ABSTRACT. Anthropologists at Durham University’s Parent-Infant Sleep Lab combine behavioural, physiological and ethnographic methods in their studies of maternal-infant sleep ecology. The outcomes of these studies have helped to change UK public health recommendations and hospital practices. This talk will explore whether an evolutionary perspective contributed to translating this research into policy and practice.

ABSTRACT. Sleep patterns are heavily impacted by technology and behavioral choices in developed countries, including through use of artificial lighting. However, little is known about sleep in “traditional” small-scale societies that lack access to electricity. Thus, we lack understanding of the extent of mismatch between our current sleep patterns and those of our ancestors. We characterized sleep in a rural community without electricity in Madagascar, and compared results to patterns of sleep found in great apes and in Western populations. Ten females and 13 males volunteered to wear actigraphic watches for up to 21 days per individual (329 nights total). Sleep onset averaged 19:21 hours (SD=3.38). Awake times were also early compared to developed countries (5:44), and showed less variation (SD=0.53), with individuals averaging 9.4 hours in bed. Of these hours, only 6.5 involved sleep. Sleep efficiency in the Malagasy population (70.7%) was grossly comparable to orangutans (73.0%), but lower when compared to Western populations (88.8%). Wake after sleep onset (2.1 hours) was more than double typical values in developed countries. A linear mixed effects model revealed that older individuals slept longer (β = 0.31, z = 2.82, p = 0.004), and farmers slept less than non-farmers (β = -0.41, z = 3.22, p = 0.001) and had more fragmented sleep. Thus, traditional human populations exhibit shorter duration and greater flexibility of sleep expression than humans in developed countries, and shorter but equally efficient sleep when compared to great apes.

ABSTRACT. Throughout human evolutionary history until the recent advent of effective contraception, virtually all women spent a majority of their reproductive years breastfeeding a succession of infants. Breastfeeding was typically on-demand and frequent, a pattern facilitated by close proximity, including co-sleeping, of a mother and her nursling. In contrast, in contemporary industrialized nations, women usually have fewer pregnancies, breastfeed less and forgo co-sleeping. In these populations, significant disruptions in the quality and quantity of their own sleep are commonplace among mothers of infants, suggesting considerable conflict between maternal attention to the infant's nocturnal needs and investment in her own somatic well-being. It is uncertain, however, whether the degree of this conflict arises largely as a consequence of current behavioral repertoires or if comparable trade-offs were faced by mothers throughout human evolution. We measured sleep and breastfeeding patterns in a natural fertility (non-contracepting) rural Bolivian population principally reliant on agropastoralism. Most homesteads lacked electricity and cooked with wood, scarce in this harsh cold environment (altitude 3800m, latitude 17°S). In contrast, those households closest to the main town were more likely to have electricity and use propane for cooking. Data are from 885 48-hour recording periods in 184 co-sleeping mother-infant pairs (infant age 22-730 days). Maternal sleep duration co-varied with natural photoperiod and was much longer than that typically reported by U.S. mothers of infants. Higher night breastfeeding rates were associated with fewer hours of maternal sleep. This association was mitigated as the nursling aged. Near-town mothers went to bed later than rural mothers. As their infants aged, near-town mothers slept less while rural mothers slept more. These patterns suggest that (1) more frequent night nursing is associated with less maternal sleep even in co-sleeping pairs, and (2) even modest increases in "modernization" (e.g., electricity) are associated with shorter maternal sleep. Funding: NSF#SBR9506107

ABSTRACT. The prevalence of Alzheimer’s disease climbs dramatically from 8% among people in their upper 70’s, to nearly 40% for those over 85. Why does the brain fail so consistently in this particular way? The weaker force of selection at advanced ages is relevant, but several recent discoveries suggest that additional evolutionary factors may be involved. First, the brain manifestations of Alzheimer’s disease appear to be far more common for humans than for other primates. Second, humans sleep vastly less than other primates, and much less than predicted based on our brain size, activity pattern, body mass, phylogeny, and other traits. Third, recently discovered glymphatic channels in mice expand by 60% during sleep, doubling the rate of amyloid beta exit from the brain. Finally, sleep deprivation causes tau accumulation in the brains of mice.

These findings lead us to propose the hypothesis that strong selection for shorter sleep in humans has compromised glymphatic function, resulting in vulnerability to Alzheimer’s disease. Selection forces shaping shorter sleep durations in humans include risks from predators because of sleeping on the ground, and from hostile conspecifics who can be more active at night thanks to the controlled use of fire. Shorter sleeping also provides benefits from social learning and relationship building during nighttime socializing. The tradeoff for these benefits of less sleep is compromised glymphatic function, which may result in amyloid beta and tau accumulation with associated dementia later in life. Our hypothesis predicts that the risk of plaques and tangles in other primates is correlated with sleep durations. If confirmed, it would support recent initiatives to manipulate sleep and glymphatic function to see they can influence the prevention or progression of Alzheimer’s disease.

ABSTRACT. Recent sleep research conducted among small-scale subsistence societies (lacking electricity) has yielded novel findings about the nature of human sleep, especially with regard to timing and duration. Building on this, we aim to 1) quantitatively characterize the typical pattern of sleep fragmentation among Tsimane hunter-horticulturalists in lowland Bolivia, and 2) to explain variation in sleep efficiency (total sleep / time in bed) and sleep interruptions in relation to the degree of environmental exposure from lacking walls on one’s house. Taking advantage of heterogeneity in the Tsimane sleep environment, we measured the normal, in-home sleep of 76 women aged (mean ± SEM) 36.5 ± 1.9 and 57 men aged 41.7 ± 2.2 for an average of 4.7 nights each (639 total). Sleep was measured using wrist-worn accelerometers, which have been validated as sleep monitors against polysomnography. 459 in-home interviews measured nocturnal awakenings and characteristics of the sleep environment. Mean total sleep was 6.7h ± .13, and the mean time awake in bed was 95.3m ± 1.8. The most common reported causes of sleep interruption were the need to perform childcare (32.3%), need to urinate (26.6%), and hearing animal noises (13.7%). Sleeping in houses missing at least one wall was associated with spending 14.4m more awake during the sleep period each night (t-test, p=.001), being 7.8% more likely to attribute sleep interruption to animal noises (t-test, p=.089), and being 16.3% more likely to attribute it to the need for childcare (t-test, p=.005). These results indicate that people sleep more soundly in fully-closed spaces, suggesting that without walls, people may need to maintain greater vigilance during sleeping hours. Based on these findings, we suggest that early humans likely faced nighttime dangers regularly, and that in response, we have evolved the ability and predisposition to inhibit sleep in response to stressors in our environment.

