From evolution and medicine to evolutionary medicine

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From Evolution and Medicine to Evolutionary Medicine

Tatjana Buklijas and Peter Gluckman

In 1991 Randolph Nesse and George C. Williams opened their classic article on “The Dawn of Darwinian Medicine” with the following assertion (Plates LI and LII):

While evolution by natural selection has long been a foundation for biomedical science, it has recently gained new power to explain many aspects of disease. (Williams and Nesse 1991).

The optimistic statement of the two pioneers of modern “Darwinian” or “evolution-ary medicine” raises many questions. Was evolution indeed a foundation for bio-medical science? Historians have traditionally located the foundations of modern medicine in clinical disciplines, anatomy, and physiology – or, from the institutional perspective, in the hospital, morgue, and the laboratory. Evolutionary and field stud-ies do not figure in any of the major medical-historical accounts (Bynum 1994; Porter 1999; Cooter and Pickstone 2000). And, if evolutionary studies indeed gained new power to explain disease, why was Nesse and Williams’s “manifesto” published in the Quarterly Review of Biology, a journal with a traditional emphasis on evolution and, at the time of publication, edited by Williams himself, rather than in a medical journal. Why has evolutionary medicine remained marginalized from the medical community?

Certainly in the two decades following the publication of this article, a new field at the junction of evolutionary biology, molecular and developmental biology, genetics, epidemiology, and clinical medicine has gained in strength, with numerous articles, books, and first advances into medical school curricula (Nesse and Williams 1995; Stearns and Koella 2008; Gluckman, Beedle, and Hanson 2009). The appeal of evo-lutionary medicine is in providing a coherent framework to organize and explain facts about human biology and disease and in pointing out the importance of ultimate as well as proximal causation in understanding the human condition. But it is still strug-gling for status and broader acceptance within medicine. Physicians by and large know little about evolution; a survey of U.S. medical school deans several years ago revealed at more than half the medical schools evolutionary biology was not regarded as important knowledge (Nesse and Schiffman 2003). Popular interest in various

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Tatja na B u k l i ja s a n d P e t e r G l u c k m a n

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thereof ) in early evolutionary theories was shaped primarily by contemporary medicine. Against the vitalism of the early 1800s, which reached for an elusive Bildungstrieb (generative force) to solve the problem of both the beginning of the indi-vidual life and the life on earth, medical scientists coming of age in the 1830s and 1840s increasingly limited their inquiry to processes accessible by observation and, increasingly, experi-ment. They wanted to explain biological phenomena in terms of laws of physics and chemistry and saw the (physiological and biochemical) laboratory as the main site of knowledge production (Cunningham and Williams 1992). Both develop-ment and evolution seemed intractable to these efforts.

Medicine’s experimental turn of the mid-nineteenth cen-tury was, then, probably the reason why Darwin’s work – in particular On the Origin of Species (1859) and The Descent of Man (1871) – produced little obvious, immediate impact on contemporary medicine. Darwin himself did not make it eas-ier with the lack of medical cases in his writings. Certainly, Darwin’s medical friends provided him with both a sound-ing board and useful examples, but most of his evidence came from artificial breeding and naturalist observations. The only major exception is The Expression of the Emotions in Man and Animals (Darwin 1872b; Gilman 1979; Browne 1985b). The central argument of the book – that human facial expressions exhibited continuity with the expressions of animals – sup-ported the Descent ’s thesis that modern humans evolved from “lower” organisms and thus did not have a special status in the nature (Darwin 1871a). Photographs and descriptions of “the insane” provided Darwin with an immediate access to human emotions “as they are liable to the strongest passions and give uncontrolled vent to them” (quoted in Pearn 2010, p. 163; see Fig. 63.1). The book was written in close collabora-tion with Dr. James Crichton-Browne, superintendent of the West Riding Pauper Lunatic Asylum and a leading Victorian psychiatrist, who provided Darwin not only with research material (photographs and case descriptions) but also with the necessary psychiatric expertise (Pearn 2010).

In his other work, Darwin drew on medical knowledge only very occasionally and nearly always in relation to repro-duction and inheritance, concepts at heart of his evolution-ary thought, as “variation which is not inherited throws no light on the derivation of species” (Darwin 1868b, 445). The Descent of Man drew on a wide range of contemporary knowledge including medicine. In the section on “homologi-cal structures,” the similarity of diseases and susceptibility to drugs and intoxicating substances between humans and apes was used in support of common descent.

