Why do immune systems harm their bearers? The evolutionary biology of "friendly fire"
SPEAKER: Andrea Graham
ABSTRACT. Immune-mediated diseases ranging from septic shock to multiple sclerosis exact a huge toll on human health. Many of the molecular and cellular mechanisms by which the immune system can harm a host’s own tissues or even cause death are well understood. However, evolutionary explanations for self-harm have received less attention. What forces of natural selection have generated such a remarkable immune system – capable of feats like memory responses that protect against particular influenza strains decades after first exposure – that also is capable of causing such tremendous damage to our own bodies?
This talk will focus on our emerging understanding of the evolutionary causes of immune-mediated disease, including important roles for susceptibility trade-offs and for long-term co-evolution with parasites such as gastrointestinal worms. For example, in wild sheep, autoimmunity is associated with enhanced resistance to infectious diseases. Hosts may thus experience a trade-off: a host could be susceptible to autoimmune diseases OR infections, but not both. Such a trade-off could help to explain the persistence of diseases like lupus. Recent tests suggest that this trade-off is borne out in human populations. Furthermore, the clearance of our co-evolved gastrointestinal worms can alter immune system balance in a way that exacerbates autoimmune disease. Will the future of medicine entail “restoration ecology” of the human gut, reinstating worms to rein in diseases like ulcerative colitis? These and other clinical implications of an evolutionary understanding of immune-mediated disease will be discussed.
The Pathomechanics of Degenerative Joint Disease: An Evolutionary, Comparative, and Functional Approach
ABSTRACT. The common body plan of vertebrates allows for the comparison across species of disease processes and treatments, a tenet of the One Health Initiative. The most common disease affecting humans and animals is degenerative joint disease (DJD, osteoarthritis) caused by pathomechanical forces, which are forces induced by how an individual structurally interacts with its environment that directly cause joint injury. Therapeutics based upon identification of the sources of mechanical stress are critically needed as treatments focused only on controlling pain and tissue pathology mostly fail to prevent disease progression. The comparative approach emphasizes that the causal relationship between pathomechanical forces and DJD are based upon the same principles across species. However, the selection of which structures to compare should be approached with caution. In some natural diseases, like DJD of the dog and of the human spine, the structures of interest (in this case the spine) can be directly correlated between species (although differences, like the presence or absence of disc degeneration, must be considered). But in other instances, as in the Achilles enthesis organ of humans and the Navicular enthesis organ of horses, different structures have developed similar adaptations to similar force regimes, a finding that would be ignored if 1:1 comparisons were the only ones being made. In the case of DJD, animal models based on pathomechanics and tissue responses rather than exact anatomic correlations, can facilitate a better understanding of the shared susceptibility to a very common disease and the transfer of therapeutic approaches between human and veterinary medicine.
Animal Models, Evolution and Drug Development
SPEAKER: Natalie Warner
ABSTRACT. The recent death of a volunteer in a Phase 1 clinical trial has emphasized concerns about the “prediction problem” associated with the use of animal models to evaluate the effect of xenobiotics in humans. Toxicology testing in 2 species, required by the regulatory authorities for compounds that will be tested in humans, predicts correctly in only approximately 70% of cases, although the result is rarely as dramatic as the death of a Phase 1 volunteer. Evolutionary similarities and differences among different species and among individuals within species underlies both the utility and the failure of animal models. Adaptations to environmental exposures, including diet, have resulted in differences in absorption, distribution, metabolism and excretion (ADME) of xenobiotics both across species and among individuals within the human population. These differences are increasingly recognized and taken into account when developing and when prescribing medications. Mice with “humanized” livers are available and genetic tests for variants in drug metabolizing enzymes are recommended prior to initiation of therapy with certain drugs. ADME is not the only area where it is important to consider both evolution based similarities and differences among species. Studies in animals have shown that genetic variants in, for example, the dystrophin or cystic fibrosis transmembrane conductance regulator genes result in different phenotypes in different species. In addition, not all individuals with a genetic variant that is associated with a disease will develop the disease phenotype and a disease phenotype may result from different genetic variants. Discovering why the interspecies and inter-individual differences occur is leading to more predictive animal models and to new therapeutic approaches. It has also led to interest in a more predictive classification of disease.
