Evolution and the Origins of Disease by Randolph M

The principles of evolution by natural selection are ﬁnally beginning to inform medicine Evolution and the Origins of Disease by Randolph M. Nesse and George C. Williams

houghtful contemplation of the human body elicits awe—in equal measure

with perplexity. The eye, for instance, has long been an object of wonder, T with the clear, living tissue of the cornea curving just the right amount, the iris adjusting to brightness and the lens to distance, so that the optimal quantity of light focuses exactly on the surface of the retina. Admiration of such apparent perfection soon gives way, however, to consternation. Contrary to any sensible design, blood vessels and nerves traverse the inside of the retina, creating a blind spot at their point of exit.

The body is a bundle of such jarring contradictions. For each exquisite heart valve, we have a wisdom tooth. Strands of DNA direct the development of the 10 trillion cells that make up a human adult but then permit his or her steady deterioration and eventual death. Our immune system can identify and destroy a million kinds of foreign matter, yet many bacteria can still kill us. These contradictions make it appear as if the body was designed by a team of superb engineers with occasional interventions by Rube Goldberg.

In fact, such seeming incongruities make sense but only when we investigate the origins of the body’s vulnerabilities while keeping in mind the wise words of distinguished geneti- cist Theodosius Dobzhansky: “Nothing in biology makes sense except in the light of evolution.” Evolutionary biology is, of course, the scientiﬁc foundation for all biology, and biology is the foundation for all medicine. To a surprising degree, however, evolutionary bi-

86 Scientific American November 1998 Copyright 1998 Scientific American, Inc. Constraints Example: The design of the human eye leads to a blind spot and allows for detached retinas. The squid eye is free of such problems. AIG KIEFER TIONS BY CR SQUID RETINA HUMAN RETINA A USTR ILL

Defenses Example: Symptoms such as cough or fever are not defects but in fact are the body’s defenses in action.

Trade-offs Example: Overdesign of any one system, such as a pair of unbreak- able arms, would upset the entire organism’s functioning.

Conflicts Example: Human beings are in con- stant battle with other organisms that have been fine-tuned by evolution. CHERS, INC. O RESEAR T HO Cholera bacterium CNRI/SPL/P

Novel environments Example: The human body has only recently adopted its current environment, filled with former rarities such as high-fat foods. CE A URIE GR A L

Copyright 1998 Scientific American, Inc. Scientific American November 1998 87 ture facilitates the destruction of patho- DEATH gens. Work by Matthew J. Kluger of the Lovelace Institute in Albuquerque, N.M., has shown that even cold-blooded liz- ards, when infected, move to warmer places until their bodies are several de- grees above their usual temperature. If prevented from moving to the warm COST part of their cage, they are at increased risk of death from the infection. In a similar study by Evelyn Satinoff of the MINOR University of Delaware, elderly rats, INCONVENIENCE who can no longer achieve the high fevers of their younger lab companions, SEVERE NO also instinctively sought hotter environ- RESPONSE SEVERE ments when challenged by infection. WITH NO RESPONSE REAL WITH REAL A reduced level of iron in the blood is THREAT THREAT another misunderstood defense mecha- JOHNNY JOHNSON nism. People suffering from chronic in- MUCH SUFFERING is unnecessary but inevitable fection often have decreased levels of because of the smoke-detector nature of our defens- blood iron. Although such low iron is es. The cost of a false alarm—a strong reaction such sometimes blamed for the illness, it ac- as vomiting in the absence of a true threat to life—is tually is a protective response: during temporary unpleasantness. But the cost of no alarm infection, iron is sequestered in the liver, in the presence of a true threat, such as a food toxin, which prevents invading bacteria from could mean death. A lack of defensive response dur- AIG KIEFER getting adequate supplies of this vital

