Mechanical and biochemical organization of three-dimensional biofilm architectures

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Over the last two decades, microbiologists have recognized that most bacterial species organize themselves into surface-attached multicellular communities called biofilms. Bacterial biofilms have been typically studied with a focus on identifying biochemical signaling pathways and regulatory genes that influence the morphology of two-dimensional macroscopic colonies, or the macroscopic amount of biofilm biomass in liquid cultures. The detailed microscopic dynamics of biofilm growth and how microscopic processes determine emergent multicellular architectural properties are less well understood. Only recently, advanced live-cell imaging tools have been developed that enable the observation of three-dimensional biofilm growth at single-cell resolution. For biofilms up to several hundred cells in size, it was found that short-range mechanical interactions between cells are sufficient to explain the observed architectures. However, it was also found that for larger biofilms, mechanical interactions alone cannot explain the experimental data. This suggests that, in order to understand the origin of biofilm architectures beyond the very early stages of biofilm development, it is necessary to integrate both mechanical interactions and biochemical cues to explain biofilm architecture development. In this proposal, I describe a data-driven approach to obtain a scale-bridging theoretical model of bacterial biofilm growth in three dimensions. In particular, my goal is to develop a cell-based model that takes into account mechanical, as well as biochemical interactions related to gene-regulatory processes, and to connect this description to suitable continuum theories. Addressing these aims will enable us to identify the minimal set and spatio-temporal variation of mechanical and biochemical interactions that are required in a growing biofilm to ensure its robust architecture development on mesoscopic scales. Working in close collaboration with experimentalists, the theoretical work will be guided by unique single-cell resolved imaging data and gene-expression reporters of growing biofilms that consist of up to 10,000 cells. By comparing the theoretical framework with experiments in which biofilms are exposed to mechanical, chemical, and genetic perturbations, we will build a quantitative description that allows us to identify the key mechanisms involved in shaping three-dimensional biofilm architectures at mesoscopic scales.