Collaborative Research: Mechanisms of Multicellular Self-Organization in Myxococcus Xanthus

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This project engages a collaborating team of experimental microbiologists, computational biologists, and mathematicians to understand the mechanisms by which soil bacterium Myxococcus xanthus aggregates into multicellular mounds in response to starvation. Using mathematical and biological approaches, the team will uncover interactions that control different stages of developmental self-organization: (1) pre-aggregation cell alignment and formation of cellular streams; (2) formation and growth of initial aggregates; and (3) aggregate coarsening, dispersal, and pulsing. This project is expected to elucidate some of the general mechanisms behind the collective behavior of motile cells in other organisms and to develop widely applicable mathematical approaches. Transition from single cells to multicellularity is fundamentally important to increase understanding of many pathogenic bacteria and to elucidate self-organization in more complex systems. Even though individual bacterial cells are considered to function independently and to be autonomous, many bacterial populations will act collectively, communicating, moving and self-organizing into multicellular structures. M. xanthus is a great model system for studying biological self-organization: its cells function fine alone, but cooperate to form variety of distinct, dynamic patterns depending on environmental conditions. However, the mechanisms of these behaviors are currently not fully understood. Broader impacts of the project will be further enhanced by training opportunities for participating students. Solving complex biological problems requires a new generation of life scientists with cross-disciplinary training in both experimental and computational methods. This research will provide those training opportunities for all participants, facilitated by close interactions such as joint meetings and trainee collaborations. This project focuses on solving one of the fundamental problems of modern developmental biology: how individual cells self-organize into multicellular structures. In particular, the goal of the research is to uncover mechanisms controlling the developmental program of a biofilm formed by M. xanthus. This soil bacterium is tractable and has a relatively simple genome and as such is an excellent model system to develop novel mathematical models and experimentally test their predictions. Under starvation, M. xanthus cells coordinate their movement in space and time, bringing tens of thousands of cells together into multicellular aggregates to differentiate into spores. This model of prokaryotic development is experimentally tractable and shares many of the complexities that are ubiquitous in developmental systems. With a combination of mathematical modeling approaches and quantitative experiments, this project will uncover the interactions and signaling mechanisms that control three distinct stages of developmental self-organization. To this end, the research builds on the previously fruitful methodology to connect these interactions with the observed population phenotypes. The emphasis of the mathematical component of this research is on the advancement of agent-based and kinetic models that go beyond the existing, oversimplified models of the phenomena that postulate and analyze a single mechanism for self-organization. The resulting predictions will be tested experimentally using genetic or environmental perturbations. Broader impacts include developing novel and widely applicable methodology to understand multicellular patterns, cross-disciplinary training for participating students, and educational and outreach activities based on the research results and methods.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.