CR ing pregnancy, for example, could kill the fetus. element. Morning sickness has long been con- ology is just now being recognized as a cell gene, which also protects against sidered an unfortunate side effect of basic medical science. The enterprise of malaria. Finally, the process of natural pregnancy. The nausea, however, coin- studying medical problems in an evolu- selection is constrained in ways that cides with the period of rapid tissue dif- tionary context has been termed Dar- leave us with suboptimal design features, ferentiation of the fetus, when develop- winian medicine. Most medical research as in the case of the mammalian eye. ment is most vulnerable to interference tries to explain the causes of an individ- by toxins. And nauseated women tend ual’s disease and seeks therapies to cure Evolved Defenses to restrict their intake of strong-tasting, or relieve deleterious conditions. These potentially harmful substances. These efforts are traditionally based on con- erhaps the most obviously useful de- observations led independent research- sideration of proximate issues, the Pfense mechanism is coughing; peo- er Margie Profet to hypothesize that the straightforward study of the body’s ple who cannot clear foreign matter nausea of pregnancy is an adaptation anatomic and physiological mecha- from their lungs are likely to die from whereby the mother protects the fetus nisms as they currently exist. In con- pneumonia. The capacity for pain is also from exposure to toxins. Profet tested trast, Darwinian medicine asks why the certainly beneficial. The rare individu- this idea by examining pregnancy out- body is designed in a way that makes als who cannot feel pain fail even to ex- comes. Sure enough, women with more us all vulnerable to problems like can- perience discomfort from staying in the nausea were less likely to suffer miscar- cer, atherosclerosis, depression and same position for long periods. Their riages. (This evidence supports the hy- choking, thus offering a broader con- unnatural stillness impairs the blood pothesis but is hardly conclusive. If Pro- text in which to conduct research. supply to their joints, which then dete- fet is correct, further research should The evolutionary explanations for the riorate. Such pain-free people usually die discover that pregnant females of many body’s flaws fall into surprisingly few by early adulthood from tissue damage species show changes in food prefer- categories. First, some discomforting and infections. Cough or pain is usually ences. Her theory also predicts an in- conditions, such as pain, fever, cough, interpreted as disease or trauma but is crease in birth defects among offspring vomiting and anxiety, are actually nei- actually part of the solution rather than of women who have little or no morn- ther diseases nor design defects but rath- the problem. These defensive capabili- ing sickness and thus eat a wider vari- er are evolved defenses. Second, conflicts ties, shaped by natural selection, are ety of foods during pregnancy.) with other organisms—Escherichia coli kept in reserve until needed. Another common condition, anxiety, or crocodiles, for instance—are a fact Less widely recognized as defenses are obviously originated as a defense in of life. Third, some circumstances, such fever, nausea, vomiting, diarrhea, anxi- dangerous situations by promoting es- as the ready availability of dietary fats, ety, fatigue, sneezing and inflammation. cape and avoidance. A 1992 study by are so recent that natural selection has Even some physicians remain unaware Lee A. Dugatkin of the University of not yet had a chance to deal with them. of fever’s utility. No mere increase in Louisville evaluated the benefits of fear Fourth, the body may fall victim to trade- metabolic rate, fever is a carefully regu- in guppies. He grouped them as timid, offs between a trait’s benefits and its lated rise in the set point of the body’s ordinary or bold, depending on their costs; a textbook example is the sickle thermostat. The higher body tempera- reaction to the presence of smallmouth