ABSTRACT. Low social status increases risk of disease due, in part, to the psychosocial stress that accompanies feeling subordinate or poor. Previous studies report that chronic stress and chronically elevated cortisol can impair cardiovascular and immune function. We test whether lower status is more benign in small-scale, relatively egalitarian societies, where leaders lack coercive authority and there is minimal material wealth to contest. Among Tsimane’ forager-horticulturalists of lowland Bolivia, we compare informal political influence among men with urinary cortisol, immune activation (innate and acquired), and morbidity as assessed during routine medical exams. After controlling for potential confounds, we find that politically influential men have lower cortisol, and that this association is partly attributable to access to social support. Cortisol is positively associated with men’s income, which may reflect chronic psychosocial stress from market involvement. Greater influence is also associated with lower probability of respiratory infection, which is a frequent source of morbidity among Tsimane’. Among men who lost influence over a 4-year period, cortisol and probability of respiratory infection were higher the greater the decline in influence. Deleterious effects of low status on health are not merely ‘diseases of civilization’ but may result from how (even subtle) status differences structure human behavior.

ABSTRACT. High blood pressure is the greatest single cause of the global burden of disease (Pouler et al. 2015). The prevalence of hypertension is higher in persons of African descent, yet there are few longitudinal cohort studies of non-communicable diseases in Sub-Saharan Africa. For 19 years we have conducted a prospective cohort study of the Dogon of Mali: following ~1700 subjects annually from early postnatal life to adulthood. Half of the subjects migrated to the capital city of Bamako where we have continued to follow ~85% annually. Our study is unique in that it longitudinally compares the health and developmental trajectories of subjects from the same cohort who either remained in the rural villages or who migrated to the city. Our statistical analyses employed linear mixed models in IBM SPSS 22. “White coat hypertension” emerged as the single variable with the largest effect size. For each additional measurement session, blood pressure fell significantly (P < 0.001) reflecting acclimation to the measurement protocol, with boys acclimating faster than girls. Controlling for the number of measurements, blood pressure increased with age, ambient temperature, height, and BMI and tended to decrease slightly with wealth. Of particular interest was that after adjusting for these variables, blood pressure was 4.6 mm Hg (P < 0.001) higher in the city than in the countryside. Thus, the increase in blood pressure in the city was not entirely mediated by body size, and may reflect the stress of adjusting to urban life. This possibility is supported by the 0.5 mm Hg (P < 0.001) decrease in blood pressure for each additional year of urban living. Research has focused on obesity and sedentary life styles, yet blood pressure is also strongly reactive to stress--an under-investigated factor in the epidemiological transition in low income countries.

ABSTRACT. The human stress response governs our ability to deal with a wide range of stimuli that life throws at us. An evolutionary approach encourages us to consider the selective advantage this system provides, particularly given its associated costs (e.g. in metabolism and immune function).

However, given that our ancestors almost certainly experienced more stress, in the form of trauma, disease and starvation for example, one may question why stress appears to play such a large role in industrialised societies. One argument is that our stress response developed in the context of physical stressors, not the mental and social ones people in industrialised societies mainly encounter today. In other words, the idea that there is a mismatch between the evolutionary context in which our stress response evolved and the environment it operates in today.

To test this hypothesis, I report results from three distinct communities in Papua New Guinea. Depending on location, these communities face notably different stages of socioeconomic transition. I looked at the interaction between social change, lifestyle, and stress. A ‘stress profile’ was built using physiological (hormonal) measures of stress and psychological indicators of anxiety alongside socioeconomic surveys and ethnographic methods. The results suggest that with urbanization and, so called ‘modernization’ come a swathe of maladaptive coping behaviours and significantly heightened stress hormone levels.

Finally, I consider the challenge of translating the results from fieldwork to meaningful, applied public health (intervention) programs. I show how evolutionary biology and psychology provided a broader framework to tackle the existing disconnect between research and (health) policy.

ABSTRACT. Disgust is widely thought to have evolved to motivate humans away from contagious disease (Curtis et al., 2004). The compensatory behavioral prophylaxis hypothesis (Fleischman & Fessler, 2011) predicts those who are the most immunologically vulnerable will show the most disgust sensitivity. There is evidence that disease cues influence immunity. Previous research has found pictures of sick people and disgust eliciting images increase serum IL-6 (Schaller et al., 2010) as well as body temperature and oral immune markers (Stevenson et al., 2012). There is also some evidence that those who have suffered a recent infection and therefore are immunologically vulnerable show increased attention to disease cues (Miller & Maner, 2011). However, no previous study has investigated the connection between baseline immunity or immune activation in response to a stress paradigm on disgust sensitivity. In the current study, 150 women in the menopause transition were exposed to a psychosocial stressor, the Trier Social Stress Test. During the protocol, plasma levels of interleukin 6 (IL-6) were collected at baseline and over a 60 minute recovery following the test. . After recovery, disgust measures including disgust response to images (Curtis et al., 2004) and the Three Domains of Disgust inventory (Tybur et al. 2009) were administered. We find that higher baseline IL-6 is associated with greater disgust sensitivity to both images and inventory items, especially those that reflect disease cues. However, we find that women who show a more robust IL-6 response to stress show lower disgust sensitivity. We hypothesize that baseline IL-6 may be indicative of recent infection or immune vulnerability but that IL-6 increase during the stress task could be indicative of healthy immune function. Results will be discussed in light of an adaptationist perspective on disgust and disease avoidance.

