Systems Biology to Unlock the Next Level of Cell-Free Synthetic Biology

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Project Summary Research in the PI’s laboratory focuses on metabolism, with applications in systems and synthetic biology. The lab has two main goals: to study and model metabolic dynamics and regulation, and to develop minimal-equipment biosensors for nutritional deficiencies for deployment to resource- poor environments. The biosensor work has broad potential global utility and impact, and also motivates some of the systems biology analyses they perform. Those metabolic studies lie at the interface of computation and experiment, and are unified via their use of metabolomics. His group uses temporal metabolomics measurements to capture the metabolic dynamics of biological systems, and then uses these data for analysis, understanding, and engineering of those biological systems. In parallel, they develop computational tools to better exploit metabolomics data, with an aim towards applying those data to new metabolic modeling frameworks. In the next five years, the PI will tackle some of the most significant yet understudied challenges in cell-free systems, the group’s current platform of choice for the development of field-deployable biosensors. In the past five years he has been a trailblazer at the interface of systems biology and cell-free synthetic biology, discovering that residual endogenous metabolism in lysate-based cell- free systems is critical in determining the total productivity of a given reaction. He will expand upon that discovery to fully characterize the impacts of endogenous metabolism on cell-free systems, and to move towards solving what is currently the key challenge to broader adoption and use of cell-free systems: early termination of expression in reactions. He will use a host of systems-scale tools, including metabolomics, proteomics, and fluxomics, to create a comprehensive (and the only) systems-scale characterization of metabolism in cell-free systems, and will complement these efforts with metabolic modeling and analysis to gain greater insight into the inner workings of the system. The PI’s overall vision is of a deeper understanding of cell-free systems that allows them to go to the next level in terms of adoption, applications, and impact. He also envisions significant biological insight coming from these cell-derived but cell-free systems, including the ability to discover regulatory interactions that might otherwise be masked by epistatic effects in vivo. He envisions the results of his work being exploited by biologists and bioengineers to enable more effective in vitro models of biological systems as well as biotechnological advances that were previously either scientifically or economically infeasible.