Cancer in Animals: Impacts of Selective Breeding, Husbandry and Domestic Environments
SPEAKER: Elizabeth Uhl
ABSTRACT. Cancer is an evolutionary process in which genetic and environmental factors have been documented as affecting the incidence of cancer in humans. Animals have been selectively bred and raised in a variety of environments quite different from those of their ancestors. Both factors have impacted the occurrence of cancer in domesticated species. Selective breeding has increased the incidence of melanoma in horses and pigs, but has had the biggest impact on cancer incidence in dogs, making them especially good models for studying cancer pathogenesis, as well as identifying phenotypes at risk. For example, osteosarcoma of the long bones is a rare cancer in most species but is very common in large breed dogs. In production animals, which have relatively short lifespans, viruses, especially those infecting the lymphatic system, induce several of the most common cancers. Environmental exposures and lifestyle (husbandry) factors also impact cancer in domestic animals. As in people, squamous cell carcinoma in a variety of animal species is induced by sun exposure, but is also exacerbated by selection for white markings. Other husbandry factors that have impacted cancer in domestic animals include spaying and neutering, which is associated with both decreases and increases in cancer risk, and the development of treatments and prophylactics against infectious diseases. Examples of the latter include the decline of tumors associated with parasite infections and the increased incidence of vaccination–induced sarcomas in cats. While comparative cross-species studies can provide important insights into both the pathogenesis and incidence of cancer, an evolutionary perspective that includes an understanding of how genetic, environmental and lifestyle/husbandry factors can interact to influence cancer development is critical. It is also important to take into account that for many cancers, the incidence data for animals is currently not very comprehensive compared to that available for humans.
Cross-Disciplinary Efforts to Understand, Treat and Prevent Ape Heart Disease, through the Great Ape Heart Project
ABSTRACT. All four great ape taxa (gorillas, orangutans, chimpanzees, bonobos) are endangered or critically endangered in the wild. Cardiovascular disease (CVD) is a significant cause of mortality in captive great apes and is documented in wild gorillas and chimpanzees. The Great Ape Heart Project (GAHP; www.greatapeheartproject.org) is a cross-disciplinary, multi-institutional, multinational effort headquartered at Zoo Atlanta. It seeks to understand, address and prevent ape heart disease, through coordinated, collaborative efforts currently funded by the Institute of Museum and Library Services. The close phylogenetic relationship between human and nonhuman apes makes it likely that a comparative approach incorporating human and veterinary medicine, evolutionary biology and genetics will provide valuable insights into contributing and ameliorating factors. Some CVD presentations, such as viral and bacterial myocarditis, have similarities among apes and humans. However, based on compiled zoo-housed ape necropsy reports, there are some species differences (e.g. aortic aneurysms are seen in gorillas, bonobos and chimpanzees, but not orangutans). In contrast, the pattern of myocardial dissecting fibrosis noted in all apes with CVD, is different from the pattern of post-myocardial infarction in humans. Atheromatous lesions in major (extrinsic) coronary arteries are common in humans, but less significant in apes. Whether these differences (or commonalities) are genetically based or multifactorial requires rigorous study. A newly-developed database, including antemortem and postmortem data, will allow future clinicopathologic analyses. Standardization of data collection (e.g., using a veterinary postmortem cardiac evaluation closer to the human autopsy approach) has been initiated. Consensus on diagnostic criteria and terminology is an ongoing goal. While nonhuman apes do not indulge in some human lifestyle choices such as smoking and alcohol consumption, other factors such as genetics, demographics, social housing, diet (e.g. salt, sugar, fiber intake), metabolic factors (obesity or diabetes), hypertension,exercise, or social stress, warrant exploration as contributing factors.
