CAREER: Emergence of Population Diversity from Stem Cell Decision Making in Asexual Planarians

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Diversity of individuals is indispensable for population survival and evolution. This CAREER project examines how diversity can emerge from decision making of individual cells in a multicellular regenerative organism. Freshwater planarians are famous for their regenerative capabilities that are based on a large number of adult pluripotent stem cells (ASCs). These ASCs allow them to reproduce by binary fission, thus creating a clonal population and raising the question of how this species is able to create sufficient diversity to survive on evolutionary time scales. Using tools from statistical physics the PI recently demonstrated that reproduction is largely random, but that reproductive patterns exist whose molecular and physical determinants remain to be investigated. This project aims at testing the hypothesis that population diversity arises from a joint effect of the specifics of planarian reproduction mechanics and epigenetic diversity of ASCs in individual worms. The PI will integrate the research objectives of this proposal into three educational initiatives, which focus on "learning through research" and long-term engagement of students: (1) The PI is establishing a partnership with Vista Magnet Middle school that allows 6th graders to work together with her lab on research projects throughout the school year. (2) The PI will continue her efforts toward participation of high school students in research. In particular, she will continue to enable students from Torrey Pines High School to engage in research in her lab throughout the year, which allows them to design and execute their own science projects. (3) The PI will continue her efforts in promoting undergraduate research, in her own group as well as through a new research-centered, quantitative biology laboratory course that she has developed. The course will launch in 2016 and is currently for incoming biology freshmen only. In the context of this proposal, the PI will widen the student population to physics freshmen by adding more physics to the curriculum, and thus create a truly interdisciplinary research-driven laboratory course at the interface of biology and physics in terms of content and student population.How cellular decision-making causes specific phenotypes in a population has received a lot of attention in the context of single celled organisms, but less is known about how epigenetic inheritance affects population diversity in multicellular organisms. This study will close this knowledge gap using planarians and a unique experimental setup, whereby thousands of individual reproductive events have already been recorded and form the statistical framework for the PI's studies on the population level. The PI's strategy is to (1) test the hypothesis that within individual planarians, ASCs are differentially distributed, in terms of spatial orientation and/or molecular and cellular characteristics (division and death rates, genetic and epigenetic diversity) through quantification of ASC localization, cellular dynamics, and single cell sequencing, (2) investigate the biomechanics of asexual reproduction to understand how resources get distributed among offspring using traction force measurements and time-lapse imaging, and (3) develop a mathematical model based on the cellular and organismal level experimental data to predict population level phenotypic diversity. The model will be tested by comparing its predictions with existing experimental data and the reproductive patterns of specially designed founder individuals in which all cells are known to originate from a single ASC, through RNA-seq and statistical analysis. Together, these approaches will allow the PI to test the hypothesis that spatial epigenetic heterogeneity of stem cells in individuals combined with a stochastic reproduction mechanism determine intraspecies phenotypic differences on the population level, which will be measured in terms of reproductive behaviors. The proposed work will shed new light onto the role of transgenerational epigenetic inheritance for the evolutionary success of asexual multicellular life. On a broader level, stem cell decision-making is currently receiving considerable attention because an understanding of how stem cells switch states stochastically and in response to environmental cues is indispensable for successful stem cell therapies.This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Cellular Cluster in the Division of Molecular and Cellular Biosciences