Human Evolutionary Biology

Embodied Capital and Extra-somatic Wealth in Human Evolution and Human History 441 (3) energetics of reproduction; (4) social relationships TABLE 26.1. Life history characteristics and diet of among men and women; (5) intergenerational resource human foragers and chimpanzees (after Lancaster and transfers; and (6) co-operation among related and Kaplan, 2008). unrelated individuals (Kaplan, 1997; Kaplan et al., Life history 2000, 2001, 2003, 2005, 2007; Kaplan and Robson, characteristics Human foragers Chimpanzees 2002; Robson and Kaplan, 2003; Gurven and Kaplan, 2006; Gurven and Walker, 2006). It describes a very Maximum life ~100 ~60 span specialized niche, characterized by: (1) the highest- Probability of 0.6 0.35 quality, most nutrient-dense, largest package size, food survival to resources from both plants and animals; (2) learning- age 15 intensive, sometimes technology-intensive, and often Expected age 54.1 29.7 co-operative, food acquisition techniques; (3) a large of death at brain to learn and store a great deal of context-dependent 15 (years) environmental information and to develop creative Mean age first 19.7 14.3 food acquisition techniques; (4) a long period of reproduction (years) juvenile dependence to support brain development and learning; (5) low juvenile and even lower adult Mean age last 39 27.7** reproduction mortality rates, generating a long productive life span (years) and a population age structure with a high ratio of Interbirth 41.3 66.7 adult producers to juvenile dependents; (6) a three- interval* generational system of downward resource flows from (months) grandparents to parents, to children; (7) biparental Mean weight at 15.7 10 investment with men specializing in energetic support age 5 (kg) and women combining energetic support with direct Mean weight at 24.9 22.5 care of children; (8) marriage and long-term reproduc- age 10 (kg) tive unions; (9) co-operative arrangements among kin Composition and unrelated individuals to reduce variance in food of diet (%) availability through sharing and to more effectively Collected 9 4 acquire resources in group pursuits. The publications cited above show that the majority Extracted 31 4 of the foods consumed by contemporary hunter- Hunted 60 2 gatherers worldwide are calorically dense, hunted, Contributions and extracted (taken from an embedded or protected by sex (%) Men Women matrix – underground, in shells, etc.) resources, Adult calories 68 32 Sexes accounting for 60% and 35% of calories, respectively. Adult Protein 88 12 independent Extractive foraging and hunting proficiency generally Caloric support 97 3 does not peak until the mid-30s, because they are for offspring learning – and technique – intensive. Hunting, in par- Protein support 100 0 ticular, demands great skill and knowledge that takes for offspring years to learn, with the amount of meat acquired per unit time more than doubling from age 20 to age 40, Notes: *Mean interbirth interval following a surviving infant. **Age of last reproduction for chimpanzee females was even though strength peaks in the early 20s. This learn- estimated as two years prior to the mean adult life expectancy. ing-intensive foraging niche generates large calorie deficits until age 20, and great calorie surpluses later in life. This life history profile of hunter-gatherer productivity is only economically viable with a long relative in phylogenetic terms. Table 26.1 presents expected adult life span. major differences in five critical parameters of life history: (1) survivorship to age of first reproduction; (2) life expectancy at the beginning of the reproductive LIFE HISTORIES OF WILD CHIMPANZEES period; (3) absolute and relative length of the postre- AND HUMAN FORAGERS productive period; (4) spacing between births of sur- viving offspring; and (5) growth during the juvenile To appreciate the implications of the human adaptive period (Kaplan et al., 2000; Lancaster et al., 2000). complex for the life histories of foragers, it is useful to The data for these analyses are based on published compare humans with the chimpanzee, another large- data sets on the only four forager groups for which full bodied, long-lived mammal, and our closest-living demographic data are available as well as food

442 Jane B. Lancaster and Hillard S. Kaplan consumption and production throughout the year for CONSUMPTION AND PRODUCTIVITY all age and sex categories (Ache ´, Hadza, Hiwi, and THROUGH THE LIFE COURSE !Kung). The data on chimpanzees are based on studies at the African field sites of Bossou, Gombe, Kibale, Table 26.1 also demonstrates the overlap in component Mahale, and Tai. The data and full citation list are categories of the diets of foraging societies and chi- presented in Kaplan et al. (2000, Table 1, p. 158). mpanzee communities as well as wide differences in Human and chimpanzee life history parameters relative proportions (Kaplan et al., 2000; Lancaster based on data from these extant groups of hunter- et al., 2000). For example, hunted meat makes up gatherers and wild chimpanzees indicate that forager about 2% of chimpanzee but 60% of forager diets. children experience higher survival to age 15 (60% vs. Chimpanzees rely on collected foods for 94% of their 35%) and higher growth rates during the first 5 years nutrition, especially ripe fruits. Such foods are nutri- of life (2.6 kg/year vs. 1.6 kg/year). Chimpanzees, how- tious and are neither hard to harvest nor learning ever, grow faster both in absolute and proportional intensive, at least relative to human resource pursuits. weight gain between the ages of 5–10 years. The early Humans depend on extracted or hunted foods for 91% high-weight gain in humans may be the result of the of their diet. The data suggest that humans specialize earlier weaning age (2.5 years vs. 5 years) followed by in rare but nutrient dense resources (meat, roots, nuts) provisioning of highly processed and nutritious foods, whereas chimpanzees specialize in ripe fruit and foods that juvenile chimpanzees could never collect to fibrous plant parts. These fundamental differences in any extent. Fast growth and weight gain during infancy diet are reflected in gut morphology and food passage and the early juvenile period may also represent an times in which chimpanzees experience rapid passage adaptation to support the energetic demands of brain of bulky, fibrous meals processed in the large intestine growth development, since a significant portion of this whereas human process nutritionally dense, lower weight gain is in the form of fat. volume meals amenable to slow digestion in the small The chimpanzee juvenile period is shorter than that intestine (Milton and Demment, 1988). for humans with age at first birth by chimpanzee Table 26.1 also summarizes the relative contribu- females about five years earlier than among forager tions of both sexes to the nutritional support of group women. This is followed by a dramatically shorter members through food sharing, one of the critical adult life span for chimpanzees. At age 15, chimpanzee features of the human adaptive pattern. This table is life expectancy is an additional 15 years, whereas for- based on contributions by sex in 10 modern forager agers can expect to live an additional 38 years having societies (Onge, Anbarra, Arnhm, Ache ´, Nukak, Hiwi, survived to age 15. Importantly, women spend more !Kung (2), Gwi and Hadza) where daily adult caloric than a third of their adult lives in a postreproductive production of meat, roots, fruits, and other has been phase, whereas few chimpanzee females spend any documented (Kaplan et al., 2000, Table 2, p. 162). time as postreproductives. The differences in overall Generally, women produce virtually no animal protein survival probabilities and life span of the two species and the carbohydrate calories they produce help to are striking: less than 10% of chimpanzees ever born support themselves and male hunters. As described in survive to age 40 and virtually none survive past 50, the next paragraph, calories and protein consumed whereas 45% of foragers reach 40 and more than 15% by children mostly comes from the large surpluses of foragers born survive to age 70! supplied by adult males. Finally, despite the fact that human juvenile and Figure 26.1 presents survivorship and net food pro- adolescent periods take longer and that human infants duction through the life course of humans and chim- are larger than chimpanzee at birth, forager women panzees (Kaplan et al., 2000). Humans consume more are characterized by higher fertility. The mean inter- than they produce for the first third of their life course. birth interval between offspring, when the first sur- In contrast chimpanzees are self-supporting by the age vives to the birth of the second, is 1.6 times longer of five. Thus, human juveniles, unlike chimpanzee among wild chimpanzees than among modern forager juveniles, have an evolutionary history of dependency populations. on adults to provide their daily energy needs. Even To summarize, human foragers show a juvenile more striking is the steady increase in productivity period 1.4 times longer and a mean adult life span over consumption among humans into their 30s and 2.5 times longer than chimpanzees. They experience early 40s. Forager males begin to produce more than higher survival at all ages postweaning, but slower they consume in their late teens, but their peak prod- growth rates during mid childhood. Despite a long uctivity builds slowly from their early 20s until their juvenile period, slower growth, an equal length repro- mid-to-late 30s and then is sustained for 20 or more ductive period, and a long postreproductive life span, years at a level of approximately 6500 kcals per day. forager women achieve higher fertility than do In contrast forager women vary greatly from group chimpanzees. to group in energy production, depending upon the

Embodied Capital and Extra-somatic Wealth in Human Evolution and Human History 443 1 Human survival 2000 Chimpanzee survival 1750 Net prod. humans 0.9 Net prod. chimps 1500 1250 0.8 1000 0.7 750 500 0.6 250 Survival 0.5 0 Net production 0.4 –250 –500 –750 0.3 –1000 0.2 –1250 –1500 0.1 –1750 0 –2000 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 Age 26.1. Survivorship and net food production through the life course of humans and chimpanzees. After Kaplan and Lancaster (2003). demands of intensive childcare (Hurtado and Hill, EMBODIED CAPITAL AND EXTRA-SOMATIC 1990). In some groups, they consume more than they WEALTH IN THE PAST 10 000 YEARS produce until sometime after menopause, when they are finally freed from childcare demands; whereas in For most of human history from perhaps 2 million others, such as the Ache ´, they remain nutritionally years until 10 000 years ago, humans depended on dependent on men throughout their lives. The provi- investments embodied in their brains and bodies to sioning of reproductive women and children has a survive and reproduce. They invested in themselves powerful effect on the production of children by and their offspring through patterns of behavior that humans by reducing the energy cost and health risk emphasized accessing high energy, hard to acquire of lactation to the mother and by lifting the burden of foods that demanded skilled, learned performances, self-feeding from the juvenile, thus permitting a food sharing, the feeding of juveniles, and a comple- shortened interbirth interval without an increase in mentary division of labor between men and women. maternal or juvenile mortality (Hawkes et al., 1998). However, about 10 000 years ago at the end of the last The human adaptive complex is both broad and flex- Ice Age, the distribution of resources that humans ible, in one sense, and very narrow and specialized in depended on and the means to access them began to another. It is broad in the sense that as foragers, humans change as a result of climate change and an increase have existed successfully in virtually all of the Earth’s in population density. At the beginning these changes major habitats. It is narrow and specialized in that it is had little effect except to promote population growth. based on a diet composed of nutrient-dense, difficult- Later their effects were so profound that patterns of to-acquire foods and a life history with a long, slow devel- marriage, investment in children, and social organiza- opment,aheavycommitmenttolearningandintelligence, tion appeared to reinvent themselves. and an age-profile of production shifted towards older In the following sections we will evaluate the ages. In order to achieve this diet, humans are very impact that changes in subsistence base and social unproductive as children, have very costly brains, are organization made on the division of labor, family extremely productive as adults, and engage in extensive formation strategies, fertility, and investment in food sharing both within and among age- and sex-classes. children in response to sedentism, horticulture, the

444 Jane B. Lancaster and Hillard S. Kaplan domestication of large animals, agriculture, extra- example, female gardening of high-protein crops on somatic wealth, social stratification, archaic despotic riverine alluvial soils, such as millet and sorghum in states, inheritance, and modern skills-based labor much of village Africa (Colson, 1960; Lancaster, 1981), markets and political systems. These hypotheses are is very different from subsistence based on manioc in generalizations informed by the archaeological, his- the thin, lateritic soils of South America. There, male toric, and cross-cultural record of today and the recent hunting is critical to balanced macronutrients in the past and must remain as our best guesses as to the diet and frequent clearing of new fields is necessary. temporal and causal relations involved. The critical need for defense of the village resource base is supplied by males as an umbrella benefit rather than to specific wives. However, since neither males Sedentism and tribal horticulture nor females produce beyond subsistence needs and Village sedentism and the domestication of plants had the means of production are held in common through a profound, yet limited, impact on human socioeco- usufruct, there is little opportunity for major differ- logy. Subsistence based on horticulture rests on land- ences in quality to develop between males beyond their extensive, slash-and-burn practices on prime resource embodied capital (age, health, hunting skill). However, patches, access to which is maintained by the social variance in male reproductive success does arise on group and defended by males against outsiders. (Land the basis of success in intergroup raiding that brings intensive horticulture is later in time and very differ- certain male warriors numerous captive wives. How- ent, being more like agriculture because it is based on ever, this advantage was much reduced under colonial long-term improvements such as irrigation in which suppression of tribal warfare and raiding. fields are heritable and represent wealth.) Within Reproduction in land-extensive, horticultural soci- the group, access is on the basis of usufruct, a system eties is associated with near universal marriage for of land tenure that gives all group members direct both sexes with reproduction beginning at sexual rights to the means of production and reproduction maturity for women and extending through the entire (Boserup, 1970; Goody, 1976). People live in small period of fecundity. Reproduction for men is some- villages, larger than hunter-gatherer bands but simi- what delayed due to the need to access wives through larly scaled in terms of face-to-face, kinship-laden either bride service (local group) or bride capture interactions. (outside group); the first being a personal cost in labor There is evidence that sedentism brought a reduc- contributed to the bride’s family and the second a cost tion in child mortality compared to hunter-gatherers, in risk. However, the possibility of polygyny extends as well as higher female fertility, although it is unclear the male reproductive period as new and younger whether the strongest effects are in reduced birth wives can be added through time. spacing or in higher rates of child survival. Bentley The high frequency of polygynous husbands asso- et al. ((2001)), in comparing the fertility changes asso- ciated with horticulture is likely because each wife is ciated with the prehistoric transition to agriculture essentially able to support herself and her children report that, when comparing subsistence modes and through her own labor (Murdock, 1967; Lancaster fertility rates, forager, horticultural, and pastoral and Kaplan, 1992). Males do not have to ponder groups had similar fertility rates whereas increases whether they can afford additional wives and children, were strongly associated with a higher dependence only how they to get and keep them. As White and on agriculture. The potential of deaths from chronic Burton (1988) found, polygyny is most associated with intergroup warfare and raiding increased. Using the fraternal interest groups, warfare for the capture of archaeological and historic record, Keeley (1996) women, absence of constraints on expansion into new found that for males the percentage mobilized in war lands and, especially for horticulturalists, environmen- often reached 35–40% and male deaths ranged from tal quality and homogeneity. The frequent practice of 10 to nearly 60%. widow inheritance by husband’s kin also increases Among contemporary horticulturalists, comple- the frequency of polygyny (Kirwin, 1979). Sororal mentarity in the male and female division of labor is polygyny (the marriage of sisters) is at its highest complex because of its link to local ecology. Garden frequency among horticulturalists perhaps due to the production by women using the digging stick and hoe ease of closely related women forming collaborative, provides the carbohydrate and caloric base of the diet horticultural work groups and child care (White and and is easily combined with childcare (Boserup, 1970; Burton, 1988). Goody, 1976). Males contribute their labor in clearing Parental investment in horticultural societies fields, in animal protein through hunting and fishing, focuses on raising healthy children without concern and in protection of the village resource base through for their marriage market endowments of extra-somatic defense. The relative contribution, type, and impera- wealth or inheritance of resources. Birth into a social tive of male help varies by ecological context. For group provides all the inheritance a child needs to

Embodied Capital and Extra-somatic Wealth in Human Evolution and Human History 445 access the means of production and reproduction. wealth in large stock in such a readily divisible and Such concepts as bastardy or disinheritance do not moveable form (as opposed to agricultural land) puts play a formal role in family dynamics. Child labor is a high premium on males as defenders and raiders. valuable to families since horticulture provides We find the warrior complex full-blown, with chronic a number of relatively low-skilled tasks that older internal warfare, blood feuds, social segregation of a children can perform (Bock, 2002b). In fact Kramer male warrior age class, fraternal interest groups, a (2005b) demonstrated that among Maya horticultura- geographic flow of women from subordinate to domi- lists older children contribute at the level of “helpers- nant groups through bride capture, and expansionist, at-the-nest,” significantly increasing their parents’ segmentary lineages based on the male line (Sahlins, fertility and without whose help their parents could 1961; DiVale and Harris, 1976; White and Burton, not add additional offspring to the family. 1988; Low, 2000). Men with strong social alliances are Variance in reproductive success is relatively low more likely to find at least some of their wives from for women because marriage is universal, and female within their own social groups, whereas men from fertility and fecundity depend on their own health, small or subordinate lineages are less likely to be productivity, and work effort (Prentice and Whitehead, offered brides and are willing to take more risks in lieu 1987; Jasienska, 2000; Ellison, 2001). Greater variance of performing bride service (Lancaster, 1981; Chagnon, among men is possible on the basis of raiding and 1988, 2000). bride capture but the social system itself is not stra- The original distinction made by Orians (1969) tified and individual men cannot amass or control between resource defense polygyny and harem defense access to resources relative to other men or pass them polygyny is relevant here. The chronic warfare of on to their sons. pastoralists (White and Burton, 1988; Manson and Wrangham, 1991; Keeley, 1996) can be understood as resource defense polygyny, as opposed to harem Tribal pastoralism and extra-somatic wealth defense polygyny described earlier for horticultural For most of human history, humans depended on som- societies. Both types of societies raid to capture women atic wealth or embodied capital to fund growth and to form polygynous unions (harems), but pastoralists reproduction. However, the domestication of animals, also raid to capture resources that can be used to particularly large herd animals such as cattle, camels, acquire and maintain new wives and their children. and horses, had a profound effect on human social and In later socially stratified societies, successful male reproductive patterns. Large, domesticated livestock resource holders do not have to do bride service, pay have intrinsic qualities that affected human social bride wealth, or capture brides; brides will flock to relationships, marriage patterns, and investment in them and their families will even pay for the opportun- children. For the first time in human history, men ity for their daughters to marry such a quality male. In could control a form of extra-somatic wealth that could a study of 75 traditional societies, the principal cause be held by individuals, thus increasing the variance in of warfare was either to capture women (45% of cases) male quality based on the resources each can control. or steal material resources to use to obtain (39% of the Secondly, herds are the basis of a domestic eco- cases), particularly in pastoral societies where bride nomy through their products of meat, milk and hides. wealth must be paid (Manson and Wrangham, 1991). There are advantages to dependence on such a Resource defense polygyny means that males will resource supply: (1) improvements in diets rich in compete to control the resources that females must animal protein; (2) stability of diet since animals are have for successful reproduction. A male’s ability to stored hedges against fluctuation in annual or seasonal successfully control more resources translates directly climatic effects; and (3) flexibility due to the divisibility into more wives and children (Borgerhoff Mulder, of herds into smaller units that can be moved about 1985, 1988b, 1989). One extraordinary result of extra- the landscape on the basis of the richness and concen- somatic wealth, particularly readily partible wealth, is tration of local resources (Barth, 1961). This improve- the institution of a new pawn on the marriage market ment in diet may result in higher survivorship of table, bride wealth. Women and their families come to women and children compared to foraging and horti- marriage negotiations with their traditional offers of culture, but also results in higher mortality for males embodied capital (youth, health, fecundity, and female due to endemic conflict. labor). Men, however, now have to come up with a Large-animal herding demands a high degree of significant payment of extra-somatic resources in the complementarity between female processing and child form of bride wealth as a preferred substitute for bride care and male risk-taking in herd management and service. Men who depend on bride service are limited defense. The products of herds require intensive pro- in their polygyny because of the years of service each cessing of meat, milk and hides, labor provided by bride’s family requires. Men who inherit resources can women. In contrast, the very existence of extra-somatic start their families early and marry often.

