Welcome by CARTA Executive Co-Director, Pascal Gagneux. Opening remarks by Event Co-chair, Stephen Stearns.
Mismatch: Human Origins and Modern Disease
Friday, May 16, 2025Abstracts
Abstracts
Cancer is the origin of a novel tissue that attracts resources, spreads beyond boundaries, avoids normal controls, and escapes immunity. A novel tissue arises in the same way that bodies are built from nothing, by development. Cancer is normal development spun out of control. It is the great plasticity and power of development, without the overarching controls that guide normal development toward an integrated adult form. Instead, whenever a newly developed kind of tissue acquires the ability to survive, grow, and resist control, there is nothing to stop it. That may be why normal adult cells are often terminally differentiated into a restricted cellular program. And it may be why wound healing, which releases the restricted cellular program and powerfully plastic tissue remodeling, is so tightly regulated and, when dysregulated, so often associates with cancer. With regard to evolutionary history, humans develop differently from their ape ancestors, and their lifestyle causes them to suffer different kinds of tissue damage. Those differences in development and wound healing likely led to new aspects of cancer disease over human history.
Pressures of life on Earth experienced by our ancestors – as multicellular beings, as hosts to parasites, and as home to microbes – shaped the evolved structure and function of our immune systems. Some of the traits favored by natural selection have conferred resistance against infections while opening vulnerabilities to autoimmune diseases. I will illustrate why analysis of the deep-time origins of mammalian immune systems reveals general principles of optimal defense and helps to explain why hosts are so profoundly variable in their susceptibility to infectious and inflammatory diseases.
Menstruation is the cyclical shedding of the endometrium triggered by falling progesterone levels. Menstruation is a rare trait found in less than 2% of mammals and likely evolved independently at least 4 times. Why do some mammals menstruate while most do not? The leading hypothesis is that menstruation occurs as a nonadaptive consequence of spontaneous decidualization of the endometrium, which evolved to increase biosensoring of embryo quality. While the trait of spontaneous decidualization (and as a byproduct, menstruation) was likely shaped by natural selection, menstruation also disposes women to conditions such as endometriosis, pre-menstrual syndrome, and bleeding disorders, especially in the contemporary context.
The rate of cancer and cancer malignancy differ greatly among mammalian species. The placental – maternal interface is also highly variable between placental mammals. Here I want to discuss recent advances that suggest that there is a causal connection between the evolution of placental biology and the biology and rate of cancer malignancy.
Cancer is a complex disease with different stages from the origin of the primary tumor to the establishment of secondary tumors in other organs than that of its origin. In this talk I will focus on the initial stages of malignancy, i.e. after the formation of a primary tumor and before the dissemination of cancer cells through the lymph vessels. This is the process of local invasion into the tumor surrounding stroma. This stage is the one that has inspired most of the comparisons between cancer and [invasive] placentation. I will present previously published work supporting the notion that the critical cell type in this process is the tumor associated fibroblast population explaining species differences in malignancy rate among species correlated with placental phenotype. Then I will present evidence that the gene expression evolution in uterine endometrial fibroblasts and skin fibroblasts is correlated, suggesting that evolutionary change in the uterus can lead to changes in the skin fibroblasts and vice versa. I like to end with some speculations how the evolutionary biology of placental implantation may be useful for translational efforts to make cancer less malignant for humans.
Phenotypic variation within the skeleton has biological, behavioral, and biomedical functional implications for individuals and species. Thus, it is critical to understand how genomic, environmental, and mediating regulatory factors combine and interact to drive skeletal trait development and evolution. One way to do this is by studying skeletal diseases that disrupt skeletal function — like osteoarthritis (OA) which is a chronic disorder characterized by the degradation of cartilage and underlying bone in joints and can lead to severe pain and mobility limitations. Of note, OA susceptibility is not uniformly present throughout the primate order, with high and steadily increasing prevalence rates in humans prompting questions about whether OA is a mismatch disease. However, while OA has a low occurrence in closely related nonhuman apes, many other animals, including other primates, can develop OA just like humans. Disentangling this evolutionary puzzle will require continued efforts to expand skeletal research efforts across species, as well as more targeted investigations of the mechanisms driving OA susceptibility and pathogenesis. Here, I will discuss what is known about OA in humans and other primates, as well as recent advances that are further informing these topics.
Relevant article: Housman G: Advances in skeletal genomics research across tissues and cells. Current Opinion in Genetics & Development 2024, 88:102245.