ABSTRACT. Much of a major part of host defense against pathogens is generally unrecognized—the active use of non-specific stressors which harm host cells as well as pathogens. These stressors include heat, reactive molecular species, nutrient and oxygen deprivation, and lactic acidosis. Hosts take advantage of two potential vulnerabilities of pathogens to stress: 1) the inherent vulnerability of growth and replication (more immediately crucial for pathogens than for host cells) and 2) the degree of localization of the pathogens. Each of the non-specific stressors listed above typically occurs within phagolysosomes (where their utility is well-recognized), as well as locally at the infected site, in the region of the infected site, and systemically as part of the acute-phase response (e.g., fever, anorexia, iron and zinc restriction). We used a simple agent-based model of a locally infected host to explore the efficacy of host defenses consisting of completely non-specific stress in controlling rapidly replicating pathogens. We found that local, regional, and systemic stress acted synergistically in eliminating pathogens. While local and regional stress functioned by restricting pathogen spread, systemic stress’s efficacy was due to pathogens using their resources for more rapid replication compared to host cells, thus having fewer reserves to withstand stress. To the extent that hosts can harm themselves to preferentially harm the pathogens within, it should be expected that hosts actively use this strategy as a defense. This evolutionarily basic strategy complements more recently evolved specific anti-pathogen defenses which cause little collateral host harm but are more susceptible to the evolution of resistance.

ABSTRACT. Last year, President Obama launched the Precision Medicine Initiative (PMI). In brief, this ambitious program aims to improve health by tailoring the prevention and treatment of disease to genetic, environmental, and lifestyle differences among individuals. The PMI grew out of a realization that the traditional “one size fits all” approach to medical care is imperfect and not always helpful or successful, because many preventive measures and therapies benefit only a small fraction of the patients who receive them. Medical practice is rapidly changing, however, at least for the treatment of patients with some forms of cancer. Because of progress in sequencing the genomes of cancer cells and in identifying mutations that are “drivers” of malignancy, the PMI will initially be focused on cancer therapy, but the leaders of this initiative plan to expand it to include virtually all diseases. Although the PMI may improve some aspects of medical practice, its potential is limited by its failure to incorporate principles of evolutionary medicine. The initiative is grounded on an appreciation of the abundant variation among individuals in susceptibility to disease and among patients in the pathophysiological pathways leading to disease but it retains a typological or essentialist view of illness. Moreover, while the PMI intends to integrate genomic information with physiological, clinical, behavioral, and environmental data, the initiative remains a gene-centric view of disease and does not give sufficient recognition to ecological determinants of illness. Finally, even though diseases of aging will be important targets of the PMI, the initiative does not yet incorporate life history theory into its analyses. The PMI can be improved by adoption of an evolutionary understanding of disease, and so this initiative offers new opportunities for members of the Evolution, Medicine, and Public Health community to contribute to medical research and practice.

ABSTRACT. Genetic adaptations of many human traits are likely highly polygenic, occurring at many loci in the genome rather than at a single locus. Human height is one such example. It is a classic polygenic trait and is known to be differentiated across Europe. Powered by successful genome-wide association studies that provided us with hundreds of known loci, we detected a signature of widespread selection at height loci across Europe. Furthermore, we honed in on the isolated Southern European population of Sardinia. Using whole genome sequencing data, we investigated the population structure of Sardinia, its demographic history and relationship to ancient European farmers to gain insight on the peopling of the island. On this unique Sardinian genetic background, we identified two loci in which the derived alleles have increased frequency compared to mainland Europe and strongly decrease height in Sardinia, as well as an overall trend of lower stature being favored on the island by selection. These results generate additional hypotheses regarding height variation around the globe, and serve as examples of studying the evolution of polygenic traits when the genetic architecture is sufficiently known.

ABSTRACT. One of the main goal of evolutionary medicine is to understand how evolution has shaped our body. During last several thousand years, mankind has been dispersed all over the world, experienced agriculture, significant increasing in population density, domestication of animals and plants, and exposure to new pathogens. All of these effects have been selfimposed. Turning point in human evolution has started with beginning of civilization when humans, instead of reacting to the environment, began to actively shape it. Therefore, we should expect significant changes in human adaptive reactions on the exposure to the artificial environment created by man, and to the natural environment changed by man. These changes should be seen as selection signals in human genomes. Identifying and analysis of these selection signals is of great importance for understanding of connection between the human organism and its environment. We analysed the effect of recent selection on humans by direct comparison of whole genome data on individuals from two civilization steps, the Bronze Age and the modern time. We used an approach allowing us to study the evolution of biochemical pathways involving many different genes and regulatory regions. Thus, we detected selection on the systemic level. We revealed the biochemical pathways indicating the selection signals which were significantly different between the two groups. Our results show that most substantial changes took place in metabolism of some amino acids, lipids, and xenobiotics, in immune system, and in processes connected with some pathologies. In conclusion, we obtained direct proof of action of recent selection on human population during last five thousand years. We believe that our study revealed the strongest selection signals and opened new perspectives for more detailed investigations about when, exactly, and how civilization has been modifying human genomes.

ABSTRACT. Qualitative theories for the evolution of mood commonly posit that it is adaptive for mood to eventually return to some baseline set point. This idea is supported by the hedonic treadmill—the observation that happiness levels are resilient to both good and bad events. However, the few mathematical models that have been developed to provide evolutionary explanations of mood do not predict that mood should return to a baseline set point. Instead, these models assume that mood functions to decrease activity when the cost is greater than the benefit, and increase it when the benefit is greater than the cost. Thus, these models predict that if conditions stay bad (or good), mood will stay low (or high).