88 Scientific American November 1998 Evolution and the Origins of Disease Copyright 1998 Scientific American, Inc. bass. The timid hid, the ordinary sim- birth defects, by interfering with the ing defenses is so often free of tragic con- ply swam away, and the bold main- mother’s defensive nausea. sequences. Because most defensive reac- tained their ground and eyed the bass. Another obstacle to perceiving the tions occur in response to insignificant Each guppy group was then left alone benefits of defenses arises from the ob- threats, interference is usually harmless; in a tank with a bass. After 60 hours, servation that many individuals regu- the vast majority of alarms that are 40 percent of the timid guppies had larly experience seemingly worthless re- stopped by removing the battery from survived, as had only 15 percent of the actions of anxiety, pain, fever, diarrhea the smoke alarm are false ones, so this ordinary fish. The entire complement of or nausea. The explanation requires an strategy may seem reasonable. Until, bold guppies, on the other hand, wound analysis of the regulation of defensive re- that is, a real fire occurs. up aiding the transmission of bass genes sponses in terms of signal-detection the- rather than their own. ory. A circulating toxin may come from Conflicts with Other Organisms Selection for genes promoting anxious something in the stomach. An organ- behaviors implies that there should be ism can expel it by vomiting, but only atural selection is unable to pro- people who experience too much anxi- at a price. The cost of a false alarm— Nvide us with perfect protection ety, and indeed there are. There should vomiting when no toxin is truly pres- against all pathogens, because they tend also be hypophobic individuals who ent—is only a few calories. But the pen- to evolve much faster than humans do. have insufficient anxiety, either because alty for a single missed authentic alarm— E. coli, for example, with its rapid rates of genetic tendencies or antianxiety failure to vomit when confronted with of reproduction, has as much opportu- drugs. The exact nature and frequency a toxin—may be death. nity for mutation and selection in one of such a syndrome is an open question, Natural selection therefore tends to day as humanity gets in a millennium. as few people come to psychiatrists com- shape regulation mechanisms with hair And our defenses, whether natural or plaining of insufficient apprehension. triggers, following what we call the artificial, make for potent selection forc- But if sought, the pathologically non- smoke-detector principle. A smoke es. Pathogens either quickly evolve a anxious may be found in emergency alarm that will reliably wake a sleeping counterdefense or become extinct. Am- rooms, jails and unemployment lines. family in the event of any fire will nec- herst College biologist Paul W. Ewald The utility of common and unpleas- essarily give a false alarm every time the has suggested classifying phenomena ant conditions such as diarrhea, fever toast burns. The price of the human associated with infection according to and anxiety is not intuitive. If natural body’s numerous “smoke alarms” is whether they benefit the host, the path- selection shapes the mechanisms that much suffering that is completely nor- ogen, both or neither. Consider the run- regulate defensive responses, how can mal but in most instances unnecessary. ny nose associated with a cold. Nasal people get away with using drugs to This principle also explains why block- mucous secretion could expel intruders, block these defenses without doing their bodies obvious harm? Part of the answer is that we do, in fact, sometimes do our- selves a disservice by disrupting defenses. Evolution of Virulence Herbert L. DuPont of the University of Texas at Houston and Richard B. hanges in virulence relate to the life history of the infectious agent and its Hornick of Orlando Regional Medical Cmode of transmission. As elucidated by Paul W. Ewald of Amherst College, in- Center studied the diarrhea caused by fection requiring direct contact will ordinarily drive a pathogen toward a state of low- Shigella infection and found that people ered virulence, because the host must remain mobile enough to interact with others. who took antidiarrhea drugs stayed sick But intermediaries that spread disease-causing agents, even from totally incapacitated longer and were more likely to have hosts, can cause a change toward more virulence. Behavioral choices, such as safer complications than those who took a sex, can also alter the makeup of the pathogen. placebo. In another example, Eugene D. Weinberg of Indiana University has documented that well-intentioned at- tempts to correct perceived iron deficien- cies have led to increases in infectious disease, especially amebiasis, in parts of Africa. Although the iron in most oral supplements is unlikely to make much difference in otherwise healthy people with everyday infections, it can severely harm those who are infected and mal- SELECTION FACTORS SELECTION FACTORS nourished. Such people cannot make FAVORING HIGHER FAVORING LOWER enough protein to bind the iron, leaving VIRULENCE VIRULENCE it free for use by infectious agents. AIG KIEFER