446 Jane B. Lancaster and Hillard S. Kaplan Bride wealth among pastoralists consists of horses, fewer wives than they could afford in the interests of cattle, or camels with sheep or goats as supplements or providing each child with a greater endowment. In lower-valued substitutes. Among African pastoralists other words, male pastoralists may pit quality against the close male kin of the groom help him with his quantity of children to preserve a lineage status and first bride-wealth payment, but the acquisition of sub- resource base and rather than simply maximizing the sequent wives is his own responsibility. Livestock immediate number of descendents (Luttbeg et al., used for bride wealth has interesting attributes: (1) it 2000; Mace, 2000). creates conflicts of interest between fathers and sons and among brothers for its use to obtain a bride Social stratification, states, and despotism (Borgerhoff Mulder, 1988a); (2) men from poor fami- lies will be more willing to take risks to obtain bride The rise of civilizations, beginning about 6000 years wealth or brides though capture (Dunbar, 1991); and ago in Mesopotamia and occurring at different times (3) livestock can be inherited. and places around the world (for example, Egypt in the Investment in children takes a novel form under a Near East, the Aztec and Inca in the Americas, and pastoralist system. The payment of bride wealth India and China in Asia) marked a critical shift in improves health and survivorship among young girls how humans organized themselves in social systems because their marriages bring in resources that can be and in relation to the environment (Goody, 1976; used by their fathers and brothers to acquire more Betzig, 1993; Summers, 2005). These civilizations wives (Borgerhoff Mulder, 1998). Sub-Saharan Africa appear to have developed independently in response is notable for the fact that in spite of the patrilineal bias to local conditions without being the products of either in so many societies, neither a survival nor a nutri- conquest or diffusion. In spite of this historical inde- tional advantage is found for boys over girls (Svedberg, pendence, they evidence significant similarities: (1) the 1990). Furthermore, among the Kipsigis, who are agro- presence of large, stratified social groupings settled pastoralists, early maturing (and presumably better fed on particularly large and productive resource patches; and healthier) women have higher lifetime reproduc- and (2) the appearance of social despots, men who tive success than late-maturing women. As a result, use coercive political power to defend their wealth they command higher bride wealth and hence consti- and reproduction and practice warfare to acquire tute a higher return on parental investment for their more resource patches and slaves (Betzig, 1986). These upbringing (Borgerhoff Mulder, 1989). They also rep- two major effects flow from the nature of the resource resent a better investment for a husband’s bride-wealth patches. payment because of a higher return in fertility. The patches upon which the first civilizations were Furthermore, children are able to provide child settled had special qualities: (1) they were highly pro- care of younger siblings as well as low-skilled labor in ductive but set in environments where there was a stock care and the processing of animal products, so rapid fall off to unproductive lands such as desert or they are able to substantially but not completely offset forest; and (2) these productive patches could not be the costs of their rearing compared to foragers (Bock, intensively utilized without complex political organiza- 2002a, 2002b). Child labor plays an important role in tion as in regional irrigation systems. Political control the economies of both pastoral and agricultural soci- and organization rested on the power of men. Although eties because their contributions through simple tasks female primates often form alliances with their female such a carrying water contribute to food production by kin to protect and control access to the resources freeing mothers to become more effective producers necessary for their reproduction (Isbell, 1991; Sterck (Blurton Jones et al., 1994; Kramer, 2005a). However, et al., 1997), the reproductive benefits of extra-somatic this reduction in cost of rearing is countered by the resources are much greater for men than for women, fact the parents of sons now have a new cost to meet; because of their impact on polygyny. The end result of the balloon payment (bride wealth) needed to establish these environmental conditions associated with early sons on the marriage market. The flow of stock social stratification was that men competed for control through families who are both bride-wealth receivers of the resources necessary for reproduction, formed and givers helps maintain the system, at the same time despotic hierarchies involving social alliances and that it creates problems for families with unfavorable stratification, with low-status men ‘agreeing’ to live ratios of sons to daughters (Borgerhoff Mulder, 1998). under political despotism because they could not rea- Finally and most significantly, there is suggestive dily move to another resource base. evidence that for the first time humans begin to repro- The increased reliability of food resources, the duce at levels that may not maximize the number of costs of warfare, and the concentrations of large popu- descendents in association with the appearance of lations into small and sometimes urban areas each had extra-somatic wealth and its inheritance. Among impacts on mortality and morbidity. A cross-cultural modern East African pastorialists men appear to marry analysis of fertility and mode of subsistence found that,

Embodied Capital and Extra-somatic Wealth in Human Evolution and Human History 447 for a 10% increase in dependence on agriculture by historic extremes in male variance in resource between two related cultures one of which moves holding and power. As Betzig (1993) notes, the extreme towards agriculture, there is a fertility increase of sizes of royal harems ranging from 4000–16 000 approximately 0.2 live births per women (Sellen and women are associated with smaller but still impressive Mace, 1997). Bentley et al. (2001), in reviewing the numbers of wives and concubines for the royal rela- cross-cultural and archaeological evidence, suggest a tives and supporters. In the case of the Inca the size of series of multidirectional effects: higher fertility due to a man’s harem was regulated by law and in direct more consistent food supply and earlier maturation; relationship to his social/political rank (Betzig, 1993). increased infectious diseases with regular visitations Among the Inca there were nine levels of political rank- as well as endemic diseases (malaria and tuberculosis) ings with polygyny ceilings for each except the top- due to long-distance trade and large urban popula- most. These harems were exclusive holdings of large tions; and a shift in peak mortality from infancy to numbers of young, fecund women with their children middle childhood. Furthermore, warfare continues to and sexual access to them was restricted to their mate reduce the numbers of young men in the mate pool. and regulated with some sophistication to optimize With social stratification comes a complex division female fertility. Many of these wives and concubines of labor with specialists in war, farming, crafts for the were collected as tribute or war booty; but others, as production of goods and services, and war captives and principal wives, probably represented important poli- slaves for the hardest manual labor, as well as long- tical alliances with their male relatives. distance trade in luxury goods and slaves. The intro- duction of the plow in Eurasia, perhaps as early as the Variance in male quality and the marriage sixth century BC, and the need for food production market beyond simple subsistence to service urban markets led to significant changes in the division of labor There are two clear outcomes of such extreme variance (Goody, 1976; Ember, 1983) and extremely high com- in male quality. The first is that many men remain plementarity between male labor and resource acquisi- unmated or have only one wife, so that male celibacy tion and female labor and child care. There is evidence or at least nonmarital sex is prominent. In the words of of increased workloads for women in spite of the fact Dickemann (1981, p. 427), polygyny in the context of that men assume more responsibility for farm labor, extreme social stratification is “characterized not only because of increased demands for women to process by arbitrary sexual rights of lords and rulers but by grains or secondary animal products such as milk, large numbers of masculine floaters and promiscuous hides, and wool (Bentley et al., 2001). semi-floaters, beggars, bandits, outlaws, kidnappers, Variance in male fertility in these first civilizations militia, and resentful slaves and serfs.” Nevertheless, in the Near East, Central and South America, and Asia these early despotic states lasted for thousands of was probably the greatest it has ever been before or years. A second outcome of variance in male resource after in human history (Betzig, 1986, 1992a, 1992b, holding and male mating success is that there tends to 1993; Summers, 2005). The reason for this is that des- be universal marriage for women with only those most potic males had enormous political and social control severely compromised by health or other personal with the ability to eliminate rivals and their entire qualities being unlikely to find a role as secondary wife families through despotic edict, to wage war to or in a minor union. For access to the mating market increase personal and state resource bases, to acquire men must bring extra-somatic wealth, power, and land slaves and war captives for labor and reproduction, in order to be favorably placed or else get wives as and to determine political succession for favored sons. high-risk booty in state warfare (Low, 2000; Clarke This extreme variance in male resource holding inevit- and Low, 2001). ably produces social and political instability due to the Women, too, bring their traditional embodied capi- creation of too many potential heirs (sons of many tal qualities of youth, health, and fecundity along with wives) and too many males (slaves) without access their labor for access to the marriage market. However, to the means of reproduction. The great wealth to be there was a historic shift in how women and their gained from domination also motivated expansion and families approached marriage negotiations that has intergroup conflict among would-be despots. been richly described by Dickemann (1979a, 1979b, Despotic males are an extreme example of resource 1981) in a series of papers on hypergyny, dowry, female defense polygyny (Orians, 1969); that is, as individuals infanticide, and paternity confidence. The extreme they control access to the resource base for reproduc- variance in male quality created by despotism and tion that females require and, with few competitors, harem polygyny forces the families of women to put polygynous marriages to them become the only family down more and more value on the mate market table to formation strategy option for many women. The access a desirable groom or to move a daughter up in mating markets of despotic systems are characterized the social hierarchy. These extra payments include

448 Jane B. Lancaster and Hillard S. Kaplan actual wealth, in the form of dowry, and guarantees estate intact and maintain the concentration of wealth, of paternity confidence (bridal virginity and wifely or in the case of the poor, to balance food supply with chastity). Guarantees of a daughter’s virginity and family size. This trend, although it occurred in chastity (a prerequisite for a bride destined to produce response to population pressure on existing resource heirs to a male lineage holding a reproductive estate) bases all over the world at different time periods, is are costly forms of embodied capital, involving female particularly well documented in premodern Europe. seclusion (special women’s quarters, harem guards, Human evolutionary ecologists in collaboration with chaperones), and female incapacitation (foot-binding historical demographers provide us with a unique and corseting) that bars their daughters from the out- record of the relationships between fertility, family side world of productive labor. formation strategies, and socioecological context Parental concern over the ability of their children during the premodern and early modern periods of to access reproductive estates transformed the nature European history (Voland, 2000). Their studies, based of the marriage market. Parental investment in these on heraldic or parish records of births, marriages, systems varies in relation to the power and wealth deaths, and inheritance of estates, can be used to dir- of the male’s family. As is to be expected, under such ectly link reproductive strategies with resource hold- conditions where male access to and control of ings. This time period witnessed developments that resources is the basis of social stratification, patrilineal had began centuries earlier but occurred without the descent and patrilocal residence are highly favored benefit of quantifiable documentation. Boone (1986a, since males are the principal resource holders 1986b), for example, traces the historic process of par- (Hartung, 1982). Resource-holding parents commit ental investment among Portuguese elites during the to a “balloon payment” in launching their children late medieval/early modern periods of the fifteenth and in marriage. This balloon payment takes the form of sixteenth centuries. Saturation and resource stress are endowments and promised inheritance for sons and evident with a progressive narrowing of the numbers of dowry as anticipatory inheritance for daughters claimants to an inheritance, first through monogamy (Goody, 1973, 1976; Dickemann, 1979a, 1979b). For to create a single bloodline of inheritors and bastardy resource-holding families then, the marriage market to disenfranchise offspring who are not the product of formed by stratified social systems proved costly in a legitimate union (Goody, 1976, 1983), followed by a terms of parental investment and forced a focus on preference for sons over daughters as inheritors, endowments for both sexes at the age of marriage. and finally by birth order effects with preference for Poor parents, on the other hand, attempted to balance primogeniture within each sex for access to resources labor demands with fertility, since in agricultural and the creation of celibate children to live as priests, systems children can be productive at low skill tasks nuns, bachelors, and spinsters (Hrdy and Judge, 1993). or child care and add to the family economy. Thus, For the first time in human history mating and they might try to regulate birth spacing to optimize reproduction is no longer a universal for women and the productivity of already born children before siblings of the same sex are pitted against each other another mouth to feed is added to the family. in competition for access to reproductive estates. With Finally, a notable characteristic of the premodern survival through child- and young adult-hood still quite period in many parts of the world is evidence for a problematic, ancillary practices develop in which both growing rural population resulting from higher fertility sons and daughters would be held in reserve in monas- and an associated growing concern regarding satu- teries and nunneries for inheritance and reproduction ration of the resource environment. This is often should their older same-sex sibling die (Goody, 1976, associated with urban growth, empire building, and 1983; Boone, 1986a, 1986b). Within the scope of these expansionism, providing opportunities for migration restrictions that limit half-sibling and sibling compe- by noninheriting or low status children to areas of both tition, parents with wealth raise as many children as higher mortality and risk but also with the potential they can but endow a select number at adulthood. for the acquisition of land, or wealth and power. It During most of this historic period there is a strong also generated a new concern about keeping the correlation between wealth, probability of marriage, family estate intact and about the management of younger age at marriage, and completed fertility (Voland, inheritance. 2000). However, restricted inheritance decreases the reproductive benefits of polygyny. The desire to concentrate wealth also limits the reproductive suc- Premodern states and narrowing the pool cess of noninheriting sons and daughters. This is a of inheritors second striking example in which reproductive and With population growth and increased saturation of parental investment behavior in response to extra- arable lands, parents adopted patterns of restricted somatic wealth results in outcomes that did not and differential inheritance in order to keep the family maximize parental fitness. In fact, towards the end

Embodied Capital and Extra-somatic Wealth in Human Evolution and Human History 449 of the period, as life expectancy improved and eco- whose main function was to produce heirs, to a nearly nomic structures became saturated, resource holding annual birth rate (among the highest for any group groups delayed marriage into the late 30s and early of women in human history). In contrast, the birth 40s for men and mid 20s for women (Szreter and spacing for wet-nurses was closer to four years (Hrdy, Garrett, 2000; Voland, 2000). 1994). A second group of women also used wet-nurses, The family reconstruction studies document very especially towards the end of this historic period. 1 different reproductive strategies according to class . These were single women working in urban centers or Generally, wealth brings higher probability of marriage, the wives of poor tradesman who found themselves in at a younger age, to a younger spouse, and more positions of servitude or trade where the incompatibi- children. However, as environments become more lity between breast-feeding and work was complete. saturated, local resource competition among siblings To the great detriment of their infants’ survival, these differentially affected resource-holding families, as women placed their children with commercial wet opposed to day laborers, and increased the likelihood nurses at baby farms (Hrdy, 1994). In these cases the of dispersal of later-born children (Clarke and Low, demands of maternal work far outweighed the needs 1992; Voland and Dunbar, 1997; Towner, 1999, 2001). of infant growth, perhaps to improve the development With saturation, the benefits to resource holders of of weaned, older children. having an above average number of children was offset The past 10 000 years of human history brought by more and more intense sibling competition for many changes to what was originally the forager adap- access to inheritance (Voland, 2000). Parents without tive niche. As the last glaciers withdrew, humans began resources had no need to manipulate their offspring to intensify their extraction of resources from the and were more likely to benefit from opportunistic environment by domesticating plants and animals. At strategies by their children (Voland and Dunbar, 1995). first, land extensive horticulture combined with Wet-nursing presents a fascinating example of hunting did little to alter the human experience of how differentiation in parental investment strategies small groups, face-to-face social networks, and subsist- develops into extreme forms for both the highest and ence economies. Family formation practices continued the lowest status groups of women. Throughout the relatively low rate of polygyny, nearly universal human history there has always existed a conflict marriage, bride service and bride capture, and the between production (acquisition of food) and repro- production of children regulated only be the health duction (lactation and child care) for women, a conflict and well-being of the mother and each child. that in fact troubles female mammals in general. The first transformation in human experience Human women are especially caught in this conflict followed from the appearance of extra-somatic wealth because they have multiple, dependent young of in the form of large domesticated animals and later differing ages and needs (Draper, 1992), which means land. Extra-somatic wealth has an intrinsic quality, it that true respite never occurs until all children are can be taken by force and stronger individuals and reared. Cross-culturally women’s work is organized by groups can amass or control access to it. This neces- its compatibility with child care (Brown, 1970); how- sarily creates much wider variance in male quality than ever, this compatibility is never complete – only more occurs in forager men dependent on embodied capital or less so (Hurtado and Hill, 1990; Lancaster, 1997; investments of health, vigor, and skill. Family forma- Lancaster et al., 2000). As a result of social stratifica- tion strategies responded by turning the old rules tion high status women are able to subvert the physio- upside down. Instead of men paying for access to wives logical capacity of lactation of other women to serve with bride service, bride wealth, or the dangers of bride their own reproductive ends. Since intense breast- capture, payments in the marriage market reversed feeding lowers the likelihood of ovulation, a wet-nurse, direction. As social groups became stratified and even if paid, sacrifices her own fecundity to another wealth differentials increased, women and their fami- (Hrdy, 1994, 1999). Typically high status women did lies began to bring and more to the bargaining table by not breast-feed their own children but used wet-nurses. offering both dowry and paternity confidence in the This increased the fertility of high status women, form of virginity and chastity. During the final phase of the premodern period, societies became obsessed with the preservation of the family’s reproductive 1 The behaviors of nobility are documented by Boone in Portugal estate by successively narrowing the possible number (Boone, 1986a; Kramer, 1998) and Dickemann in Europe, the of inheritors. First the line of inheritance went only to Middle East, China, and India (Dickemann, 1979b, 1981), and for gentry and land-holding peasants as well as day laborers by the children of the principal wife with others labeled Voland and colleagues in Germany (Voland, 1990; Voland and with bastardy, then daughters could only inherit via a Engel, 1990; Voland et al., 1991, 1997; Voland and Dunbar, dowry lower in value than a son’s inheritance, next 1995, 1997; Voland and Chasiotis, 1998; Voland, 2000), Low in Sweden (Low, 1990, 1991, 1994), Towner in the United States, only the first or a selected son could be endowed with and Hughes (1986) and Scott and Duncan (1999) in England. the family estate and the rest had to find other niches