To explain the hedonic treadmill, we investigate a different hypothesis for the function of mood: In a complex environment, the main cost of pursuing a reward may be the opportunity cost of not being able to pursue other rewards. We describe a modeling framework based on opportunity cost in which individuals are presented with a sequence of opportunities, but the cost of pursuing one of the opportunities is giving up the ability to pursue following opportunities in the near future. The optimal strategy in such an environment will often be to adjust activity levels relative to the current expected reward size. This means that activity levels and mood should return to baseline even after the environment has become consistently better or consistently worse. Because depression and bipolar disorder are characterized by mood failing to return to baseline, this modeling approach has good potential to give insights into pathological mood as well as giving an evolutionary account of normal mood.

ABSTRACT. Postpartum depression (PPD) is a critical health issue affecting women, children, and wider society. Despite injurious consequences and high incidence, PPD remains understudied and undertreated. Using data from a cohort of 308 pregnant California women studied longitudinally from early gestation through 9 years postpartum, we evaluate a new framework for understanding PPD in an evolutionary context. Previous theories are limited by narrow focus on social support ‘benefits’, and monolithic characterization of depression itself. Our approach was motivated by Nesse’s model of major depressive disorder that focuses on symptoms and situations. We expand upon that model by adding childbirth to the list of situations that instigate depression, and identify symptoms that may be adaptive in this context based on principles of evolutionary anthropology. We predict certain symptoms should be more pronounced in PPD compared to depression during other life phases. To test our hypotheses, we compare PPD symptomology between postpartum women and a separate cohort of women assessed outside the perinatal phase. Because it is unknown whether PPD is fundamentally distinct from analogous syndromes with onset during other life phases, our study has clinical relevance as the first symptom-based characterization of PPD. It also remains unknown whether gestational endocrinology differentially promotes particular symptom clusters in PPD. We hypothesize that if there is a particular set of adaptive depressive symptoms during the postpartum phase, endocrinology is the most likely regulatory biological pathway. We test this hypothesis in our longitudinal cohort by measuring gonadotropin and stress hormone levels serially across each woman’s pregnancy, and use regression models to evaluate relations between gestational hormone trajectories and postpartum depressive symptom clusters. Results suggest particular symptom profiles predicted to have adaptive relevance in PPD may be programmed by gestational endocrinology. Results also provide evidence for gestational neuroendocrinology as the target of selection, enacting psycho-behavioral adaptation.

ABSTRACT. As a product of intersecting social-environmental exposures and innate biological states, Posttraumatic Stress Disorder (PTSD) is best understood by epigenetic explanations. Recent advances in measuring epigenetic variation have led to an explosion of epigenetic data related to PTSD, advancing our understanding of biological underpinnings and providing a basis for future developments in prevention and treatment modalities. This literature conceptualizes epigenetic variation that both preexists and arises in response to trauma exposure as causal of differential PTSD risk and resiliency. Despite growing understanding of PTSD epigenetics, few studies have undertaken evolutionary analyses nor leveraged evolutionary theory to inform hypothesis generation or study design. One such evolutionary perspective that may guide studies of the epigenetic underpinnings of mental health disorders is that of Nikolaas Tinbergen’s Four Questions. Here, I present original research and interpret the contemporary literature of PTSD epigenetics to address each of Tinbergen’s Four Questions towards a theory of PTSD epigenetics that is informed by evolutionary theory. Specifically, I provide data showing that 1) epigenetic variation is involved in the physiological mechanism of PTSD, 2) epigenetic modifications are responsive to trauma and thus involved in the development of PTSD, 3) genetic potential for epigenetic regulation of PTSD has an ancient phylogenetic history, and 4) PTSD may represent a functional adaptation to the omnipresent threat of trauma. I argue that trauma responses generally and PTSD specifically represent an adaptive developmental plasticity with deep evolutionary roots that is underpinned by epigenetic variation. Appreciating these evolutionary insights, I conclude that PTSD is a biologically functional and appropriate response to trauma exposure. The “disorder” in PTSD is thus confined to a social dimension – the ills of PTSD are socially constructed, not biologically disordered. This theory of PTSD thus has far-reaching implications for research, clinical practice, and public policy.

ABSTRACT. The term “4th Trimester” reflects the anthropological concept that during the first months of life, newborns continue to function like a fetus in many ways; they require months of intense, ‘womb-like’ nurturing. An evolutionary perspective views the mother and infant as a mutually dependent unit, behaviorally and physiologically intertwined via breastfeeding and other interactions such as skin-to-skin contact. In suboptimal conditions (such as early separation, maternal distraction, lack of safety, maternal anxiety or pain), the bidirectional processes inherent in maternal-infant functioning can be so severely disrupted that health, and even infant survival, is compromised. These infant demands require a substantial transformation for mothers, as Dr. Sheila Kitzinger has noted: There is a fourth trimester to pregnancy and we neglect it at our peril.

During this critical period, many women currently experience considerable challenges, including fatigue, pain, breastfeeding difficulties, depression, lack of sexual desire and incontinence. Amid these concerns, U.S. health care is often fragmented among maternal and pediatric providers. The 4th Trimester Project brings together patients, clinicians, researchers and other stakeholders to define patient-centered priorities in the first 12 weeks after birth. Key, interrelated health themes are (1) maternal mood; (2) infant feeding; (3) sleep and fatigue; (4) sexuality, contraception, and birth spacing; (5) substances, medications, and environmental exposures; and (6) physical recovery from childbirth. To fully address the health issues of the 4th Trimester, it is vital that the systems designed to support health better consider the realities of the lives they serve. The 4th Trimester Project is an example of applying evolutionary medicine concepts to reenvision health care and implement improvements in clinical support for new families.

