Evolutionary Medicine and the Media: Engaging Stories and Tricky Concepts
SPEAKER: Carl Zimmer
ABSTRACT. In this talk, I discuss the media coverage of evolutionary medicine since it first emerged in the 1990s. Reporters have been drawn to a wide range of examples, from antibiotic resistance to the evolution of cancer defense mechanisms. But they have also neglected some of the most important concepts, including maladaptation and genetic drift, because few readers understand their scientific foundations. Journalism can help introduce the public to evolutionary medicine, but without better science education, it will be difficult to explore its full implications.
Population history and patterns of sex-biased evolution
SPEAKER: Melissa Wilson Sayres
ABSTRACT. The mammalian sex chromosomes, X and Y, originated from a pair of homologous autosomes, but, over time, suppression of recombination between them led to the degradation of the Y chromosome, and tremendous divergence between the X and Y chromosomes. This divergence, and the unique inheritance patterns of sex chromosomes, also means that sex-biased genomic regions can be used to infer the relative influences of demographic history and selection acting on populations. This is because, while natural selection and demographic history may result in similar patterns on any one genomic region, they will leave unique signatures when considering all genome regions together. By simulating patterns of variation across all genomic regions (autosomes, X chromosome, Y chromosome, and mtDNA), we characterize the consequences of different demographic scenarios (notable variance in male reproductive success and population bottlenecks) on genome-wide patterns of diversity. These patterns will form the basis for accurately interpreting empirical patterns of diversity observed across genomes, especially across human populations.
Exploring evolutionary causes of differential susceptibility to acute mountain sickness in Nepali populations from the Gaurishankar Area
ABSTRACT. Populations settled in remote Himalayan valleys coming up to the Nepali Gaurishankar mountain range at the border with the Tibetan plateau belong to three main ethnic groups that are distributed along a wide altitudinal range (900-4,900 m a.s.l.). People speaking Indo-Aryan languages appear to be biologically and culturally related to populations from the Indian subcontinent and live exclusively at low altitudes. Groups speaking Tibeto-Burman languages (e.g. Tamangs) and Sherpas are instead supposed to be tightly related to high-altitude Tibetans and to have crossed the Himalayan range in recent historical periods. Tamangs have then largely spread across Gaurishankar valleys up to ~2,500 m a.s.l., whereas most local Sherpa communities remained considerably isolated at high-altitude up to the recently abandoned Bomdok village beside the Ripimo Glacier (4,900 m a.s.l). Coupled with cases of Acute Mountain Sickness (AMS) reported for Tamangs hired as porters in mountaineering expeditions, such pattern of population structure questions their actual adaptation to hypoxia and, indirectly, their presumed common ancestry with respect to Sherpas and high-altitude Tibetans. To disentangle this complex anthropological scenario and to investigate evolutionary causes of different AMS susceptibility between Tamangs and Sherpas, we inferred their genetic histories from genome-wide data generated for more than 700,000 SNPs on 75 individuals collected during three humanitarian and scientific field expeditions. Their genomic relationships with other Sherpa, Tibetan, South Asian and East Asian populations were also explored by comparison with genotype data from 1,152 additional subjects belonging to 72 human groups. Finally, we searched for shared or private signatures of natural selection on the Tamang and Sherpa genomes that could be ascribable to adaptive processes triggered by high-altitude hypoxia and that could provide crucial insights into their different susceptibilities to AMS.
This work was supported by ERC-2011-AdG295733 to DP, NSF Award 1153911 to CMB, NSF Grant BCS-0924726 to ADR.
Evolution of homeostatic mechanisms, cryptic genetic variation, and predisposition to disease
SPEAKER: Fred Nijhout
ABSTRACT. Metabolic and physiological systems have evolved a broad diversity of homeostatic mechanisms that stabilize phenotypes against genetic and environmental variation. Deterministic mathematical models of such systems enable one to study the properties of these stabilization mechanisms and see how they are influenced by genetic and environmental variables. This work has shown that phenotypic stability in these systems is a dynamic property that is actively maintained. When homeostatic mechanisms operate normally, they allow for the accumulation of cryptic genetic variation. Incorporating data from human genetic diseases allows us to document the extent of this genetic variation and explain why it is “cryptic” at the phenotypic level even though some mutations have very severe effects at the molecular level. We show that mutations, or environmental factors, that alter the homeostatic dynamics allow certain cryptic mutations to become phenotypic, and give a natural explanation of why certain conditions “predispose” to disease. Analysis of the distributions of mutations in phenotypic landscapes, and statistical analyses of corresponding population models, allows one to design strategies for personalized medicine. Moreover, population versions of the deterministic models allow one to study how phenotypic homeostasis can evolve.
A deep sequencing tool for detecting drug resistance in polyclonal malaria infections
ABSTRACT. Current tools struggle to detect drug resistant malaria parasites when infections contain multiple parasite clones, which is the norm in high transmission settings in Africa. Our aim was to develop and apply an approach for detecting resistance that overcomes the challenges of polyclonal infections without requiring a genetic marker for resistance. Clinical samples from patients treated with artemisinin combination therapy were collected from Tanzania and Cambodia. By deeply sequencing a hypervariable locus, we quantified the relative abundance of parasite subpopulations within infections and revealed evolutionary dynamics during treatment. Slow clearance is a phenotypic, clinical marker of artemisinin resistance; we analyzed variation in clearance rates within infections by fitting parasite clearance curves to subpopulation data. In Tanzania (where resistance is not yet thought to be a problem) we found substantial variation in clearance rates within individual patients. Some parasite subpopulations cleared as slowly as resistant parasites observed in Cambodia. All else being equal, simulated infections predict that modest increases in the frequency of these subpopulations could substantially increase time to cure. Our method can detect rare, slow clearing parasites in vivo whose phenotypic effects would otherwise be masked. Since our approach can be applied to polyclonal infections even when the genetics underlying resistance are unknown, it could aid in monitoring the emergence of artemisinin resistance. Our application to Tanzanian samples uncovers rare subpopulations with worrying phenotypes for closer examination.