On the morning-sickness front, an CR antinausea drug was recently blamed for Intermediary disease vectors Casual human-to-human transmission birth defects. It appears that no consid- (Mosquitoes, health care workers’ (Sneezing, coughing, touch) eration was given to the possibility that hands, unsanitary water supplies) Protected and/or monogamous sex the drug itself might be harmless to the Unprotected and/or promiscuous sex fetus but could still be associated with

Evolution and the Origins of Disease Scientific American November 1998 89 Copyright 1998 Scientific American, Inc. speed the pathogen’s transmission to some strains of tuberculosis in New directly from person to person, low vir- new hosts or both [see “The Evolution York City are resistant to all three main ulence tends to be beneficial, as it al- of Virulence,” by Paul W. Ewald; Sci- antibiotic treatments; patients with those lows the host to remain active and in entific American, April 1993]. An- strains have no better chance of surviv- contact with other potential hosts. But swers could come from studies examining than did TB patients a century ago. some diseases, like malaria, are transmit- ing whether blocking nasal secretions Stephen S. Morse of Columbia Univer- ted just as well—or better—by the inca- shortens or prolongs illness, but few sity notes that the multidrug-resistant pacitated. For such pathogens, which such studies have been done. strain that has spread throughout the usually rely on intermediate vectors like Humanity won huge battles in the East Coast may have originated in a mosquitoes, high virulence can give a war against pathogens with the devel- homeless shelter across the street from selective advantage. This principle has opment of antibiotics and vaccines. Our Columbia-Presbyterian Medical Center. direct implications for infection control victories were so rapid and seemingly Such a phenomenon would indeed be in hospitals, where health care workers’ complete that in 1969 U.S. Surgeon predicted in an environment where hands can be vectors that lead to selec- General William H. Stewart said that it fierce selection pressure quickly weeds tion for more virulent strains. was “time to close the book on infectious out less hardy strains. The surviving In the case of cholera, public water disease.” But the enemy, and the power bacilli have been bred for resistance. supplies play the mosquitoes’ role. When water for drinking and bathing is con- taminated by waste from immobilized patients, selection tends to increase vir- New Environments Bring New Health Threats ulence, because more diarrhea enhanc- es the spread of the organism even if in- Common Threats to Health from 20,000 B.C. to Modern Times dividual hosts quickly die. But, as Ewald has shown, when sanitation improves, Accidents selection acts against classical Vibrio cholerae bacteria in favor of the more Starvation benign El Tor biotype. Under these con- Predation ditions, a dead host is a dead end. But a less ill and more mobile host, able to in- Infectious diseases fect many others over a much longer time, is an effective vehicle for a pathogen of lower virulence. In another ex- Common Threats to Health Today (in Technologically Advanced Cultures) ample, better sanitation leads to dis- placement of the aggressive Shigella Heart attack, stroke and other complications of atherosclerosis flexneri by the more benign S. sonnei. Such considerations may be relevant Cancer for public policy. Evolutionary theory predicts that clean needles and the en- Other chronic diseases associated with lifestyle and longevity couragement of safe sex will do more Noninsulin-dependent diabetes than save numerous individuals from HIV infection. If humanity’s behavior Obesity itself slows HIV transmission rates, strains that do not soon kill their hosts New infectious diseases have the long-term survival advantage over the more virulent viruses that then die with their hosts, denied the opportunity to spread. Our collective choices of natural selection, had been underes- Many people, including some physi- can change the very nature of HIV. timated. The sober reality is that patho- cians and scientists, still believe the out- Conflicts with other organisms are gens apparently can adapt to every dated theory that pathogens necessarily not limited to pathogens. In times past, chemical researchers develop. (“The war become benign after long association humans were at great risk from preda- has been won,” one scientist more re- with hosts. Superficially, this makes tors looking for a meal. Except in a few cently quipped. “By the other side.”) sense. An organism that kills rapidly places, large carnivores now pose no Antibiotic resistance is a classic dem- may never get to a new host, so natural threat to humans. People are in more onstration of natural selection. Bacteria selection would seem to favor lower danger today from smaller organisms’ that happen to have genes that allow virulence. Syphilis, for instance, was a defenses, such as the venoms of spiders them to prosper despite the presence of highly virulent disease when it first ar- and snakes. Ironically, our fears of small an antibiotic reproduce faster than oth- rived in Europe, but as the centuries creatures, in the form of phobias, prob- ers, and so the genes that confer resis- passed it became steadily more mild. ably cause more harm than any interac- tance spread quickly. As shown by No- The virulence of a pathogen is, howev- tions with those organisms do. Far more bel laureate Joshua Lederberg of the er, a life history trait that can increase dangerous than predators or poisoners Rockefeller University, they can even as well as decrease, depending on which are other members of our own species. jump to different species of bacteria, option is more advantageous to its genes. We attack each other not to get meat borne on bits of infectious DNA. Today For agents of disease that are spread but to get mates, territory and other re-