ABSTRACT. not available

ABSTRACT. Practitioners of evolutionary medicine most typically focus on the consequences of human evolution for variation in health, survival, reproduction, and susceptibility to disease. However, a full accounting for variation in each of these traits must also address the contributions of somatic cell mutation, selection, and evolution, which have been implicated in the pathogenesis of numerous medical conditions, susceptibility to disease, and response to therapy. In addition to cancer, there are non-malignant diseases, such as WHIM (warts, hypogammaglobulinemia, infection, and myelokathexis) syndrome, that arise from competition among somatic cells, hematopoietic stem cells in the case of WHIM syndrome. As demonstrated by a recent study that will be discussed in this session, clonal competition among hematopoietic stem cells can lead to reversal of a disease, specifically WHIM syndrome. It is well known that mutation and selection of B lymphocytes is essential for many humoral immune responses that protect against pathogens such as HIV-1, examples of which will be presented. Another key role for somatic cell selection and evolution involves development of resistance to therapy for cancer and strategies to prevent such resistance, a final topic to be addressed. Additional examples of somatic cell mutation, selection, or evolution that affect health will also be discussed to demonstrate the broad range of these phenomena.

ABSTRACT. The HIV-1 pandemic remains a global emergency for which there is currently no cure. Vaccination has historically been the most effective measure for controlling the transmission of infectious agents and the development of a protective HIV-1 vaccine remains a global public health priority.

Many licensed vaccines induce specific antibodies that correlate with protection. Therefore, the induction of HIV-1 broadly neutralizing antibodies (bnAbs) capable of neutralizing infectivity of the diverse population of HIV-1 is an appealing goal for a preventive HIV-1 vaccine. However, despite decades of intense research, attempts to formulate a protective HIV-1 vaccine through classic vaccine design strategies have not been successful.

Rare chronically HIV-1 infected individuals naturally develop bnAbs but this happens several years after infection - when natural eradication can no longer be achieved - and as a result of tortuous and disfavored B cell affinity maturation pathways. The application of new technologies has provided a clearer understanding of the mechanisms of induction of bnAbs, their co-evolution with autologous virus and their cooperation with other B cell lineages.

These studies have informed on how to recapitulate the key events in the naturally occurring B cell affinity maturation underlying bnAb development and provided a strategy to select HIV-1 envelope proteins that have directly participated in bnAb development to be used as immunogens.

ABSTRACT. My laboratory uses genomic, pharmacological, and biochemical approaches to define the pathways of resistance to targeted anticancer therapies. For example, we recently developed a technique in which engineered lentiviral cDNAs encoding activators of major oncogenic signaling pathways are introduced into cells and then profiled to identify those capable of conferring resistance to drugs. Using this approach, we have uncovered new pathways of resistance to a range of targeted therapies, and further, have used this information to rationally design more durable combination therapeutic strategies, some of which are currently being explored clinically. In the past two years, we have become particularly interested in the phenomenon of convergent resistance, wherein discrete resistance pathways function through common downstream signaling or transcriptional programs. By identifying these “common effectors”, it may be possible to define new, more robust therapeutic strategies that select against resistance evolution.

ABSTRACT. Warts, Hypogammaglobulinemia, Infections and Myelokathexis Syndrome (WHIMS) is a rare, autosomal dominant immunodeficiency resulting from gain-of-function mutations in the chemokine receptor CXCR4. We recently described a unique WHIMS patient who underwent spontaneous genetic and phenotypic reversion at approximately age 30 after being severely affected as a child (McDermott, et al., Cell, Feb., 2015) . Her reversion was due to a single catastrophic genetic event known as chromothripsis (chromosome shattering) resulting in the deletion of one copy of 163 genes in addition to her mutant copy of CXCR4 on chromosome 2. This event was traced to a hematopoietic stem cell (HSC) that had spontaneously repopulated her bone marrow. Using mouse models we have found that Cxcr4 haploinsufficiency markedly enhances HSC engraftment potential in recipient WHIM mice whether the donor HSC were purified from whole bone marrow cells or not, and whether the recipient was conditioned by lethal irradiation or not. Enhanced engraftment by Cxcr4 haploinsufficient donor HSC also occurred in wild-type mouse recipients, but to a lesser extent, and was also HSC intrinsic. Genome editing experiments have been successful at deleting one or both copies of CXCR4 in human cell lines in up to 40% of treated cells, and in reducing CXCR4 surface expression. While CXCR4 was already understood to be important in HSC biology, this patient and subsequent murine experiments have proven that the gene dosage of CXCR4 is a critical factor affecting HSC engraftment. Genome editing is a promising technology for deleting one copy of CXCR4, ideally the WHIM allele, in autologous HSC as a strategy to cure WHIM syndrome.

ABSTRACT. The human gut has evolved to take advantage of a diet that is higher in nutrient energy by volume compared to any other primate diet. Industrial food processing continues this trend, but have we taken it too far? An evolutionary framework suggests that cooperation and conflict between host and gut microbes may explain features of the human digestive tract and shed light on diseases linked with the Western diet. Cooperation occurs when microbes provide host energy and protection from infection, and when hosts 'feed' complex carbohydrates to microbes and maintain microbial habitat. Conflict occurs when resident microbes cause tissue destruction, divert dietary energy from the host, and disseminate widely throughout the body, often leading to escalating microbial virulence and host inflammation. According to this framework, an alignment of host and gut microbe fitness interests should promote health, and conflicting fitness interests between host and gut microbes should contribute to disease and malnutrition. Can we prevent diseases by promoting host-microbiota cooperation and limiting conflict? This presentation explores the possibilities.