450 Jane B. Lancaster and Hillard S. Kaplan in the society or migrate. Just before the onset of mod- Not all the world today has experienced the demo- ernization, the world had become full of bachelor and graphic transition, but completed family size of spinster noninheriting children with no guaranteed replacement level or less is typical of modern econo- access to the right or means of reproduction, qualities mies with skills-based labor markets as in Western of life that were part and parcel of the original human Europe, North America, Japan, China, and parts of adaptive niche. Latin America (Cuba, Chile, Costa Rica, Puerto Rico, and Trinidad and Tobago) (Population Reference Bureau, 2008). Furthermore, for the first time the The modern world and embodied capital world population is evenly divided between rural and Given rural reproductive and survival rates, the urban areas, and by 2050 urban residents are likely restricted inheritance system discussed in the previous to make up 70% of the world’s population (Population section produced excess adults without access to land Reference Bureau, 2008). This reversal in family repro- and the means of production. Colonization through ductive strategies from having as many children as conquest was one response by males to this situation, possible to only two is related to a strategic shift especially later-born sons (Boone, 1986a, 1986b; from quantity to quality, in which quality is most often Curtin, 1989). Another response by both men and expressed in education and training to be used for women was to provide services for others, and migra- access to resources, not inheritance. tion to cities in search of employment. This supply of labor and of consumers helped fuel the growth of a Modern skills-based labor markets and the skills-based, mercantile economy that was to gradually expenditure of extra-somatic wealth supplant the power- and land-based hierarchies of to embody human capital the premodern period based almost entirely on extra- somatic wealth. Changes in the nature of resource production and Those conditions set the stage for dramatic changes the economic forces that determine wages in labor in reproductive and parental investment strategies. markets appear to underlie these changes in reproductive In the early 1800s, changes in the relationship between and parental investment strategies, and explain their humans and their economies began in a small part of patterning over time and space. The directional change the world, Western Europe, including England (Clark, in the nature of labor markets towards greater wage 2007). This change has been labeled the “demographic premiums for skill- and education-based capital over transition.” For nearly all of human history, available the last two centuries is well documented (Newcomer, evidence suggests that human populations responded 1955; Burck, 1976; Herrnstein and Murray, 1994; to greater resource availability with increased fertility, Vinovskis, 1994; Clark, 2007). As the extent of the labor and reduced fertility when resources were scarce. and consumer markets grew, along with advances in Women’s reproductive physiology appears well production technologies, there was a concomitant designed to make adaptive responses to increases and increase in both private and public investments in educa- decreases in energy availability (Ellison, 2001, 2003). tion. In a sense, the relationship between embodied However, after 1800 with the demographic transi- capital and production in modern skills-based labor tion, the size of human families began to shrink, first markets is more similar to the foraging life way than to among the wealthier segments of society, even as stan- its agricultural predecessor. Rather than generating dards of living and energy availability were increasing. wealth through control of land, people now invest in Unlike before when individuals in good condition had learning to increase productivity, and individuals are free more progeny than individuals in poor condition (just to move through the environment in search of economic as is the case with other species), higher status humans opportunities because they carry their embodied capital began having fewer children than did the poor. with them. This trend only lasted for a time. Today there are These increases in educational capital investment remarkably few differences between classes or even and the nature of labor markets were accompanied by ethnicities in completed family size. For example, in improvements in the “technology” of disease preven- the United States today the average US woman tion and treatment, and by increased public and pri- produces 1.9 children, considerably below the replace- vate investments in health and mortality reduction. ment level of 2.2 children. When broken down by During the nineteenth century, there were large changes ethnicity, the numbers are 1.7 for Asian Americans, in the scientific understanding of disease (Preston and 1.8 for non-Hispanic Whites, 2.0 for Blacks and 2.3 Haines, 1991). This led to a dramatic decline in infant, for Hispanics (US Census Bureau Report, 2008). child, and adult mortality rates that continued for Although the range between the highest and the lowest close to a century. As scientific advances enabled is three-fifths of a child, the main message from this reductions in mortality rates, there was strong pressure data is consensus: two children are enough. to increase public investments in health and disease

Embodied Capital and Extra-somatic Wealth in Human Evolution and Human History 451 prevention from the protection of the water supply 1995). For example, Hart and Risley report that, by to the development of vaccines and public access to the age of three, children have heard six million words medical care. As a result, infant and child mortality if their mothers are professionals, three million rates reduced dramatically, greatly increasing the words if their mothers are “working class,” and only probability that investments in children will be realized one million words if their mothers are on welfare. By in terms of productive adulthoods. The length of the the time children enter the public education system productive adult life span, especially when time lost to there are clear differences among them in school- morbidity is taken into account, also increased signifi- related skills, and those differences are related to socio- cantly. Together, the two shifts in production processes economic status. and mortality rates favor increased human embodied Second, the rate at which a child learns may capital investment in a way that is reminiscent of the depend on the knowledge and skills she already pos- initial dietary shift leading to the hominid specializa- sesses. Much of the education offered in schools is tion discussed above (Kaplan et al., 2002). based upon the premise that knowledge is cumulative This historical process also resulted in much (Cromer, 1993). Basic skills are acquired first, and greater labor force participation by women. During those skills are used as a foundation for the acquisition the initial demographic transition in the developed of the next set of skills. This implies that the impact world, the breadwinner–homemaker family structure of the child’s time inputs would depend upon skills was dominant. With increased demand for labor that already in place. It also means that the net increase requires skill as opposed to strength and with growth in embodied capital at each age is a function of both in the service sector of the economy, wage-earning the quality of inputs, and the embodied capital opportunities for women increased. At the same time acquired at younger ages. the payoffs to “home” production decreased with Moreover, those qualities tend to be correlated labor-saving devices, such as washing machines and across inputs. Children with more educated parents refrigerators, and smaller family size reduced the also attend better schools with better teachers and number of years spent caring for small children. Over better fellow students. At the other extreme, children time the value of male strength through labor and the in developing nations often come from families in time women spent caring for small children was which neither parent has had formal schooling and reduced; thus leading to a trend from greater to lesser attend schools with very large class sizes, almost no complementarity between men and women so that library resources, and teachers with only primary edu- men and women are now closer to being interchange- cation themselves. Under those conditions, much less able units in work effort. is learned per year spent in schooling. For example, in Although the shift towards an education-based a study of a predominately Black township school in wage structure has been largely monotonic, those Cape Town, South Africa, Anderson, Kaplan and Lam changes occurred at different times in the developed (unpublished manuscript) found that on average, it and developing worlds and the details of the supply took children 15 years to complete 12 grades of and demand for labor of different levels of human schooling. By that age (20–21), only about 10% of capital have been both historically and regionally vari- students have passed the final matriculation exam able. Moreover, both within and among societies, there and earned a high school diploma. The variance in appears to be a great deal of variation in rates of return those inputs leads to an increasing differentiation in on investments in educational capital. educational capital with age. The production of human capital is also human- This within-population heterogeneity in the costs capital intensive (Becker and Barro, 1988) and associ- of embodying capital in children means that the envir- ated with a reduction of the value of children’s labor as onment does not determine diminishing returns to their time is taken up with education and training. To parental investment as it would be in primary produc- see this, it is useful to think of an “education produc- tion economies, but will be frequency-dependent. Indi- tion function.” In each year of a child’s life the amount viduals with low levels of human capital are more likely a child learns, and the changes in his or her knowledge, to be unemployed as well as having a lower income, reading, writing, logic, and mathematical skills, will when employed. This is especially true in urban areas depend upon many different inputs, such as the child’s in the developing world. The massive rural to urban time, prior abilities, parents’ time, and teachers’ time. migration over the last four decades has resulted in The value of those inputs, in terms of the educational very large populations of people with low levels of capital produced, depends on the quality of in those education competing for a limited number of low skill inputs. First, consider inputs of parents’ time. There is jobs in the economy. In many places, male unemploy- significant evidence that the nature of parent–child ment can be as high as 70% or more. This variability interaction varies with the educational level of parents in educational capital, along with its impacts on (Hart and Risley, 1995; Hoff-Ginsberg and Tardiff, income variation both across individuals and within

452 Jane B. Lancaster and Hillard S. Kaplan individuals over time, has profound effects on family investment patterns typical of most mammals? How formation and reproduction. did it alter how humans access and distribute food? In fact, the link between education and income 2. What is the impact of the socioecological context increased in intensity during the second half of the on human marriage markets and family formation twentieth century. For example, real wages actually strategies in terms of the distribution of resources dropped from 1958 to 1990 among men without high and the means to access them? school degrees in the United States. In 1958, men with 3. More and more modern societies are experiencing graduate education earned about 2.3 times as much as a reduction of completed family size to replace- men with elementary education; by 1990, they earned ment level (2.2 offspring) or below. Why should more than 3.5 times as much. Wage differentials this be so when these societies have the highest among men with some college education, bachelor’s standard of living known in human history? How degrees, and graduate degrees also increased substan- might such small family size impact parental tially. For women, wage differentials among educa- investment and family formation patterns? tional attainment levels increased substantially in the 4. Why does variation in male quality impact the 1980s (Kaplan et al., 2002). marriage market? What features in male quality have been important in different kinds of econ- omies and social organization? Are these qualities THE HUMAN ADAPTATION: SOMATIC AND inherent or acquired? How so? EXTRA-SOMATIC INVESTMENTS 5. What are the factors that have led to a division of labor in which female work is closely linked to Human history is based on a remarkable coevolved compatibility with child care? 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Part V Health and Disease “The deviation of man from the state in which he was originally placed by nature seems to have proved to him a prolific source of diseases.” Edward Jenner (1749–1823) 457



27 Evolutionary Medicine, Immunity, and Infectious Disease Michael P. Muehlenbein The purpose of this chapter is to provide readers with and pathogen virulence. Finally, the evolutionary introductions to several topics central to a modern histories of several key pathogens are discussed, spe- understanding of human evolutionary biology. Infec- cifically to illustrate the human host adaptations, both tious pathogens have placed critical selective con- biological and behavioral, to disease emergence and straints on the evolution of our hominin ancestors, evolution. Review of such a diverse topic produces an and our own species continues to coevolve with infec- admittedly large reading, but it is hoped that readers tious organisms today. Our understanding of the pro- may use this as a source for further discussion and cesses that shaped this evolutionary struggle have development. changed, and now an adaptationsist perspective offered by the discipline of evolutionary medicine helps to shed light on our vulnerabilities to infectious EVOLUTIONARY MEDICINE diseases and noninfectious degenerative diseases. It also aids in our understanding of the purpose and The central role of disease in human evolution was outcomes of our coevolutionary conflicts with the queried decades ago by John Burdon Sanderson Hal- microscopic predators that parasitize us. So as to com- dane (1892–1964). He hypothesized that much of the pete in these interactions, we have developed a marvel- biochemical diversity found in serological studies of ously complex immune system capable of dynamic, humans likely played important roles in disease resist- varied responses. Insight into these mechanisms ance (Haldane, 1949). Today, the integration of medi- provides fascinating examples of real-time Darwinian cine and evolutionary biology forms the basis of the processes of survival and fitness maximization in the discipline of evolutionary, or Darwinian, medicine. face of invading competitors within the human host. This field recognizes that medical research can benefit Interestingly the ontogeny and deployment of these significantly from a priori understanding of adaptation responses are dependent on several factors, including by natural selection and its role in the causation of genetic and ecological constraints. health-related outcomes. This might include under- The discussion offered below provides an introduc- standing the various adaptations we use to combat tion to evolutionary medicine with the specific purpose pathogens as well as the adaptations that pathogens of better understanding human-pathogen coevolution use to counter our own defense mechanisms. This also and the development of human immune responses. includes understanding the necessary costs imposed by A current, detailed description of human immunity is our current adaptations against disease, and that there included, but this discussion is far from complete. are mismatches between our current form, which Comparative aspects of evolutionary immunology are evolved in the past, and the present environments in emphasized, as are the genetic and ecological sources which we find ourselves (Williams and Nesse, 1991). of variation in these responses. Immune functions have Whereas current medial research and practices focus played important roles in the evolution of organismal on describing how we become ill with the purpose of life histories and so our discussion includes how identifying cures and preventions, evolutionary medi- immune mechanisms could be selected for via natural cine utilizes the adaptationist perspective in evolution- and sexual selections, develop according to environ- ary biology to describe why some people get sick in mental exposure and genetic factors, and then be different environments. Caution must be used in over- maintained through trade-offs and constraints. Basic applying an adaptationist paradigm in evolutionary aspects of epidemiology are also introduced but with medicine (Marks, 2008), but we must still ask what particular emphasis on host–parasite coevolution and its aspects of our physiology, morphology, and behavior consequences for the evolution of antibiotic resistance make us vulnerable to disease, why have these traits Human Evolutionary Biology, ed. Michael P. Muehlenbein. Published by Cambridge University Press. # Cambridge University Press 2010. 459

460 Michael P. Muehlenbein TABLE 27.1. Some manifestations of disease benefit the host whereas others benefit the invading pathogens. Adapted from Nesse and Williams (1996). Observations Examples Primary beneficiary Hygienic measures Killing mosquitoes, avoiding detritus Host Host defenses Immune responses, sneezing*, vomiting* Host Repair of damage Regeneration of tissue, inflammation* Host Compensation for damage Chewing on opposite side to avoid tooth pain* Host Damage to host tissue Liver damage from hepatitis* Neither Impairment of host Decreased detoxification, lameness* Neither Evasion of host defenses Molecular mimicry, change in antigens Pathogen Attack on host defenses Destruction of host cells* Pathogen Uptake and use of nutrients by pathogen Growth and proliferation of pathogens Pathogen Dispersal of pathogen Transfer of blood parasite to new host by mosquito Pathogen Note: *Some manifestations could benefit both the host and pathogen. evolved, and why do they persist today? Evolutionary Some traits may have evolved as design comprom- medicine attempts to emphasize the ultimate or evolu- ises. In this case, a trait may have been beneficial in an tionary explanations for medical phenomena rather than ancestral environment, but is no longer beneficial in just the proximate causes of morbidity and mortality. the current environment, and disease can result from For a more complete review of evolutionary medi- this mismatch (the “discordance hypothesis”). For cine, readers are encouraged to utilize the following example, a preference for fat, carbohydrates, and salt texts: Nesse and Williams (1996), Ewald (1996), in the ancestral hominin diet was beneficial, but may Trevathan et al. (2007), Elton and O’Higgins (2008), now result in cardiovascular disease and metabolic Stearns and Koella (2008). In brief, evolutionary disorders in modern, developed environments with less explanations for disease can be organized into several physical activity (Eaton and Eaton, 1999). Some traits categories, including defense mechanisms, design may be evolutionary legacies that evolved in the past, compromises, and conflict between organisms but can predispose individuals to illness in the present. (Williams and Nesse, 1991; Nesse and Williams, Immunoglobulin E (IgE), eosinophils, mast cells, and 1996). Defenses are mechanisms that have evolved to other proximate mediators of allergic responses likely prevent, limit, or eliminate disease, and we must rec- evolved to protect us against helminth and other extra- ognize which are signs and symptoms of disease that cellular infections. Improvements in sanitation and the materialize to benefit the invading pathogen, which are absence of these infections in most people in developed manifestations of disease that are actually beneficial countries may produce an imbalanced Th-cell immune host responses shaped by natural selection to defend phenotype (see below), and our systems overreact to against infection, which are side effects of infection/ novel and largely unimportant allergens, like dust disease, and which mechanisms benefit both the host mites (Yazdanbakhsh et al., 2002). Thus our evolution- and pathogen (Table 27.1). Although they may be ary legacy may be a hypersensitivity response that now unpleasant, if they are actually beneficial host predisposes us to atopy. responses, then blocking these mechanisms may cause The propensity for drug abuse is also likely a design more harm than good. Fever, nausea, and vomiting compromise and the result of a mismatch between our during pregnancy, revulsion towards odors associated bodies and modern environments: humans are vulner- with bacterial decomposition, and mental conditions able to abuse of psychoactive drugs because these sub- like fear of snakes and heights have all been proposed stances mimic the activation of neural mechanisms to be defensive mechanisms that evolved to increase involved in regulating feelings of pleasure and other host fitness. For example, fever may make it more necessary emotions (Nesse and Berridge, 1997). We difficult for certain pathogens to multiply within the have been programmed by natural selection to pursue host, and elevated temperatures may also optimize behaviors that produce such chemical incentives. immune cell activity of the host (Kluger et al., 1998). Unfortunately, these substances are now available in Inhibiting or reducing fever during infection may not forms, concentrations, and delivery systems that all too be very beneficial in certain circumstances (Doran potent and readily available. Evolutionary consider- et al., 1989; Graham et al., 1990; Kramer et al., 1991). ations suggest that “we cannot reasonably expect to Of course, high fevers can cause much more than just win the war on drug abuse, but we can use our know- discomfort, including sterility and death. ledge to develop sensible strategies for prevention,