Identifying genomic loci involved epithelial cancer using comparative genomics
ABSTRACT. Epithelial cancers, such as breast, ovary, and prostate, account for up to 20% of deaths in human populations. In our nearest living evolutionary ancestor, the chimpanzee, however, rates of epithelial cancer are significantly lower (2-4%) while rates for other types of cancers are comparable. Although part of this difference is likely due to environmental factors, we believe there is a genetic component as well. To study this difference we employ an assay in fibroblasts isolated from healthy skin tissue. Previous studies show that fibroblasts in culture exposed to a "serum challenge" engage in a pattern of gene expression that mimics that found in tumors. Therefore, we used this assay to compare how human and chimpanzee cells behave in this cancer-like response. We performed RNA-seq and DNase-seq to investigate differences in gene expression and gene regulation, respectively. Our data show significant differences in expression and in areas of open chromatin between our species. In particular, genes involved in cell adhesion, inflammation, and homeostasis pathways are differentially expressed between human and chimpanzee, which may help explain differences in epithelial cancer rates.
Cumulative early life adversity predicts longevity in wild baboons
ABSTRACT. Adverse experiences in early life can have profound and pervasive effects on human health and survival. These observations cut across study designs, national boundaries, and disease types. However, the roots of early life effects likely reach much further back in our evolutionary history. In nonhuman animals, early adversity has also been shown to predict components of fitness, especially adult fertility. Multiple adverse conditions are thought to be especially toxic, but this hypothesis has rarely been tested in a prospective, longitudinal framework, especially in long-lived mammals. Here, we use prospective data on 196 wild female baboons to show that cumulative adversity from six early life sources—drought, high density social groups, low maternal status, low maternal social integration, maternal loss, and the presence of a competing younger sibling—predicts natural adult lifespan. Females who experience ≥3 sources of early adversity die a median of 10 years earlier than females who experience ≤1 adverse circumstances (median lifespan is 18.5 years). Females who experience the most adversity are also socially isolated in adulthood, suggesting that social processes partially explain the link between early adversity and adult survival. Because age at death strongly predicts the total number of surviving offspring in this population (r=0.95), females exposed to high adversity in life paid a cost both in years of their own lives and in overall Darwinian fitness. Together, our results provide powerful evidence for the developmental origins of health and disease and indicate that close ties between early adversity and survival arise even in the absence of health habit and health care-related explanations.
Comparative genomics of innate immune responses to infection in primates
ABSTRACT. Primates exhibit striking differences in susceptibility to multiple pathogens. For example, humans are highly susceptible to bacterial sepsis and chronic hepatitis C infection, while many other catarrhines are not. Innate immunity is strongly implicated in such disease progression, however a lack of comparative immune response data from major primate clades inhibits our understanding of how this response has evolved in susceptible and resistant primates. Here we report a genome-wide comparative study of primate innate immune responses to bacterial and viral molecules associated with severe infections. We stimulated leukocytes from humans, chimpanzees, rhesus macaques, olive baboons and ring-tailed lemurs with molecular motifs representing Gram-negative bacterial (LPS) and viral (Gardiquimod) pathogens. Blood was stimulated for 4 and 24 hours and leukocytes responses assessed via RNA-seq. Overall, whole transcriptome responses agreed with species phylogeny and we found a considerable number of genes and entire regulatory networks, that showed species-specific responses (SSR) to both immune-stimuli. We show that a significant number of genes associated in SSR have signatures of rapid evolution in either their coding sequence of promoter regions, which suggests that some of the lineage-specific changes have been adaptive. We also found a considerable overlap between species-specific response genes and genes known to be associated with susceptibility to immune-related disorders in humans suggesting that the observed changes might contribute to inter-species differences in immunity and severe infection manifestation.
Understanding how evolution has shaped disease susceptibility in the Ugandan red colobus monkey (Procolobus rufomitratus tephrosceles)
ABSTRACT. The distribution and dynamics of infectious diseases are influenced by a variety of environmental and evolutionary factors. Over the past 11 years, the Kibale EcoHealth Project has documented patterns of infectious disease both within and between various species across the Kibale region in Western Uganda. It is now clear that certain aspects of these pathogen distributions cannot be explained by ecology and/or demography alone. We are thus currently using this system to investigate the influence of host genetics on disease prevalence in wild primates. In doing so, we hope to reveal the genetic architecture of primate disease phenotypes present in the Kibale community and to test evolutionary hypotheses for disease susceptibility. An initial example of this work focuses on the Ugandan red colobus, which shows individual variation in infection intensity from whipworm (Trichuris sp.) – a gastrointestinal parasite that has known zoonotic potential and human health consequences. We identified 15 SNPs located within transcription factor binding sites of the Ugandan red colobus MHC-DQA1 core promoter, two of which were associated with whipworm infection intensity. Reporter assays suggest that these two SNPs have the potential to drive expression of MHC-DQA1 differently in vitro, and we are currently investigating patterns of MHC-DQA1 expression in vivo using RNAseq. Interestingly, we also found evidence that variation in this regulatory region is associated with changes in gut microbial diversity in these animals. Lastly, we detected a strong signal of balancing selection on this MHC regulatory region that is likely maintaining these functional polymorphisms in this population. Taken together, this work suggests that evolution of regulatory regions have played an important role in shaping disease susceptibility in humans and nonhuman primates. Ongoing work in the Kibale EcoHealth Project is focusing on such approaches to further elucidate relationships between evolution and health.