ABSTRACT. Microscopic organisms of the human body are intimately involved in physiological function of their hosts, suggesting a long history of interdependency. Yet, because microbiomes and their hosts are genetically distinct, commensal relationships are only one outcome of co-evolution. Populations of the human microbiota are continually and rapidly evolving, and any genetic mutation that enables individual microbes to shift host behavior toward improved survival and reproductive success should be favored by natural selection. The idea of microbial manipulation of behavior has strong support from research on known pathogenic species: when acquired by a rodent, the protozoan parasite Taxoplasma gondii induces behavioral changes in the host to increase the probability that the parasite will be transmitted to the next required host – a feline. Bacteria that metabolize host foods could increase their access to these substances by evolving to exploit the mechanisms of host food intake. Oral bacteria that feed on dietary sugars, such as Streptococcus mutans, could be involved in shifting taste perception for sweet taste, thus increasing the intake of sugars. If sustained, excess sugar consumption mediated by oral bacteria could contribute toward the development of obesity. Use of antimicrobial oral hygiene products should moderate this effect. Oral bacterial disease (e.g., periodontitis) and obesity have long been recognized to co-occur, and some evidence for a causal link between oral bacteria and obesity has been reported, but no studies directly examining the role of antimicrobial oral hygiene in this process have been published. Because gut microbes are seeded from the mouth, microbiota present here, either as transients or colonizers, are an easily-accessible system for better understanding the well documented relationships between gut microbiome and health status. Genomic analyses of oral microbiota along with data on host diet and oral hygiene behavior will be needed to evaluate these hypotheses.

ABSTRACT. The microbes (microscopic organisms including bacteria and Archaea) living on human skin are responsible for immune system maturation, the fate of pathogens that land on the skin and production of body odors that affect mate selection. They therefore have the potential to affect both human health and fitness. Previous studies have identified numerous external and environmental factors that alter the composition and abundance of skin microbes including gender, diet and daily antiperspirant and/or deodorant usage. In order to address whether particular host genetic factors influence our skin microbiota abundance and composition, we analyzed microbial samples from participants of the Personal Genome Project through the Genomes, Environments, Traits conference in Boston in 2014. These participants have had their entire genome sequenced and often also provide their medical data to researchers. Eighty-four participants were swabbed for their axillary (armpit) microbes and answered a series of questions about their daily habits. Using high throughput sequencing, we assessed their 16S rRNA gene sequence (V4 region) to determine the abundance and composition of their axillary microbiota. After data quality control, 41 participants remained and we determined their genetic variants in 20 candidate genes associated with skin disorders or odor profiles. The abundance of key skin microbes was then compared to differences among humans in the variants of these key genes using a non-parametric Kruskal Wallis ANOVA test. We found at least five single nucleotide variants (across two genes) that associate with differential abundance of microbiota (e.g., Streptococcus, Staphylococcus and Corynebacterium). These data suggest an influence from the host genome on the microbes inhabiting our skin, and suggest future work will be valuable in identifying a more complete picture of the microbes we have co-evolved with.

ABSTRACT. Amazonian populations are exposed to diverse parasites and pathogens, including protozoal, bacterial, fungal, and helminthic infections. Yet much of our understanding of the immune system is based on industrialized populations living in evolutionarily novel environments, where these infections are rarer than they would have been through the majority of human history. We examine distributions and age-related changes in 22 measures of immune function for Bolivian forager-horticulturalists, and compare these to US and European populations. Subjects were 6,338 Tsimane aged 0-90 years. Blood samples collected between 2004-2014 were analyzed for 5-part blood differentials, C-reactive protein, erythrocyte sedimentation rate (ESR), and total immunoglobulins E, G, A, and M. Flow cytometry was used to quantify naive and non-naïve CD4 and CD8 T cells, natural killer cells, and B cells. Compared to reference populations, Tsimane have elevated levels of most immunological parameters, particularly immunoglobulins, eosinophils, ESR, B cells, and natural killer cells. However, monocytes and basophils are reduced and naïve CD4 cells depleted in older age groups. We conclude that infectious and parasitic exposures of the Tsimane ecology lead to lymphocyte repertoires and immunoglobulin profiles that differ from those observed in industrialized populations. These differences have consequences for disease susceptibility and co-vary with patterns of other life history traits, such as growth and reproduction. Moreover, an understanding of immune function under high pathogen stress may help us to understand the emergence of many non-infectious diseases in industrialized populations where pathogen stress is low.

ABSTRACT. Invertebrates lack the cellular and physiological machinery of the adaptive immune system, but show specificity in their immune response and immune priming. Functionally, immune priming is comparable to immune memory in vertebrates. Individuals that have survived exposure to a given parasite are better protected against subsequent exposures. Protection may be cross-reactive, but demonstrations of persistent and specific protection in invertebrates are increasing. This immune priming can cross generations ("trans-generational" immune priming), preparing offspring for the prevailing parasite environment. While these phenomena gain increasing support, the mechanistic foundations underlying such immune priming, both within and across generations, remain largely unknown. Using a transcriptomic approach, we show a bacterial challenge to bumblebee queens, known to induce trans-generational immune priming, alters daughter (worker) gene expression. Daughters, even when unchallenged themselves, constitutively express a core set of the genes induced upon direct bacterial exposure, including high expression of antimicrobial peptides, a beta-glucan receptor protein implicated in bacterial recognition and the induction of the toll signaling pathway, and slit-3 which is important in honeybee immunity. Maternal challenge results in a distinct upregulation of their daughters’ immune system, with a signature overlapping with the induced individual response to a direct immune challenge. This will mediate mother-offspring protection, but also associated costs related to reconfiguration of constitutive immune expression. Identification of conserved immune pathways in memory-like responses has important implications for our understanding of the innate immune system, including the innate components in vertebrates, which share many of these pathways.

ABSTRACT. The immune system is often depicted as a two-edged sword, one edge providing protection against invading pathogens and proliferating malignant cells, the other edge incurring damage to the host if the immune response is misdirected or over-expressed. Disentangling immune protection and damage has been very challenging as the relative costs/benefits of immune activation might depend on several traits, including species-specific features, infectious dose, or the immune pathway involved. Here we conducted a large survey of studies on rodent models where animals knocked out for different cytokines (th1, th2, pro-, anti-inflammatory) have been compared to wild type individuals in terms of changes in parasitemia and survival. The literature survey encompasses about 100 studies covering a large spectrum of cytokines and pathogens (from viruses to protozoa). To our knowledge, this is one of the first attempts to provide a comprehensive assessment of the relative importance of immune protection and damage in shaping disease severity.