90 Scientific American November 1998 Evolution and the Origins of Disease Copyright 1998 Scientific American, Inc. sources. Violent conflicts between indi- likely to survive famines that killed two or three years of nursing, then by viduals are overwhelmingly between their thinner companions. And we, their another pregnancy soon after. Only be- young men in competition and give rise descendants, still carry those urges for tween the end of nursing and the next to organizations to advance these aims. foodstuffs that today are anything but pregnancy will the woman menstruate Armies, again usually composed of scarce. These evolved desires—inflamed and thus experience the high levels of young men, serve similar objectives, at by advertisements from competing food hormones that may adversely affect huge cost. corporations that themselves survive by breast cells. Even the most intimate human rela- selling us more of whatever we want to In modern societies, in contrast, men- tionships give rise to conflicts having buy—easily defeat our intellect and arche occurs at age 12 or 13—probably medical implications. The reproductive willpower. How ironic that humanity at least in part because of a fat intake interests of a mother and her infant, for worked for centuries to create environ- sufficient to allow an extremely young instance, may seem congruent at first ments that are almost literally flowing woman to nourish a fetus—and the first but soon diverge. As noted by biologist with milk and honey, only to see our pregnancy may be decades later or nev- Robert L. Trivers in a now classic 1974 success responsible for much modern er. A female hunter-gatherer may have a paper, when her child is a few years old, disease and untimely death. total of 150 menstrual cycles, whereas the mother’s genetic interests may be best Increasingly, people also have easy the average woman in modern societies served by becoming pregnant again, access to many kinds of drugs, especial- has 400 or more. Although few would whereas her offspring benefits from con- ly alcohol and tobacco, that are respon- suggest that women should become tinuing to nurse. Even in the womb there sible for a huge proportion of disease, pregnant in their teens to prevent breast is contention. From the mother’s vantage health care costs and premature death. cancer later, early administration of a point, the optimal size of a fetus is a bit Although individuals have always used burst of hormones to simulate pregnan- smaller than that which would best psychoactive substances, widespread cy may reduce the risk. Trials to test serve the fetus and the father. This dis- problems materialized only following this idea are now under way at the Uni- cord, according to David Haig of Har- another environmental novelty: the versity of California at San Diego. vard University, gives rise to an arms ready availability of concentrated drugs race between fetus and mother over her and new, direct routes of administra- Trade-offs and Constraints levels of blood pressure and blood sug- tion, especially injection. Most of these ar, sometimes resulting in hypertension substances, including nicotine, cocaine ompromise is inherent in every and diabetes during pregnancy. and opium, are products of natural se- Cadaptation. Arm bones three times lection that evolved to protect plants their current thickness would almost Coping with Novelty from insects. Because humans share a never break, but Homo sapiens would common evolutionary heritage with in- be lumbering creatures on a never-end- aking