depends on our exposing our skins to sunlight. Ifwe are indoors much of each day and largely covered with clotheswhen we are out, the amount of vitamin D we synthesize will be a tinyfraction of that made by a naked forager on the African savannah,and it could be grossly inadequate for our metabolic needs. Fortu-nately, our photosynthetic capability is not our only source of thismaterial. We can also fulfill our vitamin needs by eating certainfoods. Unfortunately, a seemingly adequate diet may in fact providevery little vitamin D, and a deficiency leads to health problemsrelated mainly to abnormalities of calcium metabolism.

The most commonly recognized effect of vitamin D deficiency isrickets, a developmental disease of childhood. The symptoms aremany, but the most important is defective growth of the bones. Theybecome soft and weak from deficient calcium deposition and growabnormally. The disease is essentially unknown in the tropics, whereeveryone gets abundant sunshine, and uncommon in Japan, Scandi-navia, and other regions where traditional diets include good sourcesof vitamin D, such as fish. But at times it affected such large numbersof children in England that it was sometimes called the English disease.

Rickets was also a frequent malady in northern American citiesprior to the 1930s, when vitamin D began to be routinely added tomilk. Rickets struck black children at a higher rate than white. Theadaptive significance of human racial differences is generally dubi-ous, but the reduced vulnerability of pale-skinned people to ricketsmay be a valid example. Perhaps the first people who crossed theMediterranean and later the Alps were quite dark. They found a landcovered with trees under a sky often covered with clouds. Duringmuch of the year they spent long hours huddling in caves or draftyshelters. When they went outdoors they clothed themselves with ani-mal skins or woven fabrics and exposed very little skin to the meagersunshine. The result, for many people, may have been depressed fit-ness because of vitamin D deficiency. Those who happened to haveless heavily pigmented skins, which admitted more light for vitaminD synthesis, would have fared better than their darker neighbors.

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In this way light skin may have evolved in perhaps a few hundredgenerations. The change may have been rapid because reductions of atrait are generally easier to evolve than increases or elaborations.Cave animals may lose almost all ability to make pigment in a fewthousand generations, and this happens merely from relaxed selec-tion for the maintenance of color. If there is an actual advantage topaler skin, the change should be much faster. The same evolutionaryreduction of melanin synthesis may have happened, though to alesser extent, in the colder parts of Asia, where forests give way tograsslands and deserts and winter days are more often sunny. Thenative peoples of Siberia and northern China are darker than those ofcentral and northern Europe but paler than those of Africa or south-ern Asia. As a disease of civilization, rickets is more of a hazard forpeople with highly pigmented skin, and pale skin may be recognizedas especially adapted to a scarcity of sunshine. But then what happenswhen these pale people move back to sunny regions, such as Aus-tralia? Stay tuned for more on the sunshine problem (Chapter 12),and recall our discussion of sunburn in Chapter 5.

As noted above, the invention of agriculture led to populationdensities much greater than could be achieved by hunter-gatherereconomies, and it permitted the support of great concentrations ofpeople in cities. The spread of people into seasonally cold environ-ments led to their prolonged concentration inside caves and build-ings. Both these changes increased the number of people a givenindividual would contact in a short period of time and increased thecloseness and duration of such contacts. New infectious diseasescould then emerge that could be spread only by abundant personalcontact.

Much of the natural selection taking place in these populationsmay have consisted of the weeding out of individuals whose geneticquirks made them vulnerable to smallpox, measles, or other contact-transmitted diseases. High-cost defenses against such tropical dis-eases as malaria, for example the sickle-cell trait, would have beenlost rapidly. The effectiveness of the newly evolved defenses againstsuch diseases as smallpox was tragically shown when settlers, carry-ing what for them were well-controlled pathogens, invaded parts ofthe world where native peoples had never been exposed to the dis-eases of civilization. Far more New World people were killed byEuropean diseases such as smallpox and influenza than by Europeanweapons.

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In this chapter we have scarcely hinted at the many psychologicalproblems that may arise from modern life. Despite the family-valuesrhetoric of politicians, children raised by nuclear families in single-unit suburban dwellings are experiencing a profoundly novel socialenvironment, as are those being supervised by transient caretakers inday care centers. As adults and even as adolescents and children, wemay have to deal more often with impersonal bureaucracies thanwith familiar individuals. Most of the people we encounter on whatseems to be a normal day may be strangers. This was not the kind ofworld our ancestors evolved in. What about the prolonged winterdarkness of high latitudes and, conversely, the hours of bright indoorlighting and resulting shortened periods of real darkness we actuallyexperience? The cabin fever of snowbound Alaskan gold seekers isnow a recognized malady that is getting attention from medicalresearchers. What about night-shift workers and the jet-lagged jet set?And then there are the psychological-as well as physiological-effects of offices without windows. We have just begun to explorethe medical consequences of our novel modern environment.

CONCLUSIONS AND RECOMMENDATIONS

here is no Eden we can go back to even if such a move weredesirable. What we can do is be alert to the modern dan-gers and take reasonable steps to forestall them. As withmany other topics discussed in this book, our main rec-

ommendation for anyone faced with a problem of medical impor-tance is to consider the question: What is its evolutionarysignificance? One possibility is that it is an adaptive mechanism, butthis will normally mean adaptive in the Stone Age. Our cravings forsugar and fat, our tendencies to be lazy, and our eye-growth adjust-ments that result in myopia are evolved adaptations, but in modemenvironments they cause difficulties for many people. Other evolvedattributes, such as senescence and susceptibility to sunburn, areadaptive in no environment but may represent costs of other adapta-tions. Again and again we harp on the themes that all benefits havecosts and that many benefits are worth their associated costs.

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M [any people in temperate parts of North Americadread the day in August when ragweed first releasesits pollen, causing sneezing and wheezing and reach-ing for handkerchiefs and antihistamines. The poor

ragweed plant is just trying to reproduce, but we are the ones whosuffer. A single plant may release a million grains of pollen a day,mostly between 6 and 8 A.M., perfect timing to maximize the likeli-hood that those sex cells will find their way to receptive ragweedflowers on the morning breeze. A square mile of ragweed plants canproduce sixteen tons of pollen in a year, but an allergic response canbe provoked by one millionth of a gram. The notorious pollen grainis tiny, a sphere twenty microns in diameter that contains two livingragweed sex cells, accompanied by proteins and other nutrients. Oneof the proteins, Amb a 1, makes up only 6 percent of the protein butcauses 90 percent of the allergic activity. And what a lot of unfortu-nate activity it is. From the middle of August, those who suffer fromragweed allergy look forward to the day a few weeks before the firsthard freeze when the ragweed plants will die and stop broadcastingtheir pollen.

Ragweed is, of course, not the only culprit. Allergies are also pro-voked by inhaling other pollens, fungal spores, animal danders, andmite feces, by skin contact with many different substances, by eatingcertain foods or drugs, and by injections of drugs or toxins like beevenom. A quarter of the modern American population suffers fromsome allergy or another. You or a relative or friend may well havesought help from an allergist. If so, you probably had skin tests to try

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to identify the substance (allergen) that caused the allergy. Two kindsof advice were then forthcoming: avoid the allergen and relieve thesymptoms with this or that anthistaminic drug.

Avoiding the allergen makes sense, but what about relieving thesymptoms? We dealt with that kind of advice in discussing the treat-ment of infectious disease. Could taking antihistamine for yourallergy be analogous to taking acetaminophen for fever or giving micea pill to keep them from smelling cats? At the moment we know thatthe system that gives rise to allergy is a defense, but we do not knowfor sure what it is supposed to defend us against. We can be sure thatthe capacity for an allergic reaction is a defense against some kind ofdanger, or else the underlying mechanism, the immunoglobulin-E(IgE) part of the immune system, would not exist. It is perhaps con-ceivable that our IgE system is a remnant of a system that was usefulfor other species, but this is unlikely because systems of this com-plexity degenerate quickly if they are not maintained by natural selec-tion and even more quickly if they cause any harm. It is much morelikely that the IgE system is somehow useful.

This need not mean that every allergy attack is useful. In fact, anevolutionary view of inexpensive defensive reactions suggests thatmost individual instances will be harmful even though the system asa whole is adaptive. This is a manifestation of the smoke-detector prin-ciple. Smoke detectors are designed to warn people when a dangerousfire is in progress, but few of them ever perform this service. Theyhang there year after year doing nothing or only sounding an occa-sional false alarm from a cigar or smoky toaster. Yet the annoyingfalse alarms, and the costs of the smoke detector and its occasionalbattery change, are well justified by the protection they provideagainst a major fire. More on this principle when we discuss anxietyin Chapter 14.

Your allergist probably did not give you a discussion about theutility of the IgE system and the evolution of its regulation. If youasked why you have to be allergic to cats or oysters or whatever, yourallergist probably said something like "Well, as in everything else,people vary tremendously in their sensitivities to different allergens,and you happen to be excessively sensitive to something in cat dan-der. This excess in your sensitivity must be treated by avoiding catdander and suppressing the defensive reaction it triggers."

There are two serious difficulties with the excess-sensitivity the-ory. First, an allergy is not just a matter of degree. Allergic people

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react to minute traces of their allergens, while nonallergic peoplehave no apparent reaction to enormously greater quantities. In thisrespect allergy is quite different from an excess sensitivity to sun-shine or motion sickness. The second difficulty is more serious.Allergy is not an extreme action of some normally well behaved sys-tem with an obvious function. IgE antibody seems to do almost noth-ing, at least in modern industrial countries, except cause allergy. Itwould appear that we evolved this special IgE machinery for no bet-ter reason than to punish random individuals for eating cranberriesor wearing wool or inhaling during August.

Despite these problems, this explanation of allergies as a result ofexcess sensitivity is widely employed. For instance, a 1993 New YorkTimes article on asthma describes it as an excessive immunologicalreaction, one to be solved by finding a drug that can "interfere withthe asthmatic process" by "keeping the lungs from responding toallergens in the first place." Nowhere is the possibility consideredthat the lungs (or their IgE-carrying cells) may know something thatwe don't. A widely used textbook of immunology describes allergy ina chapter entitled "Hypersensitivity" and also makes no effort toexplain why the IgE cells exist at all.

THE MYSTERY OF THE IGE SYSTEMO- n finding a complicated feature characteristic of a speciesor larger group, one of the first things biologists want toknow is what it does. They assume that if it did not dosomething important it would not have been produced

and maintained in evolution. A short digression offers a vivid illustra-tion. The snouts of sharks contain a cluster of flask-shaped organs (theampullae of Lorenzini, named for the Renaissance anatomist who firstdescribed them). These complicated structures have a rich nerve sup-ply. For three centuries people guessed that the ampullae of Lorenziniregulated buoyancy or amplified sounds, but no serious biologist sug-gested that they were "just there." The question stayed on the tableuntil some adequate experiments finally showed that the ampullae ofLorenzini detect minute electrical stimuli, thus allowing sharks todetect muscle activity in potential prey hidden in total darkness orburied in the sand. This discovery was made only because some biol-

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ogists, habitues of the adaptationist program, assumed that the ampulelae of Lorenzini must be an adaptation.

Before we discuss possible explanations for the IgE system and theallergies it causes, we need to describe the proximate mechanisms ofallergy. When a foreign substance enters the body, it is taken intocells called macrophages (macro means "big" and phage means "toeat"), which process the proteins from the substance and then passthem on to white blood cells called helper T cells, which take the pro-teins to another kind of white cell called B cells. If the B cell happensto make antibodies to that foreign protein, it is stimulated by the Tcell to divide and make those antibodies. Most often that antibody isthe familiar immunoglobulin G (IgG), but, for certain substances, theB cell is instead induced to make IgE antibody, the substances thatmediate allergic reactions.

There is remarkably little IgE, compared to other antibodies. Itmakes up only one hundred-thousandth of the total amount of anti-body. The IgE antibody circulates in the blood, where about one outof one hundred to one out of four thousand molecules attaches to themembranes of still other cells called basophils (if they are in the cir-culation) or mast cells (if they are localized). When attached to thesecells, the IgE remains for about six weeks. Despite the small amountof IgE, there will still be between 100,000 and 500,000 IgE moleculeson each basophil, and, in an individual allergic to ragweed, about 10percent of IgE may be specific to ragweed antigens.

These mast cells are primed, like mines floating in a harbor, wait.ing for reexposure to the allergen. When it does return and is boundby two or more IgE molecules on the surface of the mast cell, the cellpours out a cocktail of at least ten chemicals in the space of eight min-utes. Some are enzymes that attack any nearby cells, some activateplatelets, some attract other white cells to the site, while others maystimulate smooth muscle (causing asthma). One, histamine, causesitching and increased permeability of membranes, unpleasant effectsthat can be blocked by antihistaminic drugs. While the details arestill being worked out, the general operations of this proximatemechanism have been known for about twenty-five years and areessentially the same in all mammals.

At this point you may be thinking: surely by now someone musthave figured out what all that IgE machinery is there for! People havetried, but so far there has not been enough serious research to arriveat a generally accepted explanation. Many thoughtful researchers are

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well aware that a system this sophisticated must have some usefulfunction. "These cells are not simply troublemakers devoid ofredeeming biological value," says Stephen Galli from Harvard, whonotes that the distribution of mast cells adjacent to blood vessels inthe skin and respiratory tract places them "near parasites and otherpathogens as well as near environmental antigens that come in con-tact with the skin or mucosal surfaces." Galli does not, however,review evidence about the possible functions of the system. A newnine-hundred-page textbook on allergy devotes only one page to theproblem. It notes that "Several roles for the possible beneficial effectof IgE antibody have been postulated," including regulation ofmicrocirculation or as a "sentinel first line of defense" against "bac-terial and viral invasion" and attacking parasitic worms. It concludes,"With 25% of the population having significant allergic diseasemediated by the IgE antibody, an offsetting survival advantage for thepresence of IgE has been suggested." But, like other textbooks, itnever seriously tries to explain the adaptive significance of allergy.

The most widely accepted view is that the IgE system is there tofight parasitic worms. Evidence for this idea comes from the obser-vation that substances released by worms may stimulate local IgEproduction and the resulting inflammation, which are interpreted asdefensive activities against the worms. Further evidence comes fromexperimental studies of rats that developed strong IgE responses toSchistosoma mansoni infections. Transfer of IgE from one rat toanother transfered protection against infection, while blocking theability of IgE to recruit other cells made the rat more vulnerable tothe worms. In people infected with schistosomes, 8 to 20 percent oftheir IgE may attack these worms, and those with a decreased abilityto make IgE have more severe infections.

Worms such as schistosomes, which cause liver and kidney fail-ure, and filaria, which cause blindness, were all substantially greaterproblems before the introduction of modern sanitation and vectorcontrol. If attacking worms is the only function of the IgE system,this supports the current practice of treating allergies in developedcountries by inhibiting allergic symptoms because an allergic reactionto anything but a worm would be maladaptive. However, the evi-dence that attacking worms is the only or even a major function ofthe IgE system remains inconclusive, and some of it may be flawed byattempts to interpret the data in terms of the only available hypothe-sis. Alternative explanations for the association of IgE phenomena

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with worms, such as the possibility that worms arouse IgE responsesfor their own benefit (by increasing the local blood supply), havebeen insufficiently considered.

There is, however, another possible function for the IgE system,one recently championed by Margie Profet, whom we met in ourchapters on signs and symptoms and on toxins. Profet proposes thatthe IgE system evolved as a backup defense against toxins. As weargued in Chapter 6, our environment is and always has been full oftoxins. Inhaled pollen, contacted leaves, and ingested plant and ani-mal products all contain potentially harmful substances. Most ofthese toxins are formed by plants to protect themselves against para-sites and insects or other plant-eating animals.

We have several kinds of defenses against these chemicals. First,we avoid them when we can. Also, the linings of our respiratory anddigestive systems are equipped with toxin-fixing antibodies of theIgA group and with detoxification enzymes that collectively decom-pose broad categories of chemical structures. Mechanical defensesprovided by mucous secretions and by the structure of our skin andabsorptive surfaces also play a role. Toxins that bypass these initialdefenses are attacked by concentrated batteries of enzymes in ourliver and kidneys.

But suppose all these defenses fail, as all adaptations must some-times. Then, according to Profet, comes the backup defense, allergy,which gets toxins out of you in a hurry. Shedding tears gets them outof the eyes. Mucous secretions and sneezing and coughing get themout of the respiratory tract. Vomiting gets them out of the stomach.Diarrhea gets them out of parts of the digestive system beyond thestomach. Allergic reactions act quickly to expel offending materials.This fits with the rapidity with which toxins can cause harm. A fewmouthfuls of those beautiful foxgloves in your garden can kill you alot faster than a phone call can summon first aid. Appropriately forProfet's theory, the only part of our immunological system thatseems to be in a great hurry is that which mediates allergy. Otheraspects of allergy that she mentions in support of her theory includethe propensity to be triggered by venoms and by toxins that bind per-manently to body tissues, the release of anticoagulants during allergicinflammation to counteract coagulant venoms, and the apparentlyerratic distribution of allergies to specific substances.

At this point we pause to line up our ducks in a row so we can aimat them, even though we don't yet have a way to shoot them. As we

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have already noted, the first and most important question is, Whatare the normal functions of the IgE system? The second question iswhy some people are especially susceptible to allergies while othersare not. The third question is why a susceptible person develops anallergy to one substance and not another, say, milk instead of pollen.The fourth question is why allergy rates seem to be rapidly increasingin recent years.

ATOPY

people who are especially susceptible to allergies are said to be"atopic." Atopy runs strongly in families. While the risk ofclinically significant allergy in the general population isabout 10 percent, the risk is closer to 25 percent if you have

one atopic parent and 50 percent if both your parents are atopic. Theresponsible genes remain elusive, but a dominant gene on chromo-some 11 may play a key role. If the genes that predispose to allergyare found, we will still need to find out why they exist. Do they, likethe sickle-cell gene, give an advantage in certain environments or pro-tection against certain infections? Or do they give an advantage whencombined with certain other genes but a disadvantage otherwise? Ormight they be "quirks" that did not cause disease until they inter-acted with modern environments?

Genes are not the whole story, though. Studies of identical twinpairs show that in half the cases, one twin has allergies while the othertwin is unaffected. So factors other than genes must be important aswell. And even among atopic individuals, one may be allergic to rag-weed while the other is allergic to shrimp. Why? As a start towardanswering this question, we will invoke two ideas, one being the ten-dency, discussed above, for defensive adaptations to make many ofthe cheap kind of mistake in preference to the expensive kind (thesmoke-detector principle). The other derives from the phenomenonof enzymatic variability, which has gotten considerable recognitionin the recent biological literature.

Specimens of the same species, human or otherwise, can beimmensely variable. Their genetic codes may be 99 percent identical,but tiny differences in genetic code can result in strikingly different

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structures and body chemistry. The parts of the code that are thesame can also code for differences, if they include instructions of theform "if A then X, else Y." In retrospect we see that the evidence forwide variation among individuals has always been there. Just con-sider how different males and females of many species can be in sizeand anatomy, reproductive processes, behavior, and often in diet,habitat, and other features. These differences may result from genesthat are expressed only if testosterone above some threshold concen-tration is present. The best examples of human variations are differ-ences in reactions to drugs. Some individuals may take ten times aslong as others to reduce a drug concentration to half its initial value.To put this into perspective, suppose you and your friend each getthe same injection of quinine; it takes you an hour to detoxify half ofit, and his system does this ten times as fast. At the end of the hour,when your concentration is still half what it was initially, his is downto less than a thousandth of its starting value. If the enzyme ischolinesterase and the drug is a cholinesterase inhibitor, often usedto relax muscles during surgery, such slow metabolism might leaveyou still paralyzed and unable to breathe hours after other patientshave been up and around. Anesthesiologists are, thankfully, on thelookout for individuals with this idiosyncrasy.

If Profet's theory is right, people may develop allergies to the spe-cific toxins to which they are especially vulnerable. Consider Presi-dent Clinton, who is allergic to cats. Could it be that this allergyprotects him from some dangerous toxin? Remember that the pito-hui bird (Chapter 6) has toxic feathers. It seems unlikely that catshave a comparable adaptation, but let's consider the possibility. Whyshould Bill Clinton be vulnerable when none of his relatives are? Per-haps merely because he inherited defective forms of some gene thatmakes an enzyme important in denaturing some cat toxin. If hetouches cat fur or inhales microscopic particles of it, the toxin wouldenter his cells and reach harmful concentrations, instead of beingquickly destroyed by the enzymes normally present. Fortunately, thepresident has mast cells and IgE-producing T cells that react to thetoxin by triggering defensive reactions, such as sneezing. This mightmean that he has to interrupt important negotiations to yank a hand-kerchief out of his pocket, but the sneeze, as a backup defense, mightsave him from some serious malady. Do you believe this explanationfor Bill Clinton's allergy to cats? We don't, but we have a good excuse

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for telling it. At the moment, there is no evidence that it is wrong. Aslong as we do not know what the IgE system is for, we will have greatdifficulty distinguishing its accomplishments from its mistakes.

We can alter the story to make the cat allergy a nuisance withoutvalue, while still basing the explanation on Profet's theory of allergy asa backup defense against toxins. Perhaps Bill Clinton's allergy is justanother example of the smoke-detector principle. Perhaps as a child heencountered bacterial toxins during a respiratory infection, and his IgEsystem went into action and reacted, not only to the dangerous mate-rial, but also to some innocent "bystander" molecules (Profet's term).Perhaps some harmless component of cat fur was mistakenly per-ceived, by a few IgE-producing cells, to be a troublesome toxin, or atleast a reliable sign of the toxin's presence. Immune cells that react to aforeign substance multiply and become far more numerous. So afterthis first episode, large numbers of anti-cat cells were poised to go intoaction on the next exposure. Do you prefer this explanation for BillClinton's allergy? We do, but we are not inclined to bet on it. There isjust not enough information for an informed decision.

If you were the president's physician, what would you recommend?Would you prescribe a drug to inhibit the allergic reaction? Theanswer should depend on whether the allergy is useful or not. Is it aneffective defense against an otherwise dangerous toxin, or is it a falsealarm? How do you decide? At the moment, you have no solid basisfor deciding. You might want to use antihistaminic drugs to suppressthe allergic reaction, since they have no known dangers, but there areno adequate antihistamine studies that would detect the kinds of dan-gers implied by Profet's theory.

The possibility of harm resulting from suppressing the symptomsof allergy is of special concern because of data suggesting that allergymay protect against cancer. Profet reports that sixteen out of twenty-two epidemiological studies found that people with allergies are lesslikely to have cancers, especially of tissues that show allergic reac-tions. On the other hand, three of the studies found no clear rela-tionship, and three others, including one large, well-controlledinvestigation, found that some allergies are associated with anincreased likelihood of developing some cancers. What are we tomake of this? It would certainly be premature to conclude that aller-gies protect against cancer, but it is not premature to begin lookingat the possible risks of long-term use of medications that suppress

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allergic responses. Unfortunately, the nonmedication treatments aremainly inconvenient or not very effective. If you've got hay fever,you may be hard put to follow your doctor's advice to stay indoorsin closed rooms as much as possible, wear a pollen mask when youmust be outdoors, or go somewhere else for the bad season. Taking apill is much more convenient.

If the antitoxin theory of allergy is correct, it has clear implica-tions for medical research. A Utopian recommendation is simple:find out just what the toxins are in pollen, cats, seafood, and so on,that induce allergy and devise techniques for their denaturation.These toxins may be different from the antigens that stimulate theallergy. If we knew just what was dangerous about ragweed pollen, wecould perhaps equip people with nose drops or inhalants that wouldchemically inactivate both the toxin and the antigen. We could treatallergenic foods in similar ways. If we knew which patients don'tneed their allergies to compensate for some deficiency in their abilityto detoxify, we could suppress their symptoms without concern.

Such studies will be inconclusive unless they can distinguish use-ful allergies from useless ones. If Profet is correct in reasoning that anallergy to eggs is consistently maladaptive, this allergy should notprotect against cancers of the digestive tract, and the inflammationcaused by the allergy might even increase the risk of cancer. Anallergy to shrimp, however, would be expected to decrease the cancerrisk for anyone who is unable to detoxify one of the many noxiouscompounds that shrimp get from their phytoplankton diets. Profet'stheory provides a basis for predicting when allergy will protectagainst cancer and when it might be irrelevant or actually increase therisk. We should emphasize that her theory is novel. Few allergistshave even heard about it; far more believe the antiworm theory. Buteither theory may be better than no theory at all. As Thomas Huxleyonce observed, truth is more likely to emerge from error than fromvagueness.

Still another possible function of the IgE system may be to defendagainst ectoparasites such as ticks, chiggers, scabies, lice, fleas, andbedbugs. A small problem for most people in modern societies,ectoparasites have been, throughout most of human evolution, notonly a constant nuisance but vectors for many diseases. Slapping,scratching, and mutual grooming are only partially effective defenses.When cows are prevented from grooming by a thick collar, their bur-

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den of ticks and lice increases steadily and then suddenly crasheswhen the cow's immune systems begin responding to a bite with aninflammatory response that makes it impossible for the parasites toget a blood meal. Prevention of ectoparasite infestation might explainmany aspects of the IgE system, especially the concentration of mastcells on the body's surfaces, the immediate massive response, and thestimulation of itching. This theory could be tested by looking to seeif the immune response that counters ticks on cows is indeed basedon IgE and by looking at the IgE responses of people who are infestedwith ectoparasites.

As with other traits, the IgE system may well have more than onefunction. Some combination of the above and other explanationsmay be correct. One of the best ways to determine the function of atrait is to observe the problems of those who lack it. The deficits of aperson who lacks eyes are obvious, and those of a person withoutkidneys soon become apparent, but the functions of many traits aremore subtle. The spleen, for instance, is usually surgically removed ifit ruptures, as it sometimes does in automobile accidents. Suchpatients have no apparent disability, but if they are stricken withpneumonia, the infection may quickly kill them because the spleen isnot there to filter infectious particles out of the blood.

What happens to people who lack the ability to make normal IgE?While some people with very low levels of IgE are healthy, others areplagued with recurrent infections of the lungs and sinuses as well asfibrosis of the lungs. While these findings could be a result of expo-sure to toxins or a secondary result of whatever factor caused the IgEdeficiency, there is also evidence for specific IgE antibodies directedagainst Staphylococcus aureus in people who cannot make otherimmunoglobulins. In a study of 190 patients with bronchial asthma,55 had IgE antibodies to substances in the bacteria Streptococcus pneu-moniae and/or Haemophilus influenza. Furthermore, one effect of thesubstances released by mast cells is to attract other immune defensecells to the area, where they are available to fight any invader. All thissuggests that the IgE system may directly or indirectly defend usagainst ordinary bacteria and viruses. The complexity of the immunesystems, with functions that overlap and back one another up, makesit difficult to identify the benefits of the IgE system. It will takepatient, well-designed research to answer the important but unan-swered question, What is the IgE system for?

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THE MOST WORRISOME QUESTION

A nother puzzling aspect of allergy, at least respiratoryallergy, is the apparent recency of its appearance as a major

,Amedical problem. John Bostock originally described hisown symptoms of hay fever for the Royal Society in 1819

and later reported that he could find only twenty-eight cases afterinvestigating five thousand patients in all of England. Records implythat hay fever was essentially unknown before 1830 in Britain and 1850in North America. In Japan its incidence was negligible in 1950, but itnow affects about a tenth of the population. If the increase is real andnot just an artifact of inadequate records, what novel environmentalfactor of the last century or two can account for this alarming phe-nomenon?

One clue comes from studies of the factors that seem to sensitizepredisposed individuals, mainly exposure to antigens in the first twoyears of life. In one study of 120 infants with high susceptibility toallergy on the basis of their IgE levels at birth, 62 were raised as a con-trol group without any intervention, while the mothers of 58 in theexperimental group were taught how to keep their homes relativelyclean of allergens, prevent mites, and avoid giving potentially aller-genic foods to their infants. At age ten months, 40 percent of the con-trol group had developed allergies compared to only 13 percent ofthe experimental group. Perhaps part of the increasing rate of allergyresults from living indoors with drapes and wall-to-wall carpets,which provide breeding places for dust mites.

When Eric Ottesen, head of the Clinical Parasitology Section atthe National Institute of Allergy and Infectious Disease, studied thesix hundred people who live on Mauke, an atoll in the South Pacificin 1973, only 3 percent of them had allergies. By 1992, the rate was upto 15 percent. He suggests that institution of treatment for worminfestations during the intervening years left the IgE system with nonatural target, so that the usual mechanisms that downregulate thesystem are inactive and the IgE begins to attack harmless antigens.

Breast-feeding decreases the incidence of allergies, so bottle-feedingmay also contribute to the rise in allergies. Perhaps babies deprived ofmaternal antibodies make more immunological mistakes in copingwith antigens on their own. Or perhaps crowded, mobile modern

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societies expose infants to a greater diversity of viral respiratory dis-eases and thereby greater exposure to miscellaneous allergens. Theincreased quantity and variety of atmospheric pollutants may fosterincreases in both helpful allergies (if such there be) and harmful ones,perhaps because chemical damage to the respiratory mucosa mayadmit antigens that would otherwise be kept out. Food allergies,although perhaps not as clearly on the increase, may have becomemore troublesome because we now have so little control over what weare really eating. Eggs, wheat, soybeans, and other possible allergensmay be present in a great variety of commercially prepared foods andbe extremely difficult to avoid, even by people who know they areallergic to them.

What are we doing today that is different from what we did just acentury ago and that makes us so much more vulnerable to so manydiverse allergies? We desperately need real answers. Respiratoryallergies affected less than 1 percent of people in industrial societiesin 1840. Now, a hundred and fifty years later, it afflicts 10 percent.What might the future hold if we remain as ignorant as we are now?

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Q n March 5, 1992, The New York Times carried an obituaryfor well-known actress Sandy Dennis, a cancer victim atfifty-four. That same day, the eighty-three-year-old actressKatharine Hepburn was enjoying her autobiography's

twenty-fifth week on the Times's best-seller list. An obvious question is,Why did cancer strike Sandy Dennis? What caused her to miss out onthe long life that her fellow actress enjoyed?

This obvious question is morally and medically a good one, butthere is a more profound biological question: How is it possible thatany of us can live several decades without dying of cancer? Cancerouscells are merely cells doing their normal thing: growing and prolifer-ating. How could so many cells do such an abnormal thing as inhibittheir growth for many decades? Obviously they must; otherwiseeveryone would die of cancer at an early age. This, of course, is theultimate explanation. Those least likely to die at an early age, fromany cause, will be most likely to survive, reproduce, and have theircancer-delaying adaptations at work in future generations. This sortof evolutionary explanation can help us understand the workings andorigins of our cancer-preventing adaptations and the prodigiousaccomplishment they represent.

Confucius once said something like: A common man marvels atuncommon things; a wise man marvels at the commonplace. To mar-vel at the commonplace of not having cancer and at the mechanismsthat make this possible may be the key to understanding how tomake cancer even more uncommon.

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THE PROBLEMT w he magnitude of the problem of avoiding cancer may beappreciated from considering the long-term history of anycell in our bodies. A cell now contributing to normal func-tioning in the liver of some Hollywood star arose by the

growth and division of some preexisting cell, probably one closelysimilar to itself. That parental cell arose from another before that,and so on. As we trace the ancestry of the liver cell, we find cells thatlook ever less like liver cells and ever more like undifferentiatedembryonic cells. Some years back in the cell lineage we come to thefertilized egg from which the entire individual arose.

That cell had a history too, a lineage through various oocytes andoogonia back to the embryonic cells that developed into the Holly-wood star's mother. Likewise, the sperm that did the fertilizing camefrom a lineage of spermatocytes and spermatogonia back into theembryonic cells of our star's father. Thus back through the mother'sand father's original zygotes into the grandparental generation, andso on in endless repetition of ever-dividing embryonic and reproduc-tive cells. Never in these sequences of cell divisions, for the billionyears or so since the origin of the first real cells, was there ever onethat did not divide, and nowhere in these lineages was there anythingthat looked like a liver cell.

We offer Figure 12-1 as an aid in understanding this essential factof life. All our ancestors had livers, but none of the cells of theseancestral livers gave rise to any of our liver cells, or to anything elsein our bodies. We arose entirely from a line of endlessly proliferatinggerm-line cells. This picture, of an eternal germ plasm giving rise toelaborate somata of individuals, which are always genealogical deadends, was first presented by August Weismann, a nineteenth-centuryDarwinian.

Now, for the first time in these eternal lines of descent and afterdozens of the cell divisions needed to create an adult soma from a sin-gle cell, we find a cell, say a liver cell, that must play a specialized rolein the life of a multicellular individual. This liver cell must do some-thing none of its ancestors ever attempted: it must stop dividing. Ifthere is an injury to the liver, the cell may be called upon to divideagain. This sort of growth and division must be in precisely the

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SomaThe bodyconsistingof many

specializedcell types

Germ CellsGeneration I Generation 2 Generation 3

FIGURE 12-1. Germ plasm concept of Weismann. The eternal line of germcells gives rise to individual bodies with a limited life span.

The individuals diagrammed can be of either sex.

amount and pattern required for normal liver function and must ceaseas soon as this machinery is fully restored. If ever, in any one of thebillions of cells of the liver, the growth and division process is turnedon inadvertently and proceeds unchecked, a tumor develops andeventually causes a lethal disruption of some physiological function.

