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A