Cavefish as a natural model for insulin resistance and fatty liver disease
ABSTRACT. Understanding the genetic basis of adaptation has broad applications not only for a basic understanding of evolution, but also for human pathologies given that many human diseases are a consequence of mis-adaptation to modern societies. The emerging model system Astyanax mexicanus has become an important fish species to address adaptation to extreme environments due to its unique ecology and the availability of genetic tools and genomic resources. Cave environments are typically dark and nutrient deprived. We have previously shown that cavefish have acquired hyperphagia (increased appetite), starvation resistance and altered feeding behaviors to cope with these conditions. Here, we have focused on the fatty livers and symptoms reminiscent of diabetes these fish develop. Interestingly, we detected only very low insulin levels in cavefish (compared to surface fish) partially due to lower numbers of beta-insulin producing cells in the pancreas. In addition, cavefish display strong insulin resistance when administered with ectopic insulin. Despite the consequential fluctuating blood glucose levels, cavefish live long and healthy lives, probing the question whether they have acquired mechanisms allowing them to cope with extreme nutritional levels. Taking advantage of the newly available genome of Astyanax mexicanus, we identified mutations in the insulin receptor of cavefish most likely responsible for the observed insulin resistant phenotype. Importantly, the same mutations were found in cases of Type-II diabetic patients in human populations. Our findings in independently derived cavefish populations suggest that cavefish are inherently insulin resistant, potentially as an additional strategy to acquire better starvation resistance. We are currently using genome editing to functionally test these and other candidate mutations in zebrafish and cavefish itself to study in detail the molecular mechanisms underlying the adaptation of cavefish to the extreme and nutrient poor environments, thereby providing potential new insights into human health.
Nephron maladaptation and progression of kidney disease: a new paradigm is needed
SPEAKER: Robert Chevalier
ABSTRACT. There is a global epidemic of chronic kidney disease (CKD): diagnosis and treatment are limited by incomplete understanding of pathophysiology. The current paradigm for progression of CKD postulates that nephron loss leads to adaptive hyperfiltration by remaining nephrons, resulting in maladaptive glomerulosclerosis and interstitial fibrosis. Recently, we have developed mouse models of CKD that point to proximal tubular injury as an early initiator of CKD, with fibrosis as a late event. Following complete ureteral obstruction, proximal tubules undergo rapid cell death with disconnection of proximal tubules from glomeruli. A similar, more gradual process takes place in polycystic kidney disease, in which intact nephrons are compressed by enlarging cysts. In contrast, cystinosis (an inherited disorder of cystine transport) results in proximal tubular oxidative injury, mitochondrial loss, and marked thinning of proximal tubular cells, with late glomerulotubular disconnection. Rather than regarding these as maladaptive physiologic responses, we have considered them as evidence of evolutionary adaptation. The kidney is the product of evolutionary adaptation, transitioning between marine, freshwater and land environments. In mammals, high glomerular filtration rates necessitated the development of energy-consuming tubular reclamation, making the proximal tubule vulnerable to hypoxia and oxidative injury. Glomerulotubular disconnection in the mammalian kidney may represent an atavism conserved by the sculpin, a marine fish that benefits from reduced filtration by decreasing urinary water losses. Thinning of the proximal tubule in cystinosis prolongs tubular integrity by reducing cystine uptake and consequent oxidative injury. Both result in energy conservation that can be allocated to reproductive success (tradeoff). Future investigation of CKD should include deep sequencing of nephron segments to elucidate proximal tubular gene regulatory networks, mitochondrial bioenergetics, and epigenetics (microRNAs). These could be complemented by newly described kidney organoids, grown from human induced pluripotent stem cells as well as those from novel model organisms to provide phylogenetic comparisons.
Primate iPSCs provide insights into the evolution of human metabolic traits
ABSTRACT. Understanding of the evolutionary basis and molecular underpinnings of many uniquely human traits and disease susceptibilities has been hampered by the limited ability to perform experiments on and access to samples from our closest relatives. The development of induced pluripotent stem cell (iPSC) lines allows one to control for genetic effects, remove environmental variability, and carry out experimental manipulations. We are using iPSCs to identify genetic, epigenetic and environmental effects on the evolution of physiology during human origins. We differentiated iPSCs from humans and chimpanzees into adipocytes, the primary cell type of white adipose tissue.. We then used RNA-seq to identify genes whose expression differs in humans, and from these data inferred how specific metabolic pathways may have changed.These results demonstrate the utility of stem cells for providing insights into key metabolic traits of both evolutionary and medical importance.