Evolutionary Medicine, Immunity, and Infectious Disease 461 treatment, and public policy to manage a problem that considering infectious diseases, their evolution, and is likely to persist because it is rooted in the fundamen- our immune responses to them. tal design of the human nervous system” (Nesse and Berridge, 1997, p. 65). Furthermore, psychoactive sub- stances that inhibit all negative emotions can also HUMAN IMMUNITY impose fitness costs. Nonpathological low mood and anxiety may be beneficial in some situations, forcing Immunity is obviously vital for defense against invad- individuals to remove themselves from potentially ing pathogens, cellular maintenance, and renewal and harmful circumstances (Nesse, 2006). protection against cancer. No discussion of infectious Despite contributing to morbidity and mortality, diseases would be complete without an introduction to some genetic and phenotypic traits can be maintained the immune system and its responses. For a compre- in a population because they are beneficial in some hensive description of immunology and human forms or in certain environments. Of course, some immunity see Paul (2008), and for a brief review see genes can be maintained in a population due to novel Delves and Roitt (2000a, 2000b). Here I provide readers mutations, genetic drift and other random processes, with an introductory review of the human immune or because they are very rare disorders. Many disease system and its complex responses. Comparative conditions are caused by organismal defects, and aspects of evolutionary immunology are emphasized these may be transmitted to future generations and as are the genetic and ecological sources of variation maintained in the population because they do not in these responses. affect people until after reproduction (Haldane, 1941; Medawar, 1952). Nonetheless, there are trade-offs Innate immunity in which traits can exhibit antagonistic pleiotropic functions, including some which are beneficial, The mammalian immune system is usually organized particularly in the genetic heterozygous state. For into two primary components: innate (constitutive) and example, individuals that are heterozygous for alleles adaptive (acquired) immune responses (Figure 27.1). on chromosome 7 (e.g., dF508, W1282X, 1677delTA) Innate immunity consists of primary nonspecific, gen- which code for cystic fibrosis may better resist disease eralized mechanisms that block or eliminate foreign from Vibrio cholerae, Salmanella typhi, Escherichia particles from invasion of the host. Such defenses coli, and even Mycobacterium tuberculosis (Poolman include anatomical barriers (mucus membranes, skin), and Galvani, 2007). resident flora (nonpathogenic bacteria), humoral Organisms are shaped by evolution in ways that factors (lysozyme, complement, and other acute phase can make disease almost inevitable. Autoimmune proteins), and cells (phagocytic cells like neutrophils, diseases, such as type I diabetes, rheumatoid monocytes, and macrophages; inflammatory medi- arthritis, and multiple sclerosis, can result from ators produced by basophils, mast cells, and eosino- overactivation of immune responses which become phils; and natural killer cells) (Delves and Roitt, targeted towards an individual’s own antigens. 2000a). Note that white blood cells (leukocytes) include Increased risk of leukemia may even be a price we macrophages, dendritic cells, granulocytes (eosino- pay for maintaining intricate and powerful immune phils, basophils, and neutrophils) and lymphocytes responses that would help to control microbial infec- (T cells and B cells). All leukocytes originate from tions (Greaves, 2006). Maintaining high testosterone hematopoietic stem cells in bone marrow. in mammalian males can augment male reproductive Macrophages are mononuclear phagocytes that effort by increasing musculoskeletal performance perform many tasks, such as phagocytosis, cytokine (which aids in work capacity, intersexual competi- secretion, chemotaxis, and antigen processing and pre- tion, intrasexual coercion, and mate choice) but can sentation (Hume et al., 2002). Interdigitating dendritic also compromise survivorship by increasing risk of cells function in antigen presentation (Medzhitov and prostate cancer, production of oxygen radicals, risk Janeway, 1997). Toll-like receptors on macrophages of injury due to hormonally augmented behaviors and dendritic cells bind to foreign antigens and initiate such as aggression, violence and risk taking, reduced the cascade of innate and adaptive immune effector tissue and organ maintenance, negative energy mechanisms (Visintin et al., 2001). Eosinophils attack balance from adipose tissue catabolism, and sup- extracellular parasites by the release of various chem- pression of immune functions (Muehlenbein and ical mediators (Wardlaw et al., 1995). Basophils and Bribiescas, 2005; Muehlenbein, 2008a). These are mast cells facilitate atopic, inflammatory reactions compromises that our genotypes and phenotypes (Abraham and Arock, 1998). Natural killer cells attack have made through evolutionary processes, and the membranes of infected or malignant target cells understanding this can be insightful for medical through a variety of processes, including antibody- research and practices. This is especially the case in dependent cellular cytotoxicity (Herberman et al.,

462 Michael P. Muehlenbein Major immune mechanisms in humans Innate immunity Adaptive immunity Lymphocytes Health behaviors B cells (antibody-mediated T cells (cellular-mediated Anatomical barriers, resident immunity) immunity) nonpathogenic bacteria Interferon, lysozyme, lactoferrin, Immunoglobulins Cytotoxic T cells Helper T cells (CD8) (CD4) transferrin, heat shock proteins (IgG, IgM, IgA, IgD, and IgE) Proinflammatory Th-1 cytokines Complement system (IFN-γ, TNF-α, IL-1β, IL-2, IL-12) Macrophages, neutrophils, basophils, mast cells, Anti inflammatory Th2 cytokines eosinophils, natural killer cells, dendritic cells (IL-4, IL-5, IL-10) Immunosuppressive Treg cytokines (IL-10, TGFβ) 27.1. Many of the major immune mechanisms in humans. 1986). Interferon is produced by virally infected cells to attack complex and a cytolytic response (Law and signal apoptosis and prevent infection of adjacent cells Reid, 1995). (Samuel, 2001). Heat shock proteins are intracellular molecules that, among other functions, aid in antigen Adaptive immunity presentation and stimulation of proinflammatory responses (Robert et al., 2003). Lactoferrin, transfer- Because of the extreme diversity and short multipli- ring, and other proteins bind circulating iron, limiting cation times of most pathogens, hosts are under inten- availability during bacterial infections (Baker et al., sive selection pressure to produce variable defensive 2002). Innate immunity also includes resident flora in responses. This is accomplished through the high the gut and other tissues that prevent pathogen colon- diversification and rapid responses of acquired, spe- ization. Health behaviors that decrease the likelihood cific immunity. In this case, effector mechanisms allow of illness, such as handwashing and avoidance of fast, secondary responses during subsequent expos- detritus, might also be included in the category of ures. First, foreign antigens are recognized by immune innate immunity, although most of these behaviors cells in the tonsils, adenoids, and Peyer’s patches after arguably have a learned component. inhalation or ingestion. Foreign substances are trans- The complement system includes enzymes that ported in the lymph and trapped in the lymph nodes or function to eliminate microorganisms by promoting transported in the blood and filtered by the spleen. In inflammatory responses, such as changes in local vas- these locations, lymphocytes react with specific patho- cular permeability and entry of immune cells into gen antigens and facilitate an adaptive immune infection sites. Complement also functions in lysis of response. Peripheral circulation of lymphocytes also foreign cells through the formation of membrane allows for continual monitoring of infection and injury attack complexes, and in mediation of phagocytosis in strategic sites throughout the body. through the coating (opsonization) of pathogens and Lymphocytes come in two main forms: B cells and infected cells (Carroll, 1998). Complement is also T cells. All lymphocytes are produced in bone marrow important for stimulating adaptive immune responses and the fetal liver, but the maturation of T cells takes (Dempsey et al., 1996). Within mammals, the presence places in the thymus. During development, those T and of foreign molecules activates one of three different B cells that auto-react to self-antigens (estimated at complement pathways (innate ¼ alternative and lectin; 98% of all T cells) are eliminated in the process of adaptive ¼ classical). In most cases, the C3 component thymic education to minimize self-reactivity (Sprent, binds to foreign molecules and activates phagocytes 1993). Positive selection for developing T cells involves and other complement components (approximately downregulating signals that would otherwise induce 30 different proteins) that produce the membrane apoptosis if auto-reactivity occurs, resulting in

Evolutionary Medicine, Immunity, and Infectious Disease 463 tolerance of self-antigens. Negative selection involves Thomson, 2001). The HLA superlocus is located on induction of apoptosis in T and B cells that autoreact chromosome 6 (Fischer and Mayr, 2001). with self-molecules on antigen-presenting cells Antibodies are glycoproteins that neutralize patho- (macrophages and interdigitizing denditic cells) in the gens and their products, block binding of parasites to thymus (Rathmell and Thompson, 1999; Sebzda et al., host cells, induce complement activation, promote cel- 1999). Without the ability to distinguish between lular migration to sites of infection, and enhance self and nonself tissues, immunopathology due to phagocytosis, among other actions. Antibodies in autoimmune disease would rampantly consume the mammals are composed of two light chains (with individual. The ontogeny of lymphocytes therefore single variable [V] and joining [J] elements) and two invokes Darwin’s principles of natural selection in evo- heavy chains (with single variable [V] and joining [J] lutionary processes that occur within an organism. elements, and multiple diversity [D] elements) bound The development of the immune system begins together by disulfide bonds (Edelman, 1973). The vari- early in gestation (Remington and Klein, 1990). able end interacts with antigens whereas the constant Acquired immunological characteristics (particularly region determines the class and subclass of antibody: immunoglobulins G and A) are transferred from IgG, IgM, IgA, IgD, and IgE. In general, IgG is the most mother to offspring via the placenta and breast milk predominant in circulation and some of its functions (Keller, 1992; Goldman, 1993). As offspring encounter include opsonization of bacteria and infected cells, new antigens, as many as 10 million different lympho- activation of the complement cascade and antibody- cytes react to these antigens to cause subsequent dependent cellular cytotoxicity. Immunoglobulin proliferation of particular lymphocytes lineages. The M activates the complement cascade and is the first entire process of antigen recognition and lymphocyte antibody produced during a response. Immunoglobu- activation and proliferation is known as “clonal selec- lin A protects mucosal surfaces from infection. tion.” Clonal selection for lymphocytes is a process of Immunoglobulin E mediates allergic reactions (imme- somatic evolution in which antigen receptor diversity diate-type hypersensitivity) and functions to clear is maximized during a critical stage of development extracellular helminth infections. The functions of the when offspring are continuously encountering new secreted form (nonmembrane bound) of IgD are not infections. The process of clonal selection produces a yet known (Wallace Taylor, 2002). diverse pool of lymphocytes with millions of different The variable region of the antibody, produced by antigen-binding possibilities, all from simple progeni- four bounded polypeptide chains, confers high specifi- tor cells (Burnet, 1959). Throughout this process, city for the target molecule, while the constant region thymus volume regresses, lymphocytes diversify, and of the antibody binds the appropriate immune effector immunoglobulin levels increase (Hannet et al., 1992; cells for activation. Genes for antigen-binding regions George and Ritter, 1996). Despite this so-called thymic on lymphocytes as well as antibodies themselves are involution, T cells still develop in this structure during randomly assorted from different gene segments or adult life (Jamieson et al., 1999). clusters (variable [V], diversity [D], joining [J] and constant [C]) on chromosomes 2, 14, and 22. This Antibody-mediated immunity random process is also susceptible to splicing errors B cells represent antibody-mediated (humoral) immu- and additional nucleotide insertions, and B cells can nity. Antigen recognition by lymphocytes promotes undergo further receptor editing in their V gene in cellular proliferation and the differentiation of B cells secondary lymphoid organs (Schatz et al., 1992; Radic into plasma cells, which secrete antibodies or “immu- and Zouali, 1996). The results are millions of different noglobulins,” and memory cells, which function in unique antibodies and antigen-binding sites on immunosurveillance. B cells have the capacity to bind lymphocytes (Tonegawa, 1983). In fact, this rearrange- “native” or free antigen. T cells, on the other hand, ment of mini-gene segments allows for much greater recognize “processed” antigen. Receptors on antigen- diversity in antigen binding (estimated 10 15 variable presenting cells (including dendritic cells and B cells) regions on T and B cells) than there are genes in the bind to antigens which are internalized, degraded, human body that could otherwise produce each indi- and presented onto the cell surface via major vidual antibody. histocompatibility complex (MHC; or human leuko- cyte antigen, HLA) class I (HLA-A, B, and C) and II Cellular-mediated immunity (HLA-DP, DQ, and DR) molecules. The MHC class I T cells represent cellular immunity, and different molecules present their antigens to killer T cells (CD8), subsets are identified by their surface markers that which initiate a cytotoxic response, whereas MHC regulate cellular activation and adhesion (CD number class II molecules present their antigens to helper refers to “cluster of differentiation”). Cytotoxic T cells T cells (CD4), which produce cytokines that facilitate (CD8) destroy infected host cells via perforin and lysis. the clonal expansion of other T and B cells (Meyer and Cytotoxic T cells and natural killer cells are particularly

464 Michael P. Muehlenbein important for eliminating intracellular pathogens allergens and pathogens may predispose individuals to (Berke, 1997). Suppressor T cells downregulate T-cell a dominant Th-2 response with high IgE levels and responses after infection (see below). subsequent allergies and asthma later in life (the Helper T cells (CD4) secrete cytokines and activate “hygiene hypothesis”) (Strachan, 1989; Cookson and B cells to secrete antibodies. Cytokines are glycopro- Moffatt, 1997; Matricardi et al., 2000; Wills-Karp teins that perform a variety of functions such as regu- et al., 2001; Yazdanbakhsh et al., 2002). Lack of per- lation of cell growth and development (Snapper, 1996). sistent exposure to allergens and pathogens may not Cytokines have several striking features; most import- allow for proper programming of an anti-inflammatory antly, they perform pleiotropic actions and interact in regulatory response, such as IL-10 production (Wills- different complex ways with each another. Cytokines Karp et al., 2001). In fact, nematode infection is asso- have pleiotropic, redundant, and epistatic (synergistic ciated with fewer allergies and less asthma in some and antagonistic) actions. That is, single cytokines can populations (Wilson and Maizels, 2004). Improve- have multiple functions, multiple cytokines can have ments in sanitation may therefore explain the dispro- similar functions, some cytokines work together to portionate increase in asthma morbidity and mortality facilitate single functions, and some cytokines have over the past 25 years, despite improvements in opposite functions to one another. There may even be medications (Von Mutius et al., 1992; Braun-Fahrlander significant heritable variation in cytokine levels et al., 1999; Yazdanbakhsh et al., 2002). Clearly, early (Williams-Blangero et al., 2004; Curran et al., 2005). life events produce various physiological effects in CD4 helper T cells are generally differentiated into later adulthood (Barker et al., 2002; Barker, 2007). two major subsets depending on the type of cytokine Childhood environments likely program the develop- produced: type 1 (Th-1) and type 2 (Th-2) phenotypes ment of immune responses, and differences in local (Mosmann et al., 1986; Mosmann and Coffman, disease exposure can explain differences in immune 1989a, 1989b; Mosmann, 1991a, 1991b; Coffman and development between populations (Mohammed et al., Mosmann, 1991; O’Garra 1998; Reiner and Seder, 1973; Lisse et al., 1997; McDade et al., 2004). 1999). Th-1 cytokines include, among others, inter- Other Th cell types include Th-17 cells that produce feron-gamma (IFN-g), tumor necrosis factor-alpha IL-17, IL-6, and related cytokines, and Tregs, or induced and -beta (TNF-a,-b), and various interleukins (IL-1b, regulatory T cells, that express Foxp3 (a forkhead IL-2, IL-3, IL-12, etc.). These cytokines activate macro- winged-helix transcription factor). The absence of Tregs phages, neutrophils and natural killer (NK) cells, medi- has been implicated in autoimmune diseases like inflam- þ ate inflammatory responses and cellular immunity matory bowel disease (Shevach, 2008). The CD25 CD4 þ (T cells), promote cytotoxicity toward tumor cells, Tregs produce IL-10 and transforming growth factor and enhance chemotaxis of leukocytes (Kobayashi beta (TGF-b) and are important for mucosal immunity et al., 1989; Gazzinelli et al., 1993; Dinarello, 2000; (Kiyono et al., 2008). Th-3 (which produces high levels þ Burger and Dayer, 2002; Trinchieri, 2003). of TGF-b), Tr1 and CD8 CD28 suppressor T cells are The Th-2, anti-inflammatory cytokines include other subsets of suppressor T cells that may be different many interleukins (IL-4, IL-5, IL-10, etc.) that induce from Tregs (Kiyono et al., 2008). humoral immunity and antibody production (B cells), eosinophil activation, mast cell degranulation, goblet Comparative aspects cell hyperplasia, mucin production, and intestinal mas- tocytosis (resulting in histamine release). This cytokine Susceptibility to host infection depends on many phenotype is important for protection against intes- factors, including whether or not the pathogen has tinal infections as well as the facilitation of allergic been encountered before, inducing acquired immun- reactions (Barrett et al., 1988; Rothwell, 1989; Cox ity. Nutritional status also plays an important role and Liew, 1992; King and Nutman, 1992; Sher and since immune responses generate significant energetic Coffman, 1992; Urban et al., 1992; Allen and Maizels, burdens (see below). Genetic predisposition also 1996; Else and Finkelman, 1998; Dinarello, 2000; accounts for differences in disease outcome in various MacDonald et al., 2002). Despite the fact that Th-1 species. There is an incredible amount of polymorph- and Th-2 cytokines act antagonistically to one another, ism in the genes that code for immune responses both are usually present within the host at any given (Trowsdale and Parham, 2004). Several HLA alleles time, although during infection one phenotype usually have been associated with resistance and susceptibility predominates. to a variety of diseases, including malaria, tubercu- Newborn humans tend to have a dominant Th-2 losis, and HIV (Hill, 1998). There is also population phenotype, whereas the Th-1 phenotype develops later variation in the alleles that code for Toll-like receptors with age (Jones et al., 2000). In the absence of a bal- on the surfaces of leukocytes that bind to antigens and anced helper T cell phenotype, atopic disease can trigger important innate inflammatory responses become more pronounced. Lack of early exposure to (Lazarus et al., 2002).

