The award, funded by the Systems and Synthetic Biology Program in the Division of Molecular and Cellular Biosciences, addresses a classic problem in evolutionary biology: understanding how organisms adapt in ever-changing environments. Many organisms rely on bet-hedging strategies to deal with unpredictable and fluctuating environments. This widespread biological trait underlies diverse phenomena from antibiotic tolerance in bacteria to immune diversity in mammals. For example, a microbial population can enhance its fitness by allowing individual cells to stochastically transition among multiple phenotypes. The resulting population diversity ensures that some cells are well-adapted for an unforeseen environmental change. Uncovering these adaptive switching mechanisms is key to understanding microbial evolution and life in ever-changing environments. Recently, it was proposed that prions - originally discovered as the cause of neurodegenerative diseases in mammals - are bet-hedging elements in fungi, maintained to promote survival in fluctuating environments. Prion proteins can switch between multiple conformational states. Conversion to a prion state has been shown to generate new, heritable phenotypes, which are beneficial in many conditions. The overarching goal of this project is to test the prion bet-hedging hypothesis. According to theory, phenotypic switching rates of bet-hedging elements evolve to be in tune with the rate of environmental fluctuations. A central focus of the project will be to test these predictions by studying prion switching in prescribed, fluctuating environmental selection. A second focus will be to use synthetic biology approaches to de novo engineer prion bet-hedging devices, thereby exploring how adaptive properties might be encoded in these elements. These studies will require the development of new genetic tools, as well as innovative technologies, such as microfluidic platforms, for simulating complex environments and studying cells in ways that are beyond the capabilities of traditional biological experimentation. This work will have broad implications for our basic understanding of evolution, development, and cellular systems. The project will also shed light on the diverse roles of prions, unique elements that are emerging to be common in the microbial world. Finally, the proposed work will have a transformative impact on synthetic biology, enabling new schemes for rationally engineering a wide array of cellular functions.
The focus on multidisciplinary approaches, both experimental and theoretical, will provide exciting opportunities for students of all levels to contribute to this largely unexplored, but significant, area of biology. A broad goal of the project is to inspire and train students from K-12 to graduate school to think conceptually about how quantitative, interdisciplinary, and engineering approaches can help in understanding life. Among the specific activities to be pursued, K-12 education will be impacted by developing a 'systems & synthetic biology bootcamp' for Boston University's Summer Challenge, a residential summer program for high school students. The hands-on activities developed will be translated to a broad high school audience via the Inspiration Ambassadors Program. At the undergraduate level, iGEM activities will be expanded and several undergraduates per year will be mentored via the project. At the graduate level, a new integrated course on quantitative systems biology will be developed. Finally, the project will promote exciting technological developments for miniaturizing and automating biological experimentation within lab-on-a-chip systems. Infrastructure for making device designs and operating software freely-available will be implemented in order to make the technology widely accessible and allow students the opportunity to readily prototype ideas.