Among Darwin’s writings, his discussion of the famil-ial predisposition to diseases in The Variation of Animals and Plants under Domestication was probably most directly linked to the concerns of contemporary medicine. He enlisted the examples of hereditary predisposition to gout, insanity, and consumption to support the dominant evidence upon which the concept of natural selection was grounded: domes-tication and artificial breeding (Darwin 1868b, 451–52). The idea of a heritable predisposition (“diathesis”) toward disease

“evolutionary” hypotheses related to human health – from the “Paleolithic diet” to the fitness advantages of “schizophrenia genes” – is a double-edged sword as the lack of empirical sup-port and the speculative nature of such hypotheses throws an unfavorable light upon the entire field. Injecting rigor into hypothesis formation and broadening the range of meth-ods used to test them is of highest importance, if evolution-ary medicine is to gain broad acceptance within biomedical research and clinical community.

This essay first examines the history of the relationship between evolution by natural selection and medicine over the past two centuries. Contrary to the image painted by the his-toriography of medicine, evolutionary knowledge has indeed informed a wide range of medical disciplines. We end by dis-cussing the current goals, status, and problems of evolution-ary medicine.

M e d i c i n e a n d e vo lu t i o n d u r i n g d a rw i n ’ s l i f et i M e

While few physicians nowadays study evolution, most early evolutionary thinking came from doctors, which was a direct consequence of limited educational and career choices for young men interested in natural sciences. Famously, Charles Darwin’s own grandfather, the country physician, naturalist, and writer Erasmus, was an evolutionary thinker along the lines of Buffon, who believed in organic transformism (Porter 1989). As this quote from the preface of his Zoonomia, or the Laws of Organic Life shows, his medical interests were inex-tricably linked to the naturalist ones, with both nature and dis-ease, in his view, reducible to basic laws of “organic life”: “The purport of the following pages is an endeavour to reduce the facts belonging to animal life into classes, orders, genre and species; and by comparing them with each other to unravel the theory of disease” (E. Darwin 1794). In revolutionary France, Jean Baptiste Lamarck had studied medicine before giving it up to pursue his interest in botany and then take up professor-ship in invertebrate zoology (Burkhardt 1995). Franz Unger, the Viennese botanist who in the 1840s argued that all plants had arisen from the same ancestor, had trained in medicine in the 1820s (Gliboff 1998). Most famously, Charles Darwin fol-lowed in his grandfather’s and father’s footsteps and enrolled into medical school – only to become “the most famous medi-cal school drop-out” (Desmond and Moore 1991).

These medical backgrounds of evolutionary scholars did not translate evolution into a foundation of medical studies and research. This may be partly explained by contemporary politics: in the 1830s England, only the radical new schools – in the first place the University of London – gave space to the controversial knowledge imported from the politically suspect France, such as Geoffroy St. Hilaire’s “unity of composition” that ordered all living beings into a single chain and implicitly challenged the dominant social order (Desmond 1989). As the German states and Habsburg Empire underwent a conserva-tive backlash in the turbulent 1800s, universities stayed away from evolution-related content. But doctors’ interest (or lack





F r o m Evo l u t i o n a n d M e d i c i n e t o Evo l u t i o na ry M e d i c i n e

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experiments that linked microbes to processes ranging from putrefaction and fermentation to plant and animal disease and that decisively rejected the possibility of spontaneous genera-tion, through Joseph Lister’s introduction of antisepsis into the surgical theater around 1870, to Robert Koch’s quest for specific causes of bacterial diseases from the mid-1870s on, and the early ideas about immunity. Yet the ways in which cli-nicians and public health experts of that era used Darwin’s theory to understand phenomena such as germ specific-ity, gradual development of the “property of infectiveness,” and virulence are still relatively unexplored (Gaudillière and Löwy 2001; Bynum 2002). Sir William Roberts (1830–99), the well-known Manchester physician and medical lecturer with an interest in microbes, explained the apparently puz-zling difference in virulence between morphologically indis-tinguishable bacterial forms with their “capacity for variation” in response to some external cause. His model was taken up by Hubert Airy, a medical inspector and Darwin’s corre-spondent, when explaining the evolved mutual relationship between humans and microbes. It would seem at first, he argued in 1882, that “natural selection” would eliminate dis-ease, but ability to withstand infection was just one of many factors determining human variability. Furthermore, the more virulent germs would attack more people and enhance their own survival. “Natural selection” could explain the demise and extinction of populations that had only recently come into contact with Europeans and, conversely, strong reaction of Europeans to diseases new to this continent. “For man the most serious contingency is that the disease may have a fatal termination: for the microzyme it is not of vital importance that its human nidus should perish; and it would seem that natural selection might find its equilibrium (though continu-ally fluctuating), and be fairly satisfied with so much variation on both sides as should leave man susceptible to infection but not in a fatal degree.”1 Airy’s ideas were further developed by Kenneth Millican in his The Evolution of Morbid Germs (1883). He argued that the process of natural selection went both ways: not only did the response of human populations change in time but also microbes modified their virulence. The variability of a species increased if one descended the evolutionary scale because the variation emerged more rap-idly in organisms with short life-spans and large populations.