From this perspective, life seems rather precarious. It suggests thatwe must have some really superb anticancer mechanisms acting inour favor. As American marine biologist George Liles observed, "thecells and organs that make life possible had better be well designed,because the job of living is formidable. Living beings-plants and ani-mals, bacteria and slime molds and fungi-every animate entity facesa set of challenges that would give pause to the most inventivedesigner." He was led to this remark in considering what might seema rather simple sort of problem, the proper routing of water throughthe feeding machinery of a mussel. How much more formidable is thechallenge of avoiding cancer for several decades in the collection often trillion cells that make up a human being!

Biologists today more or less universally believe that multicellularorganisms, such as ourselves, arose from some group of the proto-zoa, in which each cell was a functionally independent individual.Most of their reproduction was asexual, with one cell dividing toform two new ones. In some modern protozoan species these two

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new individuals do not break completely apart but stick together inpairs. In others, the offspring of pairs stick together in filaments orsheets called colonies. In a few, the colonies may differentiate intogerm cells and somatic cells, as shown in Figure 12-1. This means thatsome previously independent cells, apparently voluntarily, give upreproduction and become genealogical dead ends. They devote them-selves entirely to supplying nutrients and protection to the few germcells that ultimately participate in sexual reproduction. Some suchsequence of developmental events, as observed in the much-studiedcolonial protozoan Volvox carter, must have characterized someremote ancestor of all multicellular animals.

Can this acceptance of a sterile, servile role be explained by nat-ural selection? The answer is obviously no, if this process meansselection among cells for those best able to survive and reproduce.The answer is yes if the selection is among the genes best able to getthemselves into future generations. If the reproductive and somaticcells of a Volvox colony have the same genes, it does not matterwhich cells actually do the reproducing and which become sterile.All that matters is that the sterile cells, in their strictly somatic roles,make the colony's reproduction of genes identical to their own moresuccessful than if they too formed eggs or sperm. If colonies with tenreproductive cells and a hundred sterile ones reproduce more suc-cessfully than those with eleven and ninety-nine, the tendency formost of the colony cells to assume a somatic service role will be per-petuated.

A colony of a hundred cells, all derived in a short time from a sin-gle original cell, may well be all of about equal health and vigor andwill almost certainly be of the same genotype. The resources neededto produce a hundred cells from one may all be shared equally, andall cells have elaborate mechanisms for protecting the genetic mater-ial from damage or alteration. But what about a thousand or ten thou-sand cells? Would colonies that big be asking for trouble? Mightthere not be occasional mutations that would make cells behave inways other than those that maximally benefit the colony as a whole?For instance, might not such a mutant cell start appropriating morethan its maintenance requirements for nutrients and start growingand reproducing, even though this might be harmful for the colony?Such large colonies surely need special adaptations for maintainingdiscipline among the many component cells.

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THE SOLUTIONH Oow about a colony the size of an adult human body?What sort of special adaptation would be adequate tomaintain discipline among ten trillion cells? From anengineering perspective, it is difficult to imagine how any

quality control system would be equal to the job. An auto manufac-turer faced with turning out a mere ten thousand vehicles, not one ofthem with a serious flaw, would be well advised to quit the business.A single living cell is incomparably more complicated than any auto-mobile.

Consider the problem faced by an embryo of a hundred cells thatgives rise to one of a thousand that produces one of ten thousand andso on to the ten-trillion-cell adult. Most of these cells will die and bereplaced by others. All these cells are equipped with genes that turnout products essential to their division, and some genes are adjustedso as to stop making this product when local conditions indicate thatthe tissue is mature and no additional cells are currently needed. Ifone of these genes gets accidentally altered in a way that makes itheedless of these conditions and the gene goes on making its product,mechanisms of DNA editing and repair step in and correct the flaw-or at least they are supposed to. One out of about two hundred peo-ple has a gene that greatly increases the likelihood of colon cancer.Originally thought to be a gene that actually did something to causecancer, it is now recognized as a defective form of a normal gene thatacts in the detection and rectification of abnormal DNA structure.When this system is not working, DNA abnormalities accumulateand the chance of cancer increases drastically.

Very few such flaws actually get a chance to express themselves.How few? Let's assume that only one such gene in ten thousand cellsmakes its product when it is not supposed to. Starting with ten tril-lion cells, we can assume there are a billion altered cells, scatteredthrough the body, that are capable of initiating a cancerous growth.This is not all that reassuring. But there is another kind of geneticsafeguard in each cell: tumor-suppressor genes that actively inhibitcell growth, perhaps by destroying the product of a gene that makesa substance essential to division, when it is inappropriate. Let'sassume that this safeguard is also fantastically effective and that the

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daily rate of failure is only one in ten thousand cells. We can nowassume we have only a hundred thousand cancers beginning in thebody each day. If there were three equally reliable safeguards andabnormal cell division could not begin unless all three failed, therewould still be ten new cancer cells formed each day. This is still notvery reassuring.

The situation is analogous to the problem of command and controlof nuclear missiles. The risk of catastrophe from accidental firing is sogreat that the system is designed first and foremost to prevent acci-dental firing, even at the risk of sometimes not being able to fire whenneeded. This is the exact opposite of the smoke-detector principle wedescribed for defensive responses. Control of cell division could besaid to be based on the principle of "multiple safety catches." Thecrew in the missile silo cannot fire the missile without a secret code.Even with the code, multiple procedures must be followed insequence, including two people turning keys simultaneously in twodifferent parts of the room. The system is designed so that any irregu-larity makes it impossible to fire the missile at all. Similarly, thebody's cells have multiple safety-catch mechanisms. If failure of thesemechanisms is detected, other mechanisms stop cell growth. When,despite all previous safeguards, cells grow at an inappropriate rate,still other mechanisms cause the aberrant cells to self-destruct.

A recently discovered gene called p53 is the best example. Itmakes a protein that protects against cancer by regulating the expres-sion of other genes. In certain circumstances it can shut down cellgrowth or even make the cell self-destruct. If a person inherits oneabnormal copy of the gene that makes this protein, anything that hap-pens to the other copy can lead to catastrophe. The p53 gene isabnormal in fifty-one types of human tumors, including 70 percentof colon cancers, 50 percent of lung cancers, and 40 percent of breastcancers. As John Tooby and Leda Cosmides have pointed out, how-ever, such genetic abnormalities are not necessarily present in thetumor. Cells are often studied after they have lived for years in tissueculture, an environment that may select for genetic abnormalitiesthat increase the rate of cell division.

In addition to these various anticancer mechanisms operating incells, there are those that operate between them. They detect misbe-havior in their neighbors and secrete substances that inhibit the mis-behavior. Finally, there is the immune system, which may bring a hostof weapons into play against an incipient maladaptive growth as soon

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as it finds a difference between it and normal tissue. A detectable can-cer must somehow have achieved the highly improbable feat of gettingpast these many layers of defense. Unlike a parasitic worm or infec-tious bacterium, it cannot draw on a long history of accumulating itsown defenses against the host's defenses. It is entirely the product ofchance alterations in the cellular regulatory machinery. What cancerhas on its side is mainly the astronomical number of chances it gets toachieve success against the immense odds.

CANCER PREVENTION AND TREATMENTT - o avoid contracting cancer, the first thing you want to do isto pick your parents wisely. Susceptibility to cancer, likeso many other diseases, is hereditary. This is true both ingeneral and for particular forms of cancer, most notably

for some rare childhood cancers and those of the breast and colon.Members of families in which such cancers have occurred frequentlymay have twenty to thirty times the likelihood of contracting them asthose in cancer-free families. Even when controlled for family mem-bers' tendency to experience similar environmental conditions, theevidence for predisposition for certain kinds of cancer is strong.Mice can be bred to form cancer-prone stocks in which one cancer-control mechanism is already missing in every mouse. This enor-mously increases the likelihood of one or more kinds of cancer.Some human cancers are inherited in the same way.

Another good way to reduce the likelihood of cancer is to livedangerously: die young, and you are unlikely to get cancer. The factof senescence means that the environment of any cell and its regula-tory capabilities are deteriorating. Hormonal and local regulation ofcell growth and proliferation, like all other aspects of adaptive per-formance, becomes less effective as we go through that terminal life-history stage known as adulthood. The cell itself ages, and as thecardiovascular and digestive and excretory systems deteriorate, it willbe ever less well supplied with nutrients and other essentials and everless effectively unburdened of its waste products. An inevitable con-sequence is that its potential for growth and cell division is ever lesswell regulated. Maladaptive growths become steadily more likely tooccur and spread unchecked.

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The increasing incidence of cancer with age illustrates an impor-tant evolutionary principle. Adaptations work best in the circum-stances in which they were evolved. Our cancer-control adaptationsand other vital functions were not evolved to keep an eighty-year-oldalive. The body of anyone that old is an abnormal environment forhuman genes and their products, one that rarely existed in the StoneAge. More generally, just about all the adverse effects of modernenvironments, as discussed in Chapter 10, can be expected toincrease the incidence of cancer: X rays and other ionizing radiations,novel toxins, unnatural levels of exposure to natural toxins (such asnicotine and alcohol), and abnormal diets or other lifestyle factors.

Injuries and infections anywhere in the body can interfere withcancer-controlling mechanisms not only at the site of the problembut also at distant sites in the body. Bacteria can increase the cancerrates of infected tissues, but viruses are more likely to have sucheffects. One reason is that a virus is not very different from a singlegene in a human cell and can sometimes settle into a niche on a chro-mosome as if it belonged there. From such a position it can readilysubvert the normal machinery of the cell. Viruses, especially HIV,attack the immune system and have the incidental consequence ofimpairing that system's ability to attack cancer. Like bacteria andlarger parasites, viruses can also produce toxins that weaken cellular-control mechanisms.

The connections between environmental causes and certain can-cers are sometimes easy to understand. Food that has an abnormallyhigh concentration of salt or alcohol or is loaded with the carcinogensof smoked or broiled meats will contact the stomach cells and increasethe risk of stomach cancer. The chemicals in tobacco smoke likewisedirectly influence lung cells. Sunshine damages the genes in skin cellsand leads to melanoma. The mechanism by which a high-fat diet con-tributes to breast or prostate cancer must depend on more subtleeffects than simple contact with the substance in the food. The samecan be said for the association between smoking and bladder cancer.

Even after a tumor becomes detectable and produces alarmingsymptoms, natural control mechanisms, especially immunologicalfactors, will still be at work. They may still win the contest or at leastslow the maladaptive growth or prevent its spread to other sites.Even if never cured, some untreated cancers take many years to inca-pacitate the victim. On rare occasions, apparently incurable cancersjust go away.

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Many aspects of the contest between a cancer and its victim resem-ble those between pathogen and host, and the need for such func-tional categories as cancer-growth adaptations and efforts to suppressthem is evident. A cancer is a cellular renegade that has rebelledagainst the polity of the body and can be regarded as a parasite pur-suing its own interests in conflict with the host. Unlike an infectiouspathogen, a cancer's success can never be more than short-term,because it has no way to disperse to other hosts, and the host's deathmeans its death too. The same is true of the normal cells from whichthe cancer arose. When the host dies, the only surviving genes will bethose of the host's germ-line cells that have already been passed on tothe next generation.

Cancer is a collective term for maladaptive and uncontrolled tis-sue growths of all kinds. Cancers can arise from any cell types thatretain the capacity for growth and division, and cancers of each celltype result from a variety of initiating causes and failures of suppres-sion mechanisms. It is not surprising that cancer has proven difficultfor medical science to master, and it is unlikely that one general curewill ever be found. We are making rapid progress, however, and abetter understanding of cancer as a contest between renegade cellsand the host will surely facilitate more progress.

CANCERS OF FEMALEREPRODUCTIVE ORGANS

erhaps the best example of a group of related cancers thatshow the value of a Darwinian approach is cancers of thebreast, uterus, and ovary, all of which have recently becomemuch more frequent. Boyd Eaton, a distinguished American

researcher in both medicine and anthropology, along with other work-ers in these fields, has recently brought together a wide range of infor-mation to shed light on why these cancers are now so frequent in somehuman populations and not in others. The evidence is clear that thismodem plague is caused in part by the novel reproductive patterns ofso many women in the more privileged industrialized societies.

Part of the increase results from the boring fact that cancer is morelikely in older people, and more women are now living to old age.

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The more interesting finding is that the probability of a cancer of thefemale reproductive system at any age increases directly in relation tothe number of menstrual cycles a woman has experienced. The mostlikely victim of a cancer of the reproductive tissues is an elderlywoman who had an early menarche and late menopause and neverhad her cycling interrupted by pregnancy and lactation.

From a historical perspective, this is a most abnormal reproduc-tive pattern. Stone Age women, like those of recent hunter-gatherersocieties, had quite a different sort of reproductive life history. Theyhad much later maturation and earlier menopause, perhaps in partbecause they were less well fed and more heavily parasitized thanmodern women. A Stone Age girl may have experienced menarche atfifteen or later and would probably have been pregnant within a veryfew years. If the pregnancy miscarried, she would be pregnant againshortly thereafter. If it was successful, it would be followed by aperiod of lactation of at least two years, possibly four, with associ-ated inhibition of the menstrual cycle. Shortly after weaning (or thedeath of her infant), she would start cycling and would soon be preg-nant again. This would be the pattern until her death or menopauseat perhaps about age forty-seven. In this thirty-year period she wouldhave had four or five or maybe six pregnancies and spent more thanhalf of this thirty years lactating. Her total number of menstrualcycles could not have been much more than 150. A modern woman,even if she has two or three children, might easily experience two orthree times this number of cycles.

A menstrual cycle is characterized by wide swings of hormone con-centrations, and these changes cause cellular responses in the ovarian,uterine, and mammary tissues. These tissue responses are reproduc-tive adaptations, and, like any adaptations, they have costs, in this caseincreased vulnerability to some forms of cacer. These costs are nor-mally minimized by compensating processes that take place duringtimes when the cycling is interrupted by pregnancy and lactation. Ifthese interruptions never occur, the compensating repairs never occuror are carried out less effectively, and the costs keep accumulating.This is speculation, of course, but it seems very likely that somethingof the sort must be happening. The undeniable observation is that themore menstrual cycles a woman has, the more likely she is to get areproductive-system cancer. A more general principle is the adverseeffect, for any kind of adaptive mechanism, of conditions other thanthose in which it evolved. The modern circumstances that lead

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women to undergo three or four hundred menstrual cycles are nodoubt a good example. This evolutionary perspective is not likely toprevent much cancer in women now in their vulnerable years. Forthem we can do no better than to recommend a general avoidance ofenvironmental hazards such as nicotine and other toxins, both naturaland artificial, radiation, and, most important, diets abnormally highin fat.

The long-term implications are more interesting and promising.Obviously it would be both unethical and silly to recommend thatgirls' growth and maturation should be delayed by an inadequatediet, that they should become pregnant as soon as possible aftermenarche and frequently again thereafter, and that they should spenda total of perhaps twenty years breast-feeding their babies. Eaton andhis coworkers have more enlightened suggestions. What needs to bedone is to find out, with carefully conducted research, just how thiskind of historically normal life history makes cancer of the repro-ductive organs less likely. We envision researchers diligently search-ing for artificial means of achieving the low cancer rates that comenaturally to women in hunter-gatherer societies.

We suspect that the artificial means would take the form of hor-monal manipulations. Large numbers of women are already usingoral contraceptives, which work by artificially affecting tissues inmuch the same ways as natural hormones do. Different contraceptivemedications work in different ways to achieve the desired interfer-ence with pregnancy, and they have a diverse array of side effects.With ever more detailed knowledge of the physiological actions ofnatural and artificial hormones, we should be ever better able todevise artificial ways of mimicking the beneficial effects of Stone Agelife histories. This may not be as futuristic and utopian a possibilityas it might seem. Eaton and other workers have presented strikingevidence that some oral contraceptives can reduce the rates of ovar-ian and uterine cancer, although not breast cancer. We expect thatsome sort of hormone treatment will soon be developed to reducebreast cancer as well. None of these comments should be taken tosuggest that we should not continue the search for other environ-mental and genetic causes of cancer. Far from it! We need every bit ofknowledge that can help us combat this scourge.

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-ecause it is crucial to fitness, you might think that naturalselection has smoothly polished the path of sex and repro-duction, from the first romantic longings of adolescenceto love, marriage, sex, pregnancy, childbirth, and child-

rearing. Alas, we all know the truth too well. From unrequited loveto lover's spats, premature ejaculation, impotence, lack of orgasm,menstrual problems, the complications of birth, the special vulnera-bilities and demands of infants, and the inevitable conflicts betweenparents, and between parents and their children, reproduction isfraught with strife and suffering. Why does reproduction entail somuch conflict and misery? Precisely because it is so crucial to Dar-winian fitness. It is at the very core of intense competition and thuscauses many problems.

While our main focus in this book is on how evolutionary ideascan help to explain and prevent or cure specific medical diseases, hereand in the next chapter we broaden our view somewhat to encompassemotional and behavioral problems that may or may not be consid-ered medical disorders. Some problems associated with reproduc-tion, such as diabetes during pregnancy or sudden infant deathsyndrome, are clearly diseases, while others, such as jealousy, childabuse, and sexual problems, involve behavior and emotions. How-ever we categorize them, they cause much suffering and make moresense in the light of evolution. Help from Darwinism does not end at

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the boundary between the medical and the social or educational. Dar-winism is relevant to all aspects of human life, not just medicine.

WHY Is THERE SEX?

r e begin with a fundamental enigma, one of thosewonderful questions that is easy to overlook untilyou take an evolutionary view of life. Why does sexexist at all? It is costly to fitness in important ways,

and many organisms do nicely without it, reproducing either bydividing, like amoebae, or by having females that can lay eggs thatdevelop without fertilization, like aphids. Such creatures have a hugeshort-term fitness advantage over those who reproduce sexually.Imagine what would happen if a mutation produced a female robinthat was perfectly standard in every other respect except that she laideggs that carried all of her genes but none of her mate's and devel-oped normally without needing to be fertilized. In every generation,all the offspring would be identical females. Compared to a normalfemale, who can pass only half her genes on to each offspring andwho has half male and half female offspring, this mutant strain wouldincrease twice as fast.

So why didn't some parthenogenetic woman, ages ago, flood theworld with her progeny and drive us sexual beings to extinction? Andwhy did sex evolve in the first place? Surprising as it may seem, biol-ogists don't yet fully agree about how to answer these questions.Most believe that the function of sex is to introduce variation in off-spring, but it remains hard to understand how this variation can beuseful enough to outweigh the enormous evolutionary costs of sexualreproduction. Biologists also realize that, in the long run, the recom-bination of genes during sexual reproduction may prevent an other-wise steady accumulation of deleterious mutations, but this does notanswer the question of why asexual reproduction does not continu-ally increase in the short run.

Recently, some scientists have proposed that sexual reproductionis maintained by the selective force of the arms race with pathogens.An individual who is genetically identical to many others is vulnera-ble to any pathogen that discovers the key to exploiting this bonanza

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of susceptible individuals. If a clone of ten thousand parthenogeneticwomen are all vulnerable to influenza, they might all be wiped out bythe next epidemic, which would claim only some of their geneticallydiverse competitors. There is growing support for this hypothesis,including several studies that have found asexual reproduction morefrequent in species and in habitats with fewer parasites.

THE ESSENCE OF MALENESSAND FEMALENESS

I magine a time hundreds of millions of years ago, when cells hadbegun to exchange genetic material to provide variation butbefore the development of recognizable eggs and sperm. Suchhaphazard exchange of genetic material is fraught with conflict. A

gene that can get itself donated to many other cells has a major fitnessadvantage, while one that allows itself to be replaced by genes fromother cells is at a substantial disadvantage. The successful gene must getitself into new cells, yet not be displaced by incoming genes. In allorganisms above the bacterial level, genes from different individualsare rarely allowed to enter. Genetic recombination is instead accom-plished by the production of specialized sex cells (gametes) that can besent off with half the genes needed for the initiation of a new individ-ual. When two such cells find each other, they unite to produce a neworganism with equal genetic contributions from each parent.

Gametes face two difficulties. First, they must have sufficientenergy stores both to endure until they merge with another gamete andto nourish a developing embryo. Second, they must find anothergamete. Large gametes may have abundant energy stores, but they areexpensive to make. Small gametes can be produced in enormous num-bers at moderate cost, but they can't survive for long and have nothingto spare for nourishing an embryo. Middle-size gametes sacrifice num-bers for larger but still inadequate nutrient supplies and are eliminatedby natural selection. Multicellular organisms thus produce only largegametes, which we call eggs, and small ones, which we call sperm.

The next difficulty in understanding human sexuality is why thereshould be not only two kinds of gametes but two sexes. In other words,

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why should there be males that produce sperm and females that pro-duce eggs, rather than hermaphrodites that produce both? Many ani-mals and most plants are hermaphrodites, with both eggs and spermproduced by the same individual. The consensus among biologists isthat hermaphroditism can be expected when the same adaptations canserve both sexual functions. Big, bright petals on a flower, for instance,may attract an insect that both brings pollen that fertilizes the plant'seggs and picks up pollen to fertilize other plants' eggs. As expected,most flowering plants are hermaphrodites. In mammals, there is adearth of double-duty adaptations. A penis and secondary characteris-tics such as antlers serve male functions only. A uterus and milk glandsserve only female functions. An individual that invested its limitedresources in both male and female strategies would not be much goodas either. No species of mammal is hermaphroditic.

The investment a female makes in an egg is many times what amale makes in a sperm. Even when the egg is microscopic, as it is inhumans, it is still thousands of times bigger than a sperm, and twohundred million sperm cells are released in a single ejaculate tocompete to fertilize a single egg. This initial difference in gameteexpense is perpetuated and magnified. If most of the eggs producedare fertilized, most of the nutrients put into them will go to theresulting young. If most of the more numerous sperm die from notbeing able to fertilize an egg, nutrients put into them will seldombenefit an offspring. Extra nutrients in a sperm would be morelikely to retard its swimming and be a handicap in competing forthe limited number of eggs.

If an animal releases eggs into the water, it becomes advantageousfor the female to postpone their release until conditions are ideal andabundant sperm are nearby. If she can wait to pick a specific male, somuch the better. Genes from a robust, healthy male may give her off-spring an advantage. If she can induce males to fight over her orotherwise display their prowess, she will better her odds of pickingthe best possible mate. By retaining the eggs inside her until they arefertilized, she maximizes control over who fertilizes them, wastesfewer eggs that are never fertilized, and can protect the eggs to a laterstage of development after fertilization. People automatically think ofinternal fertilization as meaning internal to the female, but logicallythis need not be. When seahorses copulate, a female lays eggs into amale's brood pouch, analogous to a mammalian uterus, where theyoung develop to an advanced stage. This sort of development inside

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the male is exceptional in the animal kingdom. The small size andmobility of sperm cells make it easier for evolution to produce adap-tations for getting sperm into a female rather than eggs into a male.

Since the fertilization of a human egg takes place inside themother, this puts her in charge of the process. It also increases hercontrol over which male will fertilize her eggs. As with females ofother species, it is in her reproductive interest to look for maleswith demonstrable evidence of health and vigor. If females startselecting males with a particular characteristic, such as the huge,colorful feathers of the peacock or the large antlers of an Irish elk,a process of runaway selection may ensue. Males with the charac-teristic have an advantage simply because females choose them, sofemales prefer them in order to have sons that the next generationof females will prefer, thus selecting for still more of the character-istic and giving well-endowed males a still greater advantage and astill greater desirability to females. This positive feedback loopelaborates the trait to the point where it may be severely detrimen-tal to the everyday functioning of the males. The poor peacock canhardly fly, and the Irish elk's antlers became so heavy and unwieldythey have been thought responsible for the species' extinction. Thisis a fine example of how natural selection may create traits that areby no means helpful to the individual or its species, only to theindividual's genes. Helena Cronin, in The Ant and the Peacock, givesan exquisite history of this idea and of the reluctance of male scien-tists to acknowledge the power of female choice and its burden-some effects on males.

If there is internal fertilization, the young can presumably bereleased at the optimal stage. Optimal for whom? Mother? Baby?Father? We'll come to that soon. Exactly how long the young areretained is a life history feature very much subject to natural selec-tion. With the nine-month human pregnancy, in which an offspringgrows from a microscopic mite to an infant of several kilograms, amother's investment in each baby is vastly larger than that of thefather. On the other hand, she is sure the baby is hers, while her matemay well be uncertain. This uncertainty means that male expendi-tures of time and energy caring for the offspring will generally have amore dubious payoff than similar investments by females. The initialtiny difference in the cost of sperm versus the cost of an egg is greatlyamplified by human reproductive physiology and leads, as we willsee, to different reproductive strategies for males and females.

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Girls and boys are born in nearly equal numbers, as we explainedin Chapter 2, because individuals of whichever sex is in excess willhave lower reproductive success, on average. Selection therefore con-stantly shapes parents who have offspring of the scarcer sex, therebyequalizing the sex ratio in the long run. From the standpoint of max-imizing collective reproduction, this is inefficient. It takes only a fewmen to keep a large number of women reproducing at whatever ratewould maximize the women's reproductive success. This is a clearillustration of the greater importance of lower levels of selection rel-ative to higher (group) levels. If selection at the group level were at allimportant, the sex ratio would be biased toward females.

This is not a matter of merely academic interest. In India, a cul-tural preference for males has combined with a proliferation of ultra-sound imaging machines, which allow the determination of the sex ofa fetus, to severely distort the sex ratio. More than 90 percent ofabortions in India are now of female fetuses, and the sex ratio in thegeneral population is beginning to show an imbalance. Similarly, inmany areas of China, where population limitation campaigns restricta couple to one child, that child is a boy more than 60 percent of thetime. In the long run such imbalances will be tempered by naturalselection, but in the coming generation they will have unpredictablepolitical and social consequences. Our guess is that the excess menwill compete vigorously and the scarce women will gain social powerwith remarkable speed.

CONFLICT AND COOPERATION

BETWEEN THE SEXES

C onflict between the sexes is not continuous. Men andwomen can get along, sometimes for whole days at time,even weeks. This harmony is, however, inevitably dis-rupted by conflicts that originate in the differing repro-

ductive interests and strategies of men and women. From the originaldifference between the tiny sperm and the larger egg, whole separateworlds of conflicting strategies have emerged to ensnarl our lives.Women can have a limited number of babies, usually four to six,rarely even as many as twenty according to the record books. Men

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can, however, have hundreds of children and have done so in cul-tures where a combination of surplus resources and social stratifica-tion made it possible for some men to have harems of hundreds ofwomen while many others lacked even a single mate. These excep-tional cases are extreme examples of the principle that the number ofoffspring may vary more widely for men than women. This differ-ence arises from a woman's unavoidably high investment in bothtime and calories for a single baby, compared to a man's minimalexpense of a few minutes and a single ejaculate.

These differences mean that men and women can and do use dif-ferent kinds of strategies to maximize their Darwinian fitness. Awoman can maximize the number of her genes in future generationsby finding and keeping a man who will care and provide well for herand her children and who is disinclined to invest in other women.Men can use a similar strategy by finding and keeping a woman whois fertile, inclined to take good care of her children, and disinclined tomate with other men. Men also have another strategy not available towomen, that of inseminating many women while providing little orno support for them and their babies. None of this implies that menand women think through their options in order to arrive at con-scious strategies to maximize their reproductive success, and it cer-tainly implies nothing about how people ought to act. Nonetheless,natural selection has inevitably shaped our emotional machinery inways that maximize our reproduction-or that would have in StoneAge circumstances.

MATE PREFERENCEST X he problems that result from these divergent strategies areevident in courtship choices. Females of all species do bestif they can find a male who offers good genes and abundantresources. Thus, when females can choose, males compete

to prove their abilities in contests that range from the familiar buttingcontests of deer and sheep to the deep braggadocio of the bullfrog. Inother species the female mates with the male with the biggest nuptialgift, usually an insect or other source of protein, sometimes the malehimself, as when the preying mantis male is eaten by the female evenas he copulates with her. The male mantis might try harder to escape,

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but since he is unlikely to find another mate, he probably maximizeshis own reproductive success by donating his bodily protein to thefemale, who can use it to give more to their offspring.

Men, while notoriously less choosy than women, still have strongpreferences. A man maximizes his reproductive success by matingwith a woman who has been healthy and successful (indicating goodgenes) and who is maximally fertile (indicated mainly by being in thepeak reproductive years), uncommitted (indicated by lack of prioroffspring), and able and motivated for mothering. As University ofMichigan psychologist David Buss puts it:

Imagine a state in which human males had no matepreferences aside from species recognition and insteadmated with females randomly. Under these condi-tions, males who happened to mate with females ofages falling outside the reproductive years wouldbecome no one's ancestors. Males who happened tomate with females of peak fertility, in contrast, wouldenjoy relatively high reproductive success. Over thou-sands of generations, this selection pressure would,unless constrained, fashion a psychological mecha-nism that inclined males to mate with females of highfertility over those of low fertility.

So both sexes can increase their fitness by choosing their matescarefully, but they choose different characteristics. Males are rela-tively more interested in fertility and sexual loyalty, females in goodgenes and resources. In a study of 10,047 people from diverse cul-tures and religions in thirty-seven countries, Buss has confirmedthese generalizations. Earning capacity was significantly more impor-tant to women than to men in all but one of the thirty-seven samples.Youth and appearance were relatively more important to men, and intwenty-three of the thirty-seven samples, men valued chastity signifi-cantly more highly than women did, while there was no culture inwhich the reverse was true.

Mate choice is especially complicated in the human species, whereparents mate repeatedly and both provide care for the young. Thesecircumstances mean that a woman faces the risk of being desertedand so must not only assess the current status of her mate but mustalso try to predict his ability and willingness to stay and provide forher and their offspring. An enduring bond and continuing invest-

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ment by the man mean that he now also runs a new risk compared tomost other primates, that of being cuckolded. He therefore mustassess the likelihood that his prospective mate will mate with othermen, thus exposing him to the possibility of unwittingly investing ina woman who may be carrying another man's baby and, later, in theoffspring of another man.

To succeed, an individual must predict the prospective mate'sfuture behavior, an iffy task at best. Both sexes look for indicators ofloyalty and willingness to invest in offspring. Amotz Zahavi, an Israelibiologist, has suggested that these pressures might explain some oth-erwise mysterious conflicts by a mechanism he has called "testing ofthe bond." By provoking the prospective partner, he suggests, one canassess his or her willingness to continue to deliver resources and loy-alty in the face of future difficulties. Do lovers have spats to test eachother? Zahavi provides examples from the world of courting birds tosupport his theory. Female cardinals, for example, peck and chasewooing males and allow mating only after long persecution. Theirsubsequent bond lasts for season after season. No one has yet lookedin detail at human courtship to see whether we do the same.

Now we return to look at the strongest finding in the Buss study.Despite their differences, both sexes from cultures across the globeconsistently agreed on the two most important characteristics theywould look for in a mate: (1) kindness and understanding and (2) intel-ligence. Why do both sexes most of all want a caring and capable part-ner? For an answer we need to understand why there is such aninstitution as marriage. Why do men and women in every cultureform long-lasting sexual and parenting associations while most otherprimates have very different kinds of mating systems? This questioncannot be answered with certainty, but human patterns of food gath-ering and child rearing are certainly important parts of the explana-tion. In the natural environment, one caretaker cannot easily raise achild. Children are, for many years, too helpless and heavy to be takenon long foraging trips. In order to succeed, they need instruction inthe ways of their culture and help in negotiating the group hierarchy.In short, each child is so expensive that it may take more than oneindividual to raise it. To the extent that both parents have all theirchildren in common, they should have minimal conflicts of interest-except, that is, those conflicts that arise from obligations to other rel-atives. Problems with in-laws are entirely expectable, because helpingin-laws directly benefits the genes only of the spouse, not one's own.

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DECEPTIVE MATING STRATEGIESM [ating without caring for the offspring benefits men'sreproductive interests more than women's. This isconsistent with some other aspects of human sexualpatterns. First, prostitution is mainly a female profes-

sion. While erotic pleasures are possible for both sexes, the balance ofsupply and demand is such that everywhere men are willing to pay forsex while women rarely have difficulty finding willing sex partners.Second, the strategies that characterize the singles bar scene begin tomake sense. In order to get women into bed, men brag about theirability to protect and provide, exaggerating their exploits and flashingtheir fake Rolex watches as they swear that they are in love forever.Experienced women are rarely completely taken in by this charade,but these patterns of male deception nonetheless seem to work. Menoften accuse women of using the converse deceptive strategy, receiv-ing expensive gifts with excited sexual interest and then, later, indig-nantly expressing surprise that he could have imagined her to be "thatkind of woman." For thousands of years, physicians have called thiskind of emotional behavior pattern "hysteria." This name arosebecause commonly associated physical symptoms such as abdominalpain and psychogenic paralysis were thought to result from the wan-derings of the womb through the body. Had physicians usually beenwomen, they might never have invented the dubious diagnosis of"hysteria." Instead, women doctors, observing the deceptive matingstrategies of men, might have attributed the characteristics of cads toan overly mobile prostate gland and called it "prostateteria."

REPRODUCTIVE ANATOMYAND PHYSIOLOGY

T "he human female's reproductive cycles are quite differentfrom those of other primates. Many female primates adver-tise their fertile periods with odors, bright patches of skin,and changed behavior. These advertisements are useful com-

munications that increase competition and courtship by males duringthe females' fertile period and discourage sexual harassment at other

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times. In human females, ovulation is not only unadvertised, it seemsto be carefully concealed. The scheduling in women is also different,with human ovulation regularly repeated at about twenty-eight-dayintervals, while most primates ovulate only once or twice a year, oftenin synchrony with the cycles of other females they are associated with.At the end of the cycle, if there is no pregnancy, the human female losesa considerable amount of blood in the menstrual flow. Human sexualactivity is not confined to brief fertile periods but occurs throughoutthe cycle, with substantial time and energy spent on frequent sexualintercourse. Female orgasm in most primates is either absent or briefand inconspicuous, but in humans it is common and may be intense.