The genomic signature of social adversity in rhesus macaques
ABSTRACT. Social interactions can exert strong selective pressures on group-living animals, including humans. However, the proximate mechanisms that underlie such pressures remain unclear, especially on the molecular level. Recent studies suggest that changes in gene regulation may play a role, but we still know little about the biological pathways influenced by social adversity, the behaviors most responsible, and the degree to which animals continue to respond to changes in the social environment throughout life. Here, we used experimental manipulations of social status (i.e., dominance rank) in 9 rhesus macaque social groups (n=45 females) to investigate its consequences for genome-wide gene expression. Among purified populations of white blood cells, we found that Natural Killer (NK) cells were by far the most sensitive to social status, with a secondary contribution from helper T cells. This effect was partly attributable to rank-associated affiliative relationships, and to a lesser extent to rank-associated differences in aggression. Further, using an ex vivo model of bacterial infection, we found that a substantial fraction of genes exhibited an exaggerated response to immune stimulation in low ranking females. Our findings are consistent with glucocorticoid resistance and baseline inflammation in low status animals. Finally, we conducted a mid-study intervention that rearranged the ranks of all study subjects. Gene expression profiles changed in accordance with changes in rank, indicating large-scale plasticity in gene expression for social status-associated genes. Together, our findings provide novel insight into the importance of both behavioral and molecular mechanisms in linking social status to health and fitness-related consequences.
Using the gut microbiota to understand primate ecology and evolution
SPEAKER: Katherine Amato
ABSTRACT. Clinical-type research aimed at understanding the impacts of the gut microbiota on human health is currently exploding. However, while necessary for putting clinical research into context, broader, ecological and evolutionary perspectives on host-gut microbe interactions in wild animals under selective pressure are less common. Here, I integrate gut microbes into a basic model of primate bioenergetics by discussing the impact of host age and sex, seasonal shifts in host diet, and host habitat differences on the gut microbiota of wild, black howler monkeys (Alouatta pigra) in southeastern Mexico. Data suggest that the gut microbiota buffers howler monkeys against nutritional shortfalls during periods of growth and reproduction as well as during periods of reduced energy intake. Relatedly, a reduction in gut microbial diversity appears to contribute to nutritional stress and increased health risks in howler monkeys inhabiting anthropogenically degraded forests. These patterns imply that the gut microbiota has multiple effects on host nutrition, health, and ultimately, fitness, and provides an impetus for further studies of host-microbe-environment interactions in wild primates. These data also emphasize the need for recognizing the influence of gut microbes on human ecology and evolution and implications for human health.
Coffee and snacks will be provided.
An eco-immunological approach for cancer: a new role for infectious diseases?
ABSTRACT. Since the beginning of the 20th century, parasitism has emerged as a fundamental mechanism for cancer causation with a growing number of pathogens recognized as oncogenic. Meanwhile, oncolytic viruses have also attracted considerable interest as possible agents of tumor control. Lost in this dichotomy between oncogenic and oncolytic agents, the indirect influence of parasitic communities on cancer, notably through the multiple trade-offs involved in immune system, has been largely unexplored. Here, we address the various ways by which parasitic organisms can lead to immune system deregulation and then interfere with oncogenic processes. Using first a theoretical framework, we show that repeated acute infections could impact the accumulation of cancerous cells through continuous perturbation of immune system efficiency. Through a drosophila model, we report the activity of immune genes and the accumulation of cancerous cells after experimental infections to test these theoretical predictions. We finally challenge our new theory with a cutting-edge statistical analysis of databases reporting human cancer incidences and parasite occurrence throughout the world to report evidences for an indirect impact of infectious diseases on carcinogenesis. We conclude by discussing how integrating the community of parasitic organisms may improve public health strategies against most of cancer, which could represent a new step towards a “global health” perspective.
Cooperation and conflict beyond the womb: Fetal microchimerism and maternal health
ABSTRACT. During pregnancy, there is a bi-directional exchange of fetal and maternal cells across the placenta. The presence of fetal cells has been associated with both positive and negative effects on maternal health. These paradoxical effects may be due to the fact that maternal and offspring fitness interests are aligned in certain domains and conflicting in others. Here we use a cooperation and conflict theory framework to propose an explanation for this paradox. Considering the evolutionary and phylogenetic origins of microchimerism, fetal cells may have a similar function to the placenta. Just as the placenta’s physiology is designed to transfer resources from the maternal body to the offspring in the womb, the physiology of fetal cells in maternal tissues may enhance resource transfer to the offspring after parturition. This resource transfer may be mutually beneficially for both maternal and offspring fitness interests, or fetal manipulation may push maternal tissues beyond the maternal optimum leading to conflict over resource allocation. Depending on the ecological context (the mothers body), fetal cells may function both to contribute to maternal somatic maintenance (e.g. wound healing) and to manipulate maternal physiology. We suggest fetal cells may play important roles in continued maternal investment in the offspring through manipulation of lactation, thermoregulation, and attachment systems. The framework proposes fetal cells should be more common in tissues that are the site of resource transfers (e.g. the breast, thyroid, and brain) and we offer testable predictions about the role of fetal microchimerism in lactation, thyroid function, autoimmune disease, cancer and maternal emotional, and psychological health.
Coevolution of the highly complex HLA and KIR gene families impacts human immunity and reproduction.
ABSTRACT. The physiological functions of natural killer (NK) cells in human immunity and reproduction depend upon diverse interactions between killer cell immunoglobulin-like receptors (KIR) and their HLA class I ligands. The genomic regions containing the KIR and HLA class I genes are unlinked, structurally complex, and highly polymorphic. They are also strongly associated with a wide spectrum of disease, including infections, autoimmunities, cancers, and pregnancy disorders, as well as the efficacy of transplantation and other immunotherapies. Although it is clear this polymorphism directly affects NK cell function and human immunity, population studies of KIR allelic diversity have been few. To facilitate study of these extraordinary genes, we developed a method that captures, sequences and analyzes the 13 KIR genes and the HLA genes from genomic DNA. We also devised a bioinformatics pipeline that attributes sequencing-reads to specific KIR genes, determines copy number by read depth, and calls high-resolution genotypes for each of the KIR genes. To sample the world’s KIR allelic diversity, we analyzed populations of low genetic diversity from Polynesia and South America and, accounting for ancient population substructure in Africa, seven populations from sub-Saharan Africa. In all populations the majority of individuals studied had unique KIR/HLA genotypes. In every population we identified private alleles including those with dramatic effect on NK function, such as 2DL1*022, common and unique to the KhoeSan hunter-gatherers from Southern Africa that has switched specificity from one HLA ligand to another. Using phylogenetic analysis and simulations we show that natural selection is exquisitely targeted to the sites of KIR that contact HLA and demonstrate strong evidence for balancing selection of the KIR locus. We also show that co-evolution of the HLA and KIR molecules remains ongoing in extant populations. Studying the evolution of KIR and HLA has multiple benefits and insights for human health
Diagnosing Taenia serialis in wild geladas: Novel use of adapted urine Ag-ELISA for assessing wildlife health.