In contrast to the received view of “reductionist” bacteriol-ogy, evolutionary ideas strongly influenced disciplines studying microbes and parasites. A good example is the development in the 1890s of the notion of “carrier status” or the idea that sus-ceptibility to germs may vary in the population and allow some individuals to spread a germ without becoming sick themselves (Anderson 2004). Yet, by the early twentieth century, much of this influence came to be limited to the fields of parasitol-ogy and tropical medicine, which, with the demise of colonial empires, came to play a secondary role in modern medicine.

As medical education underwent radical changes in the 1870s and 1880s, evolutionary science failed to achieve a stable

was not new; indeed it went back to Hippocratic medicine (Ackerknecht 1982). But as “hereditarian” views of the body and disease came to dominate “environmental” ones in the second half of the nineteenth century, Darwin’s theory pro-vided a framework for organizing ideas – and expressing wor-ries – concerning the perceived increase in the frequency of certain diseases in modern environments. Some medics, such as the famous clinician Jonathan Hutchinson (1828−1913), went a step further by suggesting that diseases should be seen as species, placed “in natural groups, in connection with their ancestral descent” (Bynum 1983).

Infectious diseases were of greatest interest to medi-cine in this period. Historians have documented extensively the rise of the germ theory, from Pasteur’s 1850s and 1860s

Figure 63.1. Along with descriptions and depictions of expressions of emotions in the insane, Darwin also included representations of emotions in “normal” infants, whose expressions were, as they were in the insane, unin-hibited and clear. The six photographs on plate I come from two profes-sional photographers, Oscar Gustaf Rejlander of London (figs. 1, 3, 4 and 6) and Adolphe Diedrich Kindermann of Hamburg (figs. 2 and 5), and show the work of facial muscles in young children weeping and crying. From C. Darwin, Expression of the Emotions (London: John Murray). These photos are reproduced from the 1890 edition, where the same photos as the original 1872 edition are slightly rearranged.

1 See Airy 1882, cited in Bynum 2002, 62.






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suggested that the “eclipse of Darwinism” precisely at the time when American medical schools began to systematically introduce science in their curricula sealed the fate of the field for a long time (Nesse and Schiffman 2003). This argument, together with the opposition from the religious groups, may explain evolution’s status in the United States, but it does not account for challenges in Europe. These were in some way related to the contemporary political and social turbulences. For the first few decades of the twentieth century, there seems to have been a political divide between the “neo-Lamarckians” – almost all situated on the political left and often Jewish – and the adherents of a hereditarian, arguably “Darwinian” view, on the right (Graham 1977; Slavet 2008).

Darwin and Darwinism have been accused of inspiring a body of knowledge known as eugenics in the English-speaking world and social and racial hygiene in Continental Europe.2 Eugenics emerged around 1900 when an earlier faith in the positive effects of public health, especially on the mortality and morbidity of the urban poor, was replaced by an increas-ing pessimism. It was argued that for all the investment in the asylums, hospitals, and laboratory science, mental illness and consumption (tuberculosis) still reigned among the poor, who reproduced at an alarming rate: they bred disease and rebellion within the social order. The concerned middle-class physicians read Darwin’s work and argued that modern civ-ilization removed the salutary effects of natural selection, by allowing survival and reproduction of individuals with physi-cal and mental impairment (Bynum 1983). The only way to save humanity, eugenicists argued, was to control reproduction.

The idea of hereditary predisposition to disease preceded Darwin by centuries. But he provided a new account of it. In The Descent of Man, and Selection in Relation to Sex (1871), Darwin agreed that, while in primitive societies selection guaranteed the elimination of the weak (in body and mind), in civilized societies these checks were removed by our natural tendency to help the weak (Darwin 1871a; Paul 2003). But the “weakness” was not necessarily hereditary. Darwin believed that immature organisms – in contrast to the adult ones – were susceptible to environmental influences (Hodge 1985; Endersby 2003). Like his cousin Francis Galton (1822–1911), Darwin, a good Victorian, argued that better education would lead to a change in habits.