Evolutionary Medicine, Immunity, and Infectious Disease 465 The Sm1 locus on chromosome 5 hasbeen associated (Nonaka and Yoshizaki, 2004). However, adaptive with susceptibility to Schistosoma mansoni in Brazil- immunity with the ability to generate diverse antigen ian and Senegalese populations (Marquet et al., 1996), receptors on lymphocytes appears to have evolved only and Sm2 on chromosome 6 has been associated with in vertebrates. The adaptive immune system in verte- a high risk of liver fibrosis caused by S. mansoni in brates may have evolved in response to selection pres- a Sudanese population (Dessein et al., 1999). These sures by diverse parasitic flatworms, viruses, and alleles likely cause dysfunctions in cytokine and bacteria as well as longer life spans, higher metabolic lymphocyte proliferation responses to infection rates, and bigger genomes in the vertebrate hosts (Rolff, (Rodrigues et al., 1999). Research also suggests signifi- 2007). A more complex immune response may also have cant heritable variation in hookworm infection inten- been helpful in differentiating potential pathogens from sity in a Zimbabwe population (Williams-Blangero symbiotic microflora (Pancer and Cooper, 2006). et al., 1997) as well as heritable variation in Ascaris Within vertebrates, the process of producing the lumbricoides and Trichuris trichiura infection inten- lymphocyte receptor repertoire is different in the jawed sities in a Nepalese population (Williams-Blangero gnathostomes compared to the jawless agnathans, et al., 1999, 2002a). Several loci on chromosomes 1, 8, with conventional rearrangeable immunoglobulin 9, 11, 12, 13, and 18 may alter cytokine and immuno- gene segments in the former and rearrangement of globulin responses to these infection, resulting in leucine-rich repeat-encoding modules in the latter heritable variation in immune responses in these popu- (Flajnik and Kasahara, 2001; Pancer et al., 2004; Alder lations (Williams-Blangero et al., 2002b, 2008a, 2008b). et al., 2005; Cooper and Alder, 2006; Pancer and While there are certainly important genetic compon- Cooper, 2006). Jawed vertebrates adapting a predatory ents to variation in immune responses, even adaptive lifestyle may have needed more complex and robust ones, to human pathogens, the utility of heritability immune responses, particularly in their gastrointest- estimates obtained from studies not using monozygo- inal tracts (Matsunaga and Rhaman, 1998). In these tic twins is equivocal (Vitzthum, 2003). Several studies jawed vertebrates, the adaptive immune responses have reported no significant heritable variation in sus- likely evolved when a transposable element (mobile ceptibility to Schistosoma haematobium in a Kenyan DNA) produced an immunoglobulin-like gene (RAGs, population (King et al., 2004) or in infection intensity recombination activating genes). The transposon from Strongyloides fuelleborni in a population of Papua inserted itself into an Ig superfamily (IgSF) gene of New Guinea (Smith et al., 1991). the variable (V) type, leaving behind the machinery Despite these disagreements, it is well accepted that for the original receptor gene to cut and past independ- all organisms (examined to date) have some immune ent loci which allowed for somatic gene rearrangement responses, including phagocytic abilities and the abil- for the various V(D)J mini-gene combinations (Agra- ity to recognize self from nonself. Notwithstanding wal et al., 1998; Fugmann et al., 2000). The results are these similarities, there is extraordinary variation in the production of highly polymorphic combinations of the immune responses within the Animal Kingdom a/b- and g/d-chains of T-cell antigen receptors and the (Flajnik and du Pasquier, 2004). Invertebrate immun- heavy/light chains of immunoglobulin B-cell receptors. ity closely resembles innate immunity in vertebrates This mechanism is estimated to have evolved more (Hoffmann and Reichhart, 2002). Phagocytic cells cir- than 500 million years ago (Flajnik, 2002). culate in the hemolymph and encapsulate pathogens. Immune responses within all jawed vertebrates Lectins opsonize foreign antigens and interference appear to be rather conserved, with significant homo- RNA (RNAi) inhibits viral gene function. Proteins, such geneity in the defense mechanisms of different species as fibrinogen-related proteins (FREPs) in the snail (Marchalonis and Schluter, 1994; Litman et al., 2005). Biomphalaria glabrata and the products of Down’s syn- In fact, there are very few biochemical and genetic drome cell-adhesions molecule (DSCAM) genes in differences in the immune systems of humans and Drosophila melanogaster, bind invading molecules common chimpanzees (Muchmore, 2001). This is in (Adema et al., 1997; Yu and Kanost, 2002; Meister, spite of the fact that chimpanzees are less susceptible 2004; Loker et al., 2004). to some infections, like immunodeficiency virus, and Plants exhibit hypersensitivity responses that cause more susceptible to others, like pneumonia. The com- cellular apoptosis and exhibit characteristics of local- parative study of primate immunology will prove quite ized and systemic acquired resistance via antimicro- insightful for human evolutionary biologists. bial peptides and pathogen-associated molecular patterns (PAMPs) (Dangl and Jones, 2001; Innes, 2004; Evolutionary and ecological immunology Chisholm et al., 2006). Some aspects of the complement system (like the C3 component) are shared between Research on immunological stress has traditionally vertebrates, invertebrate deuterostomes (e.g., sea focused primarily on understanding somatic mainten- urchins), and even some protostomes (e.g., nematodes) ance, repair, and defense against pathogens. From an

466 Michael P. Muehlenbein evolutionary perspective, immune functions are critical (Rosenberg and Bowman, 1984; Hadju et al., 1995; for maximizing survivorship, and an optimized imm- Kramer et al., 1997; Klasing, 1998; Shephard et al., une system should always be highly selected for. 1998; Lin et al., 1998; Koski et al., 1999; Ing et al., Immune functions have therefore played important 2000). In turn, acute infection in adult humans can roles in the evolution of organismal life histories. Life cause high amount of protein loss, greater than 1 g/kg history strategies are complex adaptations for survival of body weight per day (Scrimshaw, 1992). Strenuous and reproduction via the co-ordinated evolution of exercise or participation in energetically demanding somatic and reproductive developmental processes tasks, such as migration, breeding, or molting, can also (Stearns, 1992). There exists an enormous amount compromise immune functions (Nelson et al., 2002). of variation in organismal life history strategies, For example, increased brood size is associated with and much of the physiological variation between and reduced antibody response against Newcastle disease within organisms can be explained using several con- virus and increased Haemoproteus infection intensity cepts of life history theory, most notably trade-offs in collared flycatchers (Ficedula albicollis) (Nordling and reaction norms (Stearns, 1992; Ricklefs and et al., 1998), reduced antibody response against sheep Wikelski, 2002). red blood cells in zebra finches (Taeniopygia guttata) (Deerenberg et al., 1997) and female tree swallows Immunity as an evolved reaction norm (Tachycineta bicolor) (Ardia et al., 2003), and increased Both somatic and reproductive physiologies are prevalence of Plasmodium in male great tits (Parus evolved response systems, shaped by natural and major) (Richner et al., 1995). sexual selections to adapt individuals to changing Metabolic rate, oxygen consumption and thermo- environments. This allows for a variable physiological genic activity also frequently increase following response (a “reaction norm”) in which a genotype can immune stimulation (Newsholme and Newsholme, produce a range of phenotypes (through short-term 1989; Spurlock, 1997; Lockmiller and Deerenberg, changes, such as acclimatization to altitude, and 2000). For example, house mice (Mus musculus) long-term adaptations) depending on environmental injected with the antigen keyhole limpet hemocyanin conditions. However, this phenotypic plasticity is show a 20–30% increase in oxygen consumption limited through lineage-specific effects (or the canal- (Demas et al., 1997). Likewise, blue tits (Parus caeru- ization of certain traits) as well as trade-offs. Assuming leus) immunized with diptheria-tetanus vaccine a limited supply of energy and time, organisms are exhibit an 8–13% increase in resting metabolic rate required to allocate physiological resources between a (Svensson et al., 1998), and great tits (Parus major) number of competing functions, particularly reproduc- and collared doves (Streptopelia decaocto) injected with tion, maintenance (i.e., survival) and growth (Stearns, sheep red blood cells exhibit a 9% increase in resting 1989). Organisms will therefore be under selection to metabolic rate (Ots et al., 2001; Eraud et al., 2005). In develop and maintain physiological systems that allow humans, fever typically results in a 7–15% increase in for the efficient regulation of resources between these resting metabolic rate for every 1 C rise in body tem- functions. In a stochastic environment, those organ- perature (Barr et al., 1922; Roe and Kinney, 1965; Elia, isms that can most efficiently regulate the allocation 1992). In a population of 25 adult male college students of resources between competing traits will likely sampled during and after acute upper respiratory tract exhibit increased lifetime reproductive success. infection, resting metabolic rate was, on average, 8% An individual’s immune system is an excellent higher during infection compared to samples taken example of a reaction norm that allows for short- and after complete recovery (Muehlenbein, 2008b). It is long-term phenotypic plasticity in response to environ- interesting that these metabolic values were elevated mental signals such as pathogens, allergens, and even in the absence of fever, likely reflecting increased injury. Immunocompetence, or the ability to mount energetic demands despite mild infection. Further an effective immune response, is an integral compon- research should investigate changes in metabolic rates ent of organismal life histories precisely because: (1) it of adult humans during illnesses of varying severities is crucial for maximizing evolutionary fitness; and and in individuals with different states of energy (2) it is energetically expensive to produce, maintain, balance. and activate. This important function can be character- ized as an energetic burden subject to allocation mech- Trade-offs with immunity anisms (Sheldon and Verhulst, 1996; Demas et al., 1997; “Every trait must be analyzed in terms of the costs and Raberg et al., 1998, 2002; Verhulst et al., 1999; benefits of the trade-offs in which it is involved” Owens, 2002; Schmid-Hempel, 2003; Muehlenbein and (Stearns et al., 2008, p. 11). As immune responses are Bribiescas, 2005; Muehlenbein, 2008a). For example, energetically expensive, optimized immune functions prolonged energy restriction can lead to immune sup- should trade-off with other critical life history func- pression in humans and nonhuman animals alike tions, like growth. Nutrient deficiencies can have

Evolutionary Medicine, Immunity, and Infectious Disease 467 significant, long-term negative effects on the human captive male macaques (Macaca fasicularis) is associ- immune system (Lunn, 1991; Gershwin et al., 2000), ated with significant declines in serum testosterone and these effects may begin early in life. For example, levels (Muehlenbein et al., 2006). Hypogonadism has infants in the Philippines born small-for-gestational also been reported in association with African sleeping age exhibit slower growth rates and produce less thy- sickness (Trypanosoma brucei) (Reincke et al., 1998), mopoietin as adolescents (McDade et al., 2001b). These toxoplasmosis (Toxoplasma gondii) (Oktenli et al., individuals are also less likely to produce antibodies in 2004), schistosomiasis (Schistosoma mansoni) (Saad response to typhoid vaccination (McDade et al., 2001a). et al., 1999), and filarial infection (Loa loa and Manso- Elevated concentrations of a-1 antichymotrypsin (an nella perstans) (Landsoud-Soukate et al., 1989). acute phase protein produced by the liver during Changes in testosterone levels throughout the range inflammation) are also associated with growth faltering of physiological variation may function as a basic (lower height-for-age) in Nepalese adolescents (Panter- aspect of male phenotypic plasticity and an adaptive Brick et al., 2000). Activation of proinflammatory response that facilitates the allocation of metabolic immune responses (as in the case of inflammatory resources according to available energy and disease bowel disease) is associated with delayed puberty in risk in a stochastic environment. Assuming testoster- even adequately nourished individuals (Ballinger one’s immunomodulatory actions are primarily sup- et al., 2003), and elevated C-reactive protein levels are pressive (for review see Muehlenbein and Bribiescas, associated with reduced gains in height across three 2005), depressed testosterone levels during illness or months in Tsimane children of Amazonian Bolivia injury could function to prevent immunosuppression (McDade et al., 2008). Continued work on comparative by otherwise higher testosterone levels (Wedekind developmental immunology within and between and Folstad, 1994). In addition, depressed testoster- populations will prove interesting. This will include one levels could function to limit metabolic invest- continued efforts to qualify and quantify trade-offs ment in energetically expensive anabolic functions between immunity and reproductive effort. (Muehlenbein, 2008a). Optimization of reproductive effort is of central Testosterone increases energetic costs through importance, especially for capital breeding, iteropar- direct actions on muscle tissue and metabolism ous organisms that must budget time and stored (Welle et al., 1992; Bhasin et al., 1996), and this may energy over a number of reproductive events within decrease survivorship in resource-limited environ- a lifetime. Under conditions of resource restriction, a ments (Ketterson et al., 1992; Bribiescas, 2001). The trade-off between current and future reproduction is problem would become exacerbated in pathogen-rich predicted: investments in current reproductive events environments because of the immunosuppressive may negatively affect future reproductive returns (the actions of testosterone and because investment in “cost of reproduction” argument). Investments in muscle anabolism generates a significant energetic reproduction should also compromise survivorship demand that will theoretically trade-off with the com- through depressed immune functions. Conversely, peting energetic demands of immunocompetence. An investment in immune activation should compromise evolutionary and ecological perspective on immunity reproductive effort. In mosquitoes (Anopheles gam- would suggest that natural and sexual selections favor biae), injection with lipopolysaccharide is associated individuals that can best balance the trade-offs so as to with reduced egg production (Ahmed and Hurd, maximize reproductive effort and survivorship (i.e., 2006). Deerenberg et al. (1997) have shown that only immunity) given different ecological conditions. In 47% of breeding zebra finches (Taeniopygia guttata) lower pathogen-risk environments (e.g., higher lati- produced antibodies in response to infection with tudes), less of a premium may be placed on immunity, sheep red blood cells whereas all nonbreeding birds and it may pay to select for less robust immune produced antibodies. responses (Muehlenbein, 2008a). In humans, hypogonadism (decreased levels of hor- mones from the testes or ovaries) and hypogonadotrop- Immunity and mate choice ism (decreased levels of gonadotropins from the It is also predicted that individuals should develop hypothalamus and pituitary glands) are common honest signals of survivorship (i.e., immunocompe- physiological responses to somatic injury. For example, tence) in an effort to maximize mate choice (Zahavi, in men, serum testosterone decreases during sepsis, 1975; Hamilton and Zuk, 1982). Animals should be burns, myocardial infarction, and surgery (Spratt under selective pressure to evolve preferences for those et al., 1993; Spratt, 2001). Honduran men infected mates that possess reliable indicators of pathogen with Plasmodium vivax exhibit significantly lower tes- resistance by scrutinizing characteristics that honestly tosterone levels than age-matched healthy controls reflect health or the ability to resist pathogens. (Muehlenbein et al., 2005). Similarly, experimental A number of morphological and behavioral char- Venezuelan Equine Encephalitis virus infection in acteristics appear to be honest sexual signals of