ABSTRACT. Six percent of wild geladas (Theropithecus gelada) in the Simien Mountains National Park, Ethiopia, exhibit bulging cysts caused by the tapeworm parasite Taenia serialis. This parasite, spread through contact with canid feces, can also infect humans, and anthropogenic change may affect the patterns of infection in geladas as well as the risk of infection for humans. Understanding the ecology of T. serialis is thus critical for identifying at-risk wildlife and human populations. However, identifying infection based on visual diagnosis of cysts is of limited use because internal cysts are undetectable with this method. Unfortunately, classical diagnostic imaging and serological methods are often prohibited in wild populations, and may not be available for human diagnosis in remote areas. To address this problem, we adapted a monoclonal antibody-based sandwich ELISA (Dorny et al. 2000) to non-invasively diagnose T. serialis infection in dried urine samples. Sample index values were calculated using the average negative and positive control values for the plate on which each sample was run. Because unweaned infants do not consume grass and are not exposed to T. serialis eggs, a positive cutoff was set by averaging the index values for infants (n=58) and adding two standard deviations. With this cutoff, the specificity of our test is 98.21% and the sensitivity 97.65%. While only 6.3% (n= 17) of sampled geladas had cysts, 15.1% (n=41) of sampled geladas were Taenia-positive. Furthermore, an additional 6.2% of sampled geladas (n=12) exhibited ‘transient’ infections, in which animals become positive but are presumably able to fight off infection. This system presents a unique opportunity to investigate the drivers of susceptibility and the fitness impacts of a costly parasite on a wild primate population and to identify parasites of potential risk to humans in remote areas.
Evolutionary Developmental Pathology and Anthropology: a new field linking development, comparative anatomy, human evolution, morphological variations and defects, and medicine
SPEAKER: Rui Diogo
ABSTRACT. We introduce a new subfield of the recently created field of Evolutionary Developmental Anthropology (Evo-Devo-Anth): Evolutionary Developmental Pathology and Anthropology (Evo-Devo-P'Anth). This subfield combines experimental and developmental studies of non-human model organisms, biological anthropology, chordate comparative anatomy and evolution, and the study of normal and pathological development in humans. Above all, instead of focusing on studies of other organisms to try to better understand human development, evolution, anatomy and pathology, it places humans as the central case study, i.e. as truly model organism themselves. We summarize the results of our recent Evo-Devo-P'Anth studies and discuss long-standing questions in each of the broader biological fields combined in this subfield, paying special attention to the links between: 1) Human anomalies and variations, non-pentadactyly, homeotic transformations, and "nearest neighbor" vs "find and seek" muscle-skeleton associations in limb+facial muscles vs other head muscles; 2) Developmental constraints, the notion of "phylotypic stage", internalism vs externalism, and the "logic of monsters" vs "lack of homeostasis" views about human birth defects; 3) Human evolution, reversions, atavisms, paedomorphosis and peromorphosis; 4) Scala naturae, Haeckelian recapitulation, von Baer's laws, and the parallelism between phylogeny and development, here formally defined as "Phylo-Devo parallelism"; and 5) Patau, Edwards, and Down, Syndrome (trisomies 13, 18, 21), atavisms, apoptosis, heart malformations and medical implications.
Evidence for Applications of Evolutionary Biology Across Health Care Disciplines
ABSTRACT. Background: Applications of evolutionary biology to medicine and public health have become increasingly recognized over the past 25 years. However, these two disciplines only represent a subset of all health care sciences, with physicians comprising just 13% of all licensed U.S. health professionals. Objective: To determine the frequency with which terms related to evolutionary biology are used in the literature of health care disciplines outside of medicine and public health. Method: Google Scholar, PubMed, CINAHL, and Social Services Abstracts were search for English language publications between 1980 and 2016 containing the keywords “evolutionary biology,” “biological evolution,” “natural selection,” “Charles Darwin,” and “Darwinian” anywhere in the article. The search was limited to journals with titles or subjects including the words pharmacy, dentistry, nursing, social work, physical therapy, speech and language pathology, and nutrition. Clinical psychology was excluded as evolutionary psychology is already well established. Results: Approximately 9,313 publications containing the specified keywords were found in the overall health care literature, including medicine and public health. Of these, 1,331 (14%) corresponded to disciplines outside of medicine and public health. Nutritional science accounted for the vast majority of these publications (62%) followed in descending order by nursing (25%), social work (20%), pharmacy (6%), dentistry (4%), physical therapy (1.6%), and speech and language pathology (0.5%). Discussion: Although the relative contribution of health care disciplines other than medicine and public health to the body of literature in evolutionary health sciences is low, the finding suggests that there is interest by professionals in those disciplines to apply concepts of evolutionary biology in their fields. In order to capitalize on that interest, the evolutionary health care community must actively engage these practitioners and expand educational efforts to include a broad spectrum of health care professionals.