rounds in any modern hos- sects, many of these substances also af- ing quest for calcium. More sensitive Mpital provides sad testimony to fect our nervous system. ears might sometimes be useful, but we the prevalence of diseases humanity has This perspective suggests that it is not would be distracted by the noise of air brought on itself. Heart attacks, for ex- just defective individuals or disordered molecules banging into our eardrums. ample, result mainly from atherosclero- societies that are vulnerable to the dan- Such trade-offs also exist at the ge- sis, a problem that became widespread gers of psychoactive drugs; all of us are netic level. If a mutation offers a net re- only in this century and that remains susceptible because drugs and our bio- productive advantage, it will tend to in- rare among hunter-gatherers. Epidemi- chemistry have a long history of inter- crease in frequency in a population ological research furnishes the informa- action. Understanding the details of even if it causes vulnerability to disease. tion that should help us prevent heart that interaction, which is the focus of People with two copies of the sickle cell attacks: limit fat intake, eat lots of veg- much current research from both a gene, for example, suffer terrible pain etables, and exercise hard each day. But proximate and evolutionary perspec- and die young. People with two copies hamburger chains proliferate, diet foods tive, may well lead to better treatments of the “normal” gene are at high risk of languish on the shelves, and exercise for addiction. death from malaria. But individuals with machines serve as expensive clothing The relatively recent and rapid in- one of each are protected from both ma- hangers throughout the land. The pro- crease in breast cancer must be the re- laria and sickle cell disease. Where ma- portion of overweight Americans is one sult in large part of changing environ- laria is prevalent, such people are fitter, third and rising. We all know what is ments and ways of life, with only a few in the Darwinian sense, than members good for us. Why do so many of us con- cases resulting solely from genetic ab- of either other group. So even though tinue to make unhealthy choices? normalities. Boyd Eaton and his col- the sickle cell gene causes disease, it is Our poor decisions about diet and leagues at Emory University reported selected for where malaria persists. exercise are made by brains shaped to that the rate of breast cancer in today’s Which is the “healthy” allele in this en- cope with an environment substantially “nonmodern” societies is only a tiny vironment? The question has no answer. different from the one our species now fraction of that in the U.S. They hypoth- There is no one normal human ge- inhabits. On the African savanna, where esize that the amount of time between nome—there are only genes. the modern human design was fine- menarche and first pregnancy is a cru- Many other genes that cause disease tuned, fat, salt and sugar were scarce cial risk factor, as is the related issue of must also have offered benefits, at least and precious. Individuals who had a total lifetime number of menstrual cy- in some environments, or they would tendency to consume large amounts of cles. In hunter-gatherers, menarche oc- not be so common. Because cystic fibro- fat when given the rare opportunity had curs at about age 15 or later, followed sis (CF) kills one out of 2,500 Cauca- a selective advantage. They were more within a few years by pregnancy and sians, the responsible genes would ap-