While the details remain very much at issue, there is a growing con-sensus that all these facts fit together. The key is that the woman andher mate both benefit if he is frequently present instead of away forweeks and months at a time. If her cycles were obvious, he could max-imize his reproduction by inseminating her only at fertile times, butbecause he cannot tell when she is fertile, he must stay nearby andcopulate at frequent intervals. If early Stone Age women, with theirenlarging mental capacities, could know when they were fertile andconnect sex with the pain of childbirth, they might avoid their part-ners at those times and thus decrease their reproductive success. Hereis a possibility, first suggested by ornithologist Nancy Burley, wherenot knowing something may be good for one's fitness. Concealed ovu-lation also protects the woman somewhat from being impregnated bymen more powerful than her mate since such men cannot know whenshe is fertile and take advantage of her only at that time.

The average frequency of human intercourse, every three days orso, is high enough to make it likely that an ovulation will result in apregnancy. As we noted before, however, this continuous sexual activ-ity could also mean that bacteria and viruses can hitch regular free ridesdeep into the woman's reproductive tract. One defense against suchinfection is the plug of mucus at the cervix that blocks sperm fromascending except during two or three fertile days a month, when thefibrils in the mucus align to make channels just wide enough for thesperm to swim up into the uterus. As suggested by Margie Profet, men-struation may be another defense to kill pathogens and sweep away thebeginnings of infection (see Chapter 3). In the natural environment, ofcourse, most women would experience far fewer menstrual cycles,since they would not cycle while pregnant or lactating, which would bemost of the time. Anemia from loss of menstrual blood is another of

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the many problems that result largely from novel aspects of our envi-ronment, such as celibacy and effective contraception.

Men are also different from some other male mammals in havingtesticles permanently lodged in a scrotal sac outside the body proper.This is a precarious location for organs of such vital importance, sothere must be a good reason for it. One clue is the infertility thatmany men experience from wearing tight underwear, which increasesthe temperature of the testicles. Anatomic examination shows thatthe veins bringing blood back into the body from the testicles wraparound the artery in a way that provides an effective countercurrentheat exchange mechanism to keep the testes cool. Why sperm cannotbe formed at regular body temperature is an unsolved mystery. Menmust keep their testicles cool and functioning all the time because fer-tile women may be available at any time.

The testicles of different primates vary greatly in size, and much ofthis variation can be explained by differences in mating patterns. Afemale chimp mates with several males, while female gorillas andorangutans mate with only one male. Because the reproductive successof the male chimpanzee depends not only on inseminating manyfemales but also on the success of his sperm in competing with othersperm to fertilize the egg, natural selection has increased the number ofsperm chimp males make as well as the size of their testicles. Gorillas,despite their large size and fearsomeness, have testicles that are aboutone-fourth the weight of the average chimpanzee testicles. In general,the relative testis weight is high for species in which females often matewith multiple males and low in those with little sperm competition.Where do humans fall? In between but toward the side of less spermcompetition. It appears that multiple matings have, however, occurredoften enough during human evolution to select for testicles slightlylarger than those of species with reliably monogamous mating patterns.

Two British researchers, Robin Baker and Robert Bellis, havetaken this topic of sperm competition much further. They note thathuman sperm in a single ejaculate are of several different kinds, someof which are incapable of fertilizing an egg. Many of these sperm aredesigned, they argue, specifically to find and destroy any sperm fromother men. They have also shown that the volume of ejaculate col-lected in condoms from monogamous couples increases not merelywith the amount of time since the last ejaculation but also with theamount of time the couple have been apart. This suggests an adapta-tion to increase sperm output when it may be needed to compete

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with sperm from another man. If confirmed, this will demonstratethat selection has designed our sexual machinery to compete in manydifferent ways and at very close quarters.

JEALOUSYH ' owever understandable jealousy may be, either in the the-ory of natural selection or in our intuitions, it has surelybeen responsible for a large part of the world's miseries.Perhaps the ill will and bloodshed caused by Helen's deser-

tion of Agamemnon for Paris, as described by Homer, need not betaken literally, but it is not an implausible account of the emotions suchan event could arouse. Canadian psychologists Martin Daly and MargoWilson have convincingly demonstrated that a large proportion of themurders of women arise out of male jealousy. Othello's lethal frenzyand Desdemona's tragic death have all too many parallels in real life.More commonly, jealousy merely fuels marital battles that stop shortof murder but lead to traumatic divorces and all their tragic conse-quences. In a few individuals the extremity of these feelings and falsebeliefs that the partner is unfaithful justify the clinical diagnosis ofpathological jealousy. To make sense of all this, we must understand theevolutionary origins and functions of the capacity for sexual jealousy.

Maternity is a certainty, but paternity is always a matter of opinion.A man runs the risk of spending years providing for a woman who ishaving other men's children and of unwittingly caring for children nothis own, while women always know who their children are. A manincapable of jealousy would have a greater risk for being cuckolded,with a resulting decrease in reproductive success. Men who threatenpotential interlopers and try to prevent their wives from mating withother men have an evolutionary advantage. Genes that predispose tomale sexual jealousy will thus be maintained in the gene pool.

While women do not face the same risk, they face others. A hus-band's wandering affections can lead to a drain of resources and time,to potential loss of the husband, and to the risk of sexually transmit-ted diseases. Cross-cultural data show enormous diversity in sexualmores, from cultures where extramarital liaisons are tolerated tothose where any infidelity is punished by death. However, sexual jeal-ousy is consistently reported to be more intense for men than women.

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Sexual jealousy is such a strong influence on human life that it isinstitutionalized and regulated by custom or formal law in almost allsocieties. In technologically advanced Western countries men oftentreat women as property and try to control their sexuality, but inmany traditional societies the control may be even more blatant andinstitutionalized. In some Mediterranean societies, women mustdemonstrate their virginity with blood on the marital sheet and thenare cloistered so they can associate with no men but their husband. Insome Muslim societies women must wear robes and veils that makethem unrecognizable by men outside the home. In China, women'sfeet were bound from early childhood to discourage straying. Inmany areas of Africa it remains routine for girls at puberty to havethe clitoris excised and the labia sewn shut. Everywhere men createsocial institutions to control female sexuality.

What would be the attitude, in our own society, toward a womanwho is faithful to her husband 90 percent of the time, but who hasanother lover for the remaining 10 percent of her sex life? Her husbandwould have a 90 percent probability of being the father of her nextchild, and so, from a strictly evolutionary perspective, we wouldexpect him to be 90 percent as good a father to that child as he wouldif his wife had been perfectly monogamous. Yet in many cultures a sin-gle instance of adultery by a woman may be legally considered a justifi-cation for total cancellation of the marriage and abandonment of anyensuing child by the woman's husband. Many people seem to thinkthat culture opposes such biological tendencies, but with jealousy, cul-ture and the legal system exaggerate a biological tendency. People whothink that laws should oppose our more destructive biological tenden-cies would presumably want to change the social system in ways thatwould discourage divorces based on infidelity. What do you think theworld will be like if someone invents a pill that cures jealousy?

SEXUAL DISORDERS

eople are, to put it mildly, very interested in the quality oftheir sex lives. This is ultimately because genes that result inbehaviors that increase reproduction have been selected for,while genes that make people uninterested in sex have been

eliminated. But from this point on, sex becomes more problematic.

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The ubiquity of sexual problems is confirmed by a visit to any book-store. The very existence of rows of sex therapy books documentsthe unfortunate truth. Sex is a problem not just for a few peoplesome of the time, but for many people much of the time. The bookscontain strong hints that these problems are not genetic defects, notresults of an abnormal environment, but direct products of evolu-tion. Each book has a chapter about premature orgasm in men andanother on delayed or absent orgasm in women. There are no chap-ters about too-rapid orgasms in women or too-slow orgasms in menand no explanations for why men and women differ in this regard.There are chapters on men with fetishes but no mention of similarproblems in women, and again, no comment on why the sexes differin this susceptibility. Some difficulties the sexes share: both are trou-bled, on occasion, by lack of sexual desire and difficulty gettingaroused. And both sexes (but especially men) are troubled by bore-dom with the same sexual partner. Here, at the heart of reproduction,we find a biological system that seems haphazard at best. Why shouldmen and women have so many and such different complaints?

At the very least, we might expect the evolved regulatory mecha-nisms to coordinate the orgasms of men and women. But orgasms arenot only uncoordinated, they are systematically sooner for men thanwomen. This bias is one of the more unfortunate illustrations of theprinciple that natural selection shapes us to maximize reproduction,not satisfaction. Imagine the reproductive success of a man whotends to come to orgasm very slowly. He might please his partner,but if the sex act is interrupted or his partner has been satisfied anddoes not want to continue, his sperm will sometimes not get to wherethey will do his genes any good. The same forces shape the timing ofthe female sexual response. A woman who rapidly has a singleorgasm may, on occasion, stop intercourse before her partner ejacu-lates and thus will have fewer offspring than the woman with a moreleisurely sexual response.

A closer look reveals that there may be a system to adjust male sex-ual timing according to the particular circumstances. Premature ejacu-lation is common mainly in young men, especially when they are inanxiety-provoking situations. According to anthropologists who studyhunter-gatherer cultures, the liaisons of young men are often illicit andwould be dangerous if discovered by older men. In such circum-stances, brevity of the sexual act may be especially adaptive. Theseideas are mere speculation now, but they deserve consideration.

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PREGNANCYP regnancy would seem to be the ultimate in shared goals-arefuge from conflict, perfect unity of purpose betweenmother and fetus. And the relationship between mother andfetus is about as intimate and mutual as any relationship can

be. Nonetheless, because mother and fetus share only half theirgenes, there is conflict aplenty. Whatever benefits go to the fetus helpall its genes. The fetus maximizes its fitness by appropriating what-ever maternal resources it can use short of jeopardizing the mother'sability to care for it in the future and her ability to raise full or halfbrothers and sisters (all discounted by the one half or three quartersof genes they do not have in common).

From the mother's point of view, benefits given to the fetus helponly half of her genes, so that her optimum donation to the fetus islower than the amount that is optimal for the fetus. She is also vul-nerable to injury or death from the birth of too large a baby. The fit-ness interests of the fetus and the mother are therefore not identical,and we can predict that the fetus will have mechanisms to manipulatethe mother to provide more nutrition and that the mother will havemechanisms to resist this manipulation.

People sometimes argue that there could be no net advantage to agene that benefits an offspring at a cost to its mother, because its earlyadvantage would be exactly reversed by the later cost. This is not theway things work out. Suppose, in a population in which maternal andfetal interests are served equitably, a gene arises that increases fetalnutrition slightly, at a slight cost to the mother. A fetus that enjoysthat advantage can avoid the cost half the time when it grows up,because only half its offspring will carry the gene. Also, even moreobviously, it will pay the cost only if it is female. So the cost wouldbe paid in only about 25 percent of the pregnancies of the next gen-eration. There are additional complexities-which we will not gointo-but such quantitative considerations led Harvard biologistDavid Haig to expect conflict between parent and offspring, eventhough the ideal contribution from the mother's perspective may beonly slightly less than the ideal for the fetus.

Unfortunately, these slight differences create major conflicts. Thefetus may be striving mightily to glean an extra few percent of nutrientdelivery from the mother, while the mother tries just as hard to pre-

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vent this. When the balance of power is disrupted because one partic-ipant's efforts are seriously impaired, medical problems arise. Forexample, the fetus secretes a substance, human placental lactogen (hPL),that ties up maternal insulin so that blood glucose levels rise and pro-vide more glucose to the fetus. The mother counters this fetal manip-ulation by secreting more insulin, and this makes the fetus secreteeven more hPL. This hormone is normally present in all human bod-ies, but in a pregnant woman it can reach a thousand times the normalconcentration. As Haig points out, these raised hormone levels, likeraised voices, are a sign of conflict.

If the mother happens to be deficient in her production of insulin,this can cause gestational diabetes, possibly fatal to the mother, andtherefore to the glucose-greedy fetus itself. The fetus would have beenwell advised to curtail its secretion of hPL, but all it can do is play theodds. The average mother is thoroughly competent to produceenough insulin to avoid diabetes, even when flooded by fetal hPL.

The evolutionary theory of parent-offspring conflict was workedout many years ago by Robert Trivers, but it was only in 1993 thatDavid Haig applied it to the workings of human pregnancy. It is alsoonly recently that an unexpected but highly relevant genetic phe-nomenon came to light. Experiments, mainly with mice, have shownthat the genes need not rely on the lottery of sexual reproduction toavoid the later costs of special benefits in fetal development. Theymay resort to genetic imprinting, whereby a gene is somehow condi-tioned by its parent either to start acting immediately or to avoid act-ing in the offspring. Genes from a father may be imprinted so theyside with a fetus in the conflict with the mother. These same genes,when they come from a mother, may be imprinted so they have nosuch effect. The relevance of this to human pregnancy remains to bedetermined, but in mice, genes imprinted by males produce a fetalgrowth factor and other genes imprinted by females produce a mech-anism for destroying that growth factor. Such evidence suggests thatit may not be farfetched to view the womb itself as the battlegroundon which genes play out their interests at the expense of our health.

Aside from diabetes, another scourge of pregnancy is high bloodpressure. This is called preeclampsia when it gets severe enough todamage the kidneys so that protein is lost in the urine. Haig has sug-gested that this too may result from conflict between the fetus and themother. In the early stages of pregnancy, the placental cells destroy theuterine nerves and arteriolar muscles that adjust blood flow, and this

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makes the mother unable to reduce the flow of blood to the placenta.If something constricts other arteries in the mother, her blood pres-sure will go up and more blood will therefore go to the placenta. Theplacenta makes several substances that can constrict arteries through-out the mother's body. When the fetus perceives that it is receivinginadequate nutrition, the placenta releases these substances into themother's circulation. They can damage the mother's tissues, but selec-tion may have shaped a fetal mechanism that takes this risk in order tobenefit itself even at the expense of the mother's health. Data on thou-sands of pregnancies show that moderate increases in maternal bloodpressure are associated with lower fetal mortality, and that womenwith preexisting high blood pressure have larger babies. Further sup-port is provided by findings that preeclampsia is especially commonwhen the blood supply to the fetus is restricted, and that the mother'shigh blood pressure results from increased resistance in the arteries,not from increased pumping by the heart.

We wonder if the same mechanism may explain some adult highblood pressure. Low-birth-weight infants are especially likely to developthis condition as adults. If genes that are expressed in the fetus tomake substances that increase the mother's blood pressure continueto be active, this could cause high blood pressure later in life.

From a traditional medical perspective, these explanations for dia-betes and high blood pressure in pregnancy are revolutionary, andunproven, but we suspect they may well prove correct. If so, they pro-vide extraordinary evidence for the power of looking at life from thegene's point of view, for the ubiquity of biological conflicts of interest,and for the practical utility of an adaptationist approach to disease.

Human chorionic gonadotropin (hCG) is another hormone madeby the fetus and secreted into the mother's bloodstream. It binds tothe mother's luteinizing hormone receptors and stimulates the con-tinued release of progesterone from the mother's ovaries. This hor-mone blocks menstruation and lets the fetus stay implanted. hCGseems to have originated in the contest between the fetus and themother over whether the pregnancy should continue or not. Up to78 percent of all fertilized eggs are never implanted or are abortedvery early in pregnancy. The majority of these aborted embryos havechromosomal abnormalities. Mothers seem to have a mechanismthat detects abnormal embryos and aborts them. This adaptation pre-vents continued investment in a baby that would die young or beunable to compete successfully in adult life. It is advantageous for the

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mother to cut her losses as early as possible and start over, even if thismeans culling a few normal embryos in order to avoid the risk of nur-turing an abnormal one. The fetus, by contrast, does everything it canto implant itself and to stay implanted. Producing hCG is an impor-tant early strategy for the fetus to further this goal.

It seems likely that high hCG levels are somehow detected andinterpreted by mothers' bodies as a sign of a viable fetus-if it canmake enough hCG, it is probably normal. So the embryo, to demon-strate its fitness to the mother, must now make greater amounts ofhCG, levels that say as loud as they can, "I am the makings of a greatbaby." It is also conceivable, as Haig points out, that these high levelsof hCG are a cause of nausea and vomiting in pregnancy. Do youthink this an alternative to Profet's morning-sickness theory, sum-marized in Chapter 6? Not if you understand the distinction betweenproximate and ultimate causes (Chapter 2). The hCG effect could bepart of the adaptive machinery that deters ingestion of toxins. Con-versely, it may just be an incidental consequence of high hCG levels.Only a well-designed investigation can resolve this issue.

BIRTHT w he large brains and small pelvic openings of humans havecombined to make birth especially stressful and risky. As wenoted in Chapter 9, it would be far better if the baby couldbe born through an opening in the abdominal wall, as occurs

artificially in a cesarean section, but historical constraints make thatimpossible, and the baby must still squeeze through the pelvis. The rel-ative immaturity and helplessness of human babies compared to thoseof other primates are an unavoidable cost of being small enough to beborn, but the dangers nonetheless remain for both baby and mother.

Wenda Trevathan, an anthropologist at New Mexico State Uni-versity, notes that while other primates go off alone to give birth,human mothers often seek companionship and support. She suggeststhat this may in part be explained by the unusual birth orientation ofhuman babies. In contrast to those of other primates, human babiesnormally emerge facing backward, so that if the mother were to try tofinish a difficult labor by pulling on the baby, she might injure it. Thepresence of a helper at birth greatly decreases the risk. Even in mod-

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ern times, the simple presence of a supportive woman during birthcan reduce the rate of cesarean section by 66 percent and the use offorceps by 82 percent. Six weeks after birth, mothers who had ahelper at birth are less anxious and breast-feed more easily thanmothers who gave birth without a helper.

After the baby is born, a modern obstetrician or midwife helpsextract the placenta and tries to minimize bleeding. Oxytocin is a nat-

ural hormone stimulated by nursing that constricts uterine bloodvessels at birth, and injections of extra oxytocin have stopped exces-sive bleeding and saved thousands of lives. Doctors cannot alwayspredict who will bleed excessively, and oxytocin administration isnow part of the delivery routine. There has, however, been littleresearch on the possibility that such routine administration of oxy-tocin might disrupt other mechanisms.

In some species, notably sheep, birth by cesarean section usuallyresults in the mother not accepting the offspring as her own. A ewewill kick and butt her lamb born by cesarean section. During normalbirth, pressure on her vaginal walls stimulates the release of oxytocin,which activates a brain mechanism that makes the mother bond tothe first lamb she sees in the next few minutes. Administration of adose of oxytocin enables a ewe to bond normally to a lamb deliveredby cesarean section. We don't know whether oxytocin plays a similarrole in human bonding. Because human mothers seem to attach nor-mally to cesarean babies born by cesarean section, it seems that oxy-tocin may not be necessary to bonding by human mothers. Need thismean it doesn't help? Because the issue is so important, and becauseof the frequency of cesarean sections and the routine administrationof large doses of extra oxytocin, further study of the positive andnegative effects of this hormone is needed.

INFANCYW ' hen the baby first nurses at the mother's breasts,they secrete not milk but colostrum, a watery liq-

uid full of substances that protect the baby frominfection. In a few days, the real milk comes in,

which also contains a variety of substances that protect the baby farbetter than anything in infant formula. Much has been said about

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the benefits of natural breast-feeding, and we will not belabor thepoint, except to note parenthetically how completely nonadaptivehuman behavior can be in the modern environment. For instance,four of Mozart's six children died in the first three years of life-tragic but not surprising when we learn that they were fed mainlysugar water.

Many babies now spend a few extra days in the hospital becausethey are jaundiced. The yellow color results from high levels ofbilirubin, a by-product of the breakdown of hemoglobin. At the timeof birth, fetal hemoglobin, which is well suited to the intrauterineenvironment, is being replaced by the adult form, which is bettersuited to life outside the womb. If the liver gets behind in processingthe great onslaught of hemoglobin derivatives, a certain amount ofjaundice is both understandable and unremarkable.

Physicians first recognized the dangers of high levels of bilirubin inthose babies whose blood cells had an Rh antigen that is attacked bytheir mother's antibodies. The rapid breakdown of blood cells andresulting high bilirubin levels sometimes caused permanent braindamage. Today this can usually be prevented by administering sub-stances that prevent the mother from developing Rh antibodies or bygiving the baby an exchange transfusion at birth. But many babies whodo not have Rh antigens also have visible jaundice at birth. To preventany possibility of brain damage, such babies are often treated withexposure to bright light, which changes the bilirubin in the skin to aform that can be excreted in the urine, thus hastening the disappear-ance of jaundice.

So far it looks as if the high bilirubin levels at birth are simply aglitch in the mechanism, one we can fortunately circumvent by rou-tine medical treatment. John Brett at the University of California atSan Francisco and Susan Niermeyer at the Children's Hospital inDenver have taken a more careful evolutionary look at this situation.They note that the first breakdown product of hemoglobin isbiliverdin, a water-soluble chemical that is excreted directly in birds,amphibians, and reptiles. In mammals, however, biliverdin is con-verted to bilirubin, which is then transported throughout the bodybound to the blood protein albumin. Furthermore, bilirubin levels atbirth are under partial genetic control and therefore could be low-ered by natural selection if that were beneficial. This led Brett andNiermeyer to suspect that high bilirubin levels at birth might be adap-tive. As they put it, "Given that all babies will be jaundiced well

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above the adult level within the first postnatal week and over half willbe visibly jaundiced, it seems difficult to imagine that something iswrong with all of these infants." Further investigation revealed thatbilirubin is an effective scavenger of the free radicals that damage tis-sues by oxidation. At birth, when the baby must suddenly startbreathing, the arterial oxygen concentration becomes three times asgreat, with concordant increases in damage from free radicals. Adultlevels of defenses against free radicals are only gradually imple-mented during the first weeks of life, as the bilirubin levels decrease.If Brett and Niermeyer are correct, we need to rethink our treatmentof jaundice of the newborn, perhaps saving millions of dollars inunnecessary treatment each year.

The risks of light treatment have been inadequately investigated,but we know that color vision impairments can result from continu-ous bright light in the first few days after birth. We want to make itclear that the adaptive interpretation of Brett and Niermeyer has notbeen widely accepted and strongly caution parents against refusing tolet their babies have light treatment if their doctors deem it necessary.It would be worthwhile, however, for parents to ask questions and toget second opinions, and for scientists to initiate studies to providethe decisive answers.

CRYING AND COLICT he baby is home now, and the wonderful joy is punctuated,regularly, day and night, by hours of wails that cannot beignored. It is easy enough to understand how crying bene-fits the baby. If it is hungry, thirsty, hot, cold, frightened, or

in pain, the baby cries and a parent comes to meet its needs. A babyunable to cry might be seriously neglected. How does the baby's cryaffect parents? It gets on their nerves, to put it mildly. Parents do what-ever needs to be done to stop the crying, at any time of day or night.Genes that make the cry aversive to parents are selected for becausethose same genes are in the child, who benefits from the parent's dis-comfort and resulting aid. The parent suffers, but its genes in the babybenefit-a fine example of the actions of kin selection.

If the baby cries for a good reason, all to the good. But is all cry-ing a call for necessary help? Often it is impossible to find any causeat all, and yet nothing seems to stop the baby's crying. This is the

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most common reason new mothers consult their pediatricians, whousually call the problem "colic" despite little evidence that gastroin-testinal difficulties are responsible. Ronald Barr, a pediatrician atMcGill University, has made an intensive study of infant crying. Hefinds that babies with supposed colic do not cry more often or atspecial times, just longer each time. This has led him to suggest thatsuch crying is normal, although perhaps prolonged by modern prac-tices such as long intervals between feedings. !Kung women in Africacarry their infants constantly and feed them whenever they cry, atleast once and often three or four times per hour for two minutes ateach feeding. By contrast, American mothers feed their two-month-old infants approximately seven times a day with an average of threehours between feedings. In an experimental study, Barr asked agroup of mothers to carry their babies at least three hours per day.Mothers in that group reported that their babies cried only half aslong as those whose mothers did not receive the special instructions.

Barr suggests that frequent crying increases fitness by promotingbonding with the mother and by encouraging frequent feeding,which maintains lactation and prevents any competing pregnancy.This last argument again illustrates the conflict of interests betweenthe parent and the offspring. The frequency of babies "spittingup" may be another instance in which the baby manipulates themother, in this case to make more milk than is in her interests. Or"spitting up" may be explained as a result of unnaturally infrequentbut larger feedings. An examination of the phenomenon in hunter-gatherer societies could provide an answer, but it is not the kind ofthing that anthropologists routinely report.

SUDDEN INFANT DEATHSYNDROME (SIDS)M [any a parent's greatest fear is of going to wake the

baby and finding it dead in the crib. Sudden infantdeath syndrome (SIDS) kills more babies than anyother cause of death except accidents-1.5 per 1000

babies, or more than 5000 per year in the United States alone. Thecause, however, remains unknown. James McKenna, an anthropolo-

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gist from Pomona College, has investigated SIDS from an evolution-ary and cross-cultural perspective and found that crib deaths aremany times more frequent in modern societies than in tribal cultures.The SIDS rate is especially high, as much as ten times higher, in thosecultures in which babies sleep apart from their parents instead of inthe same bed. In a series of experiments that simultaneously mea-sured the movements and brain waves of sleeping mothers and theirbabies, he found substantial relationships between the sleep cycles ofmothers and babies who sleep together. He suggests that this coordi-nation leads to intermittent arousals that sustain SIDS-vulnerablebabies through periods when their breathing might otherwise cease.The more fundamental problem, cessation of breathing, may berelated to the extreme immaturity of the human infant's nervous sys-tem, the price of avoiding the danger of the birth of babies with toolarge a skull to fit through the pelvis. None of this is to say that SIDSis in any way normal, only that the tendencies that make some infantsvulnerable to it may have been far less dangerous in a natural envi-ronment, where mothers usually sleep with their newborns.

WEANING AND BEYONDE -ventually the mother begins to discourage the baby fromnursing. In industrial societies, this usually occurs some-time in the first year, while in hunter-gatherer cultures nurs-ing lasts an average of three to four years. The interval

between births is critical to maximizing reproduction. If it is tooshort, the first infant may still need so much milk and effort that thenext infant will not survive. If the mother waits too long, she is wast-ing her reproductive potential. As you might expect from our discus-sions of parent-offspring conflict, this is yet another instance inwhich the interests of the mother and the infant diverge. There willcome a time, usually when an infant is two to four years old, when itis in the mother's genetic interests to conceive again but in the baby'sinterests to keep nursing and prevent her from having another baby.This is the weaning conflict, discussed by biologist Robert Trivers inhis classic paper that first outlined the divergent interests of parentsand their offspring. He noted that weaning conflicts have a naturalend point. Eventually, the baby can do well enough with solid foods

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and less aid from the mother that it too will benefit more from hav-ing a baby brother or sister (who shares half its genes) than from con-tinuing to monopolize its mother.

During the period of weaning conflict, how can the infant manip-ulate its mother to continue nursing? Here again Trivers had a bril-liant insight. The infant, unable to force the mother to keep nursing,can only use deception, and the best deception is to convince themother that it is in her best interest to let nursing continue. How canthe baby accomplish such deception? Simply by acting younger andmore helpless than it really is. Psychologists have long recognized thispattern and named it regression, but we believe Trivers has offered thefirst evolutionary explanation, with implications that are just begin-ning to be explored.

Parent-offspring conflicts don't end with weaning; they justchange their form. For a long period in childhood, conflicts are rela-tively routine and mild, but come adolescence, all hell breaks loose.Teenagers may want to do everything their own way and insist thatno help of any sort is needed. Then, at the least difficulty, they areback into the regression act, apparently helpless and needy and ask-ing for more than the parents want to give. This isn't so surprising,really. It is just the last major episode of parent-offspring conflict inthe long drama of development. In a few years the adolescent reallywill be independent and beginning to look longingly at a potentialpartner with whom to raise a family and start a new episode in thatongoing drama of adaptively modulated conflict and cooperationcalled sexual reproduction.

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I sometimes hold it half a sinTo put in words the grief I feel:For words, like Nature, half reveal

And half conceal the Soul within.

But, for the unquiet heart and brain,A use in measured language lies;The sad mechanic exercise,

Like dull narcotics, numbing pain.

-Alfred, Lord Tennyson,In Memoriam, canto VA young woman recently came to the Anxiety Disorders

Clinic at The University of Michigan, complaining ofl attacks of overwhelming fear that had come out of the

blue several times each week for the past ten months.During these attacks, she experienced a sudden onset of rapid pound-ing heartbeats, shortness of breath, a feeling that she might faint,trembling, and an overwhelming sense of doom, as if she were aboutto die. A few years ago, such people usually insisted that they hadheart disease, but this person, like so many now, had read about hersymptoms and knew that they were typical of panic disorder. In thecourse of the evaluation it came out that she had experienced her first

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panic attacks at about the same time as she had begun an extramaritalaffair. When the doctor asked if there might be a connection, shesaid, "I don't see what that has to do with it. Everything I read saysthat panic disorder is a disease caused by genes and abnormal brainchemicals. I just want the medicine that will normalize my brainchemicals and stop these panic attacks, that's all."

How times change! Twenty years ago, people who insisted thattheir anxiety was "physical" were often told that they were denyingthe truth in order to avoid painful unconscious memories. Nowmany psychiatrists would readily agree that depression or anxiety canbe a symptom of a biological disease caused by brain abnormalitiesthat need drug treatment. Some people, like the woman describedabove, so embrace this view that they are offended if the psychiatristinsists on attending to their emotional life. The opening lines of aninfluential review article summarize these changes:

The field of psychiatry has undergone a profoundtransformation in recent years. The focus of researchhas shifted from the mind to the brain . . . at the sametime the profession has shifted from a model of psy-chiatric disorders based on maladaptive psychologi-cal processes to one based on medical diseases.

Strong forces have pushed the field of psychiatry to adopt this"medical model" for psychiatric disorders. The change began in the1950s and 1960s with discoveries of effective drug treatments fordepression, anxiety, and the symptoms of schizophrenia. These dis-coveries spurred the government and pharmaceutical companies tofund research on the genetic and physiological correlates of psychi-atric disorders. In order to define these disorders so research findingsfrom different studies could be compared, a new approach to psychi-atric diagnosis was created, one that emphasizes sharp boundariesaround clusters of current symptoms instead of continuous grada-tions of emotions caused by psychological factors, past events, andlife situations. Academic psychiatrists focus increasingly on the neu-rophysiological causes of mental disorders. Their views are transmit-ted to residents in training programs and to practitioners viapostgraduate medical seminars. Finally, with the rise of insurancefunding for medical care during recent decades and the possibility offederal funding for universal medical coverage in the United States,

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organizations of psychiatrists have become insistent that the disor-ders they treat are medical diseases like all others and thereforedeserve equal insurance coverage.

Are panic disorder, depression, and schizophrenia medical dis-eases just like pneumonia, leukemia, and congestive heart failure? Inour opinion, mental disorders are indeed medical disorders, but notbecause they are all distinct diseases that have identifiable physicalcauses or because they are necessarily best treated with drugs.Instead, mental disorders can be recognized as medical disorderswhen they are viewed in an evolutionary framework. As is the casefor the rest of medicine, many psychiatric symptoms turn out not tobe diseases themselves but defenses akin to fever and cough. Fur-thermore, many of the genes that predispose to mental disorders arelikely to have fitness benefits, many of the environmental factors thatcause mental disorders are likely to be novel aspects of modern life,and many of the more unfortunate aspects of human psychology arenot flaws but design compromises.

EMOTIONS

U Tnpleasant emotions can be thought of as defenses akinto pain or vomiting. Just as the capacity for physicalpain has evolved to protect us from immediate andfuture tissue damage, the capacity for anxiety has

evolved to protect us against future dangers and other kinds ofthreats. Just as the capacity for experiencing fatigue has evolved toprotect us from overexertion, the capacity for sadness may haveevolved to prevent additional losses. Maladaptive extremes of anxi-ety, sadness, and other emotions make more sense when we under-stand their evolutionary origins and normal, adaptive functions. Wealso need proximate explanations of both the psychological and brainmechanisms that regulate and express these emotions. If we find whatlook like abnormalities in the brains of people who are anxious orsad, we cannot conclude that these brain changes cause the disorderin any but the most simplistic sense. Brain changes associated withanxiety or sadness may merely reflect the normal operation of nor-mal mechanisms.

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Knowledge about the normal functions of the emotions wouldprovide, for psychiatry, something like what physiology provides forthe rest of medicine. Most mental disorders are emotional disorders,so you might think that psychiatrists are well versed in the relevantscientific research, but no psychiatric training program systemati-cally teaches the psychology of the emotions. This is not as unfortu-nate as it seems, since research on the emotions has been asfragmented and confused as psychiatry itself. In the midst of ongoingtechnical debates, however, many emotions researchers are reachingconsensus on a crucial point: our emotions are adaptations shaped bynatural selection. This principle holds substantial promise for psychi-atry. If our emotions are subunits of the mind, they can be under-stood, just like any other biological trait, in terms of their functions.Doctors of internal medicine base their work on understanding thefunctions of cough and vomiting and the liver and the kidneys. Anunderstanding of the evolutionary origins and functions of the emo-tions would begin to provide something similar for psychiatrists.