468 Michael P. Muehlenbein immunocompetence in avian and other species. For (1632–1723), Ignaz Philipp Semmelweis (1818–1865), example, tail length was positively associated with and John Snow (1813–1858) (see Kiple, 1993, 2003; cell-mediated immune function in male barn swallows Porter, 2001, 2006). The actual germ theory of disease (Hirundo rustica) (Saino et al., 2002). Male barn swal- is attributed to Agostino Bassi (1773–1856) and Louis lows with longer outermost tail feathers also exhibited Pasteur (1822–1895) (see Kiple, 1993, 2003; Porter, stronger primary antibody responses following an 2001, 2006). Pasteur demonstrated that microorgan- immunization (Saino et al., 2003b), had higher testos- isms do not arise spontaneously, but are the products terone levels (Saino and Moller, 1994), and were pre- of reproduction by existing microorganisms. Around ferred by females, both as social mates and extrapair the same time, Heinrich Hermann Robert Koch copulation partners (Saino et al., 1999). Fluctuating (1843–1910), along with his mentor Friedrich Gustav asymmetry of antlers in male reindeer (Rangifer taran- Jakob Henle (1809–1885) and associate Friedrich dus) was associated with immune parameters during August Johannes Loeffler (1852–1915), provided the the rut, suggesting that low fluctuating asymmetry in scientific community with the “postulates” or experi- sexually selected ornaments may also signal the ability mental criteria to establish a causal relationship to resist parasites (Lagesen and Folstad, 1998). between these microorganisms and disease (see Kiple, Some primates may exhibit signals that honestly 1993, 2003; Porter, 2001, 2006). In brief, the agent or indicate health and survivability, such as coloration microorganism must be found in all cases of the dis- in the facial, scrotal, and perianal regions. Examples eased, but not healthy, hosts. The organism must be may include sexual colorations in adult male vervet isolated from diseased hosts and cultured. Inoculation monkeys (Cercopithecus aethiops sabaeus) (Gerald, of the culture into susceptible, healthy hosts must 2001) and mandrills (Mandrillus sphinx) (Setchell and reproduce the disease, and the agent must be reisolated Dixson, 2001). However, there have been no published from the newly infected host. This form of deductive studies to date that have investigated relationships reasoning, although criticized by many, uses observ- between immunocompetence and degree of sexual col- able, empirical evidence to test hypotheses about the oration in primates. For humans, muscle mass may be cause of infectious disease. an honest indicator of survivorship due to the signifi- Infectious organisms include thousands of species cant costs of anabolic steroids, including increased of viruses (and bacteriophages), bacteria (including energetic costs and the risk of negative energy balance, rickettsiae), parasitic protozoa and helminthes (nema- increased risk of prostate cancer, production of oxygen todes, cestodes, and trematodes), and fungi. These radicals, increased risk of injury due to hormonally parasitic organisms live all or part of their lives in or augmented behaviors such as aggression, violence, on a host from which biological necessities are derived. and risk taking, reduced tissue (especially adipose) This state of metabolic dependence usually results in and organ maintenance, and suppression of immune host energy loss, lowered survival, and reduced repro- functions (Muehlenbein and Bribiescas, 2005; ductive potential. Disease or illness is the impairment Muehlenbein 2008a). It may also be the case that of host body function done by a pathogen. morphological symmetry is a potential indicator of There is fantastic variation in the transmission immunological status in humans. Morphologically dynamics of infectious (communicable) organisms symmetric humans are frequently judged as more (Anderson and May, 1992; Combes, 2004; Poulin, attractive and are preferred as potential mates 2006). The primary infection transmission routes (Grammer and Thornhill, 1994; Gangestad and Thorn- include fecal-oral (ingestion of contaminated food, hill, 1998; Perrett et al., 1998). More research should water, or other objects), respiratory, vector-borne clearly be conducted with humans in this area, particu- (e.g., mosquitoes, ticks, flies, etc.), blood-borne, sexu- larly given the interesting sexual selection behaviors ally transmitted, vertical transmission (congenital; that humans use and the myriad of pathogens that mother to offspring), and nosocomial (hospital- can infect us. acquired). Zoonotic infections are those acquired from nonhuman animals. A reservoir is the biotic or abiotic source where a pathogen normally lives and repro- INFECTIOUS DISEASE duces. Latency is the period of inactivity of the patho- gen inside the host, or the period between initial host The initial description that diseases have natural rather infection and the subsequent ability of the infected than supernatural causes is attributed to Hippocrates host to infect new hosts. The incubation period is the of Cos (460–370 BC). However, several others further interval between initial infection and onset of clinical developed the concept of “contagion,” including illness (with signs and symptoms). This period can Marcus Terentius Varro (116–27 BC), Abu¯ Alı¯ ibn vary depending on dose of exposure, host susceptibil- Sı¯na (980–1037), Girolamo Fracastoro (1478–1553) ity, pathogenicity of the infectious agent, and other Francesco Redi (1626–1697), Anton van Leeuwenhoek factors. A carrier is an infected host that does not

Evolutionary Medicine, Immunity, and Infectious Disease 469 present any signs or symptoms of infection, but is still bacteria or transduction from bacteriophages, sexual capable of infecting other hosts. reproduction in malaria, etc.). Coevolution of organ- Epidemiology is the study of the distribution (fre- isms, and the conflict that often ensues, provides sig- quency and pattern) and determinants (etiology) of nificant selection pressure for the evolution of traits, health-related events within populations. Endemic dis- and understanding this can assist in the explanation of eases are those that occur regularly at low to moderate health-related traits. Understanding the conflicts frequency, epidemics are outbreaks that occur above between hosts and pathogens can aid in our under- endemic levels, and pandemics are epidemics that standing of why antibiotic resistance evolves and why affect a large proportion of the world’s population. some diseases are very deadly and others less so. Specifics of transmission dynamics, epidemiologic study designs, and how health-related conditions are Virulence and antibiotic resistance specifically associated with exposures will not be dis- cussed here (see Sattenspiel, 2000, for an introduction The traditional view of host–pathogen coevolution sug- to epidemiologic study designs). gested that evolutionary processes should theoretically lead to reduced antagonism or symbiosis since this would be in the best interest for both the pathogen Coevolution and host (Smith, 1934; Swellengrebel, 1940; Allee Infectious organisms offer a near-ubiquitous selective et al., 1949). Longer coexistence between hosts and evolutionary force (Levin, 1996). Many of these patho- pathogens would theoretically lead to attenuated infec- gens have infected humans and our hominin ancestors tions (Burnet and White, 1972). This “group selection- for a large part of our evolutionary history (Hoberg ist” reasoning implies some type of co-operation et al., 2001; Goncalves et al., 2003; Van Blerkom, between hosts and parasites. However, a more modern 2003). For example, hominins have certainly been view is that natural selection will favor the increase of infected with herpesviruses for millions of years fitness in both hosts and parasites, which may not lead (Sharp et al., 2008). Helicobacter pylori has likely to obligate evolution towards benign interactions. infected humans for as much as 60 000 years (Linz Virulent pathogens are characterized by high levels et al., 2007), and Salmonella typhi, the causative agent of host exploitation, producing high morbidity and of typhoid fever, has likely affected humans for 30 000 mortality. Virulence can evolve when the benefits of years (Roumagnac et al., 2006). host exploitation are outweighed by the costs to the Conflict between organisms is ubiquitous, even pathogen from host damage (Galvani, 2003). High between parents and offspring (Trivers, 1974; Haig, virulence is more common when host immobility does 1993). Just as predators and prey coevolve in an escal- not disrupt pathogen transfer. Examples include ating cycle of complexity with predators’ improved vector-borne, water-borne, and nosocomial infections hunting techniques countered by prey’s improved in which intense host exploitation comes at little cost armor or defensive adaptations, hosts and parasites to the pathogen because it is not dependent on host must evolve in order to maintain current levels of adap- mobility for transmission to new hosts (Ewald, 1996). tation (Dawkins and Krebs, 1978). Hosts and patho- Such is the case for malaria and cholera. Infectious gens coevolve together in a constant state of flux, with organisms that can survive in the external environment reciprocal modification of evolutionary strategies pro- for lengthy periods of time also often evolve high levels ducing evolutionary change in host traits in response of virulence, as is the case of anthrax (Walther and to evolutionary change in pathogen traits, and vice Ewald, 2004). Vertical transmission (mother to off- versa (Thompson, 1994). The result is oscillations in spring) is more often associated with less virulent infec- levels of host resistance and pathogen invasiveness, tions because the well-being of both the host and parasite and a subsequent arms race of specializations over time. are linked (Bull et al., 1991; Messenger et al., 1999). The struggle for existence does not get easier, not New, accidental infections in dead-end hosts may matter how well a species may adapt to its current result in high virulence, as in the case of rabies (Ebert environment because competitors and enemies are and Bull, 2008). Colonization of a new host population also adjusting, causing significant change in the adap- following successful host switching may also be asso- tive landscape (the “Red Queen hypothesis,” Van ciated with initial increases in virulence. Level of Valen, 1973). Sexual reproduction may have evolved pathogen virulence may also be a function of host specifically as a mechanism to combat against high recovery rate, the geographic and temporal distribu- pathogen evolutionary rates and infectious disease tion of the host population, and even host age (Koella potential (Howard and Lively, 1994). However, host and Turner, 2008). Pathogen–pathogen competition recombination is often met with genetic recombin- over host resources also plays an important role ation in pathogens (e.g., recombination and mutation, (Nowak and May, 1994). Within the host, pathogens lateral gene combination via conjugation between must evolve strategies to either coexist or outcompete

470 Michael P. Muehlenbein 27.2. Modes of antibiotic resistance. Bacteria can ‘eject’ (a), degrade (b), or even inactivate (c) antibiotics. Figure Antibiotic- reprinted with permission from Laurie Grace. resistance Antibiotic- genes efflux pump Antibiotic- degrading enzyme a b Antibiotic c Plasmid Antibiotic Antibiotic- altering Bacterial enzyme Antibiotic cell Chromosome other members of its own or separate species (Kim, High pathogen variability within hosts can also 1985). If within-host genetic relatedness of such patho- contribute to antibiotic resistance. Antibiotics are che- gens is great, the likelihood of evolution towards aviru- motherapeutic substances that kill or inhibit bacterial lence is increased as these pathogens should tend to growth by disrupting cell wall, nucleic acid and protein “co-operate” with each other, analogous to “kin selec- synthesis, and altering metabolic pathways and cell tion.” Alternatively, high within-host genetic related- membrane integrity (Levy, 1998). Broad-spectrum ness of pathogens may lead to increased virulence via antibiotics, like tetracyclines, are useful in controlling kin selection if the benefits associated with increased several types of bacteria, like chlamydias, rickettsias, virulence are shared across the pathogen population gram-positive and gram-negative bacteria. They are (Ewald and Cochran, 2004). often used before the pathogens are identified or anti- In contrast, high within-host genetic variability biotic susceptibility has been tested for. However, they could favor increased competition with an escalation are also more likely to negatively affect normal flora in towards high virulence. A more exploitive variant of a the body. pathogen may be more successful at reproduction, Pathogens previously susceptible to antimicrobials further increasing within-host pathogen genetic vari- are becoming increasingly resistant. The antibacterial ability and favoring parasite–parasite competition effects of penicillin, a b-lactam derived from Penicil- (between different strains or species) and increased lium mold, were described by John Tyndall (1820– virulence. One example is the high virulent outcomes 1893), Ernest Duchesne (1874–1912), Clodomiro during coinfection with multiple malaria strains Picado Twight (1887–1944), and Alexander Fleming (Conway et al., 1991). (1881–1955). Within a very short time of penicillin’s Imperfect vaccines designed to limit pathogen mass production and clinical use, resistant strains of growth and toxicity could contribute to increased Staphylococcus aureus were identified (Spink and pathogen virulence (Gandon et al., 2001; Mackinnon Ferris, 1945). Now over half of all such strains are et al., 2008). A host population imperfectly protected resistant to penicillin and its derivatives (Chambers, against morbidity and mortality could generate selec- 1997). Microbes are accomplishing resistance by tion pressure for the evolution of more virulent blocking entry of antimicrobials into cells or removing organisms. Such strains could develop to increase (drug efflux), degrading or otherwise altering the anti- competitive advantage over other strains during coin- microbials (Figure 27.2). This does occur naturally, but fection as well as increase the likelihood of successful humans have facilitated these processes by inappropri- transmission, assuming transmission is still possible ate use of antimicrobials through self-medication, lack from vaccinated hosts. This would place the unvaccin- of patient compliance (i.e., premature termination of ated host population at increased risk of death and treatments), demands on physicians to over-prescribe, disability from the new dangerous strains. and overuse in livestock (Austin et al., 1999). Millions

Evolutionary Medicine, Immunity, and Infectious Disease 471 of kilograms of antibiotics are produced per year, and worldwide prevalence (number of total cases) as great the majority of them are used in livestock (Mellon as two billion people, resulting in as many as three et al., 2001). million human fatalities annually (Bloom and Murray, Random mutations, recombination, reassortment, 1992). The highest incidence (number of new cases and lateral gene transfer (including transduction from within a given time period) of tuberculosis are pres- bacteriophages, uptake of naked DNA and transpo- ently in India, China, Indonesia, Bangladesh, Pakistan, sons, and conjugation or plasmid exchange between and several countries in Africa (Dye et al., 1999). Use bacteria) can all produce resistant microbes (Levy, of the Bacille Calmette-Gue ´rin (BCG) vaccine is 1998; Lipsitch, 2001; Levy and Marshall, 2004). The widespread, but of limited efficacy in adults (Ellner, selection pressures we impose on them provides ample 1997). Rifamycin-, isoniazid- and multidrug-resistant impetus for rapid evolution and proliferation of resist- strains have evolved and spread rapidly (Drobniewski ant species. Fortunately not all pathogen populations et al., 2002). develop resistance because resistant bacteria appear to Tuberculosis infection is spread via the inhalation compete poorly against sensitive bacteria in the of infected respiratory secretions. Macrophages absence of antibiotics, possibly because of energetic attempt to phagocytose, and then kill via reactive costs associated with carrying nonessential plasmids oxygen and nitrogen intermediates, the tubercle bacilli (Courvalin, 2008). Future chemotherapeutic agents following inhalation. Those mycobacteria which will benefit from directing actions towards virulent escape this destruction will trigger a proinflammatory pathogens, making them less competitive against cellular immune response (effector T cells with subse- benign counterparts. Simultaneous treatment with quent production of proinflammatory cytokines, like several different antibiotics also creates a more hetero- TNF-a, IL-12, and IFN-g), which are vital for control- geneous environment for bacterial populations to over- ling infection (Lenzini et al., 1977; Havlir et al., 1991; come (Bergstrom et al., 2004). Ellner, 1997; van Crevel et al., 2002). The active form of vitamin D (1,25 dihydrocholecalciferol) impairs growth of M. tuberculosis inside activated macro- Case studies in human evolutionary biology phages (Rook, 1988). Vitamin D deficiency, even due I conclude this chapter with detailed accounts from to seasonal variation in food resources, may therefore three of the most notable bacterial, viral, and proto- increase the risk of disease from tuberculosis (Douglas zoan pathogens in humans: tuberculosis, human et al., 1996; Wilkinson et al., 2000). immunodeficiency virus (HIV), and malaria. Each has In most people, infection becomes stabilized as a its own unique evolutionary history and all offer solid fibrous granuloma inhibits further growth of the insight into human–pathogen coevolution. Finally, pathogen. However, diminished Th-1 proinflammatory emerging infectious diseases, their causes, and conse- cytokine responses, caused in part by the overproduc- quences are considered so as to illustrate the import- tion of TGF-b (Toossi et al., 1995), can result in hema- ance of identifying cultural as well as biological togenous dissemination and spread of infection adaptations against human disease. throughout the lungs and other tissues (van Crevel et al., 2002). Slow progression of disease is an excellent Tuberculosis mechanism by which the likelihood of transmission to Tuberculosis is caused by one of several bacteria of the susceptible hosts is increased. The mycobacteria can genus Mycobacterium. These gram-positive bacteria exist within the phagosomes of macrophages in human are aerobic, nonmotile, and posses a thick hydrophobic lungs for years. cell wall. The Mycobacterium “complex” includes People can exhibit a wide spectrum of immune M. tuberculosis, M. africanum and M. canettii of humans, responses to tuberculosis infection (Lenzini et al., M. microti of rodents, M. caprae of various mammals 1977), and not surprisingly resistance and susceptibil- (including humans), M. pinnipedii of seals, and M. bovis ity to infection has been associated with some genetic of bovine and many other mammalian species. Many polymorphisms, particularly in the human leukocyte other atypical species are found in soil, water, and other antigens that present mycobacterial proteins to effector animals (from fish to birds to monkeys), and several of cells (Goldfeld et al., 1998). The HLA-DQB1*0503 allele these species can cause disease in humans, particularly is significantly associated with susceptibility to clinical in immunocompromised individuals. The causative tuberculosis (Goldfeld et al., 1998) as are members of agent of leprosy (Mycobacterium leprae) naturally infects the HLA-DR2 serotype (Bothamley et al., 1989; Brahma- humans, chimpanzees, armadillos, and several species of jothi et al., 1991; Rani et al., 1993). Variants of the solute monkeys, but is only distantly genetically related to carrier family 11, member 1 gene (NRAMP1) have been tuberculosis (Grosskinsky et al., 1989). associated with susceptibility to tuberculosis in a var- Mycobacterium tuberculosis is one of the most iety of human populations, including Japanese and ubiquitous pathogens in humans, with an estimated West Africans (Bellamy et al., 1998; Gao et al., 2000).

