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Programmed population control by cell–cell communication and regulated killing

Nature volume 428, pages 868–871 (2004)Cite this article

Abstract

De novo engineering of gene circuits inside cells is extremely difficult1,2,3,4,5,6,7,8,9, and efforts to realize predictable and robust performance must deal with noise in gene expression and variation in phenotypes between cells10,11,12. Here we demonstrate that by coupling gene expression to cell survival and death using cell–cell communication, we can programme the dynamics of a population despite variability in the behaviour of individual cells. Specifically, we have built and characterized a ‘population control’ circuit that autonomously regulates the density of an Escherichia coli population. The cell density is broadcasted and detected by elements from a bacterial quorum-sensing system13,14, which in turn regulate the death rate. As predicted by a simple mathematical model, the circuit can set a stable steady state in terms of cell density and gene expression that is easily tunable by varying the stability of the cell–cell communication signal. This circuit incorporates a mechanism for programmed death in response to changes in the environment, and allows us to probe the design principles of its more complex natural counterparts.

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Figure 1: A population-control circuit programmes population dynamics by broadcasting, sensing and regulating the cell density using cell–cell communication and negative feedback.
Figure 2: Experimentally measured growth curves (a) and corresponding levels of LacZα–CcdB (b) of Top10F′ cells with the population-control circuit OFF (filled squares) and ON (open squares) for pH 7.0.
Figure 3: Effects of pH on circuit behaviour.

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Acknowledgements

Y. Wang, R. Georgescu, S. Thiberge, F. Balagadde and S. Maerkle assisted with preliminary characterization of the circuit. C. Collins constructed plasmids pLuxR, pLuxR2 and pluxGFPuv. We also thank Y. Yokobayashi, M. Raizada, J. Leadbetter, M. Elowitz and M. Savageau for discussions or comments on the manuscript. This material is based on work supported by the Defense Advanced Research Projects Agency (DARPA). Any opinions, findings, and conclusions or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the views of the DARPA.

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Authors and Affiliations

  1. Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California, 91125, USA

    Lingchong You & Frances H. Arnold

  2. Division of Biology, California Institute of Technology, Pasadena, California, 91125, USA

    Robert Sidney Cox III

  3. Departments of Electrical Engineering and Molecular Biology, Princeton University, Princeton, New Jersey, 08544, USA

    Ron Weiss

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Correspondence to Frances H. Arnold.

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You, L., Cox, R., Weiss, R. et al. Programmed population control by cell–cell communication and regulated killing. Nature 428, 868–871 (2004). https://doi.org/10.1038/nature02491

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