Oxidative Stress and Facultative Adjustment of Energy Allocation
ABSTRACT. Reactive oxidative species (ROS) are a necessary byproduct of energy production. For decades, physiologists have investigated the etiological role of ROS in the disease process. While all organisms harness anti-oxidant mechanisms to combat the deleterious effects of ROS, individuals vary in their capacity to control oxidative stress, a state in which ROS production exceeds anti-oxidant efforts. More recently, evolutionary biologists have posed arguments framing oxidative stress as a potential indicator of genetic quality and/or ability to allocate energetic resources to somatic maintenance, with some preliminary empirical work in humans providing support for each of these possibilities. Here, we investigate associations between two biomarkers of oxidative stress (8-OHdG and isoprostane), activity levels, sleep patterns, and grandparental incidence of Alzheimer’s Disease/dementia in two independent non-clinical samples of young adults (Ns = 150 and 98). Oxidative stress is thought to be one consequence of sleep disruption (and associated processes such as intermittent hypoxemia) within clinical populations suffering from sleep apnea; here we find mixed support for a link between sleep quality and oxidative stress. We also find that oxidative stress biomarkers correlate positively with incidence of Alzheimer’s disease/dementia in participants’ grandparents (an effect replicated across both samples). Interestingly, in spite of past findings indicating stability in oxidative stress levels across time, many of the patterns we report diverge depending on time of collection. Oxidative stress levels assessed upon waking (possibly reflecting the extent of somatic repair processes overnight), but not at other times, relate negatively to physical activity levels, suggesting that individuals may facultatively adjust activity levels based on what they can energetically afford. Additionally, contemporary sedentary lifestyles might create an evolutionary mismatch with our evolved oxidative stress management systems. We conclude, tentatively, that an assessment of oxidative stress might provide information regarding allocation strategies, rather than overall ‘quality’ or fitness.
Coffee and snacks will be provided.
A Fiery Forge: The Industrial Revolution, Recent Human Evolution and the Global Burden of Non-Communicable Disease
ABSTRACT. The profound changes to human demography, life history, morphology, diet and environment wrought by the Industrial Revolution have been of an intensity, velocity and consequence with little precedent in the entire history of our species. These changes to have precipitated abrupt shifts in selection pressures that rival or exceed those associated with the other great transformations in human history, such as the advent of fire, weapons, language, writing, and agriculture. The growing global burden of chronic disease is a direct consequence of this upheaval and threatens to erode the hard won improvements in standard of living wrought by economic development. Here we review the dynamics that link demography, biology and genetics during this period of unprecedented change, and how they are likely to have had an impact on the recent evolution of genes associated with chronic and degenerative disease.
Why mammal meat is bad for humans (and humans only)
SPEAKER: John Pepper
ABSTRACT. Multiple studies have shown that eating red meat (mammal meat) increases illness and death from a wide range of causes, including cancer, but the reasons why haven’t been widely known. It is now clear that this wide range of negative health effects all involve chronic inflammation through auto-immunity, caused by a uniquely human peculiarity of biochemistry. This talk will review the evidence for this causal link, and explain the biochemical and evolutionary mechanisms behind it.
