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The evolution of synthetic receptor systems

Nature Chemical Biology volume 18, pages 244–255 (2022)Cite this article

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Abstract

Receptors enable cells to detect, process and respond to information about their environments. Over the past two decades, synthetic biologists have repurposed physical parts and concepts from natural receptors to engineer synthetic receptors. These technologies implement customized sense-and-respond programs that link a cell’s interaction with extracellular and intracellular cues to user-defined responses. When combined with tools for information processing, these advances enable programming of sophisticated customized functions. In recent years, the library of synthetic receptors and their capabilities has substantially evolved—a term we employ here to mean systematic improvement and expansion. Here, we survey the existing mammalian synthetic biology toolkit of protein-based receptors and signal-processing components, highlighting efforts to evolve and integrate some of the foundational synthetic receptor systems. We then propose a generalized strategy for engineering and improving receptor systems to meet defined functional objectives called a ‘metric-enabled approach for synthetic receptor engineering’ (MEASRE).

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Fig. 1: Generalized operational components of synthetic receptors.
Fig. 2: The mammalian synthetic receptor toolkit.
Fig. 3: The mammalian transcriptional programming toolkit.
Fig. 4: Synthetic receptor input–output configurations.
Fig. 5: The evolutionary history of synthetic receptor systems.
Fig. 6: Strategies for integration of synthetic receptor systems.
Fig. 7: Metric-enabled approach for synthetic receptor engineering.

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Acknowledgements

We thank M. Johnson for her critical review of this manuscript and valuable feedback. This work was supported in part by the Indo-US Science & Technology Forum (IUSSTF) and the Department of Science & Technology (DST), Government of India (J.M.); the National Science Foundation Graduate Research Fellowship Program (DGE-1842165) (H.I.E.); the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health (NIH) under Award Number 1R01EB026510 (J.N.L.); the National Institute of Biomedical Imaging and Bioengineering of the NIH under Award Number EB021030-03, the National Institute of General Medicine of the NIH award number R35 GM138256 and the National Science Foundation award number CBET-2034495 RECODE (L.M.).

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  1. These authors contributed equally: Janvie Manhas, Hailey I. Edelstein.

Authors and Affiliations

  1. Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India

    Janvie Manhas

  2. The Eli and Edythe Broad CIRM Center, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    Janvie Manhas & Leonardo Morsut

  3. Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL, USA

    Hailey I. Edelstein & Joshua N. Leonard

  4. Interdisciplinary Biological Sciences Program, Northwestern University, Evanston, IL, USA

    Joshua N. Leonard

  5. Center for Synthetic Biology, Northwestern University, Evanston, IL, USA

    Joshua N. Leonard

  6. Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA

    Joshua N. Leonard

  7. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, IL, USA

    Joshua N. Leonard

  8. Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA

    Leonardo Morsut

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L.M. is an inventor of synNotch patent US9670281B2 and receives royalty payments from licensing to Gilead Inc. through UCSF; the other authors declare no competing interests.

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Manhas, J., Edelstein, H.I., Leonard, J.N. et al. The evolution of synthetic receptor systems. Nat Chem Biol 18, 244–255 (2022). https://doi.org/10.1038/s41589-021-00926-z

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