472 Michael P. Muehlenbein Mutations in the Toll-interleukin-1 receptor domain and Toll-like receptor-2 genes are also associated with sever disease outcome (Hawn et al., 2006; Thuong et al., 2007). A single-point mutation in IFN-g receptor 1 gene is also associated with progressive infection due to downregulated cell-mediated inflammatory responses (Newport et al., 1996). There may be other genetic variants that affect susceptibility and resistance to tuberculosis. Mycobacteria have certainly been infecting human populations for a long time. The last common ancestor of all mycobacteria is estimated at 2.6–2.8 million years before present (Gutierrez et al. 2005). As there is rela- tively low variation in the housekeeping genes within M. tuberculosis, Sreevatsan et al. (1997) have con- cluded that the organism experienced an evolutionary bottleneck around 15 000–20 000 years before present. More sensitive analyses revealed genetic variation that allowed others to conclude that the M. africanum, M. microti, and M. bovis lineages likely diverged from the M. tuberculosis ancestor, not that M. tuberculosis evolved from M. bovis (Brosch et al., 2002). Mycobac- terium bovis was long considered ancestral to M. tuber- culosis because the former has a wide range of hosts, whereas the latter is human-specific (Cole et al., 1998). Genetic analyses now confirms the opposite, that M. tuberculosis is likely ancestral to the other members of the Mycobacterium complex. This complex was likely African in origin, and the youngest strains causing 27.3. A Pre-Columbian human specimen infected with tubercu- modern endemic human tuberculosis were introduced losis. The photograph shows a fused lumbar spine and sacrum into the various geographic regions. Mycobacterium from a 19–22-year-old human female recovered from the Middle bovis is actually the youngest of the complex species Mississippian Schild Cemetery, Greene County, Illinois, excav- ated by Gregory Perino in 1962. The specimen dates to 1020 AD (Smith et al., 2006). (110 years) and is genetically diagnosed with Mycobacterium Although many have argued against a bovine origin tuberculosis (Braun et al. 1998). Photograph courtesy of Della for M. tuberculosis (Mostowy et al., 2002), 20 000 years Cook. may not have been enough time for the diverse strains to develop in their respective hosts (Brosch et al., 2002). Others estimate the most recent last common geographically distinct. There is strong evidence for ancestor of the complex at around 35 000 years before phylogeographic relationships between these different present (Hughes et al., 2002). Mycobacterium canettii strains and their human hosts. For example, East Asian may have even diverged before this bottleneck individuals seem to be more susceptible to East (Gutierrez et al., 2005). Also prior to the bottleneck of Asian strains of the mycobacteria, even if the infection the complex members, M. tuberculosis likely acquired is acquired outside of East Asia, suggesting some coe- several virulence genes (e.g., Rv0986–8 that inhibit volution of the parasites with the hosts (Gagneux et al., macrophage functions) via horizontal transfer of a 2006). plasmid from a gammaproteobacterium donor species, like Agrobacterium (Rosas-Magallanes et al., 2006). Human immunodeficiency virus Several other virulence genes have now been identified Human immunodeficiency virus (HIV) is a double- in M. tuberculosis (Ernst et al., 2007). stranded RNA virus of the family Retroviridae, subfam- Tuberculosis certainly infected humans in North ily Lentivirus (see Hutchinson, 2001, and Rambaut America prior to European contact (Braun et al., et al., 2004, for review). Type 1 HIV (HIV-1) includes 1998) (Figure 27.3). Mycobacterium tuberculosis was groups N and O, found primarily in Gabon and Camer- present in North American bovids, including bison, oon, and the pandemic group M, for which there are bighorn sheep, and musk ox, at least 17 000 years eleven different subtypes or viral clusters (A–K). There before present (Rothschild et al., 2001). Presently, are eight subtypes (A–H) of HIV-2 which are mostly the various strains of M. tuberculosis are rather found in West Africa and India. Infection by HIV-2 is

Evolutionary Medicine, Immunity, and Infectious Disease 473 characterized by much slower disease progression compared to HIV-1 (Marlink et al., 1994). Transmission of HIV is through fluid exchange, primarily sexual contact, inoculation with blood or blood products, and perinatal transmission. Upon entry into the body, HIV’s envelope protein (gp120) binds to CD4 and chemokine coreceptors (e.g., CCR5 and CXCR4) on the surface of helper T cells. The virus fuses to the host cell surface and inserts its viral core. The viral genome is reverse transcribed and integrated into the host genomic DNA. Viral RNA is then tran- scribed, viral proteins are translated, viruses are assembled and bud from the infected cell (Rambaut et al., 2004). Due to the imperfect reverse transcription process, many errors accumulate, resulting in a mas- sive amount of HIV genetic diversity in a host at any 27.4. Chimpanzees are often used for bushmeat. Photograph courtesy of David Watts. given time (Rodrigo, 1999). Initial infection is followed by high viral replication and mild, ‘flu-like illness followed by an asymptomatic The source of HIV was not biological warfare or divine period of approximately 10 years. During this time, the retribution against this community. Rather, HIV ori- virus typically exhibits low replication rates and is ginated from nonhuman primate simian immunodefi- often sequestered out of peripheral circulation and into ciency viruses (SIV). Based on overwhelming genetic gut-associated lymphoid tissue (Chun et al., 2008). similarities (genome structure and protein homology), Acquired immune deficiency syndrome (AIDS) results HIV-1 groups M and N likely originated from chim- when the density of CD4 T cells drops below 200 cells panzees (Pan troglodytes troglodytes) in Cameroon per microliter of blood or when one of several indicator (Figure 27.4), and group O from Western lowland gor- conditions are present (e.g., Kaposi’s sarcoma, Bur- illas (Gorilla gorilla) in Cameroon. HIV-2 originated kitt’s lymphoma, infection with Toxoplasma, Pneumo- from sooty mangabeys (Cercocebus atys)inCote ˆ cystis, Cryptosporidium, Cytomegalovirus, etc.). Death d’Ivoire (Gao et al., 1999; Hahn et al., 2000; Peeters results from opportunistic infection, cancers, wasting, et al., 2002; Bailes et al., 2003; Apetrei et al., 2005; and neurological complications. Santiago et al., 2005; Keele et al., 2006; Van Heuverswyn The estimated global prevalence of HIV is approxi- et al., 2006). mately 33 million people with the highest prevalence There are currently 18 described strains of SIV rates are found in sub-Saharan Africa (Joint United found in 38 species of nonhuman primates, including National Programme on HIV/AIDS, 2008). Approxi- vervets, mangabeys, guenons, colobus, talapoins, man- mately 2.7 million people are infected each year, with drills, patas, baboons, chimpanzees, and gorillas (Gao approximately 2 million deaths annually. Within the et al., 1999; Hahn et al., 2000; Peeters et al., 2002; United States, the majority of those infected are young Bailes et al., 2003; Apetrei et al., 2005; Santiago et al., males (Hall et al., 2008). Although the majority of those 2005; Keele et al., 2006; Van Heuverswyn et al., 2006). infected in the United States are white non-Hispanics, Simian immunodeficiency viruses likely entered into death rates are highest in the non-Hispanic black the human population in West Africa due to cutaneous populations. However, life expectancy of HIV-infected or mucous membrane exposure to infected nonhuman individuals within the United States has generally primates. Direct exposure to nonhuman primate blood increased due to the use of highly active anti-retroviral through hunting and butchering is common (Wolfe therapy (HAART), which includes reverse transcriptase et al., 2004), and SIV has been identified in nonhuman blockers like azidothymidine (AZT), integrase blockers, primate bushmeat and pet animals in West Africa and protease inhibitors. Still the most effective means (Peeters et al., 2002; Apetrei et al., 2005). Simian at prevention is to eliminate high-risk behaviors. immunodeficiency viruses have also been reported in Because of the long latency period of infection, a sig- bushmeat hunters in Cameroon (Kalish et al., 2005). nificant proportion of infected individuals are unaware Through the hunting and butchering of nonhuman of their infection. Approximately one-quarter of all primates in West Africa, SIV likely entered into the those infected with HIV in the United States are human population many times and became estab- unaware of their HIV infection (Hall et al., 2008). lished within the human population as HIV around The modern HIV epidemic was first recognized as a 1900 in what is now the Democratic Republic of Congo cluster of Pneumocystis carinii pneumonia cases in (Worobey et al., 2008). Despite infecting humans for homosexual men in Los Angeles, California in 1981. only just over 100 years, several allelic variants appear

474 Michael P. Muehlenbein to provide protective responses against HIV infection. birds, and mammals (Garnham, 1966; Coatney et al., Historic selection pressure through high mortality 1971; Levine, 1988). Of these, only 4 naturally infect rates may account for the presence of these restriction humans (P. falciparum, vivax, ovale, and malariae), genes within human populations, but the influence of 19 infect nonhuman primates, and 19 infect various genetic drift and gene flow should not be discounted. other mammals. The majority of Plasmodium species Alterations in the morphology of the chemokine core- infect birds and reptiles. The parasites are transmitted ceptors that the virus uses to bind to and enter host by over fifty species of female Anopheles mosquitoes cells can confer resistance against HIV infection. Sev- (Kiszewski et al., 2004). During the Plasmodium life eral of these AIDS restriction genes that delay the onset cycle (Figure 27.5), sporozoites are injected from the of AIDS include CCR2-64I, HLA-B*27 and B*57 and mosquito’s salivary glands into the vertebrate host. The others (Dean et al., 2002; Winkler et al., 2004). Individ- sporozoites penetrate the parenchymal cells of the liver uals homozygous for CCR5-d32 can have complete where they remain for a variable period of time and resistance against infection (Zimmerman et al., 1997). asexually reproduce (“exo-erythrocytic schizogony”). The CCR5-d32 allele is found at high frequencies in Schizonts develop, which rupture to release merozoites many European populations (e.g., 15% in Scandinavia, into the vertebrate blood stream. These merozoites 5% in Italy) (Stephens et al., 1998). Galvani and Slatkin invade red blood cells (erythrocytes), in which they (2003) hypothesized that the huge amount of deaths develop into trophozoites, the form of the parasite that due to plague (Yersinia pestis) and smallpox (Variola essentially feeds off of the nutrient supply of the eryth- major) caused selection pressure to increase the fre- rocyte. The trophozoites undergo erythrocytic schizog- quency of the mutation. However, while there is evi- ony to produce either more merozoites (which reinfect dence that CCR5-deficient macrophages have reduced surrounding red blood cells) or the sexual gametocytes uptake of Y. pestis in vitro, the mutation appears to (macro and micro). The gameocytes are ingested by the have no protective effect in mice artificially infected Anopheles mosquito, after which they escape the eryth- with Y. pestis (Mecsas et al., 2004). Furthermore, rocyte (‘exflagellation’). Within the gut of the mosquito, recent data suggest that the CCR5 mutation is approxi- the male and female gametes fuse and form a fertilized mately 5000 years old, which predates the outbreaks of ookinete. The ookinete develops into an oocyst which is plague and smallpox in Europe (Duncan et al., 2005; implanted into the stomach wall of the mosquito. Hummel et al., 2005; Sabeti et al., 2005). With current There it undergoes sporogony. The oocyst eventually selection pressures, this HIV-resistance genotype may ruptures to release many sporozoites which migrate to increase to over 50% in South Africans within 100 the mosquito’s salivary glands. The sporozoites are years (Galvani and Slatkin, 2003). Such a change released into the vertebrate host during the next would not come without an evolutionary cost though: blood-meal (see http://www.dpd.cdc.gov/DPDx/HTML/ individuals homozygous for the CCR5-d32 allele are at malaria.htm). increased risk of fatal outcome from West Nile virus In humans, malaria causes ‘flu-like nausea with due to altered leukocyte trafficking to the brain (Glass headache and muscle pain. The parxoysms of fever et al., 2006). As discussed earlier, health-related adap- and shivering followed by sweating and fatigue corres- tations are constrained by trade-offs. pond with the length of shizogony and the synchron- ous rupture of schizonts: either every 48 hours (tertian: Malaria vivax, ovale, falciparum) or 72 hours (quartan: malar- Malaria is presently endemic in most tropical regions iae). Malaria can cause liver, spleen, and kidney failure, of the world, with approximately one billion people and cardiovascular and placental damage. Plasmodium at risk of acquiring malaria (Guerra et al., 2008). falciparum-infected red blood cells are capable of The global incidence is estimated to be more than adhering to one another, to noninfected cells, and to 300 million new clinical cases each year (Trigg and cerebral microvasculature, causing seizure and coma Kondrachine, 1998) with millions of deaths from mal- (Taylor et al., 2004). Immune responses include cell- aria annually, a majority occurring in children (World and antibody-mediated ones, with primary activation Health Organization, 1999). Five to ten percent of chil- of proinflammatory cytokines, including interleukin dren born in tropical Africa will likely die from malaria 12, TNF-a, and IFN-g (Stevenson and Riley, 2004). before the age of five (World Health Organization, Acquisition of effective immune responses to malaria 1999; Carter and Mendis, 2002). The economic and requires repeated exposure and inoculation (Carter social impacts of this disease are enormous (Gallup and Mendis, 2002). and Sachs, 2001). The evolutionary history of human malaria is an Malaria is a mosquito-borne disease caused by interesting one. These parasites are likely descended protozoa of the genus Plasmodium (phylum Apicom- from a coccidian ancestor that first parasitized the plexa, suborder Haemosporidiidea, family Plasmodii- intestinal tract of either a reptile host (Garnham, dae), with 172 named species that parasitize reptiles, 1966; Coatney et al., 1971) or aquatic invertebrate

Evolutionary Medicine, Immunity, and Infectious Disease 475 i =Infective stage d =Diagnostic stage Human liver stages Liver cell Infected liver cell Mosquito stages 2 Ruptured 12 1 i oocyst A Mosquito takes a blood meal Exo-erythrocytic cycle Release of (injects sporozoites) 11 Oocyst sporozoites i Ruptured schizont 4 3 Schizont C Sporogonic Cycle Human blood stages 5 Immature trophozoite 10 Ookinete 8 (ring stage) Mosquito takes d a blood meal (ingests gametocytes) Macrogametocyte B Erythrocytic cycle Mature d trophozoite Microgamete entering macrogamete 9 P.falciparum 6 Exflagellated Ruptured microgametocyte schizont Schizont d 7 Gametocytes d 7 P.vivax Gametocytes P.ovale P.malariae 27.5. Lifecycle of Plasmodium. The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host (1). Sporozoites infect liver cells (2) and mature into schizonts (3), which rupture and release merozoites (4). (Of note, in P. vivax and P. ovale a dormant stage [hypnozoites] can persist in the liver and cause relapses by invading the bloodstream weeks, or even years later.) After this initial replication in the liver (exo-erythrocytic schizogony [A]), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony [B]). Merozoites infect red blood cells (5). The ring stage trophozoites mature into schizonts, which rupture releasing merozoites (6). Some parasites differentiate into sexual eryth- rocytic stages (gametocytes) (7). Blood stage parasites are responsible for the clinical manifestations of the disease. The gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested by an Anopheles mosquito during a blood meal (8). The parasites’ multiplication in the mosquito is known as the sporogonic cycle [C]. While in the mosquito’s stomach, the microgametes penetrate the macrogametes generating zygotes (9). The zygotes in turn become motile and elong- ated (ookinetes) (10), which invade the midgut wall of the mosquito where they develop into oocysts (11). The oocysts grow, rupture, and release sporozoites (12), which make their way to the mosquito’s salivary glands. Inoculation of the sporozoites (1) into a new human host perpetuates the malaria life cycle. Figure and caption reprinted with permission from the US Centers for Disease Control and Prevention: http://www.cdc.gov/malaria/biology/life_cycle.htm. (Wilson and Williamson, 1997). Members of the genus Within the subgenus P. (Plasmodium), three malar- Plasmodium likely diverged from the other Haemos- ial parasites naturally infect humans: vivax, ovale, and poridiidea around 500 mya, perhaps around the time malariae. Plasmodium (Plasmodium) vivax (Grassi and of the Cambrian explosion (Escalante and Ayala, Feletti, 1890) is a malarial parasite with worldwide 1994). Biting dipteran insects were later introduced distribution (Mendis et al., 2001). It possesses a tertian into the parasite’s life cycle, possibly as early as 200 periodicity in which the process of schizogony lasts million years ago (Carter and Mendis, 2002). The Plas- approximately 48 hours. Because hypnozoites can modium radiation is thought to have occurred around remain dormant in the liver for years, relapse of illness 150 million years ago, which parallels the diversifica- can occur. A number of biomolecular investigations tion of their vector’s lineages (Escalante and Ayala, suggest that P. (Plasmodium) vivax is closely related to 1995; Ayala et al., 1998). P. (Plasmodium) cynomolgi of macaques (McCutchan