Smart genes: evolution as a driver for emerging infectious diseases
SPEAKER: Marion Koopmans
ABSTRACT. An estimated 70% of emerging infectious diseases (EID) in humans are zoonotic infections, where humans become infected after direct or indirect exposure to animals and the microbes that they carry. The impact of such zoonotic infections may be limited unless the pathogens are widespread and exposure is frequent, but zoonotic infections may become a global public health threat when they acquire the ability to spread efficiently between humans and develop into regional or global outbreaks called pandemics. The history of mankind has been shaped by such events, with for instance the plague epidemics caused by Yersinia pestis that were associated with waves of globalization in the Middle Ages through the colonial history of Europe, the emergence of HIV, introduced into the human population in the first half of the 20th century, or the history of influenza pandemics of which the Spanish flu caused a sizable dip in the projected population level life expectancy through its selective impact on young adults. While the burden of infectious diseases has been reduced hugely with the development of public health programs like water and food sanitation, and introduction of vaccines and antibiotics in the 20th century, the fast expansion of the human and livestock population and globalization of travel and (food and animal) trade have led to a rebound with increasing problems with EID outbreaks. Notable examples are the emergence and spread of avian influenza viruses (AIV) H5N1 and H7N9 in the past decade, with major impact on the animal sector and a continuing threat to human health, Middle East Respiratory Syndrome (MERS) Coronavirus that is widespread in the most popular livestock across the Arabian peninsula and continues to cause zoonotic infections and outbreaks, the West African multi-country outbreak of Ebola virus. The advances in human and veterinary medicine also have a downside and meet with the new challenge of increasing resistance to antimicrobial drugs, resulting from selective pressures on micro-organisms through selection of resistant mutants, and cross-species transmission of bacteria, plasmids and resistance genes, and decreasing resistance of the human population to new diseases due to the growing size of the population that has impaired immune systems and thereby lower barriers to infections. Combined, the changing dynamics of infectious diseases lead to the new challenge of our times: emergence of potential pandemic disease problems (PPP) resulting from complex interactions between humans, animals and their environment, each with their own healthy and disease causing microorganisms.
Coffee and snacks will be provided.
Hemoglobin concentration and reproductive success of Tibetan highlanders
ABSTRACT. Evolutionary medicine concerns adaptations and their consequences for disease vulnerability. Adaptations resulting from natural selection can be difficult to detect among arrays of phenotypes. This study considers the extent to which a distinctive phenotype of Tibetan highlanders, comparatively low hemoglobin concentration, is adaptive. To illustrate, at 3900m Andean Aymara women averaged 17.8 gm/dL hemoglobin concentration as compared with Tibetan women who averaged 14.2. The present study tested the hypothesis that relatively low hemoglobin concentration within a Tibetan sample associated with higher reproductive success and an opportunity for selection favoring associated genetic variants.
We collected reproductive histories by interviews in native dialects with a sample of 1,006 Tibetan women 39+ years of age residing at altitudes from 3000-4100m in Nepal. Fitness outcomes included the number of pregnancies and the rate of successful livebirths/pregnancy.
Six women had complete reproductive failure (no pregnancies became livebirths), 208 reported pregnancy loss and 720 had complete reproductive success (all reported pregnancies became livebirths). Hemoglobin concentration averaged 14.7 + 1.5, 14.2 + 1.3, and 13.7+ 1.5 gm/dL among women with no, intermediate and complete success in converting pregnancies to livebirths. Women married throughout their reproductive years had more pregnancies and thus more risk of pregnancy loss. Among those women, higher hemoglobin concentration correlated with a lower rate of successful livebirths.
We conclude that post-reproductive Tibetan women residing at 3000-4000m in Nepal having relatively lower hemoglobin concentrations have greater reproductive success than those with higher concentrations. Whether hemoglobin concentration itself is adaptive or is a proxy for another trait is unknown. The findings support the hypothesis that relatively low average hemoglobin concentration, as compared with Andean highlanders, reflects an adaptive phenotype among Tibetans at high altitude.
SUPPORT FROM NSF award 1153911 to CMB
Is it Time to Re-evaluate the Mismatch Concept?
