Synthetic Reconstitution of Complex Cellular Behavior

Can we build biological systems that recapitulate complex cellular functions like those seen in nature? Answering this question is the central goal of our research.

This question also forms the basis of reconstitution, an established experimental approach that reimagines how a biological process can be recapitulated outside of its natural context (e.g. outside of the cell and in a test tube) using a reduced set of molecular components. Biochemical reconstitution has been successfully applied to recreate many processes, enabling precise control over molecular parameters and a powerful way to test mechanistic models and establish sufficiency. Our vision is to implement the power and precision afforded by biochemical reconstitution within the complex environment of a living cell. If we can achieve this, then we can understand and predictably control complex cellular functions that have eluded our understanding, such as those that regulate how cells make decisions, execute responses, establish memories, and develop into multicellular organisms.

To do this, our laboratory is developing novel tools at the intersection of synthetic & systems biology, protein & cell engineering, laboratory evolution, genomics, and computation that enable us to recapitulate and control cellular behavior with synthetic circuitry. This enables us to effectively replace biochemistry with genetics. Taking this leap forward is fundamentally important for basic biology, to discover how cellular behaviors and diseases arise from complex networks of interacting molecules. It is also important for engineering and medicine, offering the potential to precisely control cellular function for next-generation therapies and to “teach” cells and organisms to solve the greatest health, climate, and engineering challenges of today.

Specifically, our laboratory develops tools of synthetic biology that allow us to construct regulatory circuits inside living cells. We are using our tools to dissect the molecular circuits that control gene regulation in eukaryotes, toward addressing the grand challenge of understanding their organization across scale and how they function to generate diverse cellular phenotypes. The basic insights we generate inform the development of platforms to program therapeutically-useful cellular functions for emerging gene and cell-based therapies, such as CAR-T cells for cancer. In addition, our team is developing novel continuous evolution technologies that are automated and scalable, and applying these to generate biomolecules with radically altered or new functions to address unmet needs in biology, medicine, and biotechnology. To broaden the impact of our basic science and medical discoveries, we make the technologies we develop widely usable and accessible to the scientific community. Overall, by learning how to build biological systems from scratch, our broad goal is to connect the molecular building blocks of life to a comprehensive understanding of cellular behavior and ultimately to clinical and other applications.

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