Many scientists have studied the functions of the emotions. Somehave emphasized communication, especially University of Californiapsychologist Paul Ekman, whose studies of the human face demon-strate the cross-cultural universality of emotions. Others emphasizethe utility of emotions for motivation or other internal regulation,but emotions have not been shaped to perform one or even severalfunctions. Instead, each emotion is a specialized state that simultane-ously adjusts cognition, physiology, subjective experience, andbehavior, so that the organism can respond effectively in a particularkind of situation. In this sense, an emotion is like a computer pro-gram that adjusts many aspects of the machine to cope efficientlywith the challenges that arise in a particular kind of situation. Emo-tions are, in the felicitous phrase coined by University of Californiapsychologists Leda Cosmides and John Tooby, "Darwinian algo-rithms of the mind."

Emotional capacities are shaped by situations that occurredrepeatedly in the course of evolution and that were important to fitness. Attacks by predators, threats of exclusion from the group, andopportunities for mating were frequent and important enough tohave shaped special patterns of preparedness, such as panic, socialfear, and sexual arousal. Situations that are best avoided shape aver-sive emotions, while situations that involve opportunity shape posi-tive emotions. Our ancestors seem to have faced many more kinds of

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threats than opportunities, as reflected by the fact that twice as manywords describe negative as positive emotions. This perspective givesthe boot to the modern idea that "normal" life is free of pain. Emo-tional pain is not only unavoidable, it is normal and can be useful. AsE. 0. Wilson put it,

Love joins hate; aggression, fear; expansiveness, with-drawal; and so on; in blends designed not to promotethe happiness and survival of the individual, but tofavor the maximum transmission of the controllinggenes.

But much emotional pain is not useful. Some useless anxiety anddepression arise from normal brain mechanisms, others from brainabnormalities. Major genetic factors contribute to the causation ofanxiety disorders, depression, and schizophrenia. In the next decade,specific genes will no doubt be found responsible for certain kinds ofmental disorders. Physiological correlates have been found for all ofthese disorders, and neuroscientists are hard at work unraveling theresponsible proximate mechanisms. The resulting knowledge hasalready improved the utility of drug treatments and offers the possi-bility of prevention. This is a bright time for psychiatry and for peo-ple with mental disorders. The advances in pharmacologic treatmenthave come so fast that many people remain unaware of their safetyand effectiveness. Treatment is now more effective than the wildesthopes of psychiatrists who went into practice just thirty years ago.

Much confusion attends these advances. The human mind tendsto oversimplify this issue by attributing most bad feelings either togenes and hormones or to psychological and social events. The messytruth is that most mental problems result from complex interactionsof genetic predispositions, early life events, drugs and other physicaleffects on the brain, current relationships, life situations, cognitivehabits, and psychodynamics. Paradoxically, it now is much easier totreat many mental disorders than it is to understand them.

Just as there are several components of the immune system, eachof which protects us against particular kinds of invasions, there aresubtypes of emotion that protect us against a variety of particularkinds of threats. Just as arousal of the immune system usually occursfor a good reason, not because of an abnormality in its regulationmechanism, we can expect that most incidents of anxiety and sadness

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are precipitated by some cause, even if we cannot identify it. On theother hand, the regulation of the immune system can be abnormal.The immune system can be too active and attack tissues it shouldn't,causing autoimmune disorders such as rheumatoid arthritis. Compa-rable abnormalities in the anxiety system cause anxiety disorders.The immune system can also fail to act when it should, causing defi-ciencies in immune function. Might there be anxiety disorders thatresult from too little anxiety?

ANXIETYE -veryone must realize that anxiety can be useful. We knowwhat happens to the berry picker who does not flee a grizzlybear, the fisherman who sails off alone into a winter storm,or the student who does not shift into high gear as a term-

paper deadline approaches. In the face of threat, anxiety alters ourthinking, behavior, and physiology in advantageous ways. If thethreat is immediate, say from the imminent charge of a bull elephant,a person who flees will be more likely to escape injury than one whogoes on chatting nonchalantly. During flight, our survivor experi-ences a rapid heartbeat, deep breathing, sweating, and an increase inblood glucose and epinephrine levels. Physiologist Walter Cannonaccurately described the functions of these components of the "fightor flight" reaction back in 1929. It is curious that his adaptationistperspective has never been extended to other kinds of anxiety.

While anxiety can be useful, it usually seems excessive and unnec-essary. We worry that it will rain at the wedding next June, we loseour concentration during exams, we refuse to fly on airplanes, and wetremble and stumble over our words when speaking in front of agroup. Fifteen percent of the U.S. population has had a clinical anxi-ety disorder; many of the rest of us are just nervous. How can weexplain the apparent excess of anxiety? In order to determine when itis useful and when it is not, we need to ask how the mechanisms thatregulate anxiety were shaped by the forces of natural selection.

Because anxiety can be useful, it might seem optimal to adjust themechanism so that we are always anxious. This would be distressing,but natural selection cares only about our fitness, not our comfort.The reason we are sometimes calm is not because discomfort is mal-

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adaptive but because anxiety uses extra calories, makes us less fit formany everyday activities, and damages tissues. Why does stress dam-age tissues? Imagine a host of bodily responses that offer protectionagainst danger. Those that are "inexpensive" and safe can beexpressed continually, but those that are "expensive" or dangerouscannot. Instead, they are bundled into an emergency kit that isopened only when the benefits of using the tools are likely to exceedthe costs. Some components are kept sealed in the emergency kit pre-cisely because they cause bodily damage. Thus, the damage associ-ated with chronic stress should be no cause for surprise and certainlyno basis for criticizing the design of the organism. In fact, recentwork has suggested that the "stress hormone" cortisol may notdefend against outside dangers at all but instead may mainly protectthe body from the effects of other parts of the stress response.

If anxiety can be costly and dangerous, why isn't the regulatorymechanism adjusted so that it is expressed only when danger is actu-ally present? Unfortunately, in many situations it is not clear whetheror not anxiety is needed. The smoke-detector principle, describedpreviously, applies here as well. The cost of getting killed even onceis enormously higher than the cost of responding to a hundred falsealarms. This was demonstrated by an experiment in which guppieswere separated into timid, ordinary, and bold groups on the basis oftheir reactions when confronted by a smallmouth bass: hiding, swim-ming away, or eyeing the intruder. Each group of guppies was thenleft in a tank with a bass. After sixty hours, 40 percent of the timidguppies and 15 percent of the ordinary guppies were still there, butnone of the bold guppies had survived.

The psychiatrist's attempt to understand how natural selectionhas shaped the mechanism that regulates anxiety is conceptually thesame as the electronics engineer's problem of determining if a signalon a noisy telephone line is actually information or just static. Signaldetection theory provides a way to analyze such situations. With anelectronic signal, the decision about whether to call a given click asignal or noise depends on four things: (1) the loudness of the signal,(2) the ratio of signals to noise, (3) the cost of mistakenly thinking thata noise is actually a signal (false alarm), and (4) the cost of mistakenlythinking that a signal is actually a noise (false negative response).

Imagine that you are alone in the jungle and you hear a branch breakbehind a bush. It could be a tiger, or it could be a monkey. You couldflee, or you could stay where you are. To determine the best course of

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action, you need to know: (1) the relative likelihood that a sound ofthis magnitude would come from a tiger (as opposed to a monkey), (2)

the relative frequency of tigers and monkeys in this location, (3) thecost of fleeing (the cost of a false alarm), and (4) the cost of not fleeingif it really is a tiger (the cost of a false negative response). What if youhear the sound of a medium-sized stick breaking behind that bush? Theindividual whose anxiety level is adjusted by an intuitive, quick, andaccurate signal detection analysis will have a survival advantage.

The analogy with the immune disorders suggests that there mightbe a whole category of people with unrecognized anxiety disorders,namely those who have too little anxiety. Isaac Marks, the anxietyexpert at the University of London, has coined the term "hypopho-bics" for such people. They don't complain and don't seek psychi-atric treatment but instead end up in emergency rooms or fired fromtheir jobs. As psychiatrists prescribe new antianxiety drugs with fewside effects, we may create such conditions. For instance, one patient,shortly after starting on an antianxiety medication, impulsively toldher husband that she wanted him to leave. He was very surprised butdid. A week later she realized that she had three small children, amortgage, no income, and no helpful relatives. A bit more anxietywould have inhibited such hasty action. Of course, no case is simple.This particular woman had long-standing marital dissatisfactions,and her emotional outburst might, in the long run, have left her bet-ter off. Her story illustrates one possible function of passions, as dis-tinct from rational decisions. As suggested by Cornell economistRobert Frank, passions motivate actions that seem impulsive butmay actually benefit the person in the long run.

NOVEL DANGERSI n the chapter on injuries, we described experiments that showedhow monkeys' fear of snakes is "prepared." Most of our exces-sive fears are related to prepared fears of ancient dangers. Dark-ness, being away from home, and being the focus of a group's

attention were once associated with dangers but now mainly causeunwanted fears. Agoraphobia, the fear of leaving home, develops inhalf of people who experience repeated panic attacks. Staying homeseems senseless until you realize that most episodes of panic in the

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ancestral environment were probably caused by close encounterswith predators or dangerous people. After a few such close calls, awise person would try to stay home when possible, would ventureout only with companions, and be ready to flee in panic at the leastprovocation: the exact symptoms of agoraphobia.

Do anxiety disorders, like many other diseases, result from novelstimuli not found in our ancestral environment? Not often. New dan-gers such as guns, drugs, radioactivity, and high-fat meals cause toolittle fear, not too much. In this sense we all have maladaptivehypophobias, but few of us seek psychiatric treatment to increase ourfear. Some novel situations, especially flying and driving, do oftencause phobias. In both cases, the fear has been prepared by eons ofexposure to other dangers. Fear of flying has been prepared by thedangers associated with heights, dropping suddenly, loud noises, andbeing trapped in a small, enclosed place. The stimuli encountered inan automobile zooming along at sixty miles an hour are novel, butthey too hark back to ancestral dangers associated with rapid move-ment, such as the rushing attack of a predator. Automobile accidentsare so common and so dangerous that it is hard to say if fear of driv-ing is beneficial or harmful.

The genetic contributions to anxiety disorders are substantial.Most people with panic disorders have a blood relative who has thesame problem, and the search is on for the responsible genes. Willthese genes turn out to result from mutant genes that have not beenentirely selected out? Will they turn out to have other benefits? Orwill we discover that genetic susceptibility to panic is simply one endof a normal distribution, like a tendency to develop a high fever witha cold or a tendency to vomit readily? When we find specific genesthat predispose to panic and other anxiety disorders, we will stillneed to find out why those genes exist and persist.

SADNESS AND DEPRESSION

epression sometimes seems like a modern plague. After| motor vehicle accidents, suicide is the second leading

cause of death of young adults in North America. Nearly10 percent of young adults in the United States have

experienced an episode of serious depression. Furthermore, the rates

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seem to have increased steadily in the past few decades, doublingevery ten years in many industrial countries.

Depression may seem completely useless. Even apart from therisk of suicide, sitting all day morosely staring at the wall can't getyou very far. A person with severe depression typically loses interestin everything-work, friends, food, even sex. It is as if the capacitiesfor pleasure and initiative have been turned off. Some people cryspontaneously, but others are beyond tears. Some wake every morn-ing at 4 A.M. and can't get back to sleep; others sleep for twelve orfourteen hours per day. Some have delusions that they are impover-ished, stupid, ugly, or dying of cancer. Almost all have low self-esteem. It seems preposterous even to consider that there should beanything adaptive associated with such symptoms. And yet depres-sion is so frequent, and so closely related to ordinary sadness, that wemust begin by asking if depression arises from a basic abnormality orif it is a dysregulation of a normal capacity.

There are many reasons to think that the capacity for sadness is anadaptive trait. A universal capacity, it is reliably elicited by certaincues, notably those that indicate a loss. The characteristics of sadnessare relatively consistent across diverse cultures. The hard part is fig-uring out how these characteristics can be useful. The utility of hap-piness is not difficult to understand. Happiness makes us outgoingand gives us initiative and perseverance. But sadness? Wouldn't webe better off without it? One test would be to find people who do notexperience sadness and see if they experience any disadvantages. Oran investigator could use a drug that blocks normal sadness, a studythat we fear may soon be conducted inadvertently on a massive scaleas more and more people take the new psychoactive drugs. While wewait for such studies to be done, the characteristics of sadness andthe situations that arouse it provide clues that may help us to dis-cover its functions.

The losses that cause sadness are losses of reproductive resources.Whether of money, a mate, reputation, health, relatives, or friends,the loss is always of some resource that would have increased repro-ductive success through most of human evolution. How can a loss bean adaptive challenge, a situation that would benefit from a specialstate of preparation? A loss signals that you may have been doingsomething maladaptive. If sadness somehow changes our behavior soas to stop current losses or prevent future ones, this would be help-ful indeed.

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How can people behave differently after a loss in a way thatincreases fitness? First, you should stop what you are doing. Just aspain can make us let go of a hot potato, sadness motivates us to stopcurrent activities that may be causing losses. Second, it would bewise to set aside the usual human tendency to optimism. Recentstudies have found that most of us consistently overestimate ourabilities and our effectiveness. This tendency to optimism helps usto succeed in social competition, where bluffing is routine, and alsokeeps us pursuing important strategies and relationships even attimes when they are not paying off. After a loss, however, we musttake off the rose-colored glasses in order to reassess our goals andstrategies more objectively.

In addition to sudden losses, there are situations in which anessential resource is simply not available despite major expendituresand our best plans and efforts. Jobs end, friendships fade, marriagessour, and goals must be abandoned. At some point one must give upon a major life project in order to use the resources to start some-thing else. Such giving up should not be done lightly. Quitting one'sjob shouldn't be done impulsively, because there are costs involvedin retraining and starting at the bottom of another hierarchy. Like-wise, it is foolish to casually give up any important relationship or lifegoal in which a major investment has already been made. So we don'tusually make major life changes quickly. "Low mood" keeps us fromjumping precipitously to escape temporary difficulties, but as diffi-culties continue and grow and our life's energies are progressivelywasted, this emotion helps to disengage us from a hopeless enterpriseso that we can consider alternatives. Therapists have long known thatmany depressions go away only after a person finally gives up somelong-sought goal and turns his or her energies in another direction.

The capacity for high and low mood seems to be a mechanism foradjusting the allocation of resources as a function of the propitious-ness of current opportunities. If there is little hope of payoff, it is bestto sit tight rather than to waste energy. Real estate agents who enterthe business during an economic downturn may be making a mis-take. Students who are failing a course would sometimes do best todrop it and try another subject. Farmers who plant their fields duringa drought may go broke. If, by contrast, we come upon a short-livedopportunity, then it may be best to make a major, intense effort,despite the possible risks, in order to have a chance at a big payoff.When a million dollars in cash fell out of the back of an armored car

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on the streets of Detroit, a few people who made an intense, briefeffort profited nicely.

A better understanding of the functions of sadness will soon beessential. We are fast gaining the capacity to adjust mood as wechoose. Each new generation of psychotropic drugs has increasingpower and specificity with fewer side effects. Decades ago there was ahue and cry about "soma," the fictional drug that made people toler-ate tedious lives in Aldous Huxley's Brave New World. Now that sim-ilar substances loom as a reality, strangely little is being said. Dopeople not realize how fast this train is moving? We certainly shouldtry to relieve human suffering, but is it wise to eliminate normal lowmood? Many people intuitively feel it is wrong to use drugs to changemood artificially, but they will have a hard time arguing against theuse of nonaddicting drugs with few side effects. The only medical rea-son not to use such drugs is if they interfere with some useful capac-ity. Soon-very soon-people will be clamoring to know whensadness is useful and when it is not. An evolutionary approach pro-vides a foundation for addressing these questions.

We are aware that this analysis is vastly oversimplified. People arenot controlled by some internal calculator that crudely motivatesthem to maximize their reproductive success. Instead, people formdeep, lifelong emotional attachments and experience loves and hatesthat shape their lives. They have religious beliefs that guide theirbehavior, and they have idiosyncratic goals and ambitions. They havenetworks of friends and relatives. Human reproductive resources arenot like the squirrel's cache of nuts. They are, instead, constantlychanging states of intricate social systems. All these complexities donot undercut our simple arguments; they just highlight the urgency ofblazing the trail of functional understanding that the adaptationistprogram may provide for human emotions.

While some low mood is normal, some is clearly pathological. Thecauses of such pathology are complex. Genetic factors are importantdeterminants of manic-depressive disorder, a condition in whichmood swings wildly from the depths of depression to aggressiveeuphoria. Having one parent with manic-depressive disorder increasesyour risk of that disorder by a factor of 5, and having two parentsincreases it by a factor of 10 to a likelihood of nearly 30 percent. Thesegenes are not rare-manic-depressive illness occurs in 1 out of 200people. Our next, by now familiar, question is, Why are these genesmaintained in the gene pool? The answer is equally familiar: They

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probably offer some advantage, either in certain circumstances or incombination with certain other genes. A study by Nancy Andreasen,professor of psychiatry at the University of Iowa, found that 80 per-cent of the faculty at the renowned Iowa Writer's Workshop hadexperienced some kind of mood disorder. Is creativity a benefit of thegenes that cause depression? The disease wreaks havoc in some indi-vidual lives, but the genes that cause it seem nonetheless to offer a fit-ness advantage either to some people with the disorder or to otherpeople in whom the gene does not cause the disorder but has other,beneficial effects.

John Hartung, an evolutionary researcher at the State University ofNew York, has suggested that depression is common in people whoseabilities threaten their superiors. If a person with lower status demon-strates his or her full abilities, this is likely to bring attack from themore powerful superior. The best protection, Hartung suggests, is toconceal your abilities and to deceive yourself about them so as tomore readily conceal your ambitions. This could well explain someotherwise mysterious cases of low self-esteem in successful people.Hartung's theory reminds us of the complexity of human emotions.

Another major effort to understand mood has come from a groupof researchers who are pursuing British psychiatrist John Price's the-ory of the role of mood in human status hierarchies. They haveargued that depression often results when a person is unable to win ahierarchy battle and yet refuses to yield to the more powerful person.They suggest that depression is an involuntary signal of submissive-ness that decreases the likelihood of attacks by dominants. In casestudies they describe how submitting voluntarily can end depression.

UCLA researchers Michael Raleigh and Michael McGuire havefound a brain mechanism that connects mood and status. In studiesof vervet monkeys, they found that the highest-ranking (alpha) malein each group had levels of a neurotransmitter (serotonin) that weretwice as high as those of other males. When these "alpha" males losttheir position, their serotonin levels immediately fell and they hud-dled and rocked and refused food, looking for all the world likedepressed humans. These behaviors were prevented by the adminis-tration of antidepressants, such as Prozac, that raise serotonin levels.Even more astounding, if the researchers removed the alpha malefrom a group and gave antidepressants to some other randomly cho-sen male, that individual became the new alpha male in everyinstance. These studies suggest that the serotonin system may func-

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tion, in part, to mediate status hierarchies and that some low moodmay be a normal part of status competitions. If this is so, one cannothelp but wonder what will happen in large corporations as more andmore depressed employees start taking antidepressants.

Still another approach to understanding depression is based onthe increase of the state that occurs when the amount of daylightdecreases in the fall. The large number of people affected with thisseasonal affective disorder (SAD) and its strong association with coldclimates have suggested to many researchers that low mood may be avariant or remnant of a hibernation response in some remote ances-tor. The preponderance of women with SAD has suggested that theresponse may somehow regulate reproduction.

Are there novel aspects of our modern environment that makedepression and suicide more likely? While every age seems to havebelieved that people are not as happy as they were in earlier times,some recent evidence suggests that we may actually be in an epidemicof depression. A team of distinguished investigators looked at datafrom 39,000 people in nine different studies carried out in fivediverse areas of the world and found that young people in each coun-try are far more likely than their elders to have experienced anepisode of major depression. Furthermore, the rates were higher insocieties with higher degrees of economic development. Muchremains to be done to confirm this finding, but it justifies an intensestudy of novel aspects of modern life that might contribute to dra-matic increases in depression. We will mention only two: mass cornmunications and the disintegration of communities.

Mass communications, especially television and movies, effectivelymake us all one competitive group even as they destroy our more inti-mate social networks. Competition is no longer within a group of fiftyor a hundred relatives and close associates, but among five billion peo-ple. You may be the best tennis player at your club, but you are prob-ably not the best in your city and are almost certainly not the bestin your country or planet. People turn almost every activity into a cornpetition, whether it be running, singing, fishing, sailing, seducing,painting, or even bird watching. In the ancestral environment youwould have had a good chance at being best at something. Even if youwere not the best, your group would likely value your skills. Now weall compete with those who are the best in all the world.

Watching these successful people on television arouses envy.Envy probably was useful to motivate our ancestors to strive for

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what others could obtain. Now few of us can achieve the goals envysets for us, and none of us can achieve the fantasy lives we see on tele-vision. The beautiful, handsome, rich, kind, loving, brave, wise, cre-ative, powerful, brilliant heroes we see on the screen are out of thisworld. Our own wives and husbands, fathers and mothers, sons anddaughters can seem profoundly inadequate by comparison. So we aredissatisfied with them and even more dissatisfied with ourselves.Extensive studies by psychologist Douglas Kenrick have shown thatafter being exposed to photos or stories about desirable potentialmates, people decrease their ratings of commitment to their currentpartners.

Our new technology also dissolves supportive social groups. Formembers of our socially oriented species, the worst punishment issolitary confinement, but many modern, anonymous groups are notmuch better. They often consist mostly of competitors with only anoccasional comrade and no blood relatives. Extended families disinte-grate as individuals scatter to pursue their economic goals. Even thenuclear family, that last remnant of social stability, seems doomed,with more than half of all marriages now ending in divorce and moreand more children being born to single women.

We have a primal need for a secure place in a supportive group.Lacking family, we turn elsewhere to meet this need. More and morepeople have their social base in groups of friends, twelve-step pro-grams such as Alcoholics Anonymous, support groups of all kinds,or psychotherapy. Many people turn to religion in part because ofthe group it provides. Some people advocate "family values" inhopes of preserving a threatened but cherished way of life. Most ofus want most of all to be loved by someone who cares about us forourselves, not for what we can do for them. For many, the search isbitter and fruitless.

LACK OF ATTACHMENT

P re-evolutionary theories, both psychoanalytic and behav-ioral, explained the bond between mother and child as theresult of feeding and caretaking. Primatologist Harry Harlowbegan to challenge these theories with studies of monkeys at

the University of Wisconsin in the early 1950s. Infant monkeys were

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separated from their mothers and provided with two surrogate moth-ers, one a wire form with a baby bottle full of milk, the other a softcloth-covered form without a bottle. Although infants got milk fromthe wire mother, it was the cloth surrogate they clung to, screaming ifit was removed. Harlow concluded that there must be a special mech-anism that evolved to facilitate the bonding of mother and infant.Inspired by Rene Spitz's studies of the social inadequacy of childrenraised in orphanages, Harlow next raised monkey infants in isolation.Such monkeys never became normal. They could not get along withother monkeys, had great difficulty in mating, and neglected orattacked any babies they had.

John Bowlby, an English psychiatrist, attended seminars with biol-ogist Julian Huxley in 1951 and was inspired to read the imprintingexperiments done by Nobel Prize-winning ethologist Konrad Lorenz.During a very specific critical period early in life, baby goslingsimprint on their mothers or any other appropriate-sized movingobject they encounter. Konrad Lorenz's boots were sufficiently simi-lar, and many photos show him being trailed by a line of goslings.Bowlby wondered if many of his patients' difficulties were sequelae ofproblems with early attachment. As he looked at their first relation-ships, he found problems everywhere. Some had mothers who hadnever wanted them, others had mothers who were too depressed torespond to smiles and coos. Many had heard their mothers threatento kill themselves and had grown up under this specter. People's earlydifficulties matched the problems they experienced as adults. Theycould not trust people, they expected to be rejected, and they felt theyhad to please people or they would be abandoned. Bowlby percep-tively recognized that some of the clinging and withdrawal behavior ofneglected babies might be adaptive attempts to engage the mother.Instead of criticizing patients for being "dependent," he recognizedthat they were trying to protect themselves from a feared separation.

Psychologist Mary Ainsworth and her colleagues did the con-trolled studies that brought Bowlby's theories to mainstream psy-chology. She put young children into a room and observed theirbehavior when the mother left and later returned. On the basis of this"strange situation" test, she classified babies into those who weresecurely attached and those who were anxiously attached or whoavoided their mothers on reunion. Which group the child fit intostrongly predicted many other characteristics from group-play pat-terns to personality characteristics many years later. Much remains

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to be done to determine what the relationship is between attachment

problems and adult psychopathology and how it relates to geneticfactors. Psychiatrists should not forget that mothers provide not onlyearly experiences for their children; they also provide genes. At pres-ent we have reason to believe that many problems adults have in get-ting along with other people may have their origins in problems withthe first attachment.

CHILD ABUSEC hild abuse seems to have become epidemic among us.How can this be? Why would we attack our own children,the vehicles of our reproductive success? Are some par-ents more likely to abuse than others? Canadian psychol-

ogists Martin Daly and Margo Wilson's evolutionary perspective ledthem to wonder if the presence or absence of a blood relationshipbetween parents and children might predict the likelihood of childabuse. Because of the vagaries in the reporting of child abuse, theylooked at an outcome that was easy to count and hard to hide-mur-ders of children by their parents. The correlation was stronger thaneven they had dared to imagine. The risk of fatal child abuse for chil-dren living with one nongenetic parent is seventy times higher than itis for children living with both biological parents. This finding wasnot explainable by any tendency of families with stepparents to havemore alcoholism, poverty, or mental illness. In several decades ofresearch, no other risk factor has proved anywhere near as powerfulin predicting child abuse. Many who have studied child abuse fordecades never thought to look at the significance of kinship, but toevolutionists this was an obvious suspect.

Daly and Wilson were inspired, in part, by studies on infanticidein animals carried out by California anthropologist Sarah Hrdy and

others. When Hrdy reported in 1977 that male languar monkeys rou-tinely tried to kill the infants of females in a group they had just takenover from another male, no one wanted to believe her. She reportedthat the monkey mothers tried to protect their infants but often didnot succeed. When they failed, nursing stopped, estrus came quickly,and the monkey mothers promptly mated with the males who hadkilled their infants. Hrdy noted that males who killed existing infants

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would increase their reproductive success because the cessation ofnursing brought the females into estrus so they could become preg-nant with the offspring of the new male sooner.

Subsequent field research has confirmed Hrdy's findings andextended them to many other species. Male lions kill existing cubswhen they begin mating with new females. Among mice, the meresmell of a strange male often induces miscarriage-apparently anadaptation to prevent wasting investment on babies that are likely tobe killed. Animals are inevitably designed to do whatever willincrease the success of their'genes, grotesque though the resultingbehavior may seem.

The tendency for male animals to kill the offspring of other malesin certain circumstances is an evolved adaptation. Is child abuse inhumans in any way related? We had thought not, both becausehuman males don't routinely take over a group of breeding femaleswith young offspring and because many foster fathers are obviouslycapable of providing excellent care for children who are not theirown. We had guessed that children are abused not because of anevolved adaptation but because a normal adaptation failed when oneof the parents had too little early contact with the child to facilitatenormal attachment. However, studies by anthropologist Mark Flinnin Trinidad have found that stepparents still treat their stepchildrenmore harshly than their natural children, regardless of the amount ofearly contact with the baby. More is involved in forming humanattachments than merely spending time together. Much moreresearch is needed to explore this murky intersection of biology andculture.

SCHIZOPHRENIAT w he symptoms of schizophrenia, unlike those of anxiety anddepression, are not a part of normal functioning. Hearingvoices, thinking that others can read your mind, emotionalnumbness, bizarre beliefs, social withdrawal, and paranoia

appear together as a syndrome not because they are parts of anevolved defense. It is more likely that one kind of brain damage cancause many malfunctions, just as heart damage can cause shortness ofbreath, chest pain, and swollen ankles. Schizophrenia disrupts the

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perceptual-cognitive-emotional-motivational system. This is anotherway of saying that we still don't know how to describe the higher lev-els of brain function.

Schizophrenia affects about 1 percent of the population in diversesocieties worldwide. The notion that it is a disease of civilization seemsto be incorrect, although there have recently been suggestions that thecourse of the disease is worse in modem societies. Compelling evi-dence suggests that susceptibility to schizophrenia depends on certain

genes. Relatives of schizophrenics are several times more likely thanother people to get the disease, even if they were raised by nonschizo-phrenic adoptive parents. If one identical twin has schizophrenia, thechance of the other getting it is about 50 percent, while the risk for anonidentical twin is about 25 percent. There is also evidence that schiz-ophrenia decreases reproductive success, especially in men.

These observations call up our standard question: What canaccount for the high incidence of genes that can decrease fitness?Selection against the genes that cause schizophrenia is strong enoughthat they should be far less common if their presence were due sim-ply to mutation balanced by selection. Furthermore, the relativelyuniform rates of schizophrenia suggest that the responsible genes didnot arise recently but have been maintained for millennia. It appearsthat the genes that cause schizophrenia must somehow confer anadvantage that balances the severe costs.

The most likely possibility is that these genes are advantageous incombination with certain other genes, or in certain environments,much in the way a single sickle-cell gene is advantageous even thoughhaving two such genes causes sickle-cell anemia. Or it might be thatthe genes that predispose to schizophrenia have other effects thatoffer a slight advantage in most people who have them, even thougha small proportion develop the disease. A number of authors havespeculated on the kinds of advantages that might accrue to peoplewho have genes that predispose to schizophrenia: perhaps theyincrease creativity or sharpen a person's intuitions about what othersare thinking. Perhaps they protect against some disease. Some havesuggested that the tendency to suspiciousness itself may compensatesomewhat for the disadvantages of schizophrenia. Evidence for theseideas remains scattered, but they are worth pursuing. Support is pro-vided by evidence of high levels of accomplishment in relatives ofschizophrenics who are not affected by the disease. This whole area isjust beginning to be explored.

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SLEEP DISORDERSS leep, like so many other bodily capacities, commands ourattention only when it goes awry, which it does for manypeople in many ways. For sleep, as for so many things, tim-ing is often the crucial factor. Most sleep problems involve

an inability to sleep at the proper time or a tendency to sleep at thewrong time. Insomnia affects more than 30 percent of the populationand is the spur to a huge industry, from over-the-counter sleepingpills to specialized medical clinics. The people who suffer from day-time sleepiness are often the same ones who don't sleep well at night.Sleepiness is a bother when you are trying to read in the evening, ahandicap after the alarm rings in the morning, and a positive dangerif it happens while you are driving.

Then there are dreams and their disorders, nightmares and nightterrors. Some people experience a kind of lack of coordination of theaspects of sleep and become conscious while still dreaming andunable to move, a frightening state indeed. People with narcolepsyslip suddenly into dreaming sleep in the midst of everyday activities,sometimes so swiftly that they fall and injure themselves. And thenthere are the people with sleep apnea, who intermittently stop breath-ing during sleep with resulting nighttime restlessness, daytime tired-ness, and even brain damage. In order to understand these problems,we need to know more about the origins and functions of normalsleep.

Is sleep a trait that has been shaped by natural selection? There areseveral reasons to think so. First, the trait is widespread among ani-mals and perhaps universal among vertebrates. In some animals thatseem not to sleep, such as dolphins, one half of the brain in factsleeps while the other stays awake, possibly because they mustrepeatedly swim to the surface to breathe. Second, all vertebratesseem to share the same sleep regulation mechanisms, with the centerthat controls dreaming sleep consistently located in the ancient partsof the brain. Third, the patterns of mammalian sleep, with its periodsof rapid eye movement and rapid brain waves, are also shared withbirds, whose evolution diverged from ours before the time of thedinosaurs. Fourth, the wide variation in the actual patterns of sleep,even in closely related mammals, suggests that whatever kind ofsleeping was done by our most recent common ancestor could evolve

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rapidly to match the species' particular ecological niche. Finally, ifdeprived of sleep, all animals function poorly.

In order to better understand sleep difficulties, we would like tounderstand how the capacity and necessity for sleep increase fitness.One major contribution to the problem came in 1975 from Britishbiologist Ray Meddis, who proposed that the amount and timing ofour sleep are set by our potential for productive activity in differentphases of the day-night cycle. As one reviewer of Meddis's book putit, our motivation to sleep at night arises from the desirability of stay-ing off the streets. If there are special dangers in being abroad in thedark and little likelihood of positive accomplishment then, we arebetter off resting. This explains why humans and other animals ben-efit from a daily cycle of activity, but it does not explain why we sleepinstead of just spending the night quietly awake, ready for any oppor-tunities or dangers that may arise. It also does not explain why wehave become so dependent on sleep that its lack makes us barely ableto function.

Here is one possible perspective on the evolutionary origins ofsleep. Imagine that some distant ancestor needed no sleep. If one lineof its descendents had experienced greater dangers at one part of theday-night cycle (let's assume for simplicity that it was night) andgreater opportunities during the day, then individuals who were inac-tive at night would have had a fitness advantage. As the species grad-ually came to confine its activity to the daylight hours, its nocturnalquiescence grew ever more prolonged and profound until it reliablyspent many hours of every night inactive.

Given such a reliable daily period of inactivity, other evolutionaryfactors would be expected to act. It is unlikely that all needed cellularmaintenance activities would proceed equally well whether an animalwere awake or asleep. If some needed processes worked more effi-ciently when the brain was disengaged from its usual tasks, selectionwould act to delay them during the wakeful day and catch up duringthe night, thus favoring development of the state we recognize as

sleep. In this way, as suggested in 1969 by Ian Oswald of EdinburghUniversity, some brain maintenance processes would be confinedmore and more to sleep and we would become more and moredependent on sleep. During this period, of course, it would be neces-sary for sleeping individuals to be quite safe, otherwise sleep wouldquickly have been selected against. Just as we became dependent ongetting vitamin C from foods only because we could reliably get

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plenty of it, the steady availability of a period of safe rest was neces-sary before certain bodily maintenance mechanisms could be carriedout only during sleep. One implication is that a search for metabolicprocesses confined to sleep, or taking place at a much greater rateduring sleep, will provide insights on why we need to sleep. Indeed,brain scans have shown that protein synthesis is greatest duringdreamless sleep and that mechanisms for synthesizing certain neuro-transmitters can't keep up with daytime utilization and thereforemust catch up at night. Furthermore, cell division is fastest in all tis-sues during sleep.