Evolution and the Origins of Disease Scientific American November 1998 91 Copyright 1998 Scientific American, Inc. the food passageway. Because natural selection cannot start from scratch, humans are stuck with the possibility that food will clog the opening to our lungs. The path of natural selection can even lead to a potentially fatal cul-de-sac, as in the case of the appendix, that vestige of a cavity that our ancestors employed in digestion. Because it no longer per- forms that function, and as it can kill APPENDIX is most likely here when infected, the expectation might to stay. Evolutionary pressure be that natural selection would have selects against the smaller ap- eliminated it. The reality is more com- pendix (above), because inflam- plex. Appendicitis results when inflammation and swelling can cut off mation causes swelling, which compress- its cleansing blood supply, makes the artery supplying blood to the ap- ing infections more life-threatening. Larger appendices are pendix. Blood flow protects against thus actually selected for. bacterial growth, so any reduction aids

AIG KIEFER infection, which creates more swelling. CR If the blood supply is cut off complete- pear to be at great risk of being elimi- contribute to more rapid aging. For in- ly, bacteria have free rein until the ap- nated from the gene pool. And yet they stance, strong immune defenses protect pendix bursts. A slender appendix is es- endure. For years, researchers mused that us from infection but also inflict contin- pecially susceptible to this chain of the CF gene, like the sickle cell gene, uous, low-level tissue damage. It is also events, so appendicitis may, paradoxi- probably conferred some advantage. possible, of course, that most genes that cally, apply the selective pressure that Recently a study by Gerald B. Pier of cause aging have no benefit at any age— maintains a large appendix. Far from Harvard Medical School and his col- they simply never decreased reproduc- arguing that everything in the body is leagues gave substance to this informed tive fitness enough in the natural envi- perfect, an evolutionary analysis reveals speculation: having one copy of the CF ronment to be selected against. Never- that we live with some very unfortunate gene appears to decrease the chances of theless, over the next decade research legacies and that some vulnerabilities the bearer acquiring a typhoid fever in- will surely identify specific genes that may even be actively maintained by the fection, which once had a 15 percent accelerate senescence, and researchers force of natural selection. mortality. will soon thereafter gain the means to Aging may be the ultimate example interfere with their actions or even Evolution of Darwinian Medicine of a genetic trade-off. In 1957 one of us change them. Before we tinker, howev- (Williams) suggested that genes that er, we should determine whether these espite the power of the Darwinian cause aging and eventual death could actions have benefits early in life. Dparadigm, evolutionary biology is nonetheless be selected for if they had Because evolution can take place only just now being recognized as a basic other effects that gave an advantage in in the direction of time’s arrow, an or- science essential for medicine. Most dis- youth, when the force of selection is ganism’s design is constrained by struc- eases decrease fitness, so it would seem stronger. For instance, a hypothetical tures already in place. As noted, the that natural selection could explain only gene that governs calcium metabolism vertebrate eye is arranged backward. health, not disease. A Darwinian ap- so that bones heal quickly but that also The squid eye, in contrast, is free from proach makes sense only when the ob- happens to cause the steady deposition this defect, with vessels and nerves run- ject of explanation is changed from dis- of calcium in arterial walls might well ning on the outside, penetrating where eases to the traits that make us vulnera- be selected for even though it kills some necessary and pinning down the retina ble to diseases. The assumption that older people. The influence of such so it cannot detach. The human eye’s natural selection maximizes health also pleiotropic genes (those having multiple flaw results from simple bad luck; hun- is incorrect—selection maximizes the effects) has been seen in fruit flies and dreds of millions of years ago, the layer reproductive success of genes. Those flour beetles, but no specific example has of cells that happened to become sensi- genes that make bodies having superior yet been found in humans. Gout, how- tive to light in our ancestors was posi- reproductive success will become more ever, is of particular interest, because it tioned differently from the correspond- common, even if they compromise the arises when a potent antioxidant, uric ing layer in ancestors of squids. The individual’s health in the end. acid, forms crystals that precipitate out two designs evolved along separate Finally, history and misunderstanding of fluid in joints. Antioxidants have tracks, and there is no going back. have presented obstacles to the accep- antiaging effects, and plasma levels of Such path dependence also explains tance of Darwinian medicine. An evo- uric acid in different species of primates why the simple act of swallowing can lutionary approach to functional analy- are closely correlated with average be life-threatening. Our respiratory and sis can appear akin to naive teleology adult life span. Perhaps high levels of food passages intersect because in an or vitalism, errors banished only recent- uric acid benefit most humans by slow- early lungfish ancestor the air opening ly, and with great effort, from medical ing tissue aging, while a few pay the for breathing at the surface was under- thinking. And, of course, whenever evo- price with gout. standably located at the top of the snout lution and medicine are mentioned to- Other examples are more likely to and led into a common space shared by gether, the specter of eugenics arises.

