Simulating a growing minimal cell: Integrating experiment and theory

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All cells share a universal, minimal set of biological processes essential for life. The search for this set led to the construction of the minimal bacterial cell JCVI-syn3A. With 493 genes in a genome of 543 kbp, JCVI-syn3A has a genome smaller than that of any independently-replicating cell found in nature, a robust morphology, and can divide every two hours in a stress-free laboratory growth medium. Nearly all genes in this minimal cell are essential, and the cell is small enough that a complete description of all cellular functions can be attempted over biological relevant length, time, and concentrations scales by exploiting graphics processing unit (GPU) computing. Recent successes in GPU computing, and 3D imaging have made it now possible to build a whole-cell computational model of this minimal bacterial cell and to investigate what are the rules of life allowing this cell to grow and divide. In this project the investigators construct a whole-cell model coupling all the cellular functions. The outcome of this project will allow the research team to predict cellular behavior under a variety of perturbations, and thus explain how a complete cell works. The educational broader impacts include the training of students and postdoctoral investigators, and outreach to the broader community through workshops and YouTube/VR platforms facilitating the public dissemination of the science.This research project addresses key components needed to make a more complete computational model of a growing minimal cell. Approximately ∼90 out of the 493 genes encode proteins of unclear cellular context, of which 30 were determined to be essential from transposon bombardment experiments. Extension of the current 3D spatial model to encompass the full cell cycle requires new hybrid stochastic-deterministic algorithms to be implemented in the GPU-based Lattice Microbe software and imaging experiments. MINFLUX microscopy will be used to provide data at the enhanced spatial and temporal resolutions needed to construct accurate models of cell growth, division, and DNA replication. The structural and functional characterization of proteins of unclear function, which recent work indicates are required for consistent morphology and division of Syn3A, are needed to extend the model and promise to reveal novel interactions and biochemical reactions. To achieve these goals, the cellular processes of Syn3A will be experimentally measured. The function of unknown genes associated with cell shape and growth will be identified. The organization of transcriptional units and MINFLUX imaging studies of cell division and initiation of DNA replication will be determined. The integration of new heterogeneous data into the existing whole-cell computational models will occur through the develop and implementation growth and cell division kinetic models. In addition, the structure of the 30 essential proteins will be identified. Finally, the gene expression kinetic model will be informed with measured transcriptional units to determine the overall impacts on protein production and the cell. The planned research will be conducted with postdocs and graduate students at the University of Illinois at Urbana-Champaign (UIUC), Johns Hopkins University (JHU), the Synthetic Biology group at JCVI, and collaborators at TU Dresden, Leiden University, and University of GroningenThis 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.