476 Michael P. Muehlenbein et al., 1984; White, 1993; Waters et al., 1993). There are The subgenus P. (Laverania) contains only two also a number of life history similarities between known species: P. (Laverania) falciparum (Welch, P. vivax and the other tertian primate malarias, includ- 1897) is the virulent tertian parasite which naturally ing P. schwetzi, P. cynomolgi, P. youngi, P. hylobati, infects humans; P. (Laverania) reichenowi (Sluiter P. pitheci, P. eyelesi, and P. jefferyi (Coatney et al., et al., 1922) is the chimpanzee and gorilla counterpart. 1971). Genetic evidence from the cicumsporozoite pro- The two species are diagnosed by the presence of ring- tein suggests that P. vivax evolved into P. simium in like trophozoites and crescentric gametocytes. Analysis South and Central American monkeys (Lim et al., 2005). of mitochondrial DNA sequence polymorphism indi- Whereas Escalante et al. (2005) have argued that cates that P. falciparum is most closely related to P. vivax originated approximately 46 000–82 000 years P. reichenowi (Conway et al., 2000). Escalante et al. before present in Asia from a macaque malaria, others (1995) analyzed the conserved regions of the gene suggest that the parasite is much older and diverged coding for the circumsporozoite protein in various from other primate malarias between 5 and 7 million Plasmodium species and confirmed the evolutionary years ago (Jongwutiwes et al., 2005). Plasmodium vivax closeness of P. falciparum and P. reichenowi. In fact, may have infected early Homo erectus in Asia and the two P. (Laverania) species are more closely related spread to Africa sometime around 1 million years to one another than either are to other malarial para- before present (Jongwutiwes et al., 2005). The parasite sites (Qari et al., 1996), and both are more closely and its hominin hosts may have both experienced related to rodent and avian malarial parasites than to significant population bottlenecks around 200 000– other primate malarial parasites (McCutchan et al., 300 000 years ago (Jongwutiwes et al., 2005). Still other 1984). Escalante and Ayala (1994) present rRNA more recent analyses suggest a most recent common evidence indicating that P. falciparum diverged from ancestor of all P. vivax at 600 000 (Tanabe et al., 2007) P. reichenowi at approximately the same time that or even 10 000 (Leclerc et al., 2004) years before chimpanzees and other hominins did, 5–10 million present. years ago. In contrast, analysis of Dhfr and Ts genes Plasmodium (Plasmodium) ovale (Stephens, 1922) is suggest that all extant populations of P. falciparum a human tertian malarial parasite that is most common may be recently derived from a single ancestral stock, in West Africa, New Guinea, and the Phillipines. Like the most recent common ancestor of which may have Plasmodium vivax, hypnozoites of Plasmodium ovale lived between 25 000 and 58 000 years ago (Rich et al., can remain dormant in the liver for years, relapse of 1998). Extremely low nucleotide polymorphism is con- illness can occur. This species is morphologically very sistent with a recent origin for P. falciparum (Rich similar to P. vivax, although P. (Plasmodium) ovale pos- et al., 1998; Conway et al., 2000; Volkman et al., 2001; sesses very characteristic oocyst and exoerythrocytic Carter and Mendis, 2002; Hartl, 2004). Worldwide cli- morphology with very large nuclei (Garnham, 1966). matic changes throughout the last glaciation and the Plasmodium (Plasmodium) ovale also bears some mor- advent of agriculture would have facilitated the spread phological resemblance to P. simium of howler of the Anopheles gambiae vector responsible for the monkeys (Garnham, 1966; Coatney et al., 1971). There radiation of Plasmodium (Coluzzi, 1999). During this appear to be no close extant genetic relatives of P. ovale agrarian revolution, higher density, sedentary human (Ayala et al., 1998). populations provided mosquitoes with necessary Plasmodium (Plasmodium) malariae (Grassi and bloodmeals and potential mosquito breeding sites Feletti, 1890) is the malarial parasite responsible for (Livingstone, 1958; Hartl, 2004). causing quartan fever (72 hour schizogony) in Still other analyses using mitochondrial DNA sug- humans. This parasite can remain in peripheral cir- gest an origin of more than 100 000 years before pre- culation of human hosts for years. Some investigators sent for P. falciparum (Hughes and Verra, 2001). Joy have suggested that there is a phylogenetic connec- et al. (2003) have predicted, based on mitochondrial tion between P. malariae of humans, P. hylobati of DNA evidence, that P. falciparum really began to gibbons, and P. brasilianum of New World monkeys spread within the human populations in Africa around since all of the parasites exhibit quartan periodicity, 10 000 years ago. There is obviously great discrepancy coarse pigment and dense cytoplasm (White, 1993). in these dates, and it will be important to continue to Escalante et al. (1995) analyzed the conserved regions elucidate the phylogenetic history of these parasites. of the gene coding for the circumsporozoite protein As malaria has been such a large evolutionary (a surface protein expressed at the sporozoite stage) driving force for humans, we have developed several in various Plasmodium species and found that resistance genetic polymorphisms (for review, see P. malariae was indistinguishable from P. brasilia- Carter and Mendis, 2002). Some of the major hemoglo- num. The genetic similarity between the two species binopathies, enzymopathies, and erythrocyte variants indicates that host switching or host sharing may common today include sickle cell disorder, the O blood have recently occurred. group, hemoglobins C and E, various glycophorins

Evolutionary Medicine, Immunity, and Infectious Disease 477 and human leukocyte antigens, ovalocytosis, a- and (Tournamille et al., 1995). Both G6PD deficiency and b-thalassemias, glucose-6-phosphate-dehydrogenase the Duffy-negative allele are thought to have evolved (G6PD) deficiency, and Duffy antigen receptor negativ- approximately 10 000 years before present, corres- ity (Livingstone, 1971; Weatherall and Clegg, 2001; ponding with the spread of agriculture (Carter and Carter and Mendis, 2002; Kwiatkowski, 2005). Mendis, 2002; Tishkoff et al., 2001). Interestingly, a Sickle cell disorder is an autosomal recessive con- Duffy-negative genotype (46C/C) is now associated dition caused by a single-point mutation from glutam- with increased susceptibility to HIV-1 infection, but ate to valine in the sixth position of the b-chain of slower disease progression, in African-American indi- hemoglobin. The condition is found throughout Africa, viduals (He et al., 2008). India, the Middle East, and the Mediterranean (Allison, 1954; Livingstone, 1967). In the homozygous state, Emerging infectious diseases sickle cell anemia causes significant morbidity and “Emerging infectious diseases” are those that have mortality (Weatherall and Clegg, 2001). Although the recently increased in incidence, expanded in geo- exact protective mechanism against malaria is equivo- graphic range, moved into a new host population, or cal, in the heterozygous state this trait could confer are caused by newly evolved pathogens (Morens et al., resistance through increased clearance or reduced 2004; Weiss and McMichael, 2004). Today, examples resetting of infected cells, reduced parasite growth in include dengue hemorrhagic fever, West Nile virus, sickled cells, and enhanced immune responses against Nipah virus, and H5N1 avian influenza (Figure 27.6). infected cells (Williams et al., 2005; Williams, 2006). However, just because new, potentially deadly diseases The a- and b-thalassemias, caused by deletions or are emerging and evolving does not necessarily mean mutations on chromosomes 16 and 11 with resultant that the entire modern human species will be wiped alterations of the a-andb-chains of hemoglobin, are also out by some exotic airborne Ebola-like virus, as the likely characterized by greater immune responses tow- cinema likes to portray. As illustrated above, humans ards malaria-infected erythrocytes (Allen et al., 1997). have been very good at developing genotypic and Hemoglobin C is found in West Africa and results phenotypic adaptations to combat infections. Interest- from a single-point mutation from glutamate to lysine ingly, the primary causes of emerging infectious dis- in the sixth position of the b-chain of hemoglobin. In eases in human populations have been through the homozygous state, there is a significant protective anthropogenic modification of the physical and social affect against death from P. falciparum (Modiano et al., environments (Daily and Ehrlich, 1996; Patz et al., 2001). In contrast, the homozygous state of ovalocyto- 2004). In the short-term, remediation of the effects of sis appears to always cause prenatal mortality (Genton these pathogens will be primarily accomplished by et al., 1995). Ovalocytosis is caused by a 27-base-pair human behavioral changes rather than genotypic deletion in the erythrocyte band 3 (AE1) gene (Allen adaptations. et al., 1999). In the heterozygous state, erythrocytes Human and livestock populations continue to grow become oval-shaped which may inhibit merozoite rapidly, increasing the number of hosts potentially invasion as well as decrease cytoadherence of infected susceptible to novel infections. Mass transportation of erythrocytes to cerebral microvessels. Individuals people, products, livestock, and vectors of disease with blood group O also exhibit significantly less bind- bring each of these closer to one another, and more ing between infected and uninfected erythrocytes quickly at that (Kimball et al., 2005). Population move- (Rowe et al., 2007). Blood group O may have evolved ments due to war, social disruption, and rural-to-urban as a mutation of blood group A in response to selective migration in addition to general urbanization increase pressure from P. falciparum just prior to the major the densities of nonimmune human hosts and pose migration of anatomically modern Homo sapiens significant sanitation problems. Natural disasters and out of African around 100 000 years ago (Cserti and bioterrorism may destroy public-health infrastructure Dzik, 2007). and other resources (Watson et al., 2007). Sex tourism, More recent protective genotypic polymorphisms intravenous drug abuse, the reuse of injectable medical include G6PD deficiency and the Duffy-negative allele. equipment, (“iatrogenic”) and improper disinfection or The former is caused by several hundred mutational ineffective protective measures in hospitals (“nosoco- variations of the X-linked G6PD gene (Ruwende et al., mial”) all contribute to the rapid evolution of resistant 1995). Again, the exact protective mechanism is and deadly pathogens. unknown, but infected cells may be more susceptible Human encroachment into previously undisturbed to phagocytosis or hemolysis. The Duffy-negative allele areas increases remote area accessibility and intro- results in a mutation at the FY locus of the Duffy duces more vectors and reservoirs of infection to new antigen receptor for chemikines (DARC). This muta- hosts. Encroachment, extensification of agricultural tion eliminates a binding site on the surface of erythro- land, urban sprawl, and habitat fragmentation all alter cytes which P. vivax requires for entry into host cells population densities and distributions of wildlife,

478 Michael P. Muehlenbein Multidrug-resistant tuberculosis Cryptosporidiosis Vancomycin-resistant Drug-resistant malaria S. aureus SARS Cyclosporiasis Diphtheria E. coli O157:H7 E. coli Hepatitis C O157:H7 vCJD H5N1 Human Lyme disease Typhoid influenza monkeypox fever West Nile virus Vancomycin- Anthrax resistant bioterrorism S. aureus Rift Valley fever HIV Lassa fever Nipah virus Whitewater arroyo virus Hendra virus Hantavirus pulmonary syndrome Entervirus 71 Human monkeypox Dengue Yellow fever Plague Cholera Marburg Ebola hemorrhagic fever hemorrhagic fever 27.6. Examples of emerging infectious diseases. Figure reprinted with permission from Morens et al. (2004). which changes disease dynamics (Patz et al., 2004). horseshoe bat (genus Rhinolophus) (Li et al., 2005). Deforestation results in loss of plant species and sub- These animals likely came into contact with civet sequent loss of undiscovered therapeutic drugs. farms, possibly through the feeding of bats to farmed Changes in water usage, such as during the construc- civets. Unfortunately, it took close to a year to contain tion of dams, culverts, and irrigation systems, can the outbreak, in no small part because of the lag of case increase the potential breeding sites of vector species reporting and under-reports of the actual casualties in like mosquitoes and snails (Keiser et al., 2005; China (Parry, 2003). Fear of decreased tourism, travel, Steinmann et al., 2006). Biodiversity loss due to global and trade eventually cost the region billions of dollars climate change, deforestation, the spread of invasive and hundreds of lives. This is an excellent example of species, overexploitation, and other causes reduces the how emphasis on national sovereignty over global soli- buffer of hosts in an environment, increasing the like- darity can produce significant negative health effects lihood of cross-species transmission (Maillard and for the global population (Heymann 2004, 2006). Gonzalez, 2006). Humans have also caused altered vector and reser- As discussed previously, the use of bushmeat has voir distributions through the production of been the source of HIV. In fact, the majority of all greenhouse gases and global climate change. The Aedes emerging pathogens in humans are zoonotic in origin aegypti mosquito has expanded its geographic range in (Jones et al., 2008), and population, ecological, and response to increased global temperatures, resulting in behavioral changes that increase contact with wildlife increased risk of Dengue virus in subtropical and tem- exacerbate emergence of these pathogens (Daszak perate climates (Hales et al., 2002). Likewise, the risk et al., 2000). Another example is the severe acute of Lyme disease (Borrelia burgdorferi) has increased respiratory syndrome caused by a coronavirus (SARS- with elevated global temperatures (Brownstein et al., CoV). It is transmitted through aerosolized particles, 2005). The outbreak of Hantavirus pulmonary syn- and symptoms include fever and pneumonia. Between drome in the southwestern United States in the early November 2002 and April 2004, SARS resulted in 774 1990s was caused by heavy summer rains associated confirmed deaths from 8098 cases in 29 countries with the El Nin ˜o Southern Oscillation effect and the (Hughes, 2004; Morens et al., 2004). The outbreak ori- subsequent proliferation of pine nuts and deer mice ginated in farmers and animal workers in the Foshan (Peromyscus maniculatus), the natural reservoir of the Municipality of the Guangdong Province of China (Yu Hantaan virus (family Bunyaviridae) (Engelthaler et al., 2003). Later, the virus was identified in Hima- et al., 1999) layan palm civets (Paguna larvata), raccoon dogs (Nyc- Nipah virus is another excellent example of how tereutes procuyoinboides), and Chinese ferret badgers human-induced ecological changes have altered the (Melongdale moschata) sold in wet markets for con- risk of emerging infectious diseases. Nipah is a single- sumption. The actual reservoir of the virus is the stranded RNA virus of the family Paramyxoviridae that

Evolutionary Medicine, Immunity, and Infectious Disease 479 causes severe acute febrile encephalitis in humans. Its huge amount of commercial poultry produced today, natural reservoir is the flying fox (genus Pteropus), and the likelihood of viral entry into the poultry and human the virus has been identified in Malaysia, Singapore, populations from wild birds has increased. Although and Bangladesh (Epstein et al., 2006). Between human-to-human transmission of the virus has been October 1997 and February 2000, Nipah virus resulted suggested in several cases (Ungchusak et al., 2005), the in 105 confirmed human fatalities in Malaysia. The avian influenza virus appears to bind to receptors deep cause of the outbreak is now attributed to a complex in the human respiratory tract, which would limit interaction of human-induced environmental changes. direct human transmission and decrease the likelihood Specifically, fire-mediated deforestation for the expan- of a pandemic (Shinya et al., 2006). However, reliance sion of oil palm plantations produced significant air on genetic adaptations against this epidemic is clearly pollution in the region. Combined with a drought pro- unwise; human genotypic adaptations to such diseases duced by the El Nin ˜o Southern Oscillation, the avail- will be delayed compared to rapid pathogen evolution. ability of flowering and fruiting forest trees was reduced The mis-governance of epidemics with decentralized (Chua et al., 2002). Bats (Pteropus vampyrus and Pter- testing, misdiagnoses, and underreporting of cases opus hypomelanus) began feeding in human orchards has resulted in slow public health responses that had been strategically planted next to pig farms so (Cyranoski, 2005; Normile, 2005). A future pandemic as to use pig waste as fertilizer for the orchards. Bat could produce considerable economic burden due to waste entered the pigsties and the virus amplified destruction of commercial poultry, high human within the swine. Despite producing severe respiratory health-care costs and loss of productivity (Meltzer disease (but low mortality), the infected pigs were dis- et al., 1999). An understanding of human evolution tributed throughout Malaysia. Economic losses were against infectious disease is incomplete and inapplic- enormous, ultimately because we were less mindful able for today’s epidemics without consideration of the about the impacts of environmental change on animal social, political, and environmental causes of morbid- ecology and human health than we should have been. ity and mortality, and the behaviors we might employ Widespread, irreversible modification and overuse to ameliorate some of these challenges. of our environments have been characteristics of most human populations over the past few thousand years, DISCUSSION POINTS but particularly the past century. Such rapid modifica- tion of the physical and social environments has 1. What contributions can evolutionary biology make increased our reliance on cultural adaptations against to medicine? disease over biological adaptations that take gener- 2. How can environmental conditions during child ations to proliferate. The current avian influenza out- development affect immune functions? break illustrates the need for this realization. Influenza 3. How does lymphocyte development resemble Dar- is a single-stranded RNA virus of the family Orthomyx- winian evolution by natural selection? oviridae, of three main types (A, B, and C), and classi- 4. How do some infectious pathogens evolve high fied into subgroups according to its glycosylated levels of virulence whereas others do not? surface antigens: hemagglutinin (H) and neuramini- 5. What genotypic and phenotypic adaptations have dase (N). The current avian influenza epidemic that humans developed to combat malaria infection? began in 2003 is caused by a type A, H5N1 virus. Influ- 6. What are some of the social and environmental enza viruses are common in wild migratory waterfowl, causes of emerging infectious diseases? particularly ducks, geese, swans, gulls, and terns (Chen et al., 2005; Olsen et al., 2006). Infection with the low pathogenic forms is typically asymptomatic in the ACKNOWLEDGEMENTS birds. However, the high pathogen forms can cause significant mortality is some species, like bar-headed Paul Ewald, Lisa Becker, Sean Prall, Laurah Jones, and geese. Influenza experts are concerned that such a two anonymous reviewers assisted with the production virus could cause a devastating pandemic. The 1918 of this manuscript. Spanish influenza (H1N1) pandemic that killed as many as 50 million people was caused by an avian influenza virus that reassorted (i.e., antigenic shift) REFERENCES within swine (Taubenberger et al., 1997, 2005; Gam- Abraham, S. N. and Arock, M. (1998). Mast cells and baso- blin et al., 2004). phils in innate immunity. Seminars in Immunology, 10, Despite the fact that the recent avian influenza 373–381. outbreak has attracted a great deal of attention, avian Adema, C. M., Hertel, L. A., Miller, R. D., et al. 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