Comparative Oncology and the Search for Better Cancer Therapeutics
SPEAKER: Joshua Schiffman
ABSTRACT. The field of Comparative Oncology continues to expand at a rapid pace. In this talk, the power of comparative oncology will be explored for identifying universal pathways for the development of cancer, as well as for the prevention of cancer. The focus will be on hereditary cancer predisposition in humans, cancer risk in canines, and cancer resistance in elephants. Special attention will be given to how comparative oncology intersects with evolutionary medicine, and what can be translated from animals into treatment and prevention for cancer in human patients.
Identifying the intrinsic and extrinsic risks of cancer.
SPEAKER: Leonard Nunney
ABSTRACT. In the past year there have been two influential articles (one in Science, the other in Nature), purporting to separate the contributions of intrinsic and extrinsic factors to the overall incidence of cancer. In this context, intrinsic factors were defined as factors causing random errors in DNA replication, while extrinsic factors were defined as environmental factors that further increase mutation rates. Unfortunately both articles derive estimates based on false assumptions. Here I adopt an evolutionary perspective to examine the feasibility of accurately defining and separating the influence of these effects.
What to do with cellular cheaters? The cheater detection problem in multicellularity and cancer susceptibility
SPEAKER: Athena Aktipis
ABSTRACT. The cheater detection problem has been widely explored in the context of human sociality. Research has shown that people detect cheating in social rules like “If you take the benefit, you must pay the cost” or “You should not ask unless you are in need.” But a similar cheater detection problem exists in cellular sociality. Multicellularity is an extreme example of cooperation and coordination, and one that is possible largely because of the close relatedness of constituent cells. However, mutations can give rise to cellular cheaters that signal for more resources than they should, proliferate when they should not and shirk their cellular duties. If unchecked, these cells grow in frequency in the population, accumulate more mutations and eventually can lead to cancer. How has multicellularity solved this problem of detecting pre-cancerous cheaters? Multicellular bodies are equipped with an arsenal of cheater suppression mechanisms, many of which employ the principles of cheater detection. One of these is the cancer suppression gene TP53. TP53 is a central node in a complex cellular information processing system that integrates diverse signals to ‘decide’ whether a cell can continue its cell cycle, requires DNA repair or should undergo programmed cell death (apoptosis). The costs and benefits of these different alternatives differ for organisms with different sizes, life spans and reproductive strategies. By applying cheater detection and signal detection theory to the problem of cancer suppression, we can better understand the function of complex gene regulatory networks that protect multicellular bodies from cancer.
Cancer Selection Intensity using Model-Averaged Clustering
ABSTRACT. Tumorigenesis is an evolutionary process associated with the accumulation of somatic mutations. Somatic mutations can be deleterious to cancer cell lineages, neutral "passenger mutations", or they can be positively selected, increasing in frequency within tumors because they enhance any of a number of hallmarks of cancer in tumor cells. While methodologies for detecting statistical significance of mutations as "drivers" have become increasingly advanced, little has been done to quantify the extent to which positive selection operates on individual mutations in cancer genes.Positively selected somatic mutations increase survival and/or reproduction of tumor cells, increasing the fitness of cell lineages and driving the genesis and progression of cancer. To quantify the selective effects of mutations, we have developed an approach to estimate selection intensity of somatic single nucleotide mutations using model-averaged clustering. We analyze the clustering of mutations within gene sequences, comparing variant frequencies to the expectation to ascertain whether genes, gene regions, or individual sites within genes have been affected by selection as well as mutation, yielding an estimate (and 95% intervals of uncertainty) for the selection intensity conveyed by mutation at every position within the gene. Our approach can be used 1) to identify genes, gene regions, and sites that contribute to tumorigenesis when mutated, 2) to estimate the relative contribution of those genes, gene regions, and mutations to the somatic evolution of cancer, and 3) to evaluate the distribution of selection coefficients of all mutations within cancer types. Estimation of the effect of mutations on growth and survival of cancer is necessary to provide guidance toward the potential of directed cancer therapeutics and to design optimal therapeutic regimens against evolving cancer tissues.
Cure by Control: Evolutionary approaches to cancer therapy and prevention
SPEAKER: Carlo Maley
ABSTRACT. Cancers are highly evolvable, with large population sizes, high mutation rates, and a large genome filled with molecular tools that can be repurposed for the fitness of the cancer cells. Most therapies attempt to cure cancers through eradication of all the cancer cells, which, in disseminated disease, typically results in selection for resistant clones, failure of the therapy, recurrence of the tumor, and death of the patient. An alternative approach is control the cancer, without necessarily eradicating it, thereby transforming cancer from an acute disease to a chronic disease. An additional way to control cancer is to target its evolvability, slowing its evolution. Since most cancers require decades to evolve from the first initiated cell to a life-threatening disease, slowing its evolution by just a factor of 2 would eliminate cancer as a cause of death in most cases. I will present results from a variety of approaches, from sensitivity analyses of evolutionary simulations in order to identify effective targets for controlling cancer, to in vitro experiments to slow the evolution of eukaryotic cells (yeast), to in vivo adaptive therapy experiments in mice, in collaboration with Bob Gatenby.
Agent-based simulation of somatic evolution: Modeling the progression of Barrett’s esophagus to Esophageal adenocarcinoma
ABSTRACT. Despite almost four decades of research since the evolutionary theory of cancer was published, little is known about the clonal evolutionary dynamics of neoplastic progression. We developed an agent-based model of Barrett’s esophagus (BE) in order to explore and make testable predictions about these dynamics. BE is a medical condition that is considered a precursor of Esophageal adenocarcinoma (EA). It provides a unique opportunity to study the evolutionary process of neoplastic progression, since BE is not removed upon diagnosis, and instead, is followed through serial endoscopies with multi-region sampling at each endoscopy. We will present a simulation study in order to assess the effect of clonal evolutionary dynamics on tumor heterogeneity and cancer progression from BE to EA. In our generative model crypts constitute the proliferative units, which can mutate, replicate, die, and expand into neighboring locations in the tissue, according to independent rates and neighbor interaction parameters. Each crypt carries its own genotype, composed of a variable number of neutral and selective loci, which modulate three types of fitness advantages (survival, reproduction and mutation rates). Importantly, this process takes place within a hexagonal 2D spatial model, which allow us to account for spatial constraints and interactions with neighbors, and the phylogenetic relationships of the crypts are traced through time. These simulations were carried out using different combinations of parameters across a range of biologically realistic values that resemble the conditions of BE crypts. Thus, we could observe whether or not clonal expansions cause transient drops in the clonal diversity of the neoplasm. Moreover, by defining cancer as the expansion of a clone with a set of sufficient mutations, we studied the sensitivity of neoplastic progression to the different parameters of the model, thereby identifying the critical aspects of neoplastic progression that are the most promising targets for cancer prevention.