ABSTRACT. Sialic acid-binding immunoglobulin-type lectins (Siglecs) are a pan-mammalian family of immune receptors whose primary function is recognition of self and inducing immune tolerance. The CD33-related (CD33r) Siglecs are a sub-group of this diverse family; CD33r Siglecs show multiple genetic and biochemical differences between primates, and are believed to be rapidly evolving. For example, Siglec 11 has acquired a human-specific expression pattern in brain microglia, while Siglecs 5 and 14 are paired receptors that coordinate immune responses to pathogens. In the context of Group B Streptococcus (GBS) infection, polymorphisms in Siglec 14 influence prematurity risk in mothers colonized with the infection. To better understand the evolutionary history of the Siglec receptor family, we use a novel homology based algorithm to identify Siglec clusters present across ten primate species as well as in mouse and dog. Additionally, we reconstruct the phylogeny of this gene family across primate species using state-of-the art phylogenetic techniques. Finally, we compare within- and between-species population fixation indices to identify the genetic structure of polymorphisms within the Siglec family. Taken together, our data suggest that the Siglec family is one of the most rapidly evolving gene families in primate genomes. Because some of the tissues and functions that Siglecs are involved exhibit major phenotypic differences between humans and other primates, our work raises the hypothesis that understanding the evolution of this gene family may be relevant for understanding certain aspects of human health.

ABSTRACT. MHC (major histocompatibility complex) genes encode cell surface glycoproteins that present antigens to lymphocyte receptors to trigger and maintain the immune response to infection. Extremely high polymorphism of classical MHC genes is maintained by natural selection. The B*57 allele of HLA-B, which is the most polymorphic MHC gene in humans, associates more strongly than any other HLA allele with slower progression of infection with the HIV-1 lentivirus into AIDS. Wild ape populations are ideal for studying such host-pathogen evolution and dynamics. Chimpanzee (Pan troglodytes) subspecies can be endemically infected with SIV (simian immunodeficiency virus), whereas bonobos (Pan paniscus) are not. We compared the polymorphism of HLA-B orthologs in wild populations of chimpanzee (Patr-B) and bonobo (Papa-B). These include the entire population of 125 P. t. schweinfurthii chimpanzees from Gombe National Park, Tanzania, which harbor SIVcpz. Also studied were 130 bonobos from six populations in the Democratic Republic of the Congo. Patr-B and Papa-B allelic variations were characterized by PCR amplification and sequencing of exons 2 and 3, using DNA extracted non-invasively from feces. In the Gombe chimpanzees, we discovered 11 Patr-B alleles, of which seven were novel. Four Patr-B alleles differed significantly in frequency between SIVcpz-infected and uninfected chimpanzees, including Patr-B*06:03. We show Patr-B*06:03 is phylogenetically related to HLA-B*57 and part of a lineage that also includes gorilla Gogo-B alleles. Patr-B*06:03 also associates with reduction in SIVcpz viral load, assessed from feces. In bonobos, we defined >20 alleles of Papa-B. These alleles are maintained within bonobo populations with number and frequency distributions similar to chimpanzee and indigenous human populations of comparable size. However, finding no alleles belonging to the conserved B*57 lineage suggests bonobo Papa-B has experienced a different history of selective pressure from immunodeficiency-causing lentiviruses than the MHC-B genes of other African apes and humans.

ABSTRACT. Many studies have investigated the origins of specific human diseases, but fewer have examined how parasite richness changed along the human lineage. Here, we investigated three hypotheses. (1) The hyper-parasitism hypothesis views humans as especially parasitized compared to other primates. This widely accepted hypothesis is attributed to contact with domesticated animals, sedentary lifestyles, and high densities. (2) Conversely, the cultural benefits hypothesis proposes that behavioral and psychological traits – like medicinal plant use, hygienic behaviors, and disgust responses – have reduced the number of parasites infecting humans. (3) The null hypothesis states that epidemiological transitions had weak effects on parasite richness, and humans therefore have as many infectious agents as expected given our characteristics.

In sheer numbers, humans host many more disease-causing organisms (1415) than any other primate (maximum of 82). This would seem to support the hyper-parasitism hypothesis. However, humans also have enormous populations, live globally, and are better studied than any other primate; these factors may account for high parasite richness without invoking distinct factors unique to humans. Thus, we built a statistical model using predictors of parasite richness in non-human primates, including population density, latitudinal range, geographic range, body mass, and phylogeny. To avoid extrapolating beyond the primate data, we focused on infectious diseases in two countries: Nigeria and Madagascar. We used species accumulation curves to estimate parasite richness when holding sampling constant, and Bayesian approaches to fit the model and make predictions.

The primate model predicts the observed virus and helminth richness of humans in Madagascar and Nigeria, consistent with the null hypothesis. Remarkably, however, these populations appear to be under-parasitized by protozoa (observations are outside the predicted 95% credible intervals), supporting the cultural benefits hypothesis. Overall, our results challenge current thinking about epidemiological transitions in humans. We are expanding the analysis to seven additional countries.

ABSTRACT. The most common breast cancers are estrogen receptor-positive, therefore risk of breast cancer in women increases with high lifetime exposure to estrogens. Many factors that increase risk of breast cancer have been identified. However, most of these factors cannot be easily modified and thus knowledge about them has a limited practical use for designing strategies of breast cancer prevention.

Studies in human reproductive ecology show that the availability of metabolic energy has a significant impact on the levels of ovarian hormones, including estrogens. Differences among women in lifetime exposure to estrogens can, in part, be explained by variation in adult lifestyle conditions that determine levels of physical activity or energy balance. In addition, the ovarian function is, to some extent, programmed in utero and subsequently influenced by the conditions experienced during childhood growth and development.