As long as those in a position of influence subscribed to Lamarckian views and the possibility of changing hereditary traits by modifying the environment, improving living con-ditions made more sense than controlling breeding. This view began to be supplanted by eugenics around 1900 with the acceptance of August Weissmann’s doctrine that “germ cells” and hereditary material are insulated from environ-mental influences (Paul 1995). The acceptance of eugenics in medicine opened doors to social intervention, based in medi-cal knowledge, which actively promoted advantageous and prevented – by isolation and sterilization – disadvantageous breeding. Literature on the history of eugenics is plentiful and

position in the curriculum. Even its champion, “Darwin’s bull-dog” Thomas Huxley, who as president of the Royal Society had considerable influence over the content of medical educa-tion in this period, believed evolution irrelevant to the prob-lems doctors had to address. Francis Maitland Balfour, the first to teach embryology at Cambridge and also a disciple of the physiologist and Huxley’s student Michael Foster, in the 1870s used Haeckel’s biogenetic law – the idea that embryos of higher species in their development pass through adult stages of lower species – to explain evolution (Blackman 2006) (Fig. 63.2). At the University of Jena students first heard about evolution in their anatomical and zoological courses, taught by the two most fervent Darwinians in Continental Europe, Karl Gegenbaur and Ernst Haeckel (Nyhart 1995, 151−53). But because the presence of evolution in curriculum depended on research interests of the teacher, it did not achieve stability. Together with embryology, zoology, and other related disci-plines, it was exposed to criticism by members of the clinical staff, who argued that it did not provide students with clini-cally relevant knowledge.

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In the early twentieth century, Darwin’s teaching was in crisis. No one doubted evolution, but natural selection as its under-lying mechanism was challenged both by neo-Lamarckians and by the new geneticists who argued that significantly new forms appeared suddenly by means of mutation. It has been

Figure 63.2. Michael Foster (1836–1907), a student of Huxley and lead-ing physiologist, followed his teacher in thinking that, although evolution is true, its relevance to medicine is minimal and has no place in medical educa-tion. This lithograph was published in January 1884 in the Midland Medical Miscellany and Provincial Medical Journal. Permission: Wellcome

2 See, for instance, and notoriously, Weikart 2004.






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synthesis saw Mendelian disorders as well-defined traits that could teach us something about evolutionary pressures in the past. In a 1949 paper, J. B. S. Haldane used the example of thalassaemia major, an inherited deficiency in the produc-tion of hemoglobin found among Mediterranean populations exposed to Plasmodium parasites, to argue that this mutation increased the fitness of heterozygotes by making erythrocytes resistant to the parasites; nonfatal anaemia associated with the disease was an acceptable cost (Haldane 1949). The idea that diseases are outcomes of balancing selection captured the geneticists’ fancy and soon led to speculations concern-ing provenances of other commonly occurring diseases with a hereditary pattern. In 1964 Julian Huxley and Ernst Mayr proposed the existence of a tentative “Sc gene” to explain the persistent prevalence of schizophrenia at around 1 percent of the population (De Bont 2010).

Others arrived at same questions from different starting points. James Neel, whose work on the effects of radiation in Japan’s atomic bomb victims established him as an authority in human genetics, published a programmatic paper in 1958 that warned of the limited value of sophisticated mathemati-cal models for understanding of the actual workings of natural selection upon humans. Instead, he called for (field) studies of selective pressures across diverse human populations (Neel 1958). It was in this paper that Neel first aired the idea that changing dietary patterns – primarily an increase in animal fat and energy intake – in combination with a decrease in physi-cal activity may expose certain selection pressures, famine in the first place, from the human past. The argument came to be known as “thrifty genotype” (Neel 1962). The reception of “Sc gene,” “thrifty genotype,” and the like was initially mixed – partly owing to the speculative nature of these pro-posals, but also because of their perceived eugenic message. But the sequencing of the human genome and the related post-1990 advances in genetics/genomics have stirred new interest in these proposals: a quest for “candidate genes” for common diseases showing hereditary or familiar transmission patterns is among the most active fields in genetics.4

These proposals, however, had little impact on contem-porary clinical medicine. Darwin’s ideas about natural selec-tion had much more influence in the fields concerned with infectious diseases and epidemiology, traditionally more open to field studies and ecological approaches (Anderson 2004). A significant application of Darwin’s evolutionary theory was Frank Macfarlane Burnet’s theory of clonal selection. Burnet – who saw himself as an evolutionary biologist in his own right, a contributor to the modern synthesis – argued that immunity

growing; here it is worth recalling that eugenics was not just taught in medical schools in subjects called “social hygiene” or (in Nazi Germany) Erbbiologie/Erblehre but also, more subtly, informed medical education across disciplines as text-books of histology and embryology reveal. A recent article on the infamous “Tuskegee experiment” – the U.S. Public Health Service clinical study of the natural history of untreated syphilis conducted upon poor African American men from 1932 until 1972 – argued that an important reason why this study kept going for so long, well after a reliable treatment was developed and after eugenics was discredited as a scien-tific paradigm, was the deep influence that early educational experience (in this case at the University of Virginia’s medical school) exercised upon the thinking of the study’s three key figures (Lombardo and Dorr 2006).