Evolving humans health: Insights from the paleopathological record
ABSTRACT. Paleopathology – the study of diseases of the past - can contribute significantly to the emerging research field of evolutionary medicine. Human disease patterns changed substantially through time. In this presentation we use various sources of “evidence” to show such short term alterations of human disease. Main influencing factors such as changes in environment, socio-economic stratification, influence prevalence and impact of diseases in pre- and historic populations. Data sources include thoughtfully interpreted text-based and iconographic evidence but also skeletal and mummified remains. Thus, state-of-the-art paleopathological studies contribute fundamental data to the understanding of the on-going evolution of human health. Disease load of the past – despite certain lack of medical data – shall be assessed hereby by using data of modern pathology reference collections (such as the Galler pathology collection at the University of Zurich) and meta-analysis data of e.g. mummies of ancient Egypt. Finally, the diagnostic pitfalls of paleopathological research and some recommendations how to improve the medical impact of such unique studies on sort term adaptation of human health shall be addressed too.
Evolutionary perspectives of rheumatologic disease
SPEAKER: Bruce Rothschild
ABSTRACT. Evolution is a term suggesting change and that does apply to infectious diseases such as tuberculosis. There is a clear transition in sequences and speciation from the earliest DNA isolation in the fossil record to that in contemporary organisms, although the skeletal damage is indistinguishable from what is observed in patients today. Identification of similar variation/evolution has actually proven elusive in both the paleontological and archeologic record of rheumatologic disease. The skeletal manifestations of rheumatoid arthritis, first recognized in 6500 ybp cemeteries from the western portion of the Tennessee and Green Rivers in the southeastern United States, are indistinguishable from those found today in contemporary patients. Diseases which occur as population phenomenon allow use of epidemiology as a valuable tool in their recognition. Such allows confident rejection of alleged cases of rheumatoid arthritis in the Old World prior to 1492. Rheumatoid arthritis was quite limited in geographic distribution for 5000 years, spreading 1000 years ago into Ohio, and beyond North America, only 300 years ago. A second form of inflammatory arthritis is actually much older. Currently referred to as spondyloarthropathy, it differs in pattern and character from rheumatoid arthritis, permitting its earliest recognition pre-dating the advent of the dinosaur. Not only are ancient patterns and character of skeletal alterations in archeologic sites dating 6000 ypb indistinguishable from those of contemporary patients, the same is true of the zoologic and paleontologic record. The prevalence varies with sanitation conditions in the archeologic record, but examination of the paleontologic record reveals a dramatic geometric increase in prevalence from the Oligocene in horses and rhinoceros from one and five percent respectively to eight and 35% today. Rheumatologic diseases have increased in prevalence over geologic time with little change, except for the appearance of a new disease in the form of rheumatoid arthritis 6500 ybp.
A medical perspective to study syphilis in human remains
ABSTRACT. The origin of syphilis has long been a subject of much debate for decades. Much of this debate centers on whether or not particular findings in human remains can be considered syphilitic in origin. Many criteria have been proposed, some highly stringent, and some quite lax. We believe that taking a medical diagnostic point of view could help to bring clarity to some of these debates. Currently, most syphilis diagnoses in developed countries are made utilizing molecular methods. However, historical methods, practices in resource poor environments, and utilization of clinical suspicion to elucidate false negatives can help illuminate methods of diagnosis in human remains. After a review of medical and paleopathological literature, we found five findings that can be considered pathognomonic for congenital or acquired syphilis. One of these, thymic cysts, are limited to mummified remains. We also found eight signs that when found with another sign, make the diagnosis of syphilis likely. The remaining signs can be used with a differential diagnosis process to determine the likelihood that they represent a syphilis infection. Two of these signs can only be found in mummified remains. We would also like to stress that we believe that several of these signs are not routinely looked for in human remains, and that methodological scrutiny for all these findings may bring further clarity to the pre-Columbian prevalence of syphilis. As several of these signs are only found in mummified remains, the use of diagnostic imaging in searching for these signs may prove fruitful. We feel as though this interdisciplinary blending of medical diagnosis and paleopathology is a unique approach that has the possibly of being utilized in the study of the origins of other human diseases.
Low back pain as a trade-off to efficient walking: A new perspective on connecting evolutionary medicine with public health
ABSTRACT. Modern man is the epitome of efficient upright walking, yet with up to 80% lifetime prevalence for low back pain (LBP) as a potential trade-off, the consequences to present day society are vast. Despite significant global resources directed at understanding and managing this condition, outcomes have not improved, incidence has not decreased, and it is projected to worsen with our ageing society. New approaches to combatting LBP are therefore urgently needed. Evolutionary adaptations of bipedalism that potentially contribute to the origin of LBP include features like our relatively long lumbar spine coupled with our characteristic spinal curves,, shortened transverse and spinous processes, vertebral invagination within the thorax, and modified disc architecture. Yet, theories defining a common denominator that underpins this susceptibility to one of the world’s most disabling diseases remain relatively immature. Here, we discuss the role of our unique capacity for trunk rotation in combination with the reorganized epaxial muscles for understanding LBP. We speculate that these muscles represent a promising target for early, informed, personalized and preventive interventions. However, it would be remiss of us to lay sole blame on evolutionary inadequacies for a condition with proven complexity, particularly when the sufferers’ beliefs and expectations are such strong determinants of outcome. But what if we can influence the latter by informing the public about the former? What if we can indicate that LBP might be expected on the basis of our ancestral beginnings? Transporting our understanding of evolution to a condition with global relevance and applying this knowledge as a basis for public health provision represents a promising approach to a new understanding and management of LBP.