Once sleep was established for physiological repair, naturalselection might well have relegated other functions to this period.Those most often suggested have been the memory-regulation func-tions. Researchers Allan Hobson and Robert McCarley haveargued that dreaming sleep supports the physiology that consoli-dates learning. Francis Crick and Graeme Mitchison have evidencethat dreaming sleep functions to purge unnecessary memories,much as we periodically discard unnecessary files from our com-puters. We won't consider these suggestions in detail but will onlypoint out only that these are not necessarily mutually exclusivealternatives, nor are they at odds with Oswald's idea that sleepevolved as a period of tissue repair. None of this contradicts Med-dis's observation that sleep regulates activity periods depending onthe animal's ecology. Like other traits, sleep undoubtedly has manyimportant functions. While each hypothesized function needs to betested, support for one alternative provides evidence againstanother only if the functions are incompatible. Studies of sleep pat-terns in many different animal groups in relation to their ways oflife and evolutionary relationship to one another could providehelpful evidence.

Now that we are seldom threatened by nocturnal predators suchas tigers, and now that artificial light makes productive activity possi-ble throughout the night, the need for regular sleep has become agreat bother, especially when we fly across the world and our bodiesinsist on living according to our original time zone. Looking for thefunctions of sleep may well provide the knowledge we need to adaptit better to our present needs-or, at the very least, to make it possi-ble to read in the evening without falling asleep and then to sleepsoundly through the night despite our worries about the crisestomorrow might bring.

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DREAMINGD -reaming has interested people since the dawn of historyand no doubt through much of prehistory. In recentyears, many theories have been proposed about the func-tions of dreams, from Freud's theory of dreams fulfilling

forbidden wishes to Francis Crick's theory that dreams erase andreorganize memories. But the debate has been so inconclusive thatsome current major authorities, like Harvard's Allan Hobson, canstill argue that dreams may have no specific function but are mainlyepiphenomena of brain activities. This seems unlikely to us, given thesimple observation that deprivation of dreaming sleep causes severepsychopathology. For instance, cats kept on tiny islands in a poolwere able to sleep, but the loss of muscle tone that accompaniesdreaming sleep slipped them into the water and woke them. Suchdeprivation of dreaming sleep made these unfortunate cats wild andhypersexual and shortened their lives.

Even without delineating the function of dreams, an evolutionaryapproach can contribute to their understanding. Donald Symons, anevolutionary anthropologist at the University of California (SantaBarbara), recently proposed that there are, for evolutionary reasons,serious constraints on the stimuli we experience in dreams. Whileindividual sleep behavior varies enormously, we tend, in dreams, toexperience a wealth of our own actions and of sights but very littlesound, smell, or mechanical stimulation. We can dream about doingthings without actually moving because our motor nerves are para-lyzed when we are in the kind of sleep that permits dreaming. Weremember what people in dreams look like and what they tell us, butwe do not remember as easily what their voices sounded like. Wemay remember enjoying a dreamworld glass of wine, but we oftencannot recall its bouquet. We can dream that someone strikes us butmay not remember what it felt like.

The reason for these constraints, Symons suggests, is that theywere required by Stone Age realities. We could afford visual hallu-cinations, because closed eyes made sight useless; it was too darkfor effective vision anyhow. By contrast, a cry of alarm, the smell ofa tiger, or the panicky grasp of a child were important cues thatrequired unimpaired vigilance of our senses of hearing, smell, andtouch. Some species sleep with their eyes open, but we sleep with

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our ears open: we cannot let our dreams distract us from importantsounds. Symon's theory explains some of the peculiarities of dream-ing (and predicts some not yet noticed), and it will stand or fallaccording to how well its expectations conform to actual findings onthe sensory composition of dreams. So far it seems to account formost of the available evidence.

THE FUTURE OF PSYCHIATRY

sychiatry has recently emulated the rest of medicine bydevising clear (if somewhat arbitrary) diagnostic categories,reliable methods of measuring symptoms, and standardrequirements for experimental design and data analysis. Psy-

chiatric research is now just as quantitative as that in the rest of med-icine. Has all this apparent rigor brought psychiatry acceptance asjust another medical specialty like neurology, cardiology, or endo-crinology? Hardly. The research findings are solid, but they are notconnected in any coherent theory. In its attempt to emulate othermedical research by searching for the molecular mechanisms of dis-ease, psychiatry has ironically deprived itself of precisely the con-cepts that provide the tacit foundation for the rest of medicalresearch. By trying to find the flaws that cause disease without under-standing normal functions of the mechanisms, psychiatry puts thecart before the horse.

Research on the anxiety disorders exemplifies the problem. Psy-chiatrists now divide anxiety disorders into nine subtypes, and manyresearchers treat each as a separate disease, investigating its epidemi-ology, genetics, brain chemistry, and response to treatments. The dif-ficulty is, of course, that anxiety is not itself a disease but a defense.To appreciate the problems this creates, imagine what would happenif doctors of internal medicine studied cough the way modern psy-chiatrists study anxiety. First, internists would define "cough disor-der" and create objective criteria for diagnosis. Perhaps the criteriawould say you have cough disorder if you cough more than twice perhour over a two-day period or have a coughing bout that lasts morethan two minutes. Then researchers would look for subtypes ofcough disorder based on factor-analytic studies of clinical character-istics, genetics, epidemiology, and response to treatment. They might

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discover specific subtypes of cough disorders such as mild coughassociated with runny nose and fever, cough associated with allergiesand pollen exposure, cough associated with smoking, and cough thatusually leads to death. Next, they would investigate the causes ofthese subtypes of cough disorder by studying abnormalities of neuralmechanisms in people with cough disorders. The discovery thatcough is associated with increased activity in the nerves that cause thechest muscles to contract would stimulate much speculation aboutwhat neurophysiological mechanisms could make these nervesoverly active. The discovery of a cough-control center in the brainwould give rise to another set of ideas as to how abnormalities in thiscenter might cause cough. The knowledge that codeine stops coughwould lead other scientists to investigate the possibility that coughresults from deficiencies in the body's codeinelike substances.

Such a plan of research is obviously ludicrous, but we recognize itsfolly only because we know that cough is useful. Because we know thatcough is a defense, we look for the causes of cough not in the nervesand muscles that generate a cough, or even in the brain mechanismsthat regulate cough, but instead in the situations and stimuli thatnormally arouse the protective cough reflex. While some rare casesof cough may be caused by abnormalities of the cough-regulationmechanisms, the vast majority are adaptive responses that expel for-eign matter from the respiratory tract. Only after searching for such anatural stimulus does a physician consider the possibility that thecough-regulation mechanism itself might be awry.

Many psychiatrists have studied individual differences in suscep-tibility to anxiety with the worthy goal of helping the many peoplewho experience panic, tension, fear, and sleeplessness throughouttheir lives. Nonetheless, this approach fosters much confusion.What if research on cough were to focus on those individuals whohave a lifelong tendency to cough in response to the least stimulus?Such people would be told they have a cough disorder. Soon therewould be campaigns to identify people predisposed to cough disor-der in order to find the genes that cause this abnormality in thecough-regulation mechanism. There undoubtedly are people with agenetic susceptibility to ready coughing, but studying them wouldtell us little about the cause of most coughs.

There are limits to this analogy. Anxiety is much more compli-cated than cough, its functions are less obvious, and it varies muchmore from individual to individual. More important, the cues that

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arouse anxiety are far less tangible than those that arouse cough.Cough is caused by foreign material in the respiratory tract, while anx-iety is aroused by diverse cues processed by the mind in mysteriousways. The most obvious anxiety cues are images of dangerous objectsor stimuli that have been paired with pain or some other noxiousstimulus. Most clinical anxiety is aroused, however, by complex cuesthat require subtle interpretation. If, for example, the boss doesn'tgreet you, you are not invited to a meeting, and a friend avoids you ona day when layoff notices are to be distributed, you may feel seriousapprehension. If it is your birthday, however, and you suspect a sur-prise party may be in the works, the same stimuli will arouse a verydifferent reaction. This example only begins to tap the complexity ofthe mental systems that regulate anxiety. Many wishes and feelingsnever make it to consciousness but nonetheless cause anxiety. Thewoman whose panic attacks started when she began an affair insistedthat the two were unrelated. Just because many of the cues that causeanxiety are hard to identify does not mean that they are not there, andit certainly does not mean that the anxiety they cause is useless or aproduct of abnormal brain mechanisms.

Conversely, just because much anxiety is normal, that does notmean it is all useful. Furthermore, many anxiety disorders are causedby genetic predispositions. We don't yet know whether these arebest understood as genetic defects or normal variations. Certainly,the kinds and dangerousness of various threats vary considerablyfrom one generation to the next, and this should maintain consider-able genetic variation in the anxiety-regulation mechanisms.

If psychiatry stays on its current course, it will be left treatingonly those disorders caused by demonstrable brain defects, whilethe pains and suffering of everyday life will be left to other clini-cians. This would be unfortunate for patients as well as psychia-trists. The rest of medicine treats normal defensive reactions; whyshouldn't psychiatry do the same? In this as well as other ways, anevolutionary view is psychiatry's route to genuine integration withthe rest of medicine. An intensive effort to understand the functionsof the emotions and how they are normally regulated would pro-vide, for psychiatry, something comparable to what physiology pro-vides for the rest of medicine. It would provide a framework inwhich pathopsychology could be studied like pathophysiology, sothat we can understand what has gone wrong with the normal func-

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tioning of bodily systems. There is every expectation that an evolu-tionary approach will bring the study of mental disorders back tothe fold of medicine, relying not on a crude "medical model" ofemotional problems but on the same Darwinian approach that is souseful in the rest of medicine.

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Nothing in biology makes sense except in the lightof evolution.

-Theodosius Dobzhansky, 1973

Y ou are crossing a heath on a well-worn path when a flashof early sunlight reflects from something lying over by anolder trail. You follow the gleam to its source, brush awaysome dirt, and discover an old-fashioned gold pocket

watch. Perhaps it is the same old watch that people have been findingfor two centuries, but some details have been overlooked.

Its perfection still elicits wonder. The seam around the case is allbut invisible; the crystal is symmetrical and gleaming; the chain ismade of exquisitely miniature gold links. The face has numeralssharply etched around the logo of the Lifetime Watch Company. Buteven as you admire the watchmaker's skill, the light reveals some sur-prising imperfections. The crystal is laced with slight distortions.And the chain, though beautiful and flexible, is thin and broken, thusexplaining why the watch is here and not in a pocket. A notch in theseam is perfectly shaped for a thumbnail but large enough for dirtand water to enter easily. Odd, these flaws. You open the back, andthe exquisite mechanism again inspires awe. How could anyone havedesigned, much less constructed, so many perfectly cut gears of rust-proof brass, the hairlike spring of steel, the balance wheel suspended

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by minuscule jewels? But when you try to set the watch, the knob isso tiny you can barely grasp it and a dozen twirls advance the handsonly a single hour. You shake the watch. It ticks for five seconds,then is stopped by flakes of rust from that steel spring. What an odddevice this is! So perfect in many respects, in others makeshift atbest. How could the creator of such a masterpiece have allowed somany obvious flaws? Inside the case is an inscription in tiny letters.You take out your magnifying glass and read:

OVERVIEW OF CAUSES OF DISEASEW 5 e now return to where we began, to a seemingincongruity at the core of medicine. Despite theirexquisite design, our bodies have crude flaws.Despite our multiple defenses, we have a thousand

vulnerabilities. Despite their capabilities for rapid and preciserepairs, our bodies inevitably deteriorate and eventually fail. BeforeDarwin, physicians could only wonder at the incongruity of it all,perhaps with the hope that our bodies are part of an unfathomabledivine plan, or with the suspicion that they are some cosmic prank.Ever since Darwin, the incongruity has often mistakenly been attrib-

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uted to the supposed weakness or capriciousness of natural selection.In the light of modern Darwinism, however, the incongruity unfoldsinto a sharply blocked tapestry with a place for each of several dis-tinct causes of disease.

Why isn't the body more reliable? Why is there disease at all? Aswe have seen, the reasons are remarkably few. First, there are genesthat make us vulnerable to disease. Some though fewer than hasbeen thought-are defectives continually arising from new mutationsbut kept scarce by natural selection. Other genes cannot be elimi-nated because they cause no disadvantages until it is too late in life forthem to affect fitness. Most deleterious genetic effects, however, areactively maintained by selection because they have unappreciatedbenefits that outweigh their costs. Some of these are maintainedbecause of heterozygote advantage; some are selected because theyincrease their own frequency, despite creating a disadvantage for theindividual who bears them; some are genetic quirks that have adverseeffects only when they interact with a novel environmental factor.

Second, disease results from exposure to novel factors that werenot present in the environment in which we evolved. Given enoughtime, the body can adapt to almost anything, but the ten thousandyears since the beginnings of civilization are not nearly enoughtime, and we suffer accordingly. Infectious agents evolve so fast thatour defenses are always a step behind. Third, disease results fromdesign compromises, such as upright posture with its associatedback problems. Fourth, we are not the only species with adapta-tions produced and maintained by natural selection, which worksjust as hard for pathogens trying to eat us and the organisms wewant to eat. In conflicts with these organisms, as in baseball, youcan't win 'em all. Finally, disease results from unfortunate histori-cal legacies. If the organism had been designed with the possibilityof fresh starts and major changes, there would be better ways ofpreventing many diseases. Alas, every successive generation of thehuman body must function well, with no chance to go back andstart afresh.

The human body turns out to be both fragile and robust. Like allproducts of organic evolution, it is a bundle of compromises, each ofwhich offers an advantage, but often at the price of susceptibility todisease. These susceptibilities cannot be eliminated by any durationof natural selection, for it is the very power of natural selection thatcreated them.

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RESEARCHM iany questions confront the infant enterprise of Dar-winian medicine. What is its long-range goal? Howshould we go about analyzing a disease from an evo-lutionary viewpoint? How should hypotheses be for-

mulated and tested? Who will pay for this research? Who will do theresearch and in what academic departments or other agencies? Whyhas it taken so long to get this enterprise started?

We begin with the long-range goal. What will medical textbookslook like when evolutionary studies of disease are well established?Current textbooks summarize what is known about a disorder undertraditional headings: signs and symptoms of the disease, laboratoryfindings, differential diagnosis, course, complications, epidemiology,etiology, pathophysiology, treatment, and outcome. Such descriptionsfall one category short. A comprehensive discussion of a disease mustalso provide an evolutionary explanation. While some current text-books have a sentence or two about the advantages of the sickle-cellgene or the benefits of cough or fever, none of them systematicallyaddresses the evolutionary forces acting on genes that cause disease,the novel aspects of environment that cause disease, or the details ofthe host-parasite arms race. Every textbook description of a diseaseshould have, in our opinion, a section devoted to its evolutionaryaspects. This section should address the following questions:

1. Which aspects of the syndrome are direct mani-festations of the disease, and which are actuallydefenses?

2. If the disease has a genetic component, why do theresponsible genes persist?

3. Do novel environmental factors contribute to thedisease?

4. If the disease is related to infection, which aspectsof the disease benefit the host, which benefit thepathogen, and which benefit neither? What strate-gies does the pathogen use to outflank our defenses,and what special defenses do we have against thesestrategies?

5. What design compromises or historical legaciesaccount for our susceptibility to this disease?

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Such questions immediately suggest important but neglectedresearch on many diseases. Even the common cold offers manyopportunities. What are the effects of taking or not taking aspirin?What are the effects of using nasal inhalers or decongestant medica-tion? To use the categories of Chapter 3, is rhinorrhea (runny nose) adefense, a means the virus uses to spread itself, or both? For the mostpart, these projects have yet to be undertaken despite their concep-tual simplicity and their obvious practical implications for us all.

Take something far more chronic and complicated, plantar fasci-itis. More often known as heel spurs, this common disorder causesintense pain on the inside edge of the heel, especially first thing in themorning. The proximate cause is inflammation at the point where theheel attaches to the plantar fascia, a band of tough tissue that con-nects the front and rear of the foot like the string on a bow, support-ing the arch of the foot. With every footstep it stretches, bearing theweight of the body thousands of times every day. Why does this fas-cia fail so often? The easy answer is that natural selection cannotshape a tissue strong enough to do the job-but by now this explana-tion should be suspect. Somewhat more plausible is the possibilitythat we began walking on two feet so recently that there has not beenenough time for natural selection to strengthen the fascia sufficiently.The problem with this explanation is that plantar fasciitis is commonand crippling. Like nearsightedness, it would, in the natural environ-ment, so drastically decrease fitness that it would be strongly selectedagainst. Some experts say plantar fasciitis arises in people who walkwith their toes pointed out, a conformation that puts increased stresson the tissue. But then why do we walk that way? Is it the modernhabit of wearing shoes? But many people who have never worn shoesalso walk with their toes pointed outward.

Two clues suggest that plantar fasciitis may result from environ-mental novelty. First, exercises that stretch the plantar fascia to make itlonger and more resilient are effective in relieving the problem. Sec-ond, many of us do something hunter-gatherers don't: we sit in chairsall day. Most hunter-gatherers walk for hours each day, instead of com-pressing their exercise into an efficient aerobic workout. When theyaren't walking, they don't use chairs, they squat, a position that steadilystretches the plantar fascia. No plantar fasciitis and physical therapy forthem, just squatting and walking for hours each day. This hypothesis,that plantar fasciitis results from prolonged sitting that allows the fasciato contract and that the disorder can be prevented and relieved by

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squatting and other stretching of the fascia, can readily be tested withepidemiological data and straightforward treatment studies.

Another good challenge for Darwinian medicine is the current con-troversy about whether it is wise to take antioxidants such as vitaminC, vitamin E, and beta-carotene. Folklore has long credited theseagents with reducing heart disease, cancer, and even the effects ofaging. Controlled studies are increasingly supporting these claims,especially for the prevention of atherosclerosis, although a majorstudy in 1994 reported that beta-carotene appeared to increase the riskof cancer in some people. The agents are still deemed controversial,and many physicians studying them recommend caution until largerstudies can assess their risks as well as benefits. We agree with thisgeneral conservatism but hope that an evolutionary view can speedthe process. Earlier in this book we noted that natural selection seemsto have resulted in high levels of several of the body's own antioxi-dants even though they cause disease. Uric acid levels are higher inspecies that live longer and are so high in humans that we are suscep-tible to gout. It appears that natural selection has acted to increase thehuman levels of uric acid, superoxide dismutase, and perhaps biliru-bin and other substances as well, because they are antioxidants thatslow some effects of aging in a species that has greatly increased its lifespan in just the past few hundred thousand years.

Why doesn't the body have antioxidant levels that are alreadyoptimal? It is possible that our antiaging mechanisms are still catchingup with the recent increase in our life span. It is also possible that thecosts of high levels of antioxidants (perhaps decreases in our resis-tance to infection or toxins?) have restricted them to levels that wereoptimal for a normal Stone Age lifetime of thirty or forty years.These possibilities suggest that adding extra antioxidants to the dietmay have benefits that exceed the costs. In contrast to the many casesin which an evolutionary view argues against excessive intervention,here it supports the active pursuit of strategies that may prevent someeffects of aging. A major part of such studies should be a search forother antioxidants in the body and an assessment of their costs andbenefits. It would be interesting to see if people with high uric acidlevels have costs other than gout and whether they show fewer signsof aging than other people. It will also be important to look for simi-lar costs and benefits in our primate relatives. With this knowledgewe will be in a better position to decide who will benefit from takingantioxidants and what the side effects might be.

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This book contains suggestions for dozens of studies, many ofwhich seem to us to be fine topics for Ph.D. theses and some of whichoffer challenges enough for a whole career. Pursuing them will be dif-ficult, however, because no government agency presently supportssuch projects. Existing funding committees are reluctant to providesupport because their mandate is to provide funds to study the prox-imate mechanisms and treatment of particular diseases. Further-more, few members of such committees know anything about theformulation or testing of evolutionary ideas, and some are likely tohave misgivings based on fundamental misconceptions about the sci-entific status of evolutionary hypotheses. The system used to assignfunding priorities ensures that even a few people with such misgiv-ings can eliminate the chances of funding.

Asking biochemists or epidemiologists to judge proposals to testevolutionary hypotheses is like asking mineral chemists to judge pro-posals on continental drift. Darwinian medicine needs its own fundingpanels staffed by reviewers who know the concepts and methods ofevolutionary biology. Realistically, the prospects are poor for majorgovernment funding soon. The best hope for rapid growth of the fieldlies in the vision of private donors or foundations that could createinstitutes to support the development of Darwinian medicine. Evenmoderate support of this sort could quickly change the course of med-icine, just as prior investments in biochemical and genetic research arenow transforming our lives. As Ren6 Dubos noted in 1965:

In many ways, the present situation of organismicbiology and especially of environmental medicine isvery similar to that of the physicochemical sciencesrelated to medicine around 1900. At that time therewas no place in the United States dedicated to thepursuit of physicochemical biology, and the scholarswho were interested in this field were treated assecond-class citizens in the medical community. For-tunately, a few philanthropists were made aware ofthis situation, and they endowed new kinds ofresearch facilities to change the trend. The Rocke-feller Institute is probably the most typical exampleof a conscious and successful attempt to providea basis of physicochemical knowledge for the artof medicine.... Organismic and especially environ-

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mental medicine constitute today virgin territorieseven less developed than was physicochemical biol-ogy 50 years ago. They will remain undevelopedunless a systematic effort is made to give them acade-mic recognition and to provide adequate facilities fortheir exploration.

WHY DID IT TAKE So LONG?W hy has it taken more than a hundred years to applyDarwin's theory systematically to disease? Histori-ans of science will eventually address this question,but from this close perspective several explanations

seem likely: the supposed difficulty in formulating and testing evolu-tionary hypotheses about disease, the recency of some advances inevolutionary biology, and some peculiarities of the field of medicine.

Biologists have long tried to figure out the evolutionary originsand functions for organismic characteristics, but it has taken a sur-prisingly long time to realize that this enterprise is fundamentally dif-ferent from trying to figure out the structure of organisms and howthey work. Harvard biologist Ernst Mayr, in The Qrowth of BiologicalThought, traces the parallel development of the two biologies. Medi-cine, while at the forefront of proximate biology, has been curiouslylate in addressing evolutionary questions. This is, no doubt, in partsimply because the questions and goals are so different. It takes awrenching shift to stop asking why an individual has a particular dis-ease and to ask instead what characteristics of a species make all of itsmembers susceptible to that disease. It has seemed a bit odd untilnow even to ask how something maladaptive like disease might havebeen shaped by natural selection. Furthermore, medicine is a practi-cal enterprise, and it hasn't been immediately obvious how evolu-tionary explanations might help us prevent or treat disease. We hopethis book convinces many people that seeking evolutionary explana-tions for disease is both possible and of substantial practical value.

If we are to assign blame for the tardiness of medicine in makinguse of relevant ideas in evolutionary biology, it rests as much withevolutionary biologists as with the medical profession. It took evolu-tionists an inexcusably long time to formulate the relevant ideas.

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Given the powerful insights of Darwin, Wallace, and a few others inthe middle of the nineteenth century, and the Mendelian revolutionin genetics in the early years of the twentieth, why was it not untilFisher's book of 1930 that we had the first fruitful idea about why thenumber of boys and girls born is nearly equal? Why was it not untilMedawar's midcentury work that we had any idea why there is sucha thing as senescence? Why was it not until Hamilton's publicationsin 1964 that there was any realization that kinship would have somerelevance to evolution? Why was it not until the 1970s and 1980s thatwe had useful ideas on how parasites and hosts, or plants and herbi-vores, influence each other's evolution? We believe that the answersto these and related questions will be found in a persistent antipathyto evolutionary ideas in general and to adaptation and natural selec-tion in particular (even among some biologists). Meanwhile, we willsimply note that medical researchers can hardly be blamed for failingto use the ideas of other sorts of scientists before those scientistsdeveloped them.

Medical scientists may also hesitate to consider functionalhypotheses because of their indoctrination in the experimentalmethod. Most of them were taught early, firmly-and wrongly-thatscience progresses only by means of experiment. But many scientificadvances begin with a theory, and much testing of hypotheses doesnot rely on the experimental method. Geology, for instance, cannotreplay the history of the earth, but it nonetheless can reach firm con-clusions about how basins and ranges got that way. Like evolutionaryhypotheses, geological hypotheses are tested by explaining availableevidence and by predicting new findings that have not yet beensought in the existing record.

Finally, medicine, like other branches of science, is especiallywary of ideas that in any way resemble recently overcome mistakes.Medicine fought for years to exclude vitalism, the idea that organ-isms were imbued with a mysterious "life force," so it continues toattack anything that is even vaguely similar. Likewise, teleology of anaive and erroneous sort keeps reappearing and must be expelled.Many people recollect from freshman philosophy class that teleol-ogy is the mistake of trying to explain something on the basis of itspurpose or goal. This admonition is wise if it establishes an aware-ness that future conditions cannot influence the present. It isunwise if it also implies that present plans for the future cannotaffect present processes and, through them, future conditions. Pres-

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ent plans may include printed recipes for baking cakes or the infor-mation in the DNA of bird's eggs. Functional explanations in biol-ogy imply not future influences on the present but a prolongedcycling of reproduction and selection. A bird embryo developswing rudiments in the egg because earlier individuals that failed todo so left no descendants. Adult birds lay eggs in which embryosdevelop wing rudiments for the same reason. In this sense, a bird'swing rudiments are preparation for its future but are caused by itspast history. Evolutionary explanations based on a trait's functiondo not imply that evolution involves any consciousness, activeplanning, or goal-directedness. While medicine is wise to be onguard against sliding back into discredited teleological reasoning,this wariness has prevented it from taking full advantage of thesolid advances in mainstream evolutionary science. Through itsefforts to keep from being dragged back, medicine has, paradoxi-cally, been left behind.

MEDICAL EDUCATIONM [edical education is similarly in trouble because of try-ing to guard against the old mistakes. The origins ofits current quandary lie in the solution to a previousone. Early in this century, the Carnegie Foundation

sponsored an extensive investigation of medical education by Abra-ham Flexner. In his cross-country travels, he reported a haphazardsystem of medical apprenticeship in which physicians, good and bad,took on assistants who, one way or another, learned something aboutmedicine. Doctors' formal study of basic science was sporadic, andeven their knowledge of basic anatomy and physiology was inconsis-tent. The Flexner report, published in 1910, formed the basis of newaccreditation standards that required medical schools to providefuture physicians with a foundation in basic science.

On this count, medical schools have far exceeded Flexner's hopes.In fact, one wonders what Flexner would say if he could see today'smedical curricula. Now medical students are not only exposed tobasic sciences, they are inundated with the latest advances by teach-ers who are subspecialist basic science researchers. At curriculummeetings in every medical school there are battles for students' time

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and minds. The microbiologists want more lab time, the anatomistswant more too. The pathologists feel they cannot possibly fit theirmaterial into a mere forty hours of lecture. The pharmacologists saythey will continue flunking 30 percent of the class until they getenough time to cover all the new drugs. The epidemiologists and bio-chemists and physiologists and psychiatrists and neuroscienceexperts all want more time, and certainly the students must keep upwith the latest advances in genetics. Then they need to learn enoughstatistics and scientific methodology to be able to read the researchliterature. And they must somehow learn, before they start theirwork on the wards, how to talk with patients, how to do a physicalexam, how to write up a patient report, how to draw blood, do a cul-ture, a spinal tap, a Pap smear, measure eyeball pressure, examineurine and blood, and, and . .. The amounts of knowledge and thelists of tasks are overwhelming, but all must be completed in the firsttwo years of medical school.

How is all this possible? It isn't. Why set impossible expectations?In part because we naively want our physicians to know everything.Another reason, however, is that no one person is in charge. When acommittee decides on the class schedule and every basic sciencewants more time, the solution is to go on increasing the total amountof class time. Thirty or more hours each week in class is not unusual.After that, the students go home to study their textbooks and notes.

One might think that students' complaints would lead to reform,but decades of polite complaints changed little. It was technologythat finally precipitated some change, technology in the form of thephotocopy machine. Instead of going to class, students hire one per-son to take notes for each lecture, then all of them receive copies. Itturns out to be a better survival strategy to stay home and study thenotes than to go to class. When only twenty students attend a classfor two hundred, professors hit the roof and curriculum reform isborn. New attempts are being made, under the strong leadership ofsome deans, to cut back on the hours, reduce the amount of material,find new ways to transmit it. If these efforts succeed, it will be won-derful indeed.

Such efforts might even make room for Darwinian medicine,except that there are no Departments of Evolutionary Medicine toadvocate inclusion of this material and few medical faculty memberswho know the material and want to teach it. It will take time and fur-

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ther leadership from medical school deans to make room in the med-ical curriculum for an introduction to the basic science of evolutionand its applications in medicine. When evolution is included, it willgive students not only a new perspective on disease but also an inte-grating framework on which to hang a million otherwise arbitraryfacts. Darwinian medicine could bring intellectual coherence to thechaotic enterprise of medical education.

CLINICAL IMPLICATIONS

W hile many clinical implications of an evolutionaryview await future research, others can immediatelytransform the way patients and doctors see disease.Let us listen in as first a pre-Darwinian and then a

post-Darwinian physician talk to a patient about gout."So, Doctor, it is gout that has my big toe flaming, is it? What

causes gout?""Gout is caused by crystals of uric acid in the joint fluid. I expect

you can imagine only too well how some gritty crystals could make ajoint painful."

"So why do I have it and you don't?""Some people have high levels of uric acid in their systems, prob-

ably because of some combination of genes and diet.""So why isn't the body designed better? You would think there

would be some system to keep uric acid levels lower.""Well, we can't expect the body to be perfect, now, can we?"At this point our pre-Darwinian physician gives up on science and

dodges the question, implying that such "why" questions need not betaken seriously. Most likely, he or she doesn't recognize the distinc-tion between proximate and evolutionary explanations, to say noth-ing of the importance and legitimacy of evolutionary explanations fordisease.

The Darwinian physician gives a different answer, one closer towhat the patient wanted and was entitled to.

"That's a good question. It turns out that human uric acid levelsare much higher than those of other primates and that uric acid levels

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in a species are correlated with its life span. The longer-lived thespecies, the higher the uric acid levels. It seems that uric acid protectsour cells against damage from oxidation, one of the causes of aging. Sonatural selection probably selected for higher uric acid levels in ourancestors, even though some people end up getting gout, becausethose higher levels are especially useful in a species that lives as long aswe do."

"So high levels of uric acid prevent aging?""Basically, that seems to be right. So far, however, there is no evi-

dence that individuals with high uric acid levels live an especially longtime, and in any case you don't want your toe to stay like that, so weare going to go ahead and get your uric acid levels down to the nor-mal range to get the gout under control."

"Sounds sensible to me, Doc."This is not an isolated example. A Darwinian perspective can

already assist in the management of many medical conditions. Takestrep throat:

"Well, it's strep all right, so you will need to take some penicillinfor seven days," says the Darwinian physician.

"That will make me better faster, right?" the patient says hoarsely."Probably, and it will also make it less likely that you will develop

diseases like rheumatic fever because of your body making immunesubstances that attack the bacteria."

"But why doesn't my body know better than to make substancesthat will attack my own heart?"

"Well, the streptococcus has evolved along with humans for mil-lions of years, and its trick is to imitate the codes of human cells. Sowhen we make antibodies that attack the strep bacteria, those anti-bodies are prone to attack our own tissues as well. We are in a con-test with the strep organism, but we can't win because the strepevolves much faster than we do. It has a new generation every houror so, while we take twenty years. Thank goodness we can still kill itwith antibiotics, although this may be a temporary blessing. Youwill do yourself and the rest of the world a favor by taking yourantibiotics even after you feel better, because otherwise you may begiving a lift to those variants that can survive short exposures toantibiotics, and those antibiotic-resistant organisms make life diffi-cult for us all."

"Oh, now I see why I have to take the whole bottle. Okay."

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Or take a patient who has had a heart attack:"So, Doctor, if my high cholesterol is caused by my genes, what

good will it do to change my diet?""Well, those genes aren't harmful in the normal environment we

evolved in. If you spent six or eight hours walking around each day tofind food, and if most of your food was complex starches and verylean meat from wild game, you wouldn't get heart disease."

"But how come I crave exactly the foods you say I shouldn't eat?No potato chips, no ice cream, no cheese, no steak? You medicaltypes want to take away all the foods that taste best."

"I'm afraid we were wired to seek out certain things that wereessential in small amounts but scarce on the African savannah. Whenour ancestors found a source of salt, sugar, or fat, it was usually agood idea for them to eat all they could get. Now that we can easilyget any amount of salt, sugar, or fat just by tossing things into the gro-cery cart, most of us eat more than twice as much fat as our ancestorsdid, and lots more salt and sugar. You are right, it is a kind of a crueljoke-we do want exactly those things that are bad for us. Eating ahealthy diet does not come naturally in the modern environment.We have to use our brains and our willpower to compensate for ourprimitive urges."

"Well, I still don't like giving up my favorite foods, but at leastthat makes it understandable."