92 Scientific American November 1998 Evolution and the Origins of Disease Copyright 1998 Scientific American, Inc. Selected Principles of Darwinian Medicine A Darwinian approach to medical practice leads to a shift in perspective. The following principles provide a foundation for considering health and disease in an evolutionary context:

DEFENSES and DEFECTS are two fundamentally different GENETIC SELF-INTEREST will drive an individual’s actions, manifestations of disease even at the expense of the health and longevity of the individual created by those genes BLOCKING defenses has costs as well as benefits VIRULENCE is a trait of the pathogen that can increase as Because natural selection shapes defense regulation well as decrease according to the SMOKE-DETECTOR PRINCIPLE, much defensive expression and associated suffering are SYMPTOMS of infection can benefit the pathogen, the unnecessary in the individual instance host, both or neither

Modern epidemics are most likely to arise from the Disease is INEVITABLE because of the way that organisms mismatch between PHYSIOLOGICAL DESIGN of our are shaped by evolution bodies and NOVEL ASPECTS of our environment Each disease needs a PROXIMATE EXPLANATION of why Our DESIRES, shaped in the ancestral environment to lead some people get it and others don’t, as well as an us to actions that tended to maximize reproductive EVOLUTIONARY EXPLANATION of why members of success, now often lead us to disease and early death the species are vulnerable to it

The body is a bundle of COMPROMISES Diseases are not products of natural selection, but most of the VULNERABILITIES that lead to disease are shaped There is no such thing as “the NORMAL body” by the process of natural selection

There is no such thing as “the NORMAL human genome” Aging is better viewed as a TRADE-OFF than a disease

Some GENES that cause disease may also have benefits, Specific clinical recommendations must be based on and others are quirks that cause disease only when they CLINICAL STUDIES; clinical interventions based only on interact with novel environmental factors theory are not scientifically grounded and may cause harm

Discoveries made through a Darwinian tionary biology to medicine is a new cies had review panels with evolution- view of how all human bodies are alike enterprise. Like biochemistry at the be- ary expertise, research would develop in their vulnerability to disease will of- ginning of this century, Darwinian med- faster, but such panels remain to be cre- fer great benefits for individuals, but icine very likely will need to develop in ated. We expect that they will. such insights do not imply that we can several incubators before it can prove The evolutionary viewpoint provides or should make any attempt to improve its power and utility. If it must progress a deep connection between the states of the species. If anything, this approach only from the work of scholars without disease and normal functioning and can cautions that apparent genetic defects funding to gather data to test their ideas, integrate disparate avenues of medical may have unrecognized adaptive sig- it will take decades for the field to ma- research as well as suggest fresh and nificance, that a single “normal” ge- ture. Departments of evolutionary biol- important areas of inquiry. Its utility and nome is nonexistent and that notions of ogy in medical schools would acceler- power will ultimately lead to recogni- “normality” tend to be simplistic. ate the process, but for the most part tion of evolutionary biology as a basic The systematic application of evolu- they do not yet exist. If funding agen- medical science. SA

The Authors Further Reading

RANDOLPH M. NESSE and GEORGE C. WILLIAMS are the authors of the 1994 Evolution of Infectious Disease. P. W. book Why We Get Sick: The New Science of Darwinian Medicine. Nesse received his Ewald. Oxford University Press, 1994. medical degree from the University of Michigan Medical School in 1974. He is now pro- Darwinian Psychiatry. M. T. McGuire and fessor of psychiatry at that institution and is director of the Evolution and Human Adap- A. Troisi. Harvard University Press, 1998. tation Program at the university’s Institute for Social Research. Williams received his doc- Evolution in Health and Disease. Edit- torate in 1955 from the University of California, Los Angeles, and quickly became one of ed by S. Stearns. Oxford University Press, the world’s foremost evolutionary theorists. A member of the National Academy of Sci- 1998. ences, he is professor emeritus of ecology and evolution at the State University of New Evolutionary Medicine. W. R. Trevathan York at Stony Brook and edits the Quarterly Review of Biology. et al. Oxford University Press (in press).