Osteoarthritis and Human Evolution
ABSTRACT. Musculoskeletal pathologies including osteoarthritis, osteoporosis and problems of the lower back, knee and shoulder are a growing contributor to health costs. In contrast to the high prevalence of musculoskeletal disorders in modern and prehistoric humans, they are surprisingly uncommon among wild-living non-human primates. This can only partly be explained by the increased lifespan of modern humans. Another hypothesis describes these disorders as evolutionary trade-offs of bipedalism. Bipedalism was the key innovation in the evolution of early hominids and involved several adaptations in the musculoskeletal system, such as the adoption of the lumbar lordosis and a reorganization of the shoulder and pelvic girdles, knee joint, foot. In contrast to the predictions of this hypothesis, however, no osteoarthritic changes are known so far from the hominid fossil record of the appendicular skeleton predating Neanderthals. The only exception is an isolated proximal femur of an Australopithecus africanus that perhaps can be explained in the context of a haematological condition like sickle cell anaemia rather than as degenerative joint disease. Here, we analyze the remarkably complete two million year old skeleton of MH2 (Australopithecus sediba) from Malapa, South Africa. Evidence from the pelvis and advanced dental attrition suggest that MH2 is a relatively old female. A close inspection of the skeleton revealed several pathological alterations at multiple large joints. These pathological findings at the skeleton of this early biped give us one of the first indications for osteoarthritis in human evolution. We discuss the implications of these findings in the context of an evolutionary theory explaining the pathogenesis of musculoskeletal disorders in correlation with bipedalism.
L-Z Last name of the submitting authors should stand by posters.
Clinical management of resistance evolution: A case study
ABSTRACT. We report the case of a patient with a chronic bacterial infection that could not be cured. Drug treatment became progressively less effective due to antibiotic resistance, and the patient died, in effect from overwhelming evolution. Even though the evolution of drug resistance was recognized as a major threat, and the fundamentals of drug resistance evolution are well understood, it was impossible to make evidence-based decisions in real time about the evolutionary risks associated with the various treatment options. An evolutionary framework is presented that considers possible routes of antibiotic resistance evolution and allows one to compare antibiotic strategies. The results of post hoc whole genome sequencing of clinical isolates from this patient reveal which of these possible routes of resistance actually evolved as a consequence of the treatment decisions that were made. This evolutionary framework will be used to highlight tractable future research directions that can improve clinical decision-making. Finally, the value of this case as a teaching resource for evolutionary medicine courses will be discussed.
When evidence-based medicine is evolutionary medicine.
SPEAKER: Joe Alcock
ABSTRACT. In the hospital and clinic an ethical obligation exists to withhold treatments when their risks outweigh the benefits. At the same time, the risks/benefits of many interventions are incompletely understood by both physicians and patients, and they continue to be used with little evidence. Evidence-based tools - the number needed to treat (NNT), and its converse, the number needed to harm (NNH) - are useful in reducing harm from powerful but overused interventions, such as antibiotics and opioids. Evolutionary concepts may speed the adoption of evidence-based treatments by providing a rationale for potential tradeoffs in their use. Can understanding the tradeoffs surrounding resistance evolution, addiction to novel substances, and interference with host defenses result in more appropriate care? This presentation will give examples of how evolutionary and evidence-based medicine can work in concert to produce better outcomes for patients.
Evolution in the Clinic
SPEAKER: Mark Schwartz
ABSTRACT. While evolutionary biology has its most profound impact as a foundational science for medicine and public health, shaping new, important, and sometimes disruptive research questions about why our bodies are vulnerable to disease, there are occasions when it can be quite useful in the clinic. It can provide clinicians with meaningful explanations for illness and offer a context for patients' suffering.
Two anecdotes typify ways clinicians might use evolutionary explanations in practice.
When the patient complains of fever and a cough productive of sputum, the doctor may begin thinking about antipyretics and cough suppressants. Alternatively, the doctor might encourage the patient for his healthy, evolved defense mechanisms saying, "your body is doing exactly what it needs to do, what it has evolved to do, to fight off this infection." And thus avoid the disruption of these well conserved defenses.
In geriatrics, caring for patients in their 80s, 90s and beyond, the doctor often hears complaints about loss - not just of old friends and family members but of energy, appetite, sleep, bowel and bladder function, memory, etc. Here evolutionary theories of senescence (antagonistic pleiotropy, disposable soma, etc.) can couch such distressing losses in the context of a patient's life history, with its inevitable tradeoffs, and entirely predictable decline in physical and mental functions.
Whether such evolutionary explanations reduce suffering or deepen meaning in illness remains to be proven, but they provide physicians with another toolkit to help their patients understand and navigate sickness.
What evolution can teach us about cancer
ABSTRACT. Genetic diversity in a population is the fuel for natural selection and is a key determinant of the rate of evolution. The more genetic and microenvironmental diversity, the more opportunities for selection to drive clonal expansions and for the neoplasm to adapt to new selective pressures, including interventions. Measures of the somatic evolutionary process itself represent new forms of biomarkers. Because all neoplasms progress through a process of somatic evolution, measures of somatic evolution have the potential to predict progression across many cancers, not just breast cancer. In essence, they may be universal biomarkers. We are applying this approach to study the earliest breast cancers, ductal carcinoma in situ and propose applying this concept to more precisely guide the management of early stage breast cancer. The heuristic is based upon application of metapopulation and dispersal theories from ecology to predict cancer progression based on their effects on natural selection. This framework represents an innovative approach that is a significant departure from traditional cancer biology, and could yield a universally applicable construct for understanding interactions between tumors and their environments.