SPEAKER: Michele Freed
ABSTRACT. The concept of “Mismatch” is inextricably linked to the psychologist, John Bowlby’s, original formulation of the Environment of Evolutionary Adaptedness, which has come under heavy criticism as evidence mounts for continuing human microevolution. That aside, the Mismatch formulation has stimulated ongoing research about human conditions including nutrition and obesity, susceptibility to cardiovascular and metabolic disorders, and the absence of helminths and prevalence of allergies, among many others. While Mismatch continues to be useful as an overarching framework, details concerning differences in lifestyle and disease prevalence among our human ancestors in prehistory continue to be illuminated, and call into question assumptions that have been made about ancestral conditions. Here, we take issue specifically with palaeodiets, prevalence of obesity, energy output, helminth infestations, specific cardiovascular conditions, and sleep patterns among ancestral populations. We argue that the palaeodiet was much more diverse across human groups than originally thought, that obesity was present among Palaeolithic populations, that exercise was more limited, that helminth infestations became much more prevalent among agriculturalists once this subsistence strategy emerged, that cardiovascular conditions such as atherosclerosis are not just limited to contemporary, sedentary populations, and that sleep deprivation may also have plagued hunter-gatherer groups. Our goal in criticising “Mismatch” is not to argue that the notion should be eliminated from common usage; rather, we argue that the concept needs to be refined further as our current knowledge expands about evolutionary medicine and its applications.
Eco-evolutionary dynamics and natural selection on health-related traits in humans
SPEAKER: Emmanuel Milot
ABSTRACT. Natural selection can alter the frequency of genetic variants affecting health when these variants also affect fitness. Moreover, demographic changes can modulate the strength of the selection exerted on these variants due to a dependency of selection on age-specific survival and fertility in a population. In theory, this can result in an evolutionary feedback loop, whereby the response to selection, i.e. the change in a variant frequency, modifies the demography and vice versa. We study this complex dynamics using the French-Canadian population as a model. Deep genealogies (> 300 years) and molecular data for this population allow measuring selection and genetic variation. We found that selection in favour of juvenile survival has increased during the history of a local population, île aux Coudres, as a result of demographic changes. This implies that mutations reducing juvenile survival where more strongly selected against after 1900 than before 1900. One of these mutations, T14484C, is located in the mitochondrial genome and causes the Leber hereditary optical neuropathy. Our genealogical analyses revealed a strong effect of T14484C on infant male mortality that was previously undocumented in the medical literature. In contrast to infant mortality, maternal mortality in childbirth, a critical concern in preindustrial societies, occurred at ages where selection on survival was very weak. These results illustrate how evolutionary approaches can provide insights into the prevalence of genetic disease in modern populations.
Cancer in an Indigenous Native South American Population: Initial insights into the natural history of cancer in traditional subsistence populations.
ABSTRACT. Little is known about the epidemiology of chronic diseases in past human populations or in populations living under traditional subsistence conditions. Evidence suggests that such populations experienced higher infectious burden throughout life, high total fertility, and different dietary and exercise regimes. We present data on cancer cases observed among Tsimane Native South Americans over a six year period from 2008 to 2014. Cancer observed among Tsimane come from two data sources; A) screening for cervical and prostate cancer, and B) other cancers seen in symptomatic patients seeking medical attention or reported in verbal autopsies (suggesting the incidence of such cases are underestimates of true rates). The observed incidence of cervical cancer was about six times higher among Tsimane compared to age-matched U.S. women. In contrast, estimated incidence of breast cancers are one sixth the U.S rate. Little cancer was observed among Tsimane men in general, with skin cancers (basal cell carcinoma and melanoma) the most commonly reported cancer among men. Strikingly, there were no reported cases of prostate cancer among the Tsimane, nor among 348 male Tsimane screened with prostate ultrasound and serum PSA; whereas prostate cancer is the leading cause of male cancer in the U.S. These results may reflect broad trends regarding cancer rates in traditional societies. Lower rates of steroid dependent breast cancer among women and prostate cancer among men may reflect different hormonal exposures throughout life. Women in traditional societies experienced fewer menstrual cycles during their lives and thus less unopposed estrogen exposure, while men in such populations appear to have lower testosterone. The high rate of cervical cancer among Tsimane women, with its infectious routes, requires reflection about its incidence in the past and how modern routes of transmission may be affecting even remote populations.