Intellectual Merit: Regulation of cell shape defined by a cytoskeleton, cell wall, or the extracellular environment is carried out in individual cells and tissues from all biological kingdoms. Robust, accurate bacterial growth requires sophisticated choreography of the cytoskeleton and cell-wall synthesis to control cell shape and maintain structural integrity, as changes in bacterial cell shape have critical consequences for motility, immune system evasion, proliferation, and adhesion. For most bacteria, the cell wall determines cell shape, although the detailed mechanisms of growth and shape maintenance remain elusive. This research will produce a versatile biophysical modeling framework bridging the fundamental principles of cell-shape determination at the molecular and cellular scales. Three critical biological challenges will be addressed: (i) the integration of cytoskeletal mechanics and dynamics with cell-wall growth, (ii) the incorporation of multilayered cell-wall growth to investigate the growth patterns of thick-walled bacteria, and (iii) the elucidation of how cells constrict during division. Each project will interrogate the roles of intracellular spatial organization, mechanical forces, and kinetics to provide theoretical predictions for experimentation. In total, this research aims to discover the simple physical rules that allow cells to achieve robust, shape-preserving growth across kingdoms. This approach should reveal general physical principles of cell growth that fundamentally link the molecular structure of the cytoskeleton, mechanisms of cell-wall synthesis, and the coordination of organismal-scale behavior, empowering the deconstruction of the evolutionary origin of cell shape and tissue polarity.
Broader Impacts: The PI will construct a wiki containing introductory lectures on bacterial morphogenesis available to the microbiology community and other educational institutions worldwide. In addition, the PI will distribute a computational platform for evaluating models of cell-shape determination, and will run an annual workshop on its implementation to aid in development of other models. This software will also serve as a platform for a high-school educational module regarding elastic networks. The PI will continue to pursue elementary-school outreach, undergraduate and graduate education, and campus-wide community building. The PI's core class on the Physical Biology of Cells, the foundation for the new Bioengineering undergraduate major at Stanford, integrates and motivates chemistry, physics, mathematics, and computer science through biological models. The PI's class on Computational Modeling of Microbial Communities (registered jointly in Bioengineering and Microbiology) will utilize project-based learning to motivate the students to employ computational modeling of metagenomics, imaging, and transcriptomics datasets and to disseminate their results. The PI will partner with a nearby group of ethnically and economically diverse fifth graders; the students will collect ecological samples of local microbial communities and visit Stanford to image their samples and to explore the microbial world through hands-on learning. The PI has also demonstrated a commitment to women and students from underprivileged socioeconomic backgrounds, both from Stanford and from neighboring schools in the Bay Area, through mentorship of undergraduates and graduate students and other outreach activities. Collectively, these efforts will achieve considerable progress toward a fundamental understanding of the unexplored frontiers of bacterial morphogenesis and integrate physics and mechanics with traditional microbiological approaches. Moreover, these theoretical approaches have direct applicability to synthetic biology, cellular community design, and the control of bacterial growth.