Exploring Clinical Applications of an Evolutionary Biology Perspective in Nursing
SPEAKER: Chelsea Landolin
ABSTRACT. Evolutionary biology provides a distinctly different perspective on what it means to be human and to be healthy. For the nurse in clinical practice, what are the advantages and disadvantages of carrying this perspective into a clinical setting? What progress has been made and what barriers exist to applications in clinical decision-making and patient education? What are the real opportunities to use knowledge of evolutionary history and evolutionary principles, and where might we stumble? What are the distinct strengths and challenges for nursing compared to other health professions? We present the case of a young man diagnosed with schizophrenia and comorbid conditions who is treated across several settings by nurses to illustrate how these issues interact in the real world.
(2016 ISEMPH special session on translating evolutionary medicine to the clinic)
ApoE alleles in the evolution of human brain aging
ABSTRACT. Humans are unique among primates and other animals in their multiple APOE alleles. APOE4 is recognized as a risk factor for Alzheimer disease (AD) that also increases damage from cerebral trauma. Moreover, APOE4 shows interactions with sex that differ by species. While male APOE4 carriers with AD have more cerebral microbleeds, mice carrying the human gene show the opposite sex difference. Nonetheless, females of both species have greater load of brain amyloid in APOE4 vs APOE3 carriers (Cacciottolo et al, Neurobiology of Aging, 2016;PMID 26686669). These findings on sex differences give a basis for examining gender differences in APOE influences on brain development and on resistance to infections. We anticipate an expanded discussion of APOE allele pleiotropies that may underlie the large differences in APOE allele frequencies between populations.
Childhood food allergies: an evolutionary mismatch hypothesis
SPEAKER: Paul Turke
ABSTRACT. Through placental transfer, breastfeeding, and the introduction of first solid foods, children are exposed to a wide range of food antigens. During the Plio-Pleistocene those early exposures would have matched the food antigen exposures expected over the remaining lifespan. With the advent of farming, long-distance trade, and the steady march of advancing technology, the potential for mismatch between early and late food antigen exposure has been increasing--slowly at first, and exponentially in the past few decades in countries where the cuisine has rapidly become less and less insular. In turn, since the development of immunological tolerance must be accomplished early in the lifespan, and since selection has accordingly honed the process to work best in the very young, each increase in the mismatch identified above is expected to produce a corresponding increase in childhood food allergies. Supporting evidence is presented.
Understanding health behaviors and outcomes in a life history framework
ABSTRACT. Life History Theory is a powerful framework that can help promote understanding of variation in health-related behavioral patterns and why they vary consistent with environmental conditions. An organism's life history reflects trade-offs made in the allocation of effort towards specific aspects of survival and reproduction across the lifespan. Human health and longevity have improved dramatically in technologically advanced societies due to scientific research and intervention. Advances in health and medical technologies continue to extend the possibilities of saving lives. However, efforts to promote healthy behaviors and discourage health adverse behaviors struggle with diminishing returns. Short time horizons, substantial future discounting, and risky behaviors contribute to a wide variety of health issues, concerns, and outcomes. The future-oriented strategies that health promotion efforts intend to promote depend on environmental conditions that will be relatively stable over time. Individuals developing in relatively less predictable environments will exhibit riskier, immediate outcome oriented, behavioral strategies because of the historical low probability of reproductive success for more cautious approaches. This study examines the relationship between psychological indicators of life history strategy and health related behaviors in a demographically representative sample in the Midwestern USA. Slower life histories and longer time horizons predicted higher levels of health promoting behaviors and lower levels of health adverse behaviors, even when controlling for relevant socio-demographic factors, and mediated the relationships of neighborhood conditions and life experiences. The analyses provide a strong test of the hypothesized relationship between life history and health behavior indicators, as life history variation co-varies with socio-demographic factors. Traditional public health efforts may be reaching their limits of effectiveness in encouraging health-promoting behaviors. Integrating an evolutionary framework may revitalize behavioral health promotion efforts. Novel methods for health promotion will be discussed.
Protective impact of ApoE4 on cognitive performance of older adult Tsimane forager-horticulturalists.
ABSTRACT. Antagonistic pleiotropy is a useful concept for understanding genes that may be beneficial only in certain environments or life stages, with otherwise deleterious consequences. One potential example is the Apolipoprotein E4 (ApoE4) allele, which is the single strongest genetic predictor for Alzheimer’s Dementia. Despite significant social and economic costs of dementia worldwide, the ApoE4 allele is common in many world regions, though whether this allele confers protective advantages is unclear. Recent evidence suggests that in high parasite environments ApoE4 allele may confer benefits to both child stature and cognitive development. We test whether there is a protective impact of the E4 allele on cognitive ageing in a subsistence population facing a high parasite load. Tsimane forager horticulturalists (n=266) aged 30-88 (mean 49.2 years, 50.9% male) participated in a cognitive battery (short and long term recall, digit forward, category fluency, visual scan), and gave blood samples for ApoE genotyping and eosinophil counts, a measure of parasitic load. Controlling for age, education, Spanish fluency, and sex, ApoE4 negatively impacted cognitive performance on all tasks (Std. β from -0.08 to -0.25), as did higher eosinophil counts (all tasks except category fluency; Std. β from -0.10 to -0.32). However, there was a significant interaction between eosinophils and ApoE4 on cognitive performance in all fluid cognition tasks including short (Std. β=0.45, p=0.013) and long term recall (Std. β=0.35, p=0.05), digit span (Std. β=0.22, p=0.035) and visual scan tasks (Std. β=0.39, p=0.01); in the presence of high eosinophil counts, individuals with ApoE4 alleles out performed those monozygotic for ApoE3. There was no significant interaction effect on category fluency tasks. These results suggest that while ApoE4 is associated with cognitive declines in industrialized populations with low pathogen loads, in the presence high rates of parasitic infection the ApoE4 variant may have protective effects on cognitive performance.