CAREER: Molecular and Cellular Mechanisms Underlying Circuit-Host Interactions

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This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2).Synthetic gene circuits are engineered circuits that allow researchers to program and design cells for a variety of biotechnology applications, including the synthesis of therapeutics, sustainable agriculture and production of renewable resources. Although many synthetic genetic circuits have been successfully used, they have a high rate of failure due in part to negative impacts on host cells. The long-term goals of this project are to better understand how synthetic circuit design impacts host cells and to use this knowledge to design circuits that are less harmful. A diverse group of high school, undergraduate, and graduate students will participate in the research project through active learning and hands-on training. American Rescue Plan funding of this project will support this researcher at a critical stage in his career.Synthetic gene circuits over the last two decades have shown remarkable functional versatility in engineering host organisms and cellular capabilities for desired functions. However, most synthetic gene circuits are highly dependent on multiple undesired factors through complicated circuit-host interactions, such as metabolic burden, cell growth feedback, and resource competition. Another critical reason is that the fundamental molecular mechanism the host cells could adopt to entertain and constrain exogenous synthetic gene circuits is still unclear. Moreover, the lack of quantitative tools to accurately predict the behavior of gene circuits and control their interactions with the host cell is impeding progress in the field. This research program aims to dissect the fundamental mechanisms of circuit-host interactions to understand the molecular and cellular organization of the host system and engineer predictable/controllable gene circuits. A library of gene circuits will be built to gain in-depth mechanistic understandings of how circuit-host interactions are established. An ensemble of mathematical models at different levels will be formulated to characterize the host-circuit mutual interactions at single-cell, population, or ecological levels. The proposed research will advance the quantitative understanding of the crosstalk between gene circuits and bacterial physiology, develop a quantitative characterizing of complex circuit-host interactions on the host cell function and behavior of engineered gene circuits, and facilitate gene circuit design to meet design specifications through practical strategies that target the circuit-host interactions.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.