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Published March 17, 2022 | Accepted Version + Submitted + Supplemental Material
Journal Article Open

Synthetic mammalian signaling circuits for robust cell population control


In multicellular organisms, cells actively sense and control their own population density. Synthetic mammalian quorum-sensing circuits could provide insight into principles of population control and extend cell therapies. However, a key challenge is reducing their inherent sensitivity to "cheater" mutations that evade control. Here, we repurposed the plant hormone auxin to enable orthogonal mammalian cell-cell communication and quorum sensing. We designed a paradoxical population control circuit, termed "Paradaux," in which auxin stimulates and inhibits net cell growth at different concentrations. This circuit limited population size over extended timescales of up to 42 days of continuous culture. By contrast, when operating in a non-paradoxical regime, population control became more susceptible to mutational escape. These results establish auxin as a versatile "private" communication system and demonstrate that paradoxical circuit architectures can provide robust population control.

Additional Information

© 2022 Elsevier Inc. Received 3 September 2020, Revised 18 November 2021, Accepted 28 January 2022, Available online 1 March 2022. We thank Igor Antoshechkin, Vijaya Kumar, and Jeff Park for technical assistance and advice; Xinying Ren and Leopold Green from Murray lab for discussion; Haley Larsen, Ke-Kuan Chow, Felix Horns, Duncan Chadly, Christina Su, Ronghui Zhu, Lucy Chong, and other members of the Elowitz lab for critical feedback on the manuscript; and Uri Alon, Omer Karin, Siyu Chen, and Matt Thomson for scientific input and advice. This work is based on work supported by the Defense Advanced Research Projects Agency under contract no. HR0011-17-2-0008, by the National Institute of Health grant R01 MH116508, by the Allen Discovery Center program under award no. UWSC10142, a Paul G. Allen Frontiers Group advised program of the Paul G. Allen Family Foundation, and by the Millard and Muriel Jacobs Genetics and Genomics Laboratory at California Institute of Technology. M.B.E. is a Howard Hughes Medical Institute investigator. A.C.L. is supported by a fellowship from the Taiwanese Ministry of Education. The content of the information does not necessarily reflect the position or the policy of the U.S. government, and no official endorsement should be inferred. Author contributions: Project direction, supervision, and funding: M.W.B., M.B.E., and R.M.M.; design of research: Y.M., M.W.B., and M.B.E.; experimental investigation: Y.M., M.W.B., J.Z., and A.C.L.; data analysis: Y.M., M.W.B., M.N.M., and M.B.E.; mathematical modeling: Y.M., M.N.M., and M.B.E.; paper writing: Y.M., M.W.B., M.W.M., and M.B.E. Declaration of interests: A patent application has been filed based on the work described here. M.W.B. is a founder and employee of Primordium Labs. Data and code availability: The targeted DNA sequencing data have been deposited at NCBI Sequence Read Archive and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. The bulk RNA sequencing data have been deposited at GEO and are publicly available as of the date of publication. Accession numbers are listed in the key resources table. The plasmid GenBank files, raw data, and processing/plotting scripts for generating the figures shown in this paper are available at data.caltech.edu. The DOI is listed in the key resources table. All original codes used for processing the images and the movies, and codes for mathematical modeling section (Figures 4 and S3) is available at github and is publicly available as of the date of publication. DOIs and links are listed in the key resources table.

Attached Files

Accepted Version - nihms-1784285.pdf

Submitted - 2020.09.02.278564v2.full.pdf

Supplemental Material - 1-s2.0-S0092867422001374-mmc1.pdf

Supplemental Material - 1-s2.0-S0092867422001374-mmc5.mp4


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August 22, 2023
December 22, 2023