The relative importance and interactive impact of different energetic factors on ovarian function are not well understood. However, it is now clear that physical activity is one of the most powerful factors with the ability to lower the estrogens levels and reduce the risk of breast cancer. Surprisingly, it is still not known what amount of physical activity is needed for a meaningful reduction in the levels of reproductive hormones. It is likely that the beneficial dose depends on fetal and childhood developmental conditions that change the sensitivity of the ovarian function to energetic factors in adulthood. Studies on the interactive effects of factors capable of influencing the levels of estrogens, operating during all life stages, are needed to suggest more effective breast cancer prevention programs.

ABSTRACT. The deployment of testosterone supplementation to healthy men, especially those that are older has become increasingly common within the United States and throughout the globe. While the reported effects include greater muscle mass, strength, increased libido, and improved affect, the long term consequences of testosterone supplementation are poorly known. Limited evidence from the clinical literature as well as from non-human animal models suggest that testosterone supplementation may lead to detrimental outcomes that are consistent with trade off predictions made by life history theory. Moreover natural variation in testosterone levels between and within populations is seldom considered by physicians or discussed within the clinical literature when considering the benefits and risks of testosterone supplementation. This presentation outlines (1) the significance of normal variation in male neuroendocrine function, specifically in regards to between population differences in testosterone levels as well as variation in age associated changes in testosterone; (2) physiological sources of variation that contribute to normal differences in testosterone levels such as production, clearance rates, carrier protein binding, and genetic variation in regulatory enzymes and gonadotropins such as luteinizing hormone. Recent anthropological, clinical, and epidemiological literature are presented to (1) illustrate that normal testosterone variation between and within populations should be considered in the development and application of testosterone supplementation in healthy men; (2) predictions from evolutionary and life history as well as field studies motivated to test these predictions can inform the risks and benefits of testosterone supplementation in health men.

ABSTRACT. Public health efforts promote the first 1000 days of life as influential for health and well-being across the lifespan. This developmental period has both vulnerability and opportunity for the integration of infant physical, behavioral, and microbial systems. Previous research of this developmental stage has primarily targeted physiological influences before birth and behavioral care during infancy, but mammals produce milk extending physiological investment post-natally. Unlike adults in Westernized, Educated, Industrial, Rich, Democratic nations, far removed from the ancestral conditions that shaped our bodies, the breastfed infant develops within an “adaptively relevant environment.” Cross-cultural investigations combined with an evolutionary approach to biomedical models yield new perspectives of mothers, milk, and infants. Most importantly milk is an integrated food, medicine, and signal as milk nourishes, protects, and informs the developing neonate through nutrients, immunofactors, and hormones. Milk varies across evolutionary time, populations, individuals within populations, and within mother longitudinally. In these ways, mother’s milk reflects the “here and now” and the “there and then.” Biological and social scientific research on this topic can directly translate to more personalized clinical recommendations and health optimization for mothers and their infants as well as substantiate the importance of infrastructure and institutional support for breastfeeding. Further, a better understanding of the composition and function of milk informs the composition of a more representative infant formula or donor milk selection for those mothers facing obstacles or contraindications to breastfeeding. Lastly, decoding mother’s milk will allow for enhanced precision medicine for the most fragile infants and children in neonatal and pediatric intensive care units. Transdisciplinary approaches to mother’s milk research, along with public engagement, facilitate discoveries at the bench and their translation to applications at the bedside.

ABSTRACT. Ovarian follicular dynamics show the ovaries to be constantly active, with consequences for fecundity and the experience of the menstrual cycle. The thickness of the endometrium also varies through the window of implantation, even among normo-ovulatory women. Variation in these aspects of reproductive physiology demonstrate that genes, life history trajectories, lived experiences, and current energetic status contribute to fecundity. They also point a path forward for understanding the responsiveness of different individuals to exogenous hormonal treatments. At this time the major points of variation in exogenous hormonal treatments for contraceptive purposes are in drug delivery methods, not concentration, of synthetic sex steroids. While many more synthetic hormone preparations exist for assisted reproductive technologies, doctors choose between these treatments based on the historical preferences of their practice. This presentation describes a path forward in leveraging our understanding of genetic and lifestyle variation in reproductive function to produce personalized medicine strategies to better meet women’s reproductive health needs. Adopting personalized medicine strategies will reduce side effects and increase efficacy of existing methods, while also pointing towards future novel therapies.

ABSTRACT. Population-based studies have documented significant variation in reproductive maturation and function among diverse human groups in relation to the socio-ecological environments in which they live. Recent empirical data show that human reproductive plasticity has, to a large extent, a developmental origin. Data on the influence of pre- and post-natal nutritional status on different human reproductive traits indicates that energetic conditions during development influence the size and characteristics of reproductive organs, levels of adult gonadal endocrine function, its regulation and its sensitivity to energetic stress. Such influences are likely to underpin the associations between developmental conditions and duration of adolescent subfertility, age at first pregnancy, proportion of ovulatory cycles and reproductive behaviour, which ultimately underlie differences in fertility. At another level, developmental conditions affect an individual’s lifetime reproductive success by determining the length of the reproductive span by influencing the tempo and timing of reproductive maturation and reproductive senescence. Medical interest in the developmental plasticity of human reproductive function is typically focused on elucidating the mechanisms involved with a goal of devising diagnostic and therapeutic tools. A life history perspective in contrast, extends beyond proximal causation and offers insights into what the costs and benefits of alternative developmental trajectories may be, in terms not only of fertility, but of survival and disease risk. In this paper I will review what we know (and don´t) about developmental plasticity of human reproductive function, analyze its impact on current epidemiological and demographic trends, compare the clinical and evolutionary approaches to the evidence, and highlight the contribution of an evolutionary viewpoint to our understanding of such patterns, particularly in the context of rapidly changing socio-economic and ecological systems worldwide.