There are a hundred more examples: advice given to a patientwith a cold or diarrhea; an explanation of aging; the significance ofmorning sickness during pregnancy; the possible utility of allergy.While most medical conditions have yet to be explored from anevolutionary view, Darwinian medicine can already be useful in theclinic.

A caveat is necessary. Doctors and patients, like all other people,are prone to extend theories too far. We have lost count of howmany reporters have called asking, "So you're saying we should nottake aspirin for a fever, right?" Wrong! Clinical principles of medi-cine should come from clinical research, not from theory. It is a mis-take to avoid aspirin just because we know that fever can be useful,and a mistake not to treat the unpleasant symptoms of some cases ofpregnancy sickness, allergy, and anxiety. Each condition needs to bestudied separately and each case considered individually. An evolu-tionary approach does, however, suggest that many such treatments

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are unnecessary or harmful and that we should do the research to seeif the benefits are worth the costs.

PUBLIC POLICY IMPLICATIONSW e have said before, but here repeat, that moral prin-ciples cannot be deduced from biological facts. Forinstance, the knowledge that aging and death areinevitable has no direct implications for how much

of our medical dollar we should spend on the very elderly. Facts can,however, help us to achieve whatever goals we decide to strive for.The current crisis in funding and organization of health care in theUnited States comes from several sources, including new fundingmechanisms, new technology, other economic changes, and socialvalues that increasingly condemn gross differences in the quality ofhealth care. In a system this complex, no general policies will pleaseeveryone, and it may not be possible to implement the best availablepolicies because of the power of politics.

While not pretending to offer solutions, we observe that the manyparticipants in this debate don't even agree on what disease is. Theyknow disease is bad but differ wildly on where it comes from and theextent to which it can be prevented or relieved. Some blame faultygenes, others emphasize the amount of disease that results fromunfortunate human predilections, especially poor diets and drug use.According to one recent authoritative article, more than 70 percentof morbidity and mortality in the United States is preventable. Thearticle argues strongly for investing in prevention because it will payoff in reduced health care costs. What a terrible irony and frighteningharbinger it is that such a noble and practical proposal to improvehuman health has to be couched as a way to save money! In the lightof history, however, this approach is understandable. Again andagain, panels of distinguished physicians and researchers have calledfor prevention instead of treatment. The field of preventive medicinenow provides some help, especially in matters of public policy, butpeople still do not get reliable advice from their physicians abouthow to stay healthy. New ways of organizing medical care may finallyprovide incentives for dedicating substantial clinical resources to pre-serving health based on principles of Darwinian medicine.

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PERSONAL ANDPHILOSOPHICAL IMPLICATIONSF X ew things are as important to us as our health. "How are

you?" we ask in greeting each other, the convention of theinquiry still not completely covering its seriousness. "I'vestill got my health," says the person who has lost everything

else. Health is vital. Without it, little else matters. We all want tounderstand the causes of disease to preserve and improve our health.

Long before there were effective treatments, physicians dispensedprognoses, hope, and, above all, meaning. When something terriblehappens-and serious disease is always terrible-people want toknow why. In a pantheistic world, the explanation was simple-onegod had caused the problem, another could cure it. In the time sincepeople have been trying to get along with only one God, explainingdisease and evil has become more difficult. Generations of theolo-gians have wrestled with the problem of theodicy-how can a goodGod allow such bad things to happen to good people?

Darwinian medicine can't offer a substitute for such explanations.It can't provide a universe in which events are part of a divine plan,much less one in which individual illness reflects individual sins. Itcan only show us why we are the way we are, why we are vulnerableto certain diseases. A Darwinian view of medicine simultaneouslymakes disease less and more meaningful. Diseases do not result fromrandom or malevolent forces, they arise ultimately from past naturalselection. Paradoxically, the same capacities that make us vulnerableto disease often confer benefits. The capacity for suffering is a usefuldefense. Autoimmune disease is a price of our remarkable ability toattack invaders. Cancer is the price of tissues that can repair them-selves. Menopause may protect the interests of our genes in existingchildren. Even senescence and death are not random, but compro-mises struck by natural selection as it inexorably shaped out bodiesto maximize the transmission of our genes. In such paradoxical bene-fits, some may find a gentle satisfaction, even a bit of meaning-atleast the sort of meaning Dobzhansky recognized. After all, nothingin medicine makes sense except in the light of evolution.

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Chapter 1. The Mystery of Disease

Page6-7 For further discussion of proximate and ultimate (evolutionary)

causation, see Ernst Mayr's The Growth of Biological Thought(Cambridge, Mass.: Belknap Press, 1982) or his brief article"How to Carry Out the Adaptationist Program," American Nat-uralist, 121:324-34 (1983). The problem of recognizing and con-firming adaptations is dealt with on pp. 38-45 of GeorgeWilliams' Natural Selection (New York: Oxford Univ. Press,1992). A terminological revision is suggested by Paul W. Sher-man in Animal Behavior, 36:616-19 (1988).

11 A history of social thought on Darwinism and of political uses ofDarwinian metaphors is provided by Carl N. Degler's In Search ofHuman Nature: The Decline and Revival of Darwinism in AmericanSocial Thought (New York: Oxford Univ. Press, 1991). The inscrip-tion on the statue at Saranac Lake is quoted on page 410 of ReneDubos's Man Adapting (New Haven: Yale Univ. Press, 1980).

Chapter 2. Evolution by Natural Selection

13 The Aristotle quotation is from p. 103 of Aristotle: Parts of Ani-mals, translated by A. L. Peck (Cambridge, Mass.: Harvard Univ.Press, 1955).

Two recent books offer superb treatments of the modem con-cept of evolutionary adaptation. They are Helena Cronin's TheAnt and the Peacock (New York: Cambridge Univ. Press, 1991)and Matt Ridley's The Red Queen (London, New York: Viking-Penguin, 1993). Cronin's account is more explicitly historical,with many quotations from Darwin, Wallace, and others. Bothcan be read with profit by both professional biologists and ama-teur naturalists.

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13-14 The moth population that quickly evolved a darker color as itsbackground darkened is discussed in many general works on evo-lution, for instance, on p. 58 of D. J. Futuyma's Evolutionary Biol-ogy, 2nd ed. (Sunderland, Mass.: Sinauer, 1986).

14 Examples of increased reproductive effort causing increased mor-tality or other costs are summarized on pages 28-9 and 188-93 ofS. C. Steams's The Evolution of Life Histories (New York: OxfordUniv. Press, 1992).

16-17 W. D. Hamilton's classic work is in Journal of Theoretical Biology,7:1-52 (1964). Any modern book on evolution or animal behav-ior will discuss Hamilton's work. Richard Dawkins's book TheSelfish Gene, new edition (Oxford: Oxford Univ. Press, 1989),offers a superb introduction to these ideas. The classic works onreciprocity are by R. L. Trivers in Quarterly Review of Biology,46:35-57 (1971), and R. M. Axelrod's The Evolution of Coopera-tion (New York: Basic Books, 1984). These works are routinelyreviewed in modern treatments of animal behavior, such as JohnAlcock's Animal Behavior: An Evolutionary Approach, 4th ed.(Sunderland, Mass.: Sinauer, 1989).

17 See E. 0. Wilson's Sociobiology (Cambridge, Mass.: Harvard Uni-versity Press, 1975) and On Human Nature (Cambridge, Mass.:Harvard Univ. Press, 1978) and Richard Alexander's Darwinismand Human Affairs (Seattle: University of Washington Press,1979) and The Biology of Moral Systems (New York: Aldine deGruyter, 1987).

17 The replay-the-tape-of-life idea is from pages 45-8 of S. J. Gould'sWonderful Life: The Burgess Shale and the Nature of History (NewYork: Norton, 1989).

18 The classic study of wing lengths of birds killed by a storm iscited in many recent works, such as John Maynard Smith's Evo-lutionary Genetics (New York: Oxford Univ. Press, 1989), whichalso explains the general topic of selection in favor of intermedi-ate values (normalizing selection). For more on the optimizationconcept, see G. A. Parker and John Maynard Smith's article inNature, 348:27-33 (1990), and The Latest on the Best: Essays on Evo-lution and Optimality, edited by John Dupr6 (Cambridge, Mass.:MIT Press, 1987).

21 The term adaptationist program was first used, disparagingly, byS. J. Gould and R. C. Lewontin in their much-cited article "TheSpandrels of San Marco and the Panglossian Paradigm: A Cri-tique of the Adaptationist Programme," Proceedings of the RoyalSociety of London, B205:581-98 (1979).

22 Gary Belovsky's work is described in American Midland Natural-ist, 11 1:209-22 (1984).

22-23 For some clear thinking on the clutch-size problem and an intro-duction to recent work, see Jin Yoshimura and William Shield'sarticle in Bulletin of Mathematical Biology, 54:445-64 (1992).

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23 It must be that Darwin and his followers seldom found them-selves at stag dances or singles bars, because the obvious minor-ity-sex advantage somehow escaped their notice until it waspointed out by R. A. Fisher on p. 159 of his 1930 book TheGenetical Theory of Natural Selection (New York: Dover, 1958reprint).

24 For very recent work that takes an evolutionary view of diseasesee G. A. S. Harrison, ed. (1993), Human Adaptation, and TheAnthropology of Disease by C. Mascie-Taylor (both Oxford:Oxford Univ. Press, 1994).

Chapter 3. Signs and Symptoms of Infectious Disease

27-29 The recent understanding of the role of fever in controlling infec-tion is discussed in M. J. Kluger's article in Fever: Basic Measure-ment and Management, edited by P. A. MacKowiac (New York:Raven Press, 1990). For an older but still valuable overview, seehis Fever, Its Biology, Evolution, and Function (Princeton, N.J.:Princeton Univ. Press, 1979). Data on acetaminophen's effects onchicken pox are presented by T. F. Doran and collaborators in anarticle in Journal of Pediatrics, 114:1045-8 (1989). The experimentson fever reduction and the progress of a cold are discussedby N. M. Graham and collaborators in Journal of Infectious Dis-ease, 162:1277-82 (1990). The quotation on p. 28 is from JoanStephenson in Family Practice News, 23:1, 16 (1993).

29-31 The sequestration of iron as a defense against bacterial pathogensis discussed by E. D. Weinberg in Physiological Reviews, 64:65-102(1984). The treatment of malaria with iron chelating agents isreported by V. Gordeuk et al. in The New England Journal of Med-icine, 327:1473-7 (1992).

31-33 For a wide-ranging review of progress in bringing evolution tobear on microbiology, see Parasite-Host Associations: Coexistenceor Conflict, edited by C. A. Toft et al. (New York: Oxford Univ.Press, 1991). A still-valuable general review of host-parasitecoevolution is P. W. Price's Evolutionary Biology of Parasites(Princeton, N.J.: Princeton Univ. Press, 1980).

33-36 Behavioral defenses against parasites are discussed by B. L. Hart inNeuroscience and Biobehavioral Reviews, 14:273-94 (1990). Thefunctions of pain and the shortened lives of those who lack it aredescribed by Ronald Melzack in The Puzzle of Pain (New York:Basic Books, 1973).

36 The biocidal action of tears is discussed by S. Hassoun in Allergieet Immunologie, 25:98-100 (1993), and that of saliva by D. J. Smithand M. A. Taubman in Critical Reviews of Oral Biology and Medi-cine, 4:335-41 (1993).

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36 A relevant article on nasal sprays is provided by R. Dockhornand collaborators in Journal of Allergy and Clinical Immunology,90:1076-82 (1992).

37 Important works on the psychology of food aversions andrelated defenses are provided by M. E. P. Seligman in Psychologi-cal Review, 77:406-18 (1970), and by John Garcia and F. R. Ervinin Communications in Behavioral Biology, (A)1:389-415 (1968).

37-38 The diarrhea article is by H. L. DuPont and R. B. Hornick in Jour-nal of the American Medical Association, 226:1525-8 (1973).

38-39 Profet's theory is presented in Quarterly Review of Biology,68:335-86 (1993). Strassman's paper was presented to the 1994Human Behavior and Evolution Society.

39-40 A good general introduction to immunology is Chapter 16 of Life:The Science of Biology, 3rd ed., by W. K. Purves, G. H. Orians, andH. C. Heller (Sunderland, Mass.: Sinauer, 1992).

41 Many dramatic examples of the ravages of parasitic diseases aredescribed, and some pictured, by Michael Katz et al. in ParasiticDiseases, 2nd ed. (New York: Springer, 1989).

42 Hemoglobin increase in compensation for decreased lung func-tion is described on pages 307 and 418 of A. J. Vander et al.'sHuman Physiology: The Mechanisms of Body Function, 5th ed. (NewYork: McGraw-Hill, 1990.

42-44 For a readable and authoritative introduction to deceptive strate-gies used by pathogens, see Ursula W. Goodenough's article inAmerican Scientist, 79:344-55 (1991). Specifically antimalarialstrategies are discussed by D. J. Roberts et al. in Nature,357:689-92 (1992). A wealth of material on autoimmune disease isprovided by The Autoimmune Diseases, vol. 2, edited by N. R.Rose and I. R. Mackay (San Diego: Academic, 1992). See espe-cially the introductory chapter by Rose and Mackay. The rela-tionship between obsessive-compulsive disorder and Sydenham'schorea is discussed by Judith Rapaport on pages 83-89 of Scien-tific American (March 1989).

44-45 Reactions and overreactions to a bacterial toxin are discussed byE. K. LeGrand in Journal of the American Veterinary Medical Asso-ciation, 197:454-6 (1990).

45 The best evolutionary perspective on AIDS is in P. W. Ewald'sEvolution of Infectious Disease (New York: Oxford Univ. Press,1993). See also B. R. Levins's article on pp. 101-11 of AIDS, theModern Plague, edited by P. A. Distler et al. (Blacksburg, Va.:Presidential Symposium, Virginia Polytechnic Institute and StateUniversity, 1993).

45-47 Viral alteration of host cell structure is discussed by ShmuelWolf et al. in Science, 246:377-9 (1989). Fungal castration ofplants is reviewed by Keith Clay in Trends in Ecology and Evolu-tion, 6:162-6 (1991). Behavior manipulation by the rabies virus is

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discussed by G. M. Baer in The Natural History of Rabies (NewYork: Academic, 1973). A general review of manipulation of hostbehavior by parasites is provided by A. P. Dobson in The Quar-terly Review of Biology, 63:139-65 (1988). Many medically impor-tant examples of host manipulation are discussed by Heven inThe Host-Invader Interplay, edited by H. Van den Bossche (Ams-terdam: Elsevier/North Holland, 1980).

47-48 Ewald's article, mentioned in our Preface, is "Evolutionary Biol-ogy and the Treatment of Signs and Symptoms of InfectiousDisease," Journal of Theoretical Biology, 86:169-76. It forms thebasis for Table 3-1. Professional conferences on evolutionaryapproaches to medicine include one in Boston at the February1993 meeting of the American Association for the Advancementof Science, another at the London School of Economics in June1993.

Chapter 4. An Arms Race Without End

49 The classic work on biological arms races is Richard Dawkins andJ. L. Krebbs' article in Proceedings of the Royal Society of London,B105:489-51 1. Alice's race with the Red Queen is in Chapter 2 ofThrough the Looking Qlass by Lewis Carroll.

50 The account of President Coolidge's son's death and its emo-tional and political effects is taken from p. 14 of an article byR. S. Robins and M. Dorn in Politics and the Life Sciences, 12:3-17(1993).

50 A superb popular account of the nature and power of naturalselection is Richard Dawkins' The Blind Watchmaker (New York:W. W. Norton, 1986).

52 Evidence of devastation of native populations by introduced dis-eases is summarized by R. M. Anderson and R. M. May's Infec-tious Diseases of Humans (New York: Oxford Univ. Press, 1991)and by F. L. Black in Science, 258:1739-40 (1992).

53-56 The quotation is from M. L. Cohen's article in Science,257:1050-5 (1992). Useful recent reviews of bacterial resistanceto antibiotics are provided by J. P. W. Young and B. R. Levin intheir article in Genes in Ecology, edited by R. J. Berry et al.(Boston: Blackwell Scientific, 1991) and by S. B. Levy's TheAntibiotic Paradox: How Miracle Drugs Are Destroying the Miracle(New York: Plenum, 1992). See also Rick Weiss in Science,255:148-50. The use of antibiotics in livestock is discussed byS. B. Levy in The New England Journal of Medicine, 323:335-37,1990. Our data on tuberculosis are mainly from B. R. Bloom andC. J. L. Murray in Science, 257:1055-64. The 1969 quote from theSurgeon General is in Bloom's article. H. C. Neu's work is in Sci-

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ence, 257:1064-73 (1992). The article by Ridley and Low is in TheAtlantic, 272(3):76-86 (September 1993).

57-58 Three examples of authoritative statements on an inevitable evo.lutionary reduction of virulence provide epigraphs for the firstchapter of Paul W. Ewald's book cited for p. 45. One not cited byEwald is the distinguished population geneticist TheodosiusDobzhansky's assertion that parasitism "is a form of relationshipwhich is unstable in the evolutionary sense, and . . . it will tend todisappear and be replaced by cooperation and mutualism," Genet-ics and the Origin of Species, 3rd ed. (New York: Columbia Univ.Press, 1951, p. 285). Genetic diversity of HIV within a host is doc-umented by several writers in Science, 254:941, 963-9 (1991);255:1134-7 (1992). Genetic diversity of a parasitic helminth pop-ulation in a single host is documented by M. Mulvey et al. in Evo-lution, 45:1628-40 (1991). The data on fluke infections of fig waspsare in E. A. Herre's article in Science, 259:1442-5 (1993).

58-60 There is a large literature on the different effects of selectionwithin and between populations. The special case of selection onparasites within and between hosts is modeled by R. L. Andersonand R. L. May's book cited for p. 52. J. J. Bull and I. J. Molineux'sexperimental verification of the expected increase in virulence ofa virus that had its fitness decoupled from that of its host is pre-sented in Evolution, 46:882-95 (1992). Other important works areR. B. Johnson's in Journal of Theoretical Biology, 122:19-24 (1986),and S. A. Frank's in Proceedings of the Royal Society of London,B259:195-7 (1992).

60 Our favorite account of the Semmelweis story is the 1909 classicby William J. Sinclair, Semmelweis, His Life and His Doctrine(Manchester: The University Press).

62-63 A good introduction to mimicry is provided by J. R. G. Turner'sarticle on pp. 141-61 of The Biology of Butterflies, edited by R. I.Vane-Wright and P. R. Ackery (London and Orlando: Acade-mic, 1984). Works on molecular mimicry and related phenom-ena are cited for pp 43-44.

63-64 Most of our information on the effects of novel environments oninfection is from R. M. Krause's article in Science, 257:1073-8(1992). Detailed data on the Ebola virus are provided by P. H.Sureau's article in Reviews of Infectious Diseases, 11(4):790s-793s(1989).

Chapter 5. Injury

66 The quotation at the beginning of the chapter is from Chapter 6of Mark Twain's The Adventures of Huckleberry Finn.

68 John Garcia's classic work, with F. R. Ervin, is cited for p. 37.

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68-69 The work on monkeys' conditioned fear of snakes is by SusanMineka and collaborators in Animal Learning and Behavior,8:653-63 (1980).

69-70 Repair of mechanical damage is discussed by P. L. McNeil inAmerican Scientist, 79:222-35, and by Natalie Angier in The NewYork Times, November 9, 1993, pp. Cl, C14.

70-71 Many of the special aspects of burn healing are discussed inBurn Care and Rehabilitation: Principles and Practice, edited byR. L. Richard and M. J. Staley (Philadelphia: F. A. Davis, 1994).See especially Chapter 5, by D. G. Greenhalgh and M. J. Staley.

72 The trout-hatchery story and a general discussion of damage bysunlight are provided by Alfred Perlmutter in Science, 133:1081-2(1961).

73-75 UV-B effects on Langerhans cells are discussed by M. Vermeer etal. in Journal of Investigative Dermatology, 97:729-34 (1991). Anepidemiological study of the increase in melanoma rates is pro-vided by J. M. Elwood and collaborators in International Journalof Epidemiology, 19:801-10 (1990). A less technical discussion,with emphasis on immunological aspects of melanoma, is DavidConcal's in New Scientist, 134:23-8 (1991). Interactions betweenthe nervous system and Langerhans cells are discussed byJ. Hosoi et al. in Nature, 159-63 (1993). The role of sunscreens incausing excess exposure to UV-A is discussed by P. M. Farr andB. L. Diffey in The Lancet, 1(8635):429-31 (1989). Eye damage bysunlight is discussed by L. Semes in Optometry Clinics, 1(2):28-34(1991). The beneficial effects of sunscreen use are reported byS. C. Thompson and collaborators in The New England Journal ofMedicine, 329:1147-51 (1993).

75-76 The work of R. J. Goss in the Journal of Theoretical Biology, 159:241-60 is a good introduction to the literature and current con-troversies on the evolution of regeneration.

Chapter 6. Toxins: New, Old, and Everywhere

77 Works by McNeil and by Angier, cited for pp. 69-70, are rele-vant to the sort of damage the whisky caused to Don Birnham'sstomach.

78-81 An introduction to the work of Bruce Ames et al. is provided ina 1991 response by Ames and L. S. Gold to criticisms of their ear-lier work (Science, 251:607-8). Timothy Johns' With Bitter HerbsThey Shall Eat It (Tucson: Univ. of Arizona Press, 1990), reviewsmany aspects of human ecology in relation to plant toxins. It alsodetails a fascinating history of human dealings with potatoes andtheir toxins, and of medicinal uses of plant toxins. A more tech-nical work is Toxic Plants, edited by A. D. Kinghorn (New York:

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Columbia Univ. Press, 1979). An early but unexcelled review ofchemical defenses in arthropods is by Thomas Eisner on pp.157-217 of Chemical Ecology, edited by Ernest Sondheimer and

J. B. Simeone (New York: Academic, 1970). The first serious dis-cussion of trade-offs between chemical defenses and other values,such as rapidity of development, was by G. H. Orians and D. H.Janzen in the American Naturalist, 108:581-92 (1974). For a dra-matic account of plant defenses, with details of electrical signal-ing and rapid adaptation, see Paul Simons' The Action Plant(Boston: Blackwell, 1992). It includes a discussion of the role ofaspirinlike hormones in plants.

80 Our interpretation of nectar toxins is based on D. F. Rhoadesand J. C. Bergdahl's article in American Naturalist, 117:798 -803(1981).

81 A dramatic account of the consequences of fungal toxins forhuman life is provided by Mary K. Matossian's Poisons of the Past:Molds, Epidemics, and History (New Haven: Yale Univ. Press,1989).

82-83 The high incidence of PTC tasting in the Peruvian Andes is doc-umented by R. M. Barruto and coauthors in Human Biology,47:193-9 (1975). The study of oxylate kidney stones is that ofG. C. Curhan et al. in The New England Journal of Medicine,328:833-8 (1993). Our kidney-stone discussion is also based onthat of S. B. Eaton and D. A. Nelson, "Calcium in EvolutionaryPerspective," in American Journal of Clinical Nutrition, 54:281s-287s. For a wide-ranging review of the evolution of chemical andother defense mechanisms, see D. H. Janzen's article on pages145-64 of Physiological Ecology: An Evolutionary Approach toResource Use, edited by C. R. Townsend and Peter Calow(Oxford: Blackwell, 1981).

84 Maize processing is described by S. H. Katz et al., in Science,184:765-73 (1973).

84 The information on tannins in acorns and the detoxification ofarum by cooking is from pp. 63-5 in Timothy Johns's book citedfor pp. 78-80.

85 The toxicity of disease-resistant potatoes is discussed on pages106-59 of Johns's book cited for pages 78-80.

86 Bacterial resistance to antibiotics in people with dental fillingsis discussed by A. 0. Summers et al. in Antimicrobial Agents andChemotherapy, 37:825-34 (1993). Examples of unrealistic argu-ments on environmental toxins can be found in Biosphere Poli-tics (New York: Crown, 1991) and other works by JeremyRifkin.

87-89 The antiteratogen theory of morning sickness is presented byMargie Profet on pp. 327-65 of The Adapted Mind, edited byJ. H. Barkow et al. (New York: Oxford Univ. Press, 1992).

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89 The reluctance of regulatory agencies to take fetal sensitivities intoaccount is discussed by Ann Gibbons in Science, 254:25 (1991).

Chapter 7. Genes and Disease: Defects, Quirks, and Compromises

92-94 A recent general treatment of medical genetics is T. D. Gelehrterand F. S. Collins' Principles of Medical Genetics (Baltimore:Williams & Wilkins, 1990). A number of articles describingadvances in the understanding of genetic diseases and progress ingene therapy were published in 1992 and 1993 in Science(256:773-813, 258:744-5, 260:926-32). For a vivid personal viewof the development of modem medical genetics and wise com-mentary on its implications, we recommend James Neel's Physi-cian to the Genome (New York: Wiley, 1994). Another thoughtfultreatment of the ethics of genetic counseling can be found inGenetic Disorders and the Fetus, edited by Aubrey Milunsky (Balti-more: Johns Hopkins Univ. Press, 1992); see especially the chap-ter by J. C. Fletcher and D. C. Wertz.

96-99 Selection against unfavorable genes, their rate of loss by suchselection, their expected equilibrium frequencies in populations,and related quantities can be related to one another algebraically,as explained by any textbook of population genetics, such asJ. Maynard Smith's Evolutionary Genetics (New York: OxfordUniv. Press, 1989). Our presentation in this chapter is greatlysimplified. Huntington's Disease, edited by P. S. Harper (London:Saunders, 1991), summarizes the history and epidemiology ofthis condition. It would be difficult to find a modem textbook ofgenetics or evolution that does not discuss the sickle-cell gene.Our favorite treatment is by Jared Diamond in Natural History,June 1988, pp. 10-13.

100-101 Our information on G6PD deficiency is from an article byErnest Beutler in The New England Journal of Medicine,324:169-74 (1991). The quotation from F. S. Collins is from hisarticle in Science, 774 (1992). Complications in cystic fibrosisgenetics are reviewed by Gina Kolata in The New York Times,November 16, 1993, pp. Cl, C3, and related evolutionary prob-lems by Natalie Angier in The New York Times, June 1, 1994, p.B9. Contributions to the study of Tay-Sachs disease are offeredby B. Spyropoulos and Jared Diamond in Nature, 331:666(1989); by S. J. O'Brien in Current Biology, 1:209-11 (1991); andby N. C. Myrianthopoulos and Michael Melnick in "Tay-SachsDisease: Screening and Prevention," in Palm Springs Interna-tional Conference on Tay-Sachs Disease edited by M. M. Kaback(New York: Liss, 1977). Our information on the human fragile-X syndrome is from F. Vogel et al.'s article in Human Genetics,

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86:25-32 (1990). Jared Diamond has written a number of nicelyreasoned articles on hidden benefits of genes that cause disease.Some of these are in Discover, November 1989, pp. 72-8, and inNatural History, June 1988, pp. 10-13, and February 1990, pp.26-30, Worthy examples of the voluminous literature on thegenetic aspects of disease and health are Teresa Costa et al.'sarticle in American Journal of Human Genetics, 21:321-42 (1985),and in a group of five articles on anthropological aspects ofgenetic disease in American Journal of Physical Anthropology,62(1) (1983).

101 The effect of PKU on miscarriage rates is discussed by L. I.Woolf et al. in Annals of Human Genetics, 38:461-9 (1975). Arecent statement of Richard Dawkins' idea that a body is thegenes' way of making more genes is his The Selfish Gene, new ed.(New York: Oxford Univ. Press, 1989).

101-102 The fitness effects of the T-locus in mice are discussed by PatriciaFranks and Sarah Lenington in Behavioral Ecology and Sociobiol-ogy, 18:395-404 (1986). Medical aspects of mitochondrial DNAare discussed by Angus Clarke in Journal of Medical Genetics,27:451-6 (1990). For general treatments of intragenomic conflict,see Leda Cosmides et aI.'s classic work in Journal of TheoreticalBiology, 89:83-129 (1981), and David Haig and Alan Grafen's arti-cle in Journal of Theoretical Biology, 153:531-58 (1991).

102-103 Familial and environmental aspects of cardiac malfunction arediscussed by M. P. Stern on pp. 93-104 in Genetic Epidemiology ofCoronary Heart Disease: Past, Present, and Future, edited by M. P.Stern (New York: Liss, 1984).

103-105 Piggy's extreme dependence on his glasses, and the tragic resultsof their damage and spiteful theft, are depicted in Chapters 10and 11 of Lord of the Flies by William Golding. The quotation isfrom Chapter 11. The sudden emergence of myopia in the chil-dren of urbanized Eskimos is documented by F. A. Young et al.in American Journal of Ophthalmology, 46:676-85 (1969). Generaldiscussions of the genetics and etiology of myopia are providedby Elio Raviola and T. N. Wiesel's article in The New EnglandJournal of Medicine, 312:1609-15 (1985); by B. J. Curtin's TheMyopias (Philadelphia: Harper & Row, 1988); and by G. R. Bockand Kate Widdows in Myopia and the Control of Eye Growth(Chichester, New York: Wiley, 1990). A brief summary of recentresearch is provided by Jane E. Brody in The New York Times,June 1, 1994, p. ClO.

105 Information on the genetics of alcoholism is in M. A. Schickit'sarticle in Journal of the American Medical Association, (1985); inJ. S. Searles' in Journal of Abnormal Psychology, 97:153-67 (1988);and in M. Mullen's in British Journal of Addictions, 84:1433-40(1989).

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106 The quotations are from pp. 89-90 of Melvin Konner's The Tan-gled Wing: Biological Constraints on the Human Spirit (New York:Harper Colophon, 1983) and p. 215 of Richard Dawkins' TheSelfish Gene (New York: Oxford Univ. Press, 1976).

Chapter 8. Aging as the Fountain of Youth

107 The Irish ballad is on p. 103 of 100 Irish Ballads (Dublin: Wal-ton's, 1985). For the general reader, an excellent overview of theevolution of aging is provided by several articles in the February1992 issue of Natural History and by R. Sapolsky and Caleb Finchon pp. 30-8 of the March-April 1991 issue of The Sciences. Excel-lent recent technical works are available in M. R. Rose's article inTheoretical Population Biology, 28:342-58 (1984); in his Evolution-ary Biology of Aging (New York: Oxford Univ. Press, 1991); andin Caleb Finch's Longevity, Senescence, and the Qenome (Chicago:Univ. of Chicago Press, 1991).

108-109 Death rates in the United States are from Vital Statistics in theUnited States, 1989 (Washington, D.C.: U.S. National Center forHealth Statistics, 1992). The demographic aspects of aging arewell reviewed by J. F. Fries and L. M. Crapo in Vitality and Aging(San Francisco: Freeman, 1981).

110 Figure 8-1 is redrawn from Figure 3-2 in Vitality and Aging withpermission.

111-112 Figure 8-3 is redrawn from Figure 9.2 in Vitality and Aging withpermission. We got the story about people fleeing a tiger fromHelena Cronin's The Ant and the Peacock (New York: CambridgeUniv. Press, 1992).

111-112 The lines about the "one-hoss shay" are from "The Deacon's Mas-terpiece" on pp. 158-60 of The Complete Poetical Works of OliverWendell Holmes (Boston: Houghton Mifflin, 1908). The apparentcoordination of aging effects is discussed by B. L. Strehler andA. S. Mildvan in Science, 132:14-21 (1960).

113 The quotation is from August Weismann's "The Duration ofLife," in A. Weismann: Essays upon Heredity and Kindred BiologicalProblems, edited by E. B. Poulton et al. (Oxford: Clarendon Press,1891-2). The article by 0. C. Williams is in Evolution, 1 1:398-41 1(1957).

113-114 The J. B. S. Haldane reference is to New Paths in Genetics (NewYork: Harper, 1942). The P. B. Medawar quotation is from p. 38of his article "Old Age and Natural Death," reprinted on pp.17-43 of his The Uniqueness of the Individual (London: Methuen,1957). See also his An Unsolved Problem in Biology (London: M. K.Lewis, 1952). The classic theoretical treatment of the subject isW. D. Hamilton's in Journal of Theoretical Biology, 12:12-45 (1968).

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114-115 For important recent comments on the evolution of menopause,see A. R. Rogers' article in Evolutionary Ecology, 7:406-20, KimHill and A. M. Hurtado's in Human Nature, 2:313-50 (1991),S. N. Austad in Experimental Gerontology, 29:255-63 (1994). AlexComfort's book is The Biology of Senescence, 3rd ed. (New York:Elsevier, 1979).

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115-116 Figure 8-4 is adapted from R. M. Nesse's article in ExperimentalGerontology, 23:445-53 (1988). R. L. Albin's article is in Ethologyand Sociobiology, 9:371-82 (1988). Hemochromatosis is reviewedby J. F. Desforges in the New England Journal of Medicine,328:1616-20 (1993).

116-117 For recent findings on the genetics of Alzheimer's disease, see thearticle by W. Strittmatter et al. in Proceedings of the NationalAcademy of Sciences (U.S.), 90:1977-81 (1993). S. I. Rapoport'swork is in Medical Hypotheses, 29:147-50.

117 R. R. Sokal's and other experimental studies of the role ofpleiotropic genes in senescence are summarized in M. R. Rose'sbook, cited for the beginning of the chapter. See especially hispp. 50-6 and 179-80.

118-120 Work on dietary restriction is reviewed by J. P. Phelan and S. N.Austad in Growth, Development, and Aging, 53(1-2):4-6 (1989).For evidence on the beneficial effects of antioxidants and theirmechanism of action, see R. G. Cutler's article in American Jour-nal of Clinical Nutrition, 53:373s-379s (1991). The quotation ongout is from p. 622 of Lubert Stryer's Biochemistry, 3rd ed. (NewYork: Freeman, 1988). S. N. Austad's reasons for believing thatthe aging process may be quite different in different species arepresented in Aging, 5:259-67 (1994). His opossum work is inJournal of Zoology, 229:695-708 (1994).