So what role, then, did Darwin’s theory of evolution play in eugenics? Darwin never supported intervention into human breeding. Indeed, Darwin’s political and social out-look was shaped by the social and political concerns of the 1820s and 1830s, with the antislavery movement playing a crucial role (Desmond and Moore 2009). Imposing a twen-tieth-century eugenic outlook upon him is anachronistic. Yet Darwin’s ambiguous writing combined with readers’ confus-ing his ideas with those of others writing on similar topics – such as Herbert Spencer’s “survival of the fittest,” first coined in 1864 – may have contributed to these problematic inter-pretations. Furthermore, while it is true that some scientists who were both “neo-Lamarckian” and politically leftist, such as the controversial Viennese biologist Paul Kammerer, held eugenicist beliefs (Kammerer 1925), nowhere was Darwin received as enthusiastically as in Germany, and nowhere did eugenics – in an extreme form and couched in Darwinian rhetoric – have such a catastrophic impact, with doctors play-ing a prominent role. But Nazis did not obtain from Darwin a coherent set of ideas: the historian Richard Evans has argued that what they got was a credible language they could use to justify social policies. Darwinism should thus be exculpated of the responsibility for Nazi crimes. Nonetheless, the shadow of these events would hang over studies of humans from an evolutionary perspective.3

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Eugenics began to lose ground as early as the 1930s, and its fall was helped by the discovery of atrocities committed by the Nazi regime – although its demise was much more gradual than commonly believed. Nonetheless, the interest in the evo-lutionary role and impact of hereditary diseases persisted post 1945. In contrast to earlier views, advocates of the modern

4 The efforts to locate “schizophrenia” or “thrifty” genes have encoun-tered a range of criticisms, from observations that “candidate genes” explain only a small proportion of the disease risk and ignore the impact of environmental cues during sensitive developmental peri-ods, to the critiques of anthropologists and social scientists who warn of problems potentially arising from this approach (neglect of social determinants of disease or the use of ill-defined ethnic and racial cate-gories to describe risk of disease). See, for example, McDermott 1998; Montoya 2007.

3 Peter Bowler recently argued that, even if Darwin had never existed, we would have accepted an evolutionary view and possibly a type of social interventionism similar to eugenics. Still, Darwinism, with its emphasis on inheritance at the individual level and especially anal-ogy with artificial selection, may have given rise to a particularly strict form of intervention. See Bowler 2008.






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The rejection of evolutionary explanations of disease, or indeed any that favored “nature” over “nurture,” in the 1960s and 1970s had to do with social and generational changes in this period. In the early 1960s, Julian Huxley, a leading British eugenicist, could openly state that his interest in a “schizo-phrenia gene” had an eugenic purpose (Kevles 1985; De Bont 2010). Yet, as the postwar generation came of age and rebelled against established social and medical culture, the implicit biological determinism of evolutionary explanations of dis-ease attracted considerable criticism. Especially controver-sial were the studies of human behavior and mental abilities, best demonstrated by the controversy surrounding Edward Wilson’s Sociobiology (1975) (Ruse 1979). Sociobiology was a field that developed in the 1960s, as classical behaviorism waned, to explain social behavior across the animal world by the evolutionary advantages it conferred. It successfully resolved the long-standing paradox of natural selection oper-ating on individuals, while many species exhibit forms of socially beneficial behavior; it showed that, by helping (the related) others, one helped one’s own genetic inheritance propagate. As long as sociobiology was focused on animals only, it was not controversial. Yet Wilson’s attempt to extend his conclusions to humans met with enormous criticism. The fiercest opponents were two Harvard colleagues, Stephen Jay Gould and Richard Lewontin, who saw Wilson’s work as a return into the 1930s eugenics. “I have a strong sense of the historical continuity of biological deterministic arguments at the same time my professional mature arguments have shown me how poorly they are grounded in the nature of the physical world” wrote Lewontin. The questions raised by sociobiology were taken on by other disciplines, particularly evolutionary psychology. Yet here too skepticism rapidly appeared when extreme arguments about the evolution of mental modules in a prehistoric “environment of evolutionary adaptedness” attempting to explain a full range of behaviors were put for-ward by evolutionary psychologists, notably John Cosmides and Leda Tooby. Given the difficulty of proving hypotheses in this domain (R. C. Richardson 2007), and the clash of cultures surrounding disciplines wishing to explain human behavior, it was perhaps inevitable that the field would be contentious and not accepted as mainstream. Other, less extreme, approaches of integrating psychology with evolution have since emerged (Laland and Brown 2002; Nettle 2009).

