Pearl Memorial Lecture Issues in Evolutionary Medicine STEPHEN C. STEARNS* Department of Ecology and Evolutionary Biology, Yale University, New Haven, Connecticut 06520-8160 ABSTRACT This paper illustrates the utility of applying evolutionary thought to medical issues with three examples: selection arenas, aging, and tradeoffs. First, the human female reproductive tract functions as a selection arena at two levels: in the ovaries, where atresia reduces the number of oocytes by more than 99.99% before any are ovulated, and in the uterus, where early embryos homozygous for immune genes are spontaneously aborted. These selective filters early in life have implications both for eugenics and for the anti-abortion movement. Second, the evolu- tionary theory of aging predicts that intrinsic mortality should reflect extrinsic mortality: if life for adults is risky, then it does not pay to invest in maintenance at the expense of reproduction. This idea is well confirmed, at least in populations where density effects are not important. While only organisms that reproduce asymmetrically should age, even bacteria reproduce asymmetrically, and they do age, suggesting that all organisms reproduce asymmetrically and therefore age. Third, tradeoffs are central to theories of phenotypic design, but the mechanisms that cause them remain obscure. A method is suggested to get at the mechanisms of tradeoffs by examining conflicts among functions over gene expression. It could be applied in humans to the tradeoff between reproductive performance and disease resistance. Am. J. Hum. Biol. 17:131–140, 2005. # 2005 Wiley-Liss, Inc. Evolutionary thinking can be used to under- stand human health and disease in many ways. Does the history of Homo’s colonization of the planet, with its unique exposures of populations to particular diseases and its many genetic bottlenecks, shed light on our striking local variation in incidence of genetic diseases, capacity to process drugs, and resis- tance to pathogens? Does the life-history evolution of pathogens tell us whether their virulence will increase or decrease? Have humans been selected to invest differentially in sons or in daughters depending on how environmental circumstances skew the fitness gains through each sex? The answer to all these questions, and many more, is yes (see chapters in Stearns, 1998): the scope of evolutionary medicine is much greater than the scope of this lecture. Here I discuss only three topics in this large field to which I have contributed directly: selection arenas, the evo- lution of aging, and the nature of tradeoffs. SELECTION ARENAS: WHEN DOES IT PAY TO DISCARD OFFSPRING? Selection arenas defined A selection arena is a selection process that occurs inside an entity that is a unit of selection in its own right at a higher level. Usually that entity is a parent that arranges for active selection or passive neglect, leading to selection among offspring. The arena can be an ovary containing oocytes, a uterus containing zygotes or embryos, a nest containing nestlings, a pod containing seeds, or a branch bearing fruit. The act of selection can consist of apoptosis (programmed cell death), of spontaneous abortion (miscarriage or fruit abortion), or of siblicide. In such cases, natural selection has produced an adaptation that uses natural selection to achieve its effect (Stearns, 1987). Something very similar occurs in the verte- brate immune system when just one of the vast number of combinations of major histo- compatibility complex (MHC) gene products turns out to bind to the surface coat of a pathogen and a cell lineage is first selected to produce that antibody and then stored to remember it for future use. Selection arenas only make sense as adapta- tions if investment in one offspring whose potential fitness is low creates the opportunity ß 2005 Wiley-Liss, Inc. *Correspondence to: Stephen C. Stearns, Box 208106, Yale University, New Haven, CT 06520-8106. E-mail:stephen.stearns@yale.edu Received 18 November 2004; Accepted 28 November 2004 Published online in Wiley InterScience (www.interscience. wiley.com). DOI: 10.1002/ajhb.20105 AMERICAN JOURNAL OF HUMAN BIOLOGY 17:131–140 (2005)