CAREER: Cell Size and Cell Cycle Control in the Presence of Fluctuations in Bacteria

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Intellectual Merit An exquisite, quantitative relationship between growth and cell cycle exists in bacteria. Strikingly, the onset of DNA replication is assumed to coincide with achievement of a specific cell mass (critical mass), a phenomenon that is independent of growth rate. This was one of the most important quantitative ideas in the field of bacterial physiology during the 1950s and the 1960s, and it still serves as the foundation for our current understanding of cell cycle control. Surprisingly, however, we do not yet understand how the molecular-level regulation controls the global relationship between growth and cell cycle. To this end, this project will employ state-of-the-art microscopy to visualize replication and cell division machinery in living cells, allowing us to precisely measure cell growth, DNA replication and cell division timing. In particular, the project will study how the cell responds to physiological perturbations at the single-cell level. Single-cell approach is important, because we can acquire critical molecular-level information related to intracellular fluctuations that is inevitably lost in population-level studies. Importantly, this project will employ two evolutionarily divergent model organisms, Escherichia coli and Bacillus subtilis, permitting us to determine which aspects of cell cycle regulation are likely to be broadly conserved. In doing so, this project will provide a definitive answer to the fundamental question of whether or not cells grow to a critical cell mass to initiate a specific cell-cycle event. The strength of this research lies in its ability to bridge the gap between experiment and theory. In addition to the experimental component described above, the theory component involves quantitative modeling of the acquired data to make experimentally testable predictions. The outcome of the research will have implications for our fundamental understanding of the growth of all cells.Broader Impacts Quantitative biology is more than adding numbers to what biologists already know. The power of the approach is to bring quantitative rigor from physical sciences to identify and solve important and interesting problems in biology. As part of the new initiative of quantitative biology at the University of California at San Diego, the project aims to spread the culture of quantitative approaches to biology from K12 to graduate level education in the San Diego area. This integrative project places great emphasis on the importance of interdisciplinary research experiences at the undergraduate level. To inspire not only the students and educators but also the general public, an annual summer interdisciplinary research bootcamp will be offered for undergraduate students, and possibly senior high-school students, in the San Diego area. Students from under-represented minority groups will be particularly encouraged to participate, and a Hispanic Serving Institution (San Diego State University) will collaborate in the project. A former instructor from the Cold Spring Harbor Laboratory Courses joins the project to design and co-teach the bootcamp modules that incorporate molecular biology, quantitative microscopy, microfluidics, and image analysis. The overall goal is to design exemplary undergraduate research modules and integrate them into standard undergraduate research curricula in quantitative biology at UCSD, SDSU, and other universities. This award is cofounded by the programs in Cellular Dynamics and Function and the Physics of Living Systems.