122 E. T. Whittaker's discussion of postulates of impotence is mainlyon pp. 58-60 of his From Euclid to Eddington. A Study of Concep-tions of the External World (New York: Dover, 1958).

Chapter 9. Legacies of Evolutionary History

For authoritative and accessible overviews of human evolution,we suggest Roger Lewin's In the Age of Mankind: A SmithsonianBook of Human Evolution (Washington, D.C.: SmithsonianBooks, 1988) and Jared Diamond's The Third Chimpanzee (NewYork: HarperCollins, 1992). For an engrossing biography of acontemporary hunter-gatherer woman, we recommend MarjorieShostack's Nisa: The Life and Words of a !Kung Woman (NewYork: Vantage Books, 1983).

125 The quotation from Charles Darwin is from p. 191 of the firstedition of The Origin of Species (London: John Murray, 1859).

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125-127 A more dramatic account of the unfortunate effect of humanspeech adaptations on traffic control in the throat is provided inChapter 10 of Elaine Morgan's The Scars of Evolution (London:Penguin, 1990). More technically detailed information can befound in Philip Lieberman and Sheila E. Blumstein's Speech Phys-iology, Speech Perception, and Acoustic Phonetics (Cambridge, Eng-land: Cambridge Univ. Press, 1988).

131 Our use of the book by George Estabrooks, Man, The MechanicalMisfit (New York: Macmillan, 1941), is at variance with its spirit.While it does describe many design flaws of the human body, itsmain message is the misfit between that design and the uses towhich it is put in modem times. It is also a eugenicist tract.

135 "Stone Agers in the Fast Lane" is the title of an article by S. B.Eaton et al. in The American Journal of Medicine, 84:739-49 (1988).

136-137 Luigi Cavalli-Sforza et al. in Science, 259:639-46 (1993), estimatethe current population at about a thousand times that of theStone Age. The prevalence of human infanticide, and compara-ble behavior in other species, has recently gotten detailed atten-tion. See Infanticide: Comparative and Evolutionary Perspectives,edited by G. Hausfater and S. B. Hrdy (New York: Aldine, 1984).

137 For details of the symptoms of protozoan and helminth diseases,see Part XV (pp. 1714-78) of The Cecil Textbook of Medicine,edited by J. B. Wyngaarden and L. H. Smith (Philadelphia: Saun-ders, 1982). Many of the unpleasant effects of parasites aredescribed, and some pictured, in the book by M. Katz et al. citedfor p. 41. Richard Alexander's quote is from p. 138 of the bookcited for p. 17.

140 A 15,000-year antiquity for domesticated dogs is suggested byVitaly Shevoroshkin and John Woodward in their article on pp.173-97 in Ways of Knowing. The Reality Club 3, edited by JohnBrockman (New York: Prentice Hall, 1991).

142 The quotation about cave paintings is from p. 57 in Melvin Kon-nor's The Tangled Wing: Biological Constraints on the Human Spirit(New York: Harper Colophon, 1983).

Chapter 10. Diseases of Civilization

144-145 For more on the origins of agriculture and husbandry, see Chap-ters 10 and 14 of Jared Diamond's book, cited for the beginning ofChapter 9.

145-146 Use of wild plant products to cure scurvy is discussed by IngolfurDavidsson in Natturufraedingurinn, 42:140-4 (1972). Nutritionaldeficiencies and other problems evident in the 1500-year-oldAmerind skeletons are documented by J. Lallo et al. on pp. 213-38of Early Native Americans, edited by D. L. Browman (The Hagueand New York: Moulton, 1980).

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147 The supernormal stimulus idea is discussed in many generalworks and textbooks, for instance, on pp. 27-9 of John Alcock'sbook cited for pp. 16-17.

148-149 For discussions of the role of dietary fat in modern medical prob-lems, see H. B. Eaton's article in Lipids, 27:814-20 (1992); West-ern Diseases, Their Emergence and Prevention, edited by H. C.Trowell and D. P. Burkitt (Cambridge, Mass.: Harvard Univ.Press, 1981), and H. B. Eaton et al's The Paleolithic Prescription(New York: Harper and Row, 1988). For a convincing work onthe profound role of environment in public health and the rela-tive unimportance of medicine, see Thomas McKeown's TheRole of Medicine: Dream, Mirage, or Nemesis? (Princeton, N.J.:Princeton Univ. Press, 1979).

149-150 The discussion of thrifty genotypes follows J. V. Neel's article inSorono Symposium, 47:281-93 (1982), and Gary Dowse and PaulZimmet's in British Medical Journal, 306:532-3 (1993). The effectsof intermittent dieting are discussed in an article by J. 0. Hill etal. in International Journal of Obesity, 12:547-55 (1988). The find-ings on artificial sweeteners are presented by D. Stellman andL. Garfinkel in Preventive Medicine, 15:195-202 (1986). Evidencefor a long-term metabolic effect of intermittent food restriction ispresented by G. L. Blackburn et al. in American Journal of Clini-cal Nutrition, 49:1105-9 (1989). Our conclusions and recommen-dations on diet and weight control summarize a detaileddiscussion published in a series of articles in The New York Times,November 22-5, 1992.

150 The incidence of dental caries in prehistoric Georgia is discussedby C. S. Larsen et al. in Advances in Dental Anthropology, editedby M. A. Kelley and C. S. Larsen (New York: Wiley-Liss, 1991).

151 For an example of a tribal society's use of a psychotropic drug,see Napoleon Chagnon's discussion of the use of ebene inVenezuela in Yanomamo: The Last Days of Eden (New York: Har-court Brace Jovanovich, 1992).

152 The inheritance of susceptibility to substance abuse is discussedby C. R. Cloninger in Archives of General Psychiatry, 38:961-8(1981); by M. A. Schuckit in Journal of the American MedicalAssociation, 254:2614-7 (1985); and by J. S. Searles in Journal ofAbnormal Psychiatry, 97:153-7 (1988). See also R. M. Nesse's arti-cle in Ethology and Sociobiology (in press).

154 Alan Weder and Nickolas Schork have published their theory inHypertension, 24: 145-56 (1994).

155-156 Skin color in relation to rickets is discussed by W. M. S. Russellin Ecology of Disease, 2:95-106 (1983). The rapid evolutionaryloss of pigment and eyes by animals living in caves is discussed byR. W. Mitchell and collaborators in "Mexican Eyeless Fishes,Genus Astyanax: Environment, Distribution and Evolution,"

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Special Publications. The Museum. Texas Tech University, 12:1-89(1977). Evidence for the importance of introduced diseases in thedestruction of New World peoples is summarized by F. L. Blackin Science, 258:1739-40. See also the work of M. Anderson andR. M. May cited for p. 52.

Chapter 11. Allergy

A good introduction to pollen allergies is N. Mygind's EssentialAllergy (Oxford: Blackwell, 1986). A more detailed review is inAllergic Diseases: Diagnosis and Management, edited by R. Patter-son (Philadelphia: J. B. Lippincott, 1993). A useful book onpollen is R. B. Knox's Pollen and Allergy (Baltimore: UniversityPark Press, 1978).

159 For details on the IgE system, see 0. L. Frick's article on pp.197-227 of Basic and Clinical Immunology, 6th ed., edited by D. P.Stites, J. D. Stobo, and J. V. Wells (Norwich, Conn.: Appleby andLange, 1987), and C. R. Zeiss and J. J. Prusansky's on pp. 33-46 ofAllergic Diseases: Diagnosis and Management (Philadelphia: J. B.Lippincott, 1993). Amos Bouskila and D. T. Blumstein provide adetailed discussion of what we call the smoke-detector principle inAmerican Naturalist, 139:161-76 (1992).

160 The New York Times quotation is from section 6, p. 52, March 28,1993. The textbook quoted is E. S. Golub's Immunology: A Syn-thesis (Sunderland, Mass.: Sinauer, 1987).

160-161 The history of ideas on the function of the ampullae of Lorenziniis discussed in a delightful article, "The Sense of Discovery andVice Versa," by K. S. Thomson in American Scientist, 71:522-5(1983). More recent work is reviewed by H. Wissing et al. inProgress in Brain Research, 74:99-107 (1988).

162-163 For discussions of IgE in relation to helminth infections, seeA. Capron and J.-P. Dessaint's work in Chemical Immunology,49:236-44 (1990), and K. Q. Nguyen and 0. G. Rodman's inInternational Journal of Dermatology, 32:291-7 (1984).

163 Profet's article is in Quarterly Review of Biology, 66:23-62 (1991).164-166 For more information on the apparently increasing incidence of

allergy, see works by L. Gamlin in the June 1990 issue of New Sci-entist and by Ronald Finn in Lancet, 340:1453-5 (1992). Thegenetics of atopy is reviewed by J. M. Hopkins in Journal of theRoyal College of Physicians (London), 24:159-60 (1990). Evidenceof the prevalence of genetic deficiencies in detoxificationenzymes is reviewed by M. F. W. Festing in Critical Reviews inToxicology, 18:1-26. Unfortunately, most of the research relatesto variation in detoxification of drugs, not to routinely encoun-tered toxins.

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169 The study of prevention of allergy is by S. H. Arshad et al. and ispublished in Lancet, 339:1493-97 (1992).

169-170 See citations for pp. 162-64 for indications of the increasing fre-quency of allergies. The redundancy and complexity of theimmune system are well described in S. Ohno in ChemicalImmunology, 49:21-34 (1990).

Chapter 12. Cancer

172-174 Our perspective on cancer derives from Leo Buss's book TheEvolution of Individuality (Princeton, N.J.: Princeton Univ. Press,1987). Liles's article is in MBL Science, 3:9-13 (1988).

175-177 Our account of the cellular, hormonal, and immunologicalmechanisms of cancer control is a greatly simplified retelling ofthat provided by two collections of articles in Science,254:1131-73 (1991) and 259:616-38 (1993). The data on the p53gene are from Elizabeth Culotta and D. E. Koshland's article inScience, 262:1958-61 (1993). Many of our statements on geneticfactors in cancer are supported by Chapter 5 of D. M. Prescottand A. S. Flexner's Cancer. The Misguided Cell, 2nd ed. (Sunder-land, Mass.: Sinauer, 1986). Cosmides and Tooby's observationswere made in a talk presented to the 1994 meeting of the HumanBehavior and Evolution Society.

178 On sunshine as carcinogen and its effects on the immune system,we recommend David Concar's easily readable account in theNew Scientist, 134 (1821):23-8 (1992).

179-181 Our discussion of women's reproductive cancers summarizesthat of W. B. Eaton et al. in Quarterly Review of Biology, 69:353-67(1994). The reduction in uterine and ovarian cancer risk as aresult of oral contraceptive use is documented by B. E. Hender-son et al. in Science, 259:633-8 (1993).

Chapter 13. Sex and Reproduction

183-184 The current debate over the evolutionary origins of sex is wellpresented in Matt Ridley's The Red Queen (New York: Macmil-lan, 1993). For a more technical discussion, see R. E. Michod andB. R. Levin, editors, The Evolution of Sex (Sunderland, Mass.: Sin-auer, 1988). For the parasite theory of sexuality, see W. D.Hamilton, R. Axelrod, and R. Tanese's article in Proceedings ofthe National Academy of Sciences, 87:3566-73 (1990). For someorigins of the current debate, see G. C. Williams' Sex and Evolu-tion (Princeton, N.J.: Princeton Univ. Press, 1975) and J. May-nard Smith's The Evolution of Sex (New York: Cambridge Univ.

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Press, 1978). A recent review by S. Sarkar appears in BioScience,42(6):448-54 (1992). The evolution of genetic diversity isreviewed by Wayne K. Potts and Edward K. Wakeland in Trendsin Ecology and Evolution, 5:181-7 (1990)

184-185 For a discussion of why there are large eggs and small sperm, seepp. 151-5 of Maynard Smith's The Evolution of Sex, cited above.Pp. 130-9 of the same work present the currently accepted viewof why some organisms are hermaphrodites and others have sep-arate sexes. A more detailed treatment is found in E. L.Chamov's The Theory of Sex Allocation (Princeton N.J.: PrincetonUniv. Press, 1982).

184-187 Current controversies on the theory of sexual selection, whichdeals with male-female differences in reproductive adaptations,are discussed in Sexual Selection: Testing the Alternatives, edited byJ. W. Bradbury and M. B. Anderson (New York: Wiley-Inter-science, 1987). The historical development and current form ofthis theory are beautifully presented by Helena Cronin's The Antand the Peacock (New York: Cambridge Univ. Press, 1991).

187 The problems expected as a result of a female-biased sex ratio arediscussed by P. Secord in Personality and Social Psychology Bul-letin, 9(4):525-43 (1983).

187-188 The application of the theory of sexual selection to human sex dif-ferences is discussed in several eminently readable works: DavidBuss's The Evolution of Desire (New York: Basic Books, 1994);Donald Symons' The Evolution of Human Sexuality (New York:Oxford Univ. Press, 1979); and Sarah B. Hrdy's The Woman ThatNever Evolved (Cambridge, Mass.: Harvard Univ. Press, 1981).Sex, Evolution and Behavior by Martin Daly and Margo Wilson(Boston: Willard Grant Press, 1983) offers an authoritative, yetclear and entertaining overview of animal and human sexuality.The same authors have a short, up-to-date chapter titled "TheMan who Mistook His Wife for a Chattel," pp. 289-322 inJ. Barkow, L. Cosmides, and J. Tooby, editors, The Adapted Mind(New York: Oxford Univ. Press, 1992). For a series of detailedreview articles, see L. Betzig, M. B. Mulder, and P. Turke, editors,Human Reproductive Behavior: A Darwinian Perspective (Cam,bridge: Cambridge Univ. Press, 1988).

188 For an authoritative report on male despotism and harems, seeLaura L. Betzig's Despotism and Differential Reproduction: A Dar-winian View of History (New York: Aldine, 1986).

189 The quotation from David Buss is from p. 249 in a chapter in TheAdapted Mind (see above) on "Mate Preference Mechanisms."

189 David Buss's data are in Behavioral and Brain Sciences, 12:1-49(1989). See also Bruce J. Ellis's "The Evolution of Sexual Attrac-tion: Evaluative Mechanisms in Women" in The Adapted Mind,cited above.

267

NOTES

190 The bond-testing idea is from Amotz Zahavi's "The Testing of aBond," Animal Behaviour, 25:246-7 (1976).

192 Information on orgasm in primates is in Donald Symons' The Evo-lution of Human Sexuality (New York: Oxford Univ. Press, 1979).

192 For information on concealed ovulation in humans, see BeverlyStrassmann's article in Ethology and Sociobiology, 2:31-40 (1981);Paul W. Turke's in Ethology and Sociobiology, 5:33-44 (1984); andNancy Burley's in The American Naturalist, 114:835-58 (1979).

193 The data on testis size are from R. V. Short's chapter in Repro-ductive Biology of the Great Apes, edited by C. E. Graham (NewYork: Academic, 1984). See also A. H. Harcourt and collabora-tors' article in Nature, 293:55-7 (1981).

193 See R. R. Baker and M. A. Bellis's "Human Sperm Competition:Ejaculate Adjustment by Males and the Function of Masturba-tion," Animal Behavior, 46:861-85 (1993), and R. R. Baker andM. A. Bellis, "Human Sperm Competition: Ejaculation Manipu-lation by Females and a Function for the Female Orgasm," Ani-mal Behavior, 46:887-909 (1993). Baker and Bellis's work onsperm counts is in "Number of Sperm in Human EjaculatesVaries as Predicted by Sperm Competition Theory," AnimalBehavior, 37:867-9 (1989). For a review of work on sperm com-petition, see M. Gomendio and E. R. S. Roldan's "Mechanismsof Sperm Competition: Linking Physiology and Behavioral Ecol-ogy," Trends in Ecology and Evolution, 8(3):95-100 (1993).

194 For the work on jealousy, see Martin Daly and collaborators'"Male Sexual Jealousy," Ethology and Sociobiology, 3:11-27(1982), and Martin Daly and Margo Wilson's Homicide (NewYork: Aldine, 1989). This book contains abundant data on anddetailed discussion of murders motivated by jealousy.

196 For discussions of sex differences in human reproductive strate-gies, see the works by Buss, Ridley, Cronin, and Symons men-tioned above.

197-200 David Haig's work is in Quarterly Review of Biology, 68:495-532(1993). Sexually antagonistic genes are discussed by W. R. Rice inScience, 256:1436-9 (1992). The classic paper on parent-offspringconflict is R. L. Trivers's in American Zoologist, 14:249-64 (1974).A good description is also found in his book Social Evolution(Menlo Park, Calif.: Benjamin/Cummings, 1985). For a recentreview and further references, see D. W. Mock and L. S. Forbes'article in Trends in Ecology and Evolution, 7(12):409-13 (1992).

200-201 The work on human birth is in a paper presented by Wenda Tre-vathan at the February 1993 American Academy of Sciencesmeeting in Boston. Also see her book Human Birth: An Evolution-ary Perspective (Hawthorne, N.Y.: Aldine de Gruyter, 1987).

201 The work on the role of oxytocin in bonding in sheep is by E. B.Keverne et al. in Science, 219:81-83 (1983).

268

NOTES

202 We got our information on the Mozarts' family tragedies mainlyfrom pages 98-102 of Mozart in Vienna 1781-1791 by VolkmarBraunbehrens (New York: Grove Weidenfeld, 1989).

202 On jaundice in the newborn, see John Brett and Susan Niermeyer'sarticle in Medical Anthropology Quarterly, 4:149-61 (1990).

203 Defective color discrimination and other visual impairmentsfrom exposure to round-the-clock bright light in infancy are dis-cussed by I. Abramov et a]. in Journal of the American OptometryAssociation, 56:614-19 (1985).

203-204 On babies' crying, see R. G. Barr's "The Early Crying Paradox: AModest Proposal," Human Nature, 1(4):355-89 (1990).

204-205 On SIDS, see James J. McKenna's "An Anthropological Perspec-tive on the Sudden Infant Death Syndrome (SIDS): The Role ofParental Breathing Cues and Speech Breathing Adaptations,"Medical Anthropology, 10:9-54 (1986).

205-206 On parent-offspring conflict, see the Trivers citations for pp.195-99. Also see pp. 55-58 and 234-35 of Martin Daly andMargo Wilson's Sex, Evolution, and Behavior, 2nd ed. (Boston:Willard Grant Press, 1983).

Chapter 14. Are Mental Disorders Diseases?

Cases are composites to protect confidentiality.The Moral Animal by Robert Wright (New York: Pantheon

Books, 1994) offers an excellent introduction to evolutionarypsychology.

A fine overview of work on evolution and psychiatry is BrantWenegrat's Sociobiological Psychiatry: A New Conceptual Frame-work (Lexington, Mass.: Lexington Books, 1990). Forthcoming isEvolutionary Psychiatry, by Michael McGuire and Alfonso Troisi.For an excellent introduction to animal behavior, see JohnAlcock's Animal Behavior: An Evolutionary Approach (Sunder-land, Mass.: Sinauer, 1993). For excellent introductions to socio-biology, see R. D. Alexander's Darwinism and Human Affairs(Seattle: University of Washington Press, 1979); R. Dawkins' TheSelfish Qene (New York: Oxford Univ. Press, 1976); E. 0. Wil-son's Sociobiology (Cambridge, Mass.: Harvard Univ. Press, 1975);E. 0. Wilson's On Human Nature (Cambridge, Mass.: HarvardUniv. Press, 1978); and R. Trivers' Social Evolution (Menlo Park,Calif.: Benjamin/Cummings, 1985). For recent progress in evolu-tionary psychology, see The Adapted Mind, cited for p. 320.

208-209 For the review that documents and emphasizes the medical ori-entation in current psychiatry, see Robert Michaels and Peter M.Marzuk in New England Journal of Medicine, 329:552-60 and628-38 (1993).

269

NOTES

209-212 For reviews of evolutionary approaches to emotions, see R. M.Nesse's "Evolutionary Explanations of Emotions," Human Nature,1:261-89 (1990); R. Plutchik and H. Kellerman's Theories of Emo-tion, vol. I (Orlando, Fla.: Academic, 1980); Paul Ekman's "AnArgument for Basic Emotions," Cognition and Emotion, 6:169-200(1992); Robert L. Trivers's "Sociobiology and Politics," in Sociobi-ology and Human Politics, edited by E. White (Toronto: Lexington,1981); John Tooby and Leda Cosmides's article in Ethology andSociobiology, 11:375-424 (1990); R. Thornhill and N. W. Thorn-hill's chapter in Sociobiology and the Social Sciences, edited by R. Bell(Lubbock, Tex.: Texas Tech Univ. Press, 1989); and E. 0. Wilson'sSociobiology (Cambridge, Mass.: Harvard University Press, 1975).

212 For a recent discussion on trade-offs between avoiding predationand other values, see A. Bouskila and D. T. Blumstein's article inAmerican Naturalist, 139:161-76 (1992).

212-213 Walter B. Cannon's classic is Bodily Changes in Pain, Hunger, Fear,and Rage. Researches into the Function of Emotional Excitement (NewYork: Harper and Row, 1929). Also see I. M. Marks' Fears, Pho-bias, and Rituals (New York: Oxford Univ. Press, 1987); A. Ohmanand U. Dimberg in Sociopsychology, edited by W. M. Waid (NewYork: Springer, 1984); 1. M. Marks and Adolf Tobena in Neuro-science and Biobehavioral Reviews, 14:365-84 (1990); D. H. Barlow'sAnxiety and Its Disorders (New York: Guilford, 1988); and SusanMineka et al. in Journal of Abnormal Psychology, 93:355-72 (1984).

213 The fearful guppies are described by A. L. Dugatkin in BehavioralEcology, 3:124-127 (1992).

213-214 For a review of signal detection theory, see D. M. Green and J. A.Swets, Signal Detection Theory and Psycho-physics (New York:Wiley, 1966).

214 R. H. Frank's ideas are in his book Passions Within Reason: TheStrategic Role of the Emotions (New York: Norton, 1988).

215-216 The increasing rate of depression is documented by the Cross-National Collaborative group in "The Changing Rate of MajorDepression. Cross-National Comparisons," Journal of the Ameri-can Medical Association, 268:3098-105 (1992).

215-221 For general information on depression, see P. C. Whybrow et al.Mood Disorders: Toward a New Psychobiology (New York: Plenum,1984); Emmy Gut's Productive and Unproductive Depression (NewYork: Basic Books, 1989); Paul Gilbert's Human Nature and Suffer-ing (Hove, England: Erlbaum, 1989); and R. E. Thayer's The Biopsy-chology of Mood and Arousal (New York: Oxford Univ. Press, 1989).

219 The data on writers are from N. C. Andreasen's article in TheAmerican Journal of Psychiatry, 144:1288-92 (1987).

219 John Price's original article is in Lancet, 2:243-6 (1967). Also seeRussell R. Pardner, Jr., in The Archives of Qeneral Psychiatry,39:1436-41 (1982), and J. S. Price and Leon Sloman's article inEthology and Sociobiology, 8:85s-98s (1987).

270

NOTES

219 The data on serotonin in vervet monkeys are in M. J. Raleigh etal. article in Brain Research, 559:181-90 (1991).

220 For information on seasonal affective disorder, see N. E. Rosen-thal and M. C. Blehar's Seasonal Affective Disorders and Photother-apy (New York: Guilford, 1989); D. A. Oren and N. E. Rosenthalin Handbook of Affective Disorders, edited by E. S. Paykel (NewYork: Churchill Livingstone, 1992); and David Schlager, J. E.Schwartz, and E. J. Bromet in British Journal of Psychiatry, 163:322-6 (1993). The large study suggesting an increasing rate ofdepression is cited for p. 214.

221-222 On the studies of infant monkeys, see H. F. Harlow's Learning toLove (New York: Aronson, 1974).

222-224 For sources of information on attachment, see Robert Karen'sreview "Becoming Attached," The Atlantic, February 1990, pp.35-70; John Bowlby's summary of his work in The AmericanHandbook of Psychiatry, vol. 6, edited by D. D. Hamburg andH. K. H. Brodie (1969); and M. D. Ainsworth et al. Patterns ofAttachment: A Psychological Study of the Strange Situation (Hills-dale, N.J.: Erlbaum, 1978). For a readable review of genetic focusthat may influence attachment, see Galen's Prophecy (New York:Basic Books, 1994).

223-224 On child abuse, see Martin Daly and Margo I. Wilson's Homicide(New York: Aldine, 1989); their "Abuse and Neglect of Children inEvolutionary Perspective" in Natural Selection and Social Behavior:Recent Research and Theory, edited by R. D. Alexander and D. W.Tinkle (New York: Chiron Press, 1981); S. B. Hrdy's "Infanticideas a Primate Productive Strategy," American Scientist, 65:40-9(1977); and R. J. Gelles and J. B. Lancaster, editors, Child Abuse andNeglect (New York: Aldine, 1987). Mark Flinn's article is in Ethol-ogy and Sociobiology, 9:335-69 (1988).

224-225 On schizophrenia, see J. L. Karlsson's article in Hereditas,107:59-4 (1987), and J. S. Allen and V. M. Sarich's in Perspectivesin Biology and Medicine, 32:132-53 (1988). The idea that suspi-ciousness may be beneficial is in a chapter by L. F. Jarvik and S. B.Chadwick in Psychopathology, edited by M. Hammer, K. Salzinger,and S. Sutton (New York: Wiley, 1972). For an interesting andtestable idea about schizophrenia and its possible relationship tosleep cycles, see Jay R. Feierman's article in Medical Hypotheses,9:455-79 (1982).

226-228 Ray Meddis's ideas are expounded mainly in his book The SleepInstinct (London: Routledge and Kegan Paul, 1977); he has ashorter presentation in Animal Behavior, 23:676-91 (1975). Fora general review of sleep among the Mammalia, see M. Elgar,M. D. Pagel, and P. H. Harvey's article in Animal Behavior,40:991-5 (1990). For general reviews of sleep and sleep research,see Alexander Borbdly's Secrets of Sleep (New York: Basic Books,1986), and Jacob Empson's Sleep and Dreaming (London: Faber

271

NOTES

and Faber, 1989). For the physiology of dreaming and the possi-ble irrelevance of psychological functions, see J. A. Hobson's TheDreaming Brain (New York: Basic Books, 1988); Ian Oswald,"Human Brain Proteins, Drugs, and Dreams," Nature, 223:893-7(1969); and Francis Crick and Graeme Mitchison, "The Functionof Dream Sleep," Nature, 304:111-14 (1983).

229-230 For sensorimotor constraints on dreaming, see Donald Symons'article "The Stuff That Dreams Aren't Made Of: Why Wake-State and Dream-State Sensory Experiences Differ," Cognition,47:181-217 (1993).

Chapter 15. The Evolution of Medicine

The quotation at the beginning of this chapter is the title of anarticle by the eminent geneticist Theodosius Dobzhansky, pub-lished in American Biology Teacher, 35:125-9 (1973).

234-235 Readers may recognize the watch metaphor from RichardDawkins' fine introduction to evolution, The Blind Watchmaker(New York: Norton, 1986). He extended the often cited ideafrom William Paley's 1802 masterpiece Natural Theology. WhilePaley's book was intended to clinch the case for creationism, hismany examples of exquisite design provided others, includingDarwin, with superb evidence for the power of natural selection.Of particular interest is Paley's attempt to explain convoluteddesign, which he attributes to the Deity's wish to reveal His pres-ence to man by "contrivances" of unnecessary complexity, andby constraining His creation within the bounds of fixed laws.Paley provides a sensible view of the utility of pain but thenclaims that death, sickness, and their unpredictability are all nec-essary parts of a divinely perfect world. It was thinking of thissort that inspired Voltaire to ridicule optimists like Dr. Panglossin his novel Candide.

239 For the role of antioxidants in aging, see Richard G. Cutler's"Antioxidants and Aging," American Journal of Clinical Nutrition,53:373s-379s (1991). For a brief review of current research on vit-amin E, see C. H. Hennekens, J. E. Buring, and R. Peto's"Antioxidant Vitamins-Benefits Not Yet Proved," New Eng-land Journal of Medicine, 330:1080-1 (1994).

240-241 The quote is from pp. 445-6 of Ren6 Dubos's Man Adapting(New Haven, Conn.: Yale Univ. Press, 1965, revised 1980).

241 The full title of Ernst Mayr's work is The Growth of BiologicalThought: Diversity, Evolution, and Inheritance (Cambridge, Mass.:Belknap Press of Harvard Univ. Press, 1982).

241-243 Several good books address the logic of formulating questionsabout function, and we recommend them to those who harbor

272

NOTES

suspicions that evolutionary arguments are fundamentally illegit-imate. It is a shame that such a simple misunderstanding shouldinhibit development of a whole field. See John Maynard Smith'sDid Darwin Get It Right? (New York: Chapman and Hall, 1989);E. Mayr's "Teleological and Teleonomic, A New Analysis,"Boston Studies in the Philosophy of Science, 14:91-117 (1974); JohnAlcock's Animal Behavior: An Evolutionary Approach, 4th ed.(Sunderland, Mass.: Sinauer, 1989); Michael Ruse's The Darwin-ian Paradigm (London: Routledge, 1989), George Williams' Nat-ural Selection (New York: Oxford Univ. Press, 1992); and hisAdaptation and Natural Selection: A Critique of Some Current Evo-lutionary Thought (Princeton, N.J.: Princeton Univ. Press, 1966).

243 The Flexner report is Medical Education in the United States andCanada, The Carnegie Foundation for the Advancement ofTeaching, Bulletin No. 4 (1910).

248 For an informed view of the problems of modem medicine, seeMelvin Konner's The Trouble with Medicine (London: BBC Books,1993).

248 The article that calls for preventive health care is James F. Friesand collaborators' "Reducing Health Care Costs by Reducing theNeed for Medical Services," The New England Journal of Medi-cine, 329:321-5 (1993).

273

INDEX

Aacetaminophen, 26, 27-28acorns, 79, 80, 84adaptionist program, 21-25addictions, 151-52African Americans, 99African sleeping sickness, 41, 43aging, 3, 10, 18, 19-20, 21, 107-8

absence of aging, effects of,109, 110

Alzheimer's disease, 116-17antioxidants and, 118-20, 239,

246cancer and, 177-78, 179-80death rates by age, 108-9, 110dietary restriction and

longevity, 118DNA damage and, 119-20early benefits, senescence genes

with, 113-18free radicals and, 118-20marathon runners and, 111,

112

mechanisms of senescence,118-20

medical implications of evo-lutionary view of,121-22

menopause and, 114pleiotropic theory of, 114relative longevity of humans,

133senescence defined, 108-9,

111-12sex differences in, 120-21theories of, 112-18uric acid, gout and, 119, 239,

245-46agoraphobia, 214-15agriculture, 85, 135, 143-44, 145,

146AIDS, 45, 61, 63, 64. See also

human immunodeficiencyvirus (HIV)

Ainsworth, Mary, 222Albin, Roger, 116

275

INDEX

alcohol, 77-78, 89, 151alcoholism, 105, 152cancer and, 178

Alexander, Richard, 17, 138allergies, 158-60

antihistaminic drugs for, 159,161, 166-67

atopy, 164-65bacteria and viruses, as defense

against, 168breastfeeding and, 169cancer and, 166-67cat allergy, 165-66ectoparasite defense, as, 167-68food allergies, 164, 167, 170hypersensitivity explanation of,

159-60IgE system, function of,

159-60, 161-64, 165-68increase in, 169-70major medical problem, as,

169-70Mauke atoll study of, 169mechanisms of, 161President Clinton's allergy,

165-66shrimp allergy, 167toxins, as backup defense

against, 163, 165-67useful from useless, 167variations in human response,

164-65worms, response to, 162-63,

167Alzheimer's disease, 3, 116-17Ames, Bruce, 78-79amoebic dysentery, 41, 58amoxicillin, 54ampicillin, 54ampullae of Lorenzini, 160-61amyotrophic lateral sclerosis, 119

Andreasen, Nancy, 219anemia, 192-93Angiostrongylus cantonensis

(worm), 41ankles, 131Ant and the Peacock, The (Cronin),

186antibiotics, 86, 246

farm animals, use in, 55-56,149

golden age of, 52-53resistance of bacteria to, 53-57

antibodies, 39-40, 51-52damage to host by, 43-44IgE activity, 159-60, 161-64.