Musculoskeletal disorders are one of the most important challenges of modern medicine worldwide, both in terms of socioeconomic costs and disability-adjusted life-years (DALYs). They are often attributed to maladaptations of our body to our peculiar form of locomotion, upright bipedalism. In my presentation, I will explore the evolutionary origin of major musculoskeletal disorders such as back problems and hip joint osteoarthritis. I will show that these problems represent a relatively recent phenomenon, occurring only during the last few decades, and thus are unrelated to our skeletal adaptations. Another trade-off between our skeletal adaptation for upright bipedal locomotion and our large brain size is often said to explain the unusually difficult birth in humans compared to other mammals. I will demonstrate that this evolutionary compromise has a much deeper origin and was not caused by the enormous enlargement of our brains but instead was likely a prerequisite for the evolution of our cognitive capabilities.
The essence of Being Human is the practice of Biocultural Reproduction (BCR). BCR is defined as the set of marriage and kinship based rules for extra-maternal cooperation in the production, feeding, and care of offspring. Human evolution theory needs to explain how people successfully combined a vastly extended period of offspring dependency and delayed reproduction with helpless newborns — with large heads and much body fat (even with problems giving birth) -- a short duration of breast-feeding, an adolescent growth spurt, and vigorous post-menopause valuable grandmothers. Are these characteristics a package or a mosaic?
The human gut microbiome is tightly linked our health. Our analyses of diverse human populations from around the globe, ranging from hunter-gatherer to industrialized, show that the gut microbiome is profoundly influenced by lifestyle. With a large collaborative team, we conducted deep metagenomic sequencing of the gut microbiomes of Tsimane horticulturalists from Bolivia and compared them to those of Hadza hunter-gatherers from Tanzania. Despite their ancestors diverging tens of thousands of years ago, these two Indigenous, non-industrialized populations share >1200 microbial species—most of which are absent in industrialized populations. Population genetic analyses of shared bacterial species revealed signatures of microbial divergence and gene flow consistent with prehistoric human-microbiome co-migration. Estimated split times broadly align with major events in human migration, including the out-of-Africa dispersal and the peopling of the Americas. These findings support the hypothesis that a diverse gut microbiome co-migrated with humans during our global dispersal and has persisted over millennia. However, many of these microbial species are now disappearing from industrialized microbiome, with unclear implications for human health. We are also investigating whether diet and microbial therapies can address deficiencies in the industrialized gut community. Molecular mechanisms of host-microbial interaction are pursued using an array of technologies and experimental approaches including gnotobiotic and conventional mouse models, quantitative imaging, and a metabolomics pipeline focused on investigating microbiota-dependent metabolites.
Three smokes were inhaled during evolution of the human exposome. The first frequent inhalation of pre-H. sapiens was smoke from domestic fires, followed most recently by globally expanding wildfires. Two modern smokes are tobacco and air pollution from fossil fuels of roadway exhaust and power plants. The three smokes derive from partially combusted plant-material. Their microscopic particles of 0.1-10 µm share chemistry of nitrogen and sulfur oxides, and carcinogenic polycyclic hydrocarbons. Tobacco and roadway exhaust increase the risks of lung cancer and dementia, but also childhood adiposity, with supra-additivity. While the basis for these synergies is unknown, air pollution from fossil fuels is being understood in terms of biochemistry and gene regulation. Rodent and cell models are exposed to size-defined particulate material, e.g. (PM2.5µ) from roadway exhaust air pollution, including standardized diesel exhaust particles. Acute and multi-week exposures cause oxidative stress with compromised glutathione metabolism. Brain responses include increases of the amyloid peptides of Alzheimer’ dementia. Multiple gene responses are mediated by the transcription factors NFkB and Nrf2. Potential protection from the dementia risk of air pollution is a new drug that attenuates an enzyme of amyloid production (GSM-15606) which partly inhibited brain amyloid responses of mice to air pollution components. Genetic susceptibility to air pollution is increased by ApoE4 in some human populations and in transgenic mice. Did the Alzheimer resistant ApoE3 allele evolve 200,000 years ago in some relation to its benefit to smoke inhalation?
Finch, CE. (2018). The Role of Global Air Pollution in Aging and Disease: Reading Smoke Signals. Academic Press.
Trumble, B. C., & Finch, C. E. (2019). The exposome in human evolution: From dust to diesel. The Quarterly Review of Biology, 94(4), 333–394. https://doi.org/10.1086/706768
Finch, C. E., & Thorwald, M. A. (2024). Inhaled pollutants of the Gero-Exposome and later-life health. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 79(7). https://doi.org/10.1093/gerona/glae107
Godoy-Lugo, J. A., Thorwald, M. A., Cacciottolo, M., D’Agostino, C., Chakhoyan, A., Sioutas, C., Tanzi, R. E., Rynearson, K. D., & Finch, C. E. (2024). Air pollution amyloidogenesis is attenuated by the gamma-secretase modulator GSM-15606. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 20(9), 6107–6114. https://doi.org/10.1002/alz.14086
Question and answer session with all speakers. Wrap-Up by symposium co-chair, Ruslan Medzhitov. Closing remarks by CARTA Executive Co-Director, Pascal Gagneux.
