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Published April 29, 2021 | Accepted Version
Journal Article Open

Programmable protein circuit design


A fundamental challenge in synthetic biology is to create molecular circuits that can program complex cellular functions. Because proteins can bind, cleave, and chemically modify one another and interface directly and rapidly with endogenous pathways, they could extend the capabilities of synthetic circuits beyond what is possible with gene regulation alone. However, the very diversity that makes proteins so powerful also complicates efforts to harness them as well-controlled synthetic circuit components. Recent work has begun to address this challenge, focusing on principles such as orthogonality and composability that permit construction of diverse circuit-level functions from a limited set of engineered protein components. These approaches are now enabling the engineering of circuits that can sense, transmit, and process information; dynamically control cellular behaviors; and enable new therapeutic strategies, establishing a powerful paradigm for programming biology.

Additional Information

© 2021 Elsevier Inc. Available online 12 April 2021. We thank E. Winfree, J. Gregrowicz, F. Horns, L. Chong, S. Boyken, A. Askary, and M. Budde for helpful discussions. This work was supported by National Institutes of Health grant R01 MH116508, the Allen Discovery Center program under award number UWSC10142, a Paul G. Allen Frontiers Group-advised program of the Paul G. Allen Family Foundation, and by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under award number R01EB030015. Z.C. was supported by the Damon Runyon Cancer Research Foundation DRG-2388-20 and is a fellow of the Burroughs Wellcome Fund Career Awards at the Scientific Interface. M.B.E. is a Howard Hughes Medical Institute investigator. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Declaration of interests: Z.C. and M.B.E. are inventors on patents and patent applications related to protein circuit design.

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August 20, 2023
December 22, 2023