See also allergiesantigens, 39-40antihistaminic drugs, 159, 161,

166-67antioxidants, 118-20, 203, 239,

246anxiety, 5, 16, 19, 212-15, 230-32appendicitis, 50, 129-30Aristotle, 13, 20artificial sweeteners, 150Ashkenazic Jews, 100aspirin, 27, 28asthma, 168atherosclerosis, 5, 6, 148Atlantic Monthly, The, 56attachment problems, 221-23Austad, Steven, 118, 120autoimmune diseases, 62automobiles, 19AZT, 56, 57

Bbacteria. See specific subject head-

ing, bacterium or diseaseBaker, Robin, 193

276

INDEX

Barr, Ronald, 204beavers, 22Bellis, Robert, 193Belovsky, Gary, 22Bendectin, 89beta-carotene, 239birds, 18, 22-23, 243birth, 130-31, 200-201birth defects, 89-90bladder cancer, 178bonding, mother and child, 201,

204, 221-22bones, 4, 5, 18Bonney, Barbara, 28-29Bostock, John, 169Bowiby, John, 222brain, 42, 130-31, 133Brave New World (Huxley), 218breast cancer, 9, 176, 178, 179-81breastfeeding, 169, 181, 201-2,

204, 205-6Brett, John, 202-3broccoli, 82, 83, 90Brussels sprouts, 82bubonic plague, 64Burley, Nancy, 192burns, 70-71

sunburn, 71-74Buss, David, 189, 190

Ccabbage, 82cabin fever, 157caffeine, 82calcium, 82calluses, 34cancer, 16, 86, 87, 149, 171

aging and, 177-78, 179-80alcohol and, 178allergies and, 166-67

avoidance problem, 172-77bacteria, viruses and, 178between-cell secretions against,

176bladder cancer, 178breast cancer, 9, 176, 178,

179-81cell history and, 172-75colon cancer, 175detectable tumors, natural con-

trol of, 178diet and, 178environmental factors and, 178female reproductive organs, in,

179-81genetic factors in, 175-77HIV and, 178immune system response to,

176-77injuries, infections and, 178lung cancer, 176, 178menstrual cycles and, 180-81ovarian cancer, 179-81p53 gene protection, 176prevention of, 177, 181prostate cancer, 178regeneration capabilities and,

75-76safety mechanisms against,

175-77skin cancer, 3, 72, 73-74, 178smoking and, 178stomach cancer, 178Stone Age contrast, 178, 180

success of, 179treatment of, 179tumor-suppressor genes,

175-76uterine cancer, 179-81

Cannon, Walter, 212Carnegie Foundation, 243

277

INDEX

Carroll, Lewis, 49cat allergy, 165-66cataracts, 74-75cauliflower, 82cervical mucus, 38, 192cesarean section, 200, 201chicken pox, 27-28child abuse, 223-24childbirth, 130-31, 200-201chlamydia, 44choking, 5, 11, 123-127

evolution of air-food trafficproblem, 124-27

cholera, 54, 60, 116ciprofloxacin, 53civilization, 143-45

addiction as disease of, 151-52agriculture, 85, 135, 143-44,

145, 146competition and mass commu-

nications, 220-21dental cavities and, 150-51depression and sadness, epi-

demic of, 220-21developmental problems,

153-54excesses in modern nutrition,

147-51exercise, lack of, 151, 153-54high blood pressure and, 154inadequacies in modern diet,

145-47infant crying and colic, 203-4mass communications, 220-21psychological problems of

modern life, 157, 207-9.See also mental disorders

sudden infant death syndrome(SIDS) and, 205

vision development and, 154

vitamin D requirement and,155-56

clay, eating of, 84, 90Clinton, Bill, 165-66coffee, 82, 89Cohen, Mitchell, 53colds, 26, 28, 29, 42-43, 45, 47, 238

nasal mucus and, 36virulence of, 58-59

colic, 204Collins, Francis, 100colon cancer, 175, 176Comfort, Alex, 115, 117community disintegration, 220,

221compensatory adjustments, 41-42Confucius, 171Connecticut Yankee in King

Arthur's Court, A (Twain),142

Coolidge, Calvin, 50corn, 84Cosmides, Leda, 176, 210coughs and cough reflex, 8-9, 21,

36-37, 163anxiety disorder compared to,

230-32choking. See chokingmanipulation by pathogen,

46, 57cowpox, 44cows, 167-68crack cocaine, 152Crafoord Prize, 16creativity, 219Crick, Francis, 228, 229"Crisis in Antibiotic Resistance,

The" (Neu), 56Cronin, Helena, 186crying of baby, 203-4

278

INDEX

cyanide, 79, 81-82cystic fibrosis, 100

DDaly, Martin, 194, 223Darwin, Charles, 47, 48, 125, 235,

242Darwinian medicine. See evolu-

tionary medicineDarwinism and Human Affairs

(Alexander), 17Dawkins, Richard, 15, 101, 106DDT, 86defecation, 33defenses, 8-9

infections, against. See infectionstoxins, against, 81-85

Dennis, Sandy, 171depression. See mental disordersdesign compromises or flaws, 10,

18-20appendix, 129-30arbitrary historical legacies, 133choking on air-food traffic,

123-27pelvis and childbirth, 130-31,

200random departures from opti-

mum, 132retina design, 127-29skull padding and size, 130-31uprightness and two-footed-

ness, 131-32vitamin C requirement, 130

diabetes, 98, 100-101, 198Diamond, Jared, 100-101diarrhea, 37-38, 46-47, 81, 100,

163diazepam, 82

diet, 5, 9adaptive cravings and modern

life, 147-51cancer and, 178clay, eating of, 84, 90cooking of food, 84-85diversification of, 83excesses in modern nutrition,

147-51high-fat diets, 148-49, 178inadequacies in modern diet,

145-47longevity and dietary restric-

tion, 118restriction on, 118, 149-50toxins in. See toxinsvitamin C requirements, 130,

145-46digitalis, 82dioxins, 86disease (generally). See also specific

subject headingsmystery of, 3-5overview of causes of, 235-36proximate and evolutionary

explanations, 6-7Dobzhansky, Theodosius, 234, 249dogs, 68dreaming, 228, 229-30drugs

antihistaminic drugs, 159, 161,166-67

fever blockers, 28-29genetic factors in abuse of, 105mental disorders, for, 208, 214,

218, 219-20pregnancy and, 89-90

Dubos, Ren6, 240-41DuPont, H.L., 38dyslexia, 105

279

INDEX

EE. coli bacteria, 54ears

ear wax, 36human hearing acuity, 134infections, 43

Eaton, Boyd, 179Eaton, S.B., 82Ebola virus, 64ectoparasites, 167-68education in medicine, 237, 243-45eggs

bird eggs, 22-23, 243iron and, 29

Ehrlich, Paul, 53Ekman, Paul, 210elephantiasis, 137emotions, 209-12environmental factors, 9

cancer and, 178epidemics, as cause of, 63-65genetic factors combined with,

103-5mental disorders. See mental

disordersmismatches, 9modern environment for Stone

Agers, 134-35natural selection, particularity

of, 13-14Stone Age EEA, 138-42

envy, 220-21epidemics, 52

AIDS, 45, 61, 63, 64depression, modern epidemic

of, 220-21novel environmental factors,

63-65. See also environ-mental factors

Epstein-Barr virus, 42erythropoietin, 42

Estabrooks, George, 131eugenics, 11evolutionary medicine. See also

specific subject headingsclinical implications of,

245-48delay in development of,

241-43disease causation, overview of,

235-36funding for, 240-41importance of, 12, 47-48,

245-48medical education, problems

in, 237, 243-45personal and philosophical

implications of, 249public policy implications of,

248research recommendations,

238-41Social Darwinism, distin-

guished from, 11textbook recommendations,

237Ewald, Paul, 47-48, 59-60exercise, lack of, 151, 153-54eyebrows, 24eyes, 4

cataracts, 74-75color vision defects, 154, 203human visual acuity, 133nearsightedness, 3, 5, 9-10, 16,

91-92, 103-4, 105, 106,154

neonatal jaundice treatment,effects of, 154, 203

retina, design flaws of, 127-29sun damage to, 74-75tear, 30, 36, 163vision, development of, 154

280

INDEX

Ffarm animals

antibiotic use in, 55-56, 149fat substitutes, 150fear, 67-69fescue, 78fetal alcohol syndrome, 89fevers, 51

animals, in, 27infection, as defense against,

26-29interference with, 28-29

fig wasps, 58filaria worms, 41, 137Finn, Huckleberry, 66Fisher, R.A., 24, 242fleas, 167-68Fleming, Alexander, 53Flexner, Abraham, 243Flinn, Mark, 224flu. See influenzaFord, Henry, 19foxes, 49, 68fragile-X syndrome, 100Frank, Robert, 214free radicals, 118-20, 203Freud, Sigmund, 229frostbite, 71fruits, 80

GGalli, Stephen, 162Garcia, John, 68genetic factors, 9-10, 91-92. See

also natural selectionbeneficiaries of disease-causing

genes, 98cancer and, 175-77common genes causing disease,

94, 98-101

developmental process, 94-96environmental factors, com-

bined with, 103-5heterozygote advantage, 98-99Human Genome Project,

93-94, 100outlaw genes, 10, 98, 101-2quirks, 102-5rare genes causing disease, 94,

96-98reproduction vs. health/

longevity, 14, 15-16, 97,100-101

research, importance of, 106screening for genetic disorders,

93senescence genes with early

benefits, 113-18. Seealso aging

genetic imprinting, 198germ plasm concept, 172-73goiter, 82gonorrhea, 41, 43, 53, 54Gould, Stephen Jay, 17gout, 16, 119, 239, 245-46grooming in animals, 34-35Groundhog Day (film), 123, 125growth of Biological Thought, The

(Mayr), 241G6PD deficiency, 100Guthrie, Woody, 97

HHageman's factor, 44Hague, William, 102Haig, David, 197, 198, 200Haldane,J.B.S., 16, 113, 114Hamilton, William, 16, 242Harlow, Harry, 221-22Hart, Benjamin, 34Hartung, John, 219

281

INDEX

healingburns and frostbite, of, 70-71injury repair, 69-71pathogen damage repair, 42regeneration of body parts,

75-76hearing. See earsheart, 4, 21, 42heart disease, 3, 9, 16

atherosclerosis, 5, 6, 148congestive heart failure, 132genetic factors in, 102-3heart attacks, 3, 6, 102-3, 148,

247hemochromatosis, 116hemoglobin, 42Hemophilus influenza bacteria, 43hepatitis, 41Hepburn, Katharine, 171herding, 144-45hermaphrodites, 185heroin, 152high blood pressure, 154, 198-99Hill, Kim, 114Hobson, Allan, 228, 229Holmes, Oliver Wendell, 111Homer, 194hookworms, 137hormone system, 4Hornick, Richard, 38hospitals, 60Hrdy, Sarah, 223-24human chorionic gonadotropin

(hCG), 199-200Human Genome Project, 93-94,

100human immunodeficiency virus

(HIV), 45, 56, 57cancer and, 178virulence and transmission of,

humor and laughter, 142Huntington's disease, 96-97Huxley, Aldous, 218Huxley, Julian, 222Huxley, Thomas, 167hygiene, 33-34, 60hypophobia, 214, 215hysteria, 191

immune system, 133. See also anti-bodies; infections

age bias of, 116allergic reactions (IgE). See

allergiesattack on host defenses,

44-45autoimmune diseases, 62cancer and, 176-77costs and benefits, 61-62evasion of, 42-44

inactivity, 35-36infancy

attachment problems in,221-23

bonding, mother and child,201, 204, 221-22

breastfeeding, 201-2, 204,205-6

crying and colic, 203-4jaundice treatment, 154, 202-3"spitting up," 204sudden infant death syndrome

(SIDS), 204-5weaning, 205-6

infections, 9, 31-33cancer and, 178classification of phenomena by

function, 32, 47-48damage and repair in, 41-42

282

INDEX

defenses of hostattack mechanisms, 39-40compensatory adjustment,

41-42expulsion defenses, 36-39,

46-47fevers, 26-29hygiene, 33-34iron deficiency, 7, 29-31MHC system, 40, 51pain and malaise, 35-36skin barrier, 34-35, 42

fevers as defense against, 26-29functional approach to, 32,

47-48functional approach to disease,

32, 47-48iron deficiencies and, 7, 29-31leukocyte endogenous media-

tor (LEM), release of, 30menstruation as defense

against, 38-39, 192pathogen strategies

attack on host defenses,44-45

dispersal, 45-46evasion of host defenses,

42-44manipulation of host, 36,

46-47reproductive physiology,

defenses in, 38-39, 192Stone Age, in, 137strategies and counterstrategies

in, 31-33influenza, 30, 64, 156, 168injury, 66-67

avoidance of, 67-69bums, 70-71cancer and, 178frostbite, 71

human intelligence in avoid-ance of, 69

pain and fear, 67-69repair of, 69-71sun damage, 71-75

insomnia, 226iron

eggs, in, 29infections and, 7, 29-31

itches, 33

Jjaundice treatment, 154, 202-3jealousy, 194-95Johns, Timothy, 78-79, 83Jordan, Michael, 132Justo Doria, Antonio, 97

Kkalaazar, 137Kenrick, Douglas, 221kidney stones, 82kidneys, 4, 133kin selection, 16-17Kluger, Matt, 27, 30knees, 131Konner, Melvin, 106Krause, Richard, 63

LLack, David, 23lactoferrin, 30Lascaux cave paintings, 141-42learning consolidation, 228Legionnaires' disease, 64LeGrand, Edmund, 44-45lemmings, 15, 16leukocyte endogenous mediator

(LEM), 30

283

INDEX

lice, 167-68Liles, George, 173lipopolysaccharide (LPS), 44-45liver, 41, 42, 44

cells and cancer, 172-73detoxification by, 81, 83

liver fluke, 58lizards, 27Lomotil, 38Lorenz, Konrad, 222Lou Gehrig's disease, 119Low, Bobbi, 56lung cancer, 176, 178lungworms, 137lupus erythematosus, 62Lyme disease, 64

MMcCarley, Robert, 228McGuire, Michael, 219McKenna, James, 204-5macrophages, 39major histocompatibility complex

(MHC), 40, 51malaise, 35-36malaria, 10, 17, 27, 30-31, 41, 43,

59, 98-100, 137, 156dispersal of, 45-46MHC antimalarial antigen, 51

Man, The Mechanical Misfit(Estabrooks), 131

manic-depressive disorder, 97,218-19

Marks, Isaac, 214marriage

in-laws, 190jealousy in, 194-95reasons for, 190

Masai people, 29mass communications, 220-21

Mauke atoll, 169Mayr, Ernst, 241measles, 63-64Medawar, Peter, 113-14, 242Meddis, Ray, 227, 228memory regulation, 228, 229Mendel, Gregor, 242meningitis, 43, 50menopause, 114menstruation, 116, 192-93

cancer and number of cycles,180-81

infection defense, 38-39, 192mental disorders, 157, 207-9

agoraphobia, 214-15anxiety, 5, 16, 19, 207-8,

212-15, 230-32attachment problems, origins

in, 221-23child abuse, 223-24community disintegration and,

220, 221cough analogy, 230-32depression and sadness

creativity and, 219manic-depressive disorder,

97, 218-19modern epidemic of, 220-21seasonal affective disorder

(SAD), 220simple sadness, 216-18status and mood, 219-20

drugs for, 208, 214, 218,219-20

emotions and, 209-12hypophobia, 214, 215manic-depressive disorder, 97,

218-19mass communications and,

220-21novel dangers, 215

284

INDEX

panic disorder, 207-8, 209psychiatry, changes in, 208-9,

230-33sadness, 216-18schizophrenia, 224-25seasonal affective disorder

(SAD), 220sleep disorders and functions,

226-30mercury, 86methicillin, 53Mildvan, A.S., 112mimicry, 32, 62-63Mineka, Susan, 68-69miscarriage, 100-101Mitchison, Graeme, 228modern life. See civilizationmonkeys, 18, 68-69mononucleosis, 65Morgan, Elaine, 131morning sickness, 7, 87-90, 200mosquitoes, 33, 45-46, 59-60mumps, 52myopia. See nearsightedness

Nnarcolepsy, 226Native Americans, 52, 82, 84, 85,

146, 149, 156natural selection, 13-14. See also

specific subject headingsadaptionist program method of

investigation, 21-25chance, influence of, 17compromises in design, 10,

18-20environmental particularity,

13-14genetic priority of, 15-16group selection, fallacy of, 15

hypotheses, testing of, 20-25kin selection, 16-17misconceptions regarding, 14,

15, 17perfection in nature, 18reproductive (not health) prior-

ity of, 14, 15-16, 97,100-101

sex ratio, of, 23-24"survival of the fittest," 14

nausea, 37. See also vomitingpregnancy, in, 7, 87-90, 200

nearsightedness, 3, 5, 9-10, 16,91-92, 103-4, 105, 106,154

Neisseria gono7rhoeae bacteria, 43Nelson, D.A., 82nervous sytem, 4, 5Neu, Harold, 56New England Journal of Medicine,

The, 30-31New York Times, The, 160, 171nicotine, 86, 152, 178Niermeyer, Susan, 202-3nightmares, 226nose and nostrils, 11, 20, 21, 36,

124, 125, 127nuclear families, 157, 221nuts, 80

0obsessive-compulsive disorder,

43-44onions, 90opossums, 120orgasm, 192, 196Oswald, Ian, 227, 228Otteson, Eric, 169ovarian cancer, 179-81oxylate, 82oxytocin, 201

285

INDEX

paindefense against disease, as,

35-36emotional pain, 209-12. See

also mental disordersinjury, avoidance of, 67-68

panic disorder, 207-8, 209Pasteur, Louis, 47pathogen evolution. See Red

Queen PrinciplePCBs, 86pellagra, 84pelvis and childbirth, 130-31, 200penicillin, 53, 54pepsinogen 1, 116pesticides, 78, 85-86, 149p53 gene, 176phenylketonuria (PKU), 101, 106,

116phenylthiocarbamate (PTC), 82plant toxins, 78-81

children and vegetables, 90defenses against, 81-85, 87-90

plantar fasciitis, 238-39Plasmodium. See malariaPlato, 138pneumonia, 3, 8-9, 43, 53, 54, 168poisons. See toxinspolio, 64-65polycystic ovaries, 102potatoes, 81, 82, 85praying mantis, 188-89preeclampsia, 198, 199pregnancy

birth defects, 89-90childbirth, 130-31, 200-201conflict between mother and

fetus, 197-200diabetes in, 198gene screening in, 93

genetic imprinting in, 198high blood pressure in, 198-99human chorionic gonadotropin

(hCG) secretions, 199-200human placental lactogen (hPL)

secretions, 198miscarriage, 100-101nausea in, 7, 87-90, 200oxytocin in, 201

Price, John, 219Profet, Margie, 7, 38, 88-89, 163,

165-66, 167, 192, 200prostate cancer, 178protozoan ancestry, 173-74Prozac, 219-20psychological problems. See men-

tal disorderspublic policy, 248

Rrabbits, 14, 19, 27, 49, 68rabies virus, 42, 46Raleigh, Michael, 219Rapoport, S.I., 117reciprocity theory, 17Red Queen Principle

antibiotics, bacterial resistanceto, 52-57

antibodies vs. pathogens,51-52

arms race analogy, 49-50defined, 49epidemics, rapid evolution of

resistance in, 52evolution, past and current,

51-52rabbits and foxes, 49, 51

regression in children, 206research recommendations,

238-41

286

INDEX

retina inversion, 127-29retrovirus, 56rheumatic fever, 43rheumatoid arthritis, 62rhinovirus, 42-43. See also coldsrickets, 155-56Ridley, Matt, 56ringworm, 45Rogers, Alan, 114roundworms, 40

Ssadness, 216-18saliva, 30, 36Salmonella flexneri, 54Scars of Evolution, The (Morgan),

131schistosomes, 44schizophrenia, 224-25scurvy, 146seahorses, 185seasonal affective disorder (SAD),

220seeds, 80Selfish Gene, The (Dawkins), 15Seligman, Martin, 37Semmelweis, Ignaz, 60senescence. See agingsensorimotor system, 4sex and reproduction, 5

anatomy and physiology of,191-94

bilirubin levels and jaundice,202-3

bonding, mother and child,201, 204, 221-22

breastfeeding, 169, 181, 201-2,204, 205-6

cancer of female reproductiveorgans, 179-81

cell divisions and cancer. Seecancer

cesarean section, 200, 201child abuse, 223-24childbirth, 130-31, 200-201choices of mate, 186, 188-90concealed ovulation, 192conflict in

male and female, 182-83,193-95, 196

mother and child, 197-200,203-4, 205-6

crying and colic, 203-4deceptive mating strategies, 191disorders, 195-96egg and sperm, 185-86, 187,

193-94female choice and male burden,

186function of sexual reproduc-

tion, 183-84hermaphrodites, 185India and China, in, 187infancy, 201-5. See also infancyinfection defenses, 38-39, 192infidelity, 189-90, 193-95jealousy, 194-95maleness and femaleness,

184-87marriage, 190, 194-95mate preferences, 186, 188-90menstruation, 38-39, 116,

180-81, 192-93orgasm, 192, 196pregnancy, 7, 87-90, 93,

100-101, 197-200. Seealso pregnancy

premature ejaculation, 196priority over health or

longevity, 14, 15-16, 97,100-101

287

INDEX

sex and reproduction (continued)sex ratio, 23-24, 187sperm competition, 193-94testicles, size and position of,

193testing the bond, 190weaning, 205-6

sharks, 160-61shigellosis, 58, 60shivering, 21shock, 44-45shrimp allergy, 167sialic acid, 44sickle-cell anemia, 10, 17, 98-99,

156skin, 34-35, 42, 44

cancer, 3, 72, 73-74, 178jaundice, 154, 202-3pneumonia, sign of, 8-9rickets and pigmentation,

155-56sun damage to, 71-74

skulls, 130-31, 133sleep disorders and functions,

226-28dreaming, 228, 229-30

smallpox, 51, 63-64, 156smell, 37Smith, John Maynard, 16smoking, 86, 89, 152sneezing, 36, 46, 47, 57, 64,

163Social Darwinism, 11Sociobiology (Wilson), 17Sokal, Robert, 117Spencer, Herbert, 14sperm. See sex and reproductionsperm-borne pathogens, 38-39spices, 89Spitz, Rene, 222spleen, 168

staphylococcus bacteria, 44, 53,64, 168

status and mood, 219-20Stein, Gertrude, 25sterility, 28Stevens, Dennis, 28stomach acid, 18, 36, 81, 116stomach cancer, 178Stone Age hunter-gatherers

birth rates, 136cancer comparisons, 178,

180death in Stone Age, 135-38,

140-41environment of evolutionary

adaptedness (EEA),138-42

famine, 137-38, 140infectious diseases, 137life of, 138-42modern environment of,

134-35plantar fasciitis and, 238reproductive history of

women, 180strife among, 138sugar, fat and salt in diet of,

147-49Strassmann, Beverly, 39Strehler, B.L., 112streptococcus bacteria, 43-44,

168, 246strokes, 148sudden infant death syndrome

(SIDS), 204-5sugar, 86, 147, 148suicide, 215, 216, 220Summers, Anne, 86sun damage, 71-75superoxide dismutase (SOD),

119

288

INDEX

Sydenham's chorea, 43-44Symons, Donald, 229-30syphilis, 27, 52-53

TT cells, 39, 45, 161, 165tannin, 80, 84tapeworms, 41taste, 37Tay-Sachs disease, 100tears, 30, 36, 163teeth, 21, 35, 41

civilization and cavities, 150-51jaw exercise and, 153

Tennyson, Alfred, Lord, 207testicles, 193textbooks, 237thyroid gland, 35ticks, 167-68tobacco

smoking, 86, 89, 152, 178tobacco mosaic virus, 46

tomatoes, 81tongue, 24Tooby, John, 176, 210toxic shock syndrome, 64toxins

alcohol, 77-78allergies as defense against, 163,

165-67children and vegetables, 90chronic vs. occasional threats,

83cooking of food and, 84-85cultural defenses, 84-85defenses against, 87-90defenses against natural toxins,

81-85digestive system defenses, 37disease-resistant plants, in, 85

mutagens and teratogens, 87-90novel toxins, 78, 85-86pesticides, 78, 85-86, 149plant toxins, 78-81pregnancy defenses, 87-90vulnerability by age, 87, 88, 90

transferrin, 30Trevathan, Wendy, 200Trivers, Robert, 17, 198, 205-6Trudeau, E.L., 11trypanosomes, 41, 43tuberculosis, 18, 40, 51, 53, 64,

100, 116resistance to antibiotics, 53, 54

Turke, Paul, 116Twain, Mark, 5, 66, 142Tylenol, 26, 27-28

Uulcers, 18, 116uric acid, 119, 239, 245-46urination, 37uterine cancer, 179-81

Vvaccinia, 44varicose veins, 132vector, 45-46

cultural vectors, 60-61virulence and, 59-61

virulenceantibiotics, resistance to, 53-57evolution of, 57-61HIV evolution, 61hospitals, 60vectors and, 59-61within, and between-host selec-

tion, 58-59vision. See eyes

289

INDEX

vitamin C, 130, 145-46, 239vitamin D, 155-56vitamin E, 239Volvox carteri protozoa, 174vomiting, 37, 46, 81, 163infant "spit-up," 204

WWagner-Jauregg, Julius, 27Wallace, Alfred Russel, 242weaning, 205-6Weil, Jennifer, 132Weismann, August, 113,

172-73

Whitman, Walt, 123Williams, George, 113-14Wilson, E.O., 17, 211Wilson, Margo, 194, 223With Bitter Herbs Thou Shalt Eat It

(Johns), 79, 83worms, 40, 41, 45, 137

allergies as response to, 162-63,167

ZZahavi, Amotz, 190zidovudine. See AZTZulu people, 29

290

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FAQs

How do you write a summary for homework? ›

A summary should include all of the main points or ideas in the work but avoid smaller details or ideas. You don't want to provide every aspect of the plot or smaller points in your summary. Your summary should be written using your own words.

Do you think writing a summary can help students understand better? ›

Why teach summarizing? It helps students learn to determine essential ideas and consolidate important details that support those ideas. It enables students to focus on key words and phrases of an assigned text that are worth remembering.

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Why students struggle with summary writing? ›

Often they are not aware of the "main idea", or if they are, they cannot use the same summary skills they use to speak for summary writing. They are not able to grasp the main idea and summarize it in writing, even if they can do so when they speak.

How do you write a summary of answers? ›

A good summary should give an objective outline of the whole piece of writing. It should answer basic questions about the original text such as "Who did what, where, and when?", or "What is the main idea of the text?", "What are the main supporting points?", "What are the major pieces of evidence?".

What are the 5 steps of summary writing? ›

There are five key steps that can help you to write a summary:

Read the text.
Break it down into sections.
Identify the key points in each section.
Write the summary.
Check the summary against the article.

Nov 23, 2020

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What are the 7 steps in writing a summary? ›

To do this effectively, consider following these steps:

Reread the original text. ...
Make a list of key points. ...
Note supporting evidence. ...
Start with a context sentence. ...
Describe the key concept of the text. ...
Follow up with supporting evidence. ...
Write a thesis statement.

Feb 3, 2023

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What are the benefits of summary writing? ›

What Are the Benefits of Summary Writing?

Extracts the Key Points From a Paragraph. ...
Gives Your Writing More Credibility. ...
Helps to Keep Track of the Original Source. ...
Offers Various Perspectives. ...
Makes Learning Fast-Paced and Easier. ...
Structures the Key Concepts in a Meaningful Way.

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What is summary writing useful for? ›

When you write a summary, you are demonstrating your understanding of the text and communicating it to your reader. To summarize is to condense a text to its main points and to do so in your own words. To include every detail is neither necessary nor desirable.

What is the purpose of summary writing? ›

The purpose of a summary is to quickly give the reader or listener an idea of what this material is saying. You may create summaries of material by other authors, such as articles, plays, films, lectures, stories, or presentations.

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What is a common mistake that people make when writing summaries? ›

Mistake #1 - Writing Too Much

Your executive summary needs to be concise. While you want to introduce your project and help capture the attention of reviewers, you do not want to write too much and lose their focus.

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What are the problems with summary writing? ›

Summary writing problems

they could not find the main ideas of the text and finally lost focus, especially when they had to write a summary on an unfamiliar topic and had limited time. Someone spent too much time reading the source text. since they directly affected their understanding.

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What are the disadvantages of summary writing? ›

Since summary only gives you an idea about the original book, you may end up interpreting facts in a different path from that of the author. You might also misjudge realities, the particulars, and other specifics the wrong way, similar to on the come up summary, which is irrepressible.

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How can I improve my summary writing skills? ›

4 Tips for Writing a Good Summary

Find the main idea. A useful summary distills the source material down to its most important point to inform the reader. ...
Keep it brief. A summary is not a rewrite—it's a short summation of the original piece. ...
Write without judgment. ...
Make sure it flows.

Jun 7, 2021

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What is the easiest way to write a summary? ›

A summary begins with an introductory sentence that states the text's title, author and main point of the text as you see it. A summary is written in your own words. A summary contains only the ideas of the original text. Do not insert any of your own opinions, interpretations, deductions or comments into a summary.

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What are the three skills that are needed to make a good summary? ›

Know the three essential characteristics of a summary

A good summary has three basic characteristics: conciseness, accuracy, and objectivity. Conciseness: unlike paraphrase, summary condenses information.

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What is the five finger rule for summarizing? ›

The Five Finger Retell Reading Strategy is designed to help students recall the five key elements of a story. The five key elements of a story are the setting, characters, problems, events, and solution. When a reader can recall these five key elements, he or she should be able to successfully summarize most stories.

What are the six things a summary must include? ›

Six elements a research summary should include

Why is this study necessary and important? ...
Who were the participants? ...
What were the methods used? ...
What were the key findings of the study? ...
What conclusion was drawn from the research? ...
What kind of relevance does the research have for the wider world? (the big why)

Feb 7, 2023

Is summary writing a skill? ›

Summary writing is an important form of writing skills that will come in handy for students throughout their academic journey and even in competitive exams such as Bank exams, MBA exams, etc.

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What skills are developed by summary writing? ›

Summarising and paraphrasing are essential skills in academic work. They involve extracting the key points from a source text, turning these key points into an abbreviated version (a summary) of the original, and, importantly, expressing this information in your own words.

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What are the three importance of a summary? ›

Thus we have three main functions of summaries: (1) they clarify the content of an article and thus help readers decide whether or not they want to read it, (2) they help readers organise their thoughts about what is to follow and (3) they aid the recall of important features in the article.

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What makes a bad summary? ›

Missing or inaccurate content and detail – e.g. that individual sources are heavily relied on, that key claims are missing or obscured. Surface features (grammar, spelling, style) Evidence used (e.g. citations) – e.g. that citation of quotes, ideas, and specific claims are missing.

What are the keys to a good summary? ›

In order to identify the main points, think of your summary as the lead paragraph in a newspaper article: it ought to answer the questions who, what, where, when, why, and how in a general way: Who wrote the article; what the article concerns; where and when it takes place; why the author has written about it; and how ...

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What are 3 words for summary? ›

1. Summary, brief, digest, synopsis are terms for a short version of a longer work. A summary is a brief statement or restatement of main points, especially as a conclusion to a work: a summary of a chapter.

What are 3 very important things to remember and do when writing an academic summary? ›

Remember that writing a summary requires: The knowledge of the text, obtained through repeated readings. Identification and formulation of the main ideas using short sentences. Rephrasing the main ideas into longer sentences.

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How do you start writing a summary? ›

A summary begins with an introductory sentence that states the text's title, author and main point of the text as you see it. A summary is written in your own words. A summary contains only the ideas of the original text. Do not insert any of your own opinions, interpretations, deductions or comments into a summary.

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What is a good example of a summary? ›

The act of summarizing is much like stating the plot of a play. For instance, if you were asked to summarize the story of Shakespeare's 'Hamlet,' you might say: It's the story of a young prince of Denmark who discovers that his uncle and his mother have killed his father, the former king.

How do you write a summary example? ›

How to write a summary

Read the text thoroughly. Read the text several times to ensure you understand everything about the author's message. ...
Take notes to identify the main idea. ...
Identify the main arguments. ...
Prepare your draft. ...
Write the summary. ...
Quote the author. ...
Conclude the summary. ...
Correct and refine.

Mar 10, 2023

What are good ways to start a summary example? ›

Begin the summary by acknowledging the source. For instance, you could begin with a sentence such as: "This is a summary of the article XXXX written by XXXX published in XXXX." 3. Next, write a topic sentence that conveys the main idea of the text.

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What makes a good summary? ›

A good summary should be comprehensive, concise, coherent, and independent. These qualities are explained below: A summary must be comprehensive: You should isolate all the important points in the original passage and note them down in a list.

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What is the best starting line for a summary? ›

The first line of your summary paragraph should list the title, author, and publication date of your original text. This section should also feature a brief note about the type of text you're referencing, which could be a story, article, novel or textbook.

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What is a good summary sentence starter? ›

In conclusion, … In brief, … To summarise, … To sum up, …

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How many sentences should be in a summary? ›

Keep it brief.

A summary is not a rewrite—it's a short summation of the original piece. A summary paragraph is usually around five to eight sentences. Keep it short and to the point. Eliminate redundancies or repetitive text to keep your paragraph clear and concise.

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How do you write a good summary for a paragraph? ›

To summarize, you must read a passage closely, finding the main ideas and supporting ideas. Then you must briefly write down those ideas in a few sentences or a paragraph. It is important to understand the difference between a summary and a paraphrase. A paraphrase is simply a rewriting of a passage in your own words.

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What are the 4 steps of an summary? ›

Use a four-step process to write a summary of a reading.

Step 1: Identify the main idea of the reading. ...
Step 2: Identify the supporting details. ...
Step 3: Identify the author's purpose. ...
Step 4: Write a summary of the reading. ...
Step 1: Identify the main idea of the reading.

More items...

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What are the 5 easy techniques in summarizing? ›

The Five W's, One H strategy relies on six crucial questions: who, what, when, where, why, and how. These questions make it easy to identify the main character, important details, and main idea. Who is the story about? What did they do?

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What are the 3 easy techniques in summarizing? ›

There are three important summarization techniques. They are selection, rejection and substitution.
...
They are discussed hereunder.

Selection : Selection is an important summarization technique. ...
Rejection : Rejection is an important summarization technique. ...
Substitution : It is also an important summarization technique.

Sep 7, 2010

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How long is a short summary? ›

They are most often no more than 200-400 words. Brief summaries contain only the most important information to prepare the reader for what is to come.

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Summary writing | Biology homework help (2023)

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