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New interest in the ways in which natural selection shaped the landscape of the human disease emerged in the 1980s. Much of the early work focused on the evolutionary “arms race” between humans and pathogens (Ewald 1987, 1980). It has been argued that this renewed interest arose out of the contem-porary concerns around the emergence of AIDS and the rise of antibiotic resistance (Anderson 2004). But the real boost to the study of evolutionary origins of human disease came from an unlikely pair, a young psychiatrist with an interest in evolu-tion, Randolph Nesse, and an older, established evolutionary

relies on the selection and multiplication of lymphocytes, the receptor of which fitted with the antigen (Anderson 2004; Park 2006) (Fig. 63.3).

Perhaps the strongest and most obvious exchanges took place within psychiatry and psychology in the 1950s and 1960s, by way of ethology, a discipline studying animal and human behavior that reached its peak in this period. On the basis of his research on birds ( jackdaws), the founder of ethol-ogy, Konrad Lorenz (1903−89) – who around 1950 became famous for his work on behavioral imprinting – argued that maternal love was essential for healthy infant development and that consequently the child’s tie to the mother was a result of an evolved instinctual need (Vicedo 2009). After the Second World War, this argument was taken up by the psychoanalyti-cally inclined U.S. and British psychiatric profession, seeking to boost its scientific credentials by allying with a biological discipline. The emphasis on the (evolutionary) significance of close mother-infant attachment also fed into the contem-porary social concerns about the women’s work outside the house. Experimental primate research and observational stud-ies followed; while in many cases evidence could not support the “mother love” hypothesis, it remained commonly accepted until the decline of psychoanalytic psychiatry in the 1970s (Vicedo 2010). Later incursions of evolutionary biologists into psychiatry, such as Niko Tinbergen’s attempt to explain autism as an outcome of parenting, especially mothering, styles, were met with skepticism or open disapproval (Silverman 2010).

Figure 63.3. Frank Macfarlane Burnet (1899–1985), noted Australian virologist, saw selection involved in the functioning of the immune system. This photograph was taken by Bernie Faingold of Denver, photographer renowned for his portraits of famous people such as American presidents. Permission: Wellcome






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minded clinicians. In response, it has been argued that evo-lutionary medicine provides an essential perspective in inte-grating the various domains of human biology. By providing explanations of ultimate causation, it assists in understanding the context in which proximate mechanisms associated with dysfunction lead to symptoms and disease. Because of this, it is argued, evolutionary medicine should be considered a core basic science of medicine; while it does not directly affect decision making, it changes the understanding of both doctor and patient and therefore has considerable value (Gluckman, Beedle, and Hanson 2009). Formal classifications of the path-ways by which evolutionary processes impinge on disease risk have been developed (Nesse and Stearns 2008; Gluckman, Beedle, and Hanson 2009; Gluckman et al. 2011). Some important principles have been highlighted including the key point that evolution operates to optimize fitness rather than acting primarily to promote health or longevity: this point alone requires physicians to rethink their understanding of human biology. Other principles include the importance of life history trade-offs, the distinction between proximate and ultimate causation, the importance of multiple forms of her-itability, and the genetic inertia that puts humans at health risk when environments such as the nutritional environment change rapidly.

A potentially even more serious challenge arises from within the field. While in the first two decades evolutionary medicine has mostly contented itself with collecting knowl-edge from established fields such as anthropology, genetics, and clinical medicine, some participants have begun to argue that it needs to develop its own questions, methods, and expertise. Some of the proposed questions and themes have a long history, as we have shown earlier – for instance, coevo-lution with pathogens, symbionts, and commensals and the ways in which perturbation of one component of the relation-ship can affect the other species involved. Others are new and include some of the fundamental questions coming from con-temporary evo-devo studies. They reflect the current critique of the strongly gene-oriented modern synthesis – for instance, the place of adaptive plasticity in individual development and species evolution; substitution of the genotype-driven model of evolution with an evo-devo model of phenotype evolu-tion; the role of epigenetic inheritance in maintaining traits in a population; and the interaction of biology and culture in determining fitness and, consequently, the implications for the rate and direction of human evolution.

Humans might seem an especially challenging model for evolutionary studies because of their long generation times, few offspring, specific life history, and reproductive patterns, as well as special cultural status limiting the opportunities for intervention. Yet they are also a species the genotype and phe-notype of which has been unusually well documented, offering important opportunities to study contemporary evolutionary processes, in particular the ways in which organisms respond to rapidly changing environments (Gluckman and Hanson 2006a, 2006b; Gluckman et al. 2011). Novel ways in which data collected in clinical studies and medical records could

biologist, George C. Williams, best known for his work on the evolution of senescence and for his arguments undermining group selection. Starting from infections but broadening their outlook to include other human pathological conditions and symptoms – from genetic disorders to mechanical injuries and fevers – in a series of theoretical articles and reviews that sum-marized the contemporary evolutionary knowledge from the medical perspective, they tackled the question, “Why has evo-lution left the human bodies vulnerable to disease?” Rather than offering solutions for the “improvement” of humankind, as eugenics once did, the goal of evolutionary (also known as Darwinian) medicine was to provide physicians with a strong framework for organizing facts about the body and disease, and researchers with an innovative outlook that would help them generate new hypotheses. The key ideas were first sum-marized in a 1991 article (Williams and Nesse 1991) and then further refined and expanded in a book on Why We Get Sick: The New Science of Darwinian Medicine (Nesse and Williams 1995). Nesse and Williams were not the first to try to engage physicians in evolutionary science in the posteugenics era: yet earlier attempts received little public recognition (Zampieri 2009). The increase in interest may be explained by the gen-erational shift and a change of medical and social climate in this period. As the Human Genome Project, begun in 1990, promised to provide biomedical researchers a new platform from which they could launch “their assault on disease” (Watson and Cook-Deegan 1990), “nature” once again began to outweigh “nurture” in the consideration of disease causa-tion. In the 2000s, universities have begun to introduce first courses on evolutionary medicine; meetings, conferences, and publications abound; and while the field began in the United States, it has attracted international contributors and audiences (Ellison et al. 2009).

At the same time, the interest in evolutionary medicine is still limited to a relatively small group of supporters. Even in the medical fields traditionally inclined toward (and under-pinned by) evolutionary biology such as infectious diseases, and even when discussing phenomena as relevant as the evo-lution of antibiotic resistance, the very word “evolution” is conspicuously absent from the literature (Antonovics et al. 2007). The strongest interest in evolutionary medicine comes from outside medicine, from anthropology and human biol-ogy. Indeed, evolutionary medicine has been a mainstream component of anthropological curricula for more than two decades. While much of that work has been based in solid paleontological and primate research as well as modern bio-logical and anthropological approaches, some health anthro-pologists have tried to explain a range of human conditions using controversial and untestable hypotheses. At times professional antagonism between the anthropological and the medical community appears reflected in the literature (Trevathan, Smith, and McKenna 2008). This too may have inhibited acceptance of evolutionary thought into the medical framework.

A major problem and challenge for evolutionary med-icine is its apparent lack of immediate utility for practically






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accelerated development (Walker et al. 2006), it is likely that it was low (Gluckman and Hanson 2006a). As the female pel-vis does not reach its maximal dimensions until at least four years after menarche (Rosenberg and Trevathan 1995), mater-nal constraint would have been critical in the Paleolithic to match the firstborn fetus to the somatic size of the mother at the time of the pregnancy. A second hypothesis, which is not mutually exclusive, argued that energetically it made sense for the mother to conserve nutrients for subsequent pregnan-cies in which survival was likely to be higher (Metcalfe and Monaghan 2001). This argument is supported by the find-ing that short interbirth intervals are linked with small size at birth, reflecting the depleted energetic state of mother (Baker et al. 2009).

Yet the size of the firstborn would not have necessarily been of interest to clinical medicine were it not for their sub-sequent growth and morbidity patterns. While born small, the firstborn in the course of their first year show rapid catch-up growth and overshoot other infants (Ong et al. 2002). There is an extensive literature linking low (but even extending to normal range) birth weight, catch-up growth, and later meta-bolic compromise (Hales and Ozanne 2003). The initial evolutionary arguments for this relationship have been sum-marized as “the thrifty phenotype hypothesis,” arguing that the fetus in difficult circumstances trades off growth to sur-vive in utero but might then suffer later adverse consequences (Hales and Barker 1992). More recently, that hypothesis has been extensively refined as predictive adaptive response hypothesis (Gluckman, Hanson, and Spencer 2005). Briefly, this hypothesis posits that the fetus sets its developmental tra-jectory in accord with the nutritional information it receives from its mother, to optimize its fitness for the environment it anticipates on the basis of the received cues that will be operative later in life. Greater maternal constraint biases the prediction toward a poor nutrition environment (Gluckman and Hanson 2004b). Such a prediction would have had no adverse consequences in a Paleolithic environment, as the predicted environment would have corresponded with the experienced one; yet in the modern nutritional environment, it is inappropriate and mismatched. Obesity arises because the offspring developed with a physiology appropriate for a low-nutrition plane is exposed to a high plane of nutrition, invisible during the fetal period because of the constraint pathways.

Building on these observations and hypotheses, Gluckman and Hanson (2004a) postulated that firstborn children would be more at risk of obesity in middle age. This observation was confirmed in a modern U.K. population for which it was found that at any maternal body weight firstborn children were signif-icantly more obese as adults (between twenty-seven and thirty years old) than children of higher birth order, and that the increase in fat was largely central (Reynolds et al. 2010). The favored explanation of how being born smaller leads to greater visceral obesity relies on epigenetic mechanisms operative in utero affecting intermediary metabolism (Godfrey et al. 2009) and appetite regulatory mechanisms (Vickers et al. 2000).

be used to track and evaluate the evolution of human traits – including the evolution of disease – have been suggested, and first attempts in this direction have been carried out (Byars et al. 2010; Stearns et al. 2010).

A recent example of how an evolutionary hypothesis may be tested in a clinical environment and how it may con-tribute knowledge of practical medical and public health sig-nificance comes from the area within evolutionary medicine focusing on life history and the role of adaptive plasticity in development and evolution. The basis for the hypoth-esis was a consistent finding that, at any maternal age and in developed and developing countries alike, the firstborns are born smaller than later-born children. The 1991 U.S. statistics, for instance, showed that second-born weighed at least 500 grams more on average than the firstborn chil-dren; firstborn also had a lower proportion of high, and higher proportion of low, birth weight (Cogswell and Yip 1995). Gambian firstborns had significantly depressed birth weights in comparison with infants of higher birth orders (Prentice, Cole, and Whitehead 1987). The phenomenon underlying the limitation of fetal growth is known as “mater-nal constraint” (Gluckman and Hanson 2004b). The limita-tion of fetal growth is caused by reduced supply of nutrients to the fetus and is generally thought to be caused by lesser dilatation of uterine arteries in the first pregnancy in com-parison with later pregnancies, as the first pregnancy leads to disruption of connective tissue in the vascular wall, allow-ing greater dilation, and thus greater uterine blood flow, in subsequent pregnancies. While maternal constraint operates in all pregnancies, it is greater in first pregnancies as well as young and short mothers.

Evolutionary biology has provided a convincing explana-tion for maternal constraint: it has evolved to protect a small female from giving birth to a large infant following mating by a large male. If fetal growth was not constrained, obstructive labor and maternal and fetal death would have ensued. Studies have shown that fetal growth is primarily regulated by the size of the mother and that it may be demonstrated in all mono-tocous species: the classic experiments were those of Arthur Walton and John Hammond, who studied cross-breeding in horses in the 1930s University of Cambridge School of Agriculture (Walton and Hammond 1938). In human preg-nancies involving surrogate mothers, birth size correlates bet-ter with the recipient’s than donor mother’s size (A. A. Brooks et al. 1995). In hominins, an additional reason for constrain-ing fetal growth is the adoption of bipedal posture and the consequent change in the shape of the pelvic canal. Further, as hominins evolved with larger brain sizes relative to other primates, they had to be born at a more altricial stage to allow the large head to exit the pelvis.

It is a reasonable presumption that in the Paleolithic women were mated soon after menarche. While fertility is low in the first year after menarche, within a few years it reaches its maximum. The age of puberty in the Paleolithic is unknown but, on the basis of studies of modern hunter-gatherers where high extrinsic mortality creates a strong selective pressure for






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Yet, in spite of such promising initiatives, the biggest chal-lenge for evolutionary medicine remains developing a coher-ent set of approaches to test evolutionary hypotheses. This is a field where “idle Darwinizing,” to use Lewontin’s famous phrase, is easy, yet it requires increasingly formal evaluation – though it is limited by the generally historical nature of the argument. Nevertheless, there are formal approaches that are possible and are increasingly being followed (Nesse 2011). As the rigor is applied, the discipline will strengthen, and its value to clinical medicine in providing an essential core med-ical competency may be accepted. Erasmus Darwin’s vision may, then, become reality.

Different parental attitudes toward infant feeding and thus juvenile weight gain may contribute toward a different weight gain pattern. Either way, even in infancy firstborn children gain weight faster (Stettler et al. 2000). In the current social, clinical, and public health environment, where the family size is fall-ing dramatically and where in China as well as many European countries more than 50 percent of all children are now first-born, the significance of this phenomenon is evident. While much of the described clinical and laboratory research is ongo-ing, this example persuasively shows how evolutionary biol-ogy, epidemiology, and clinical and laboratory medicine can be jointly recruited to construct and test hypotheses.





From evolution and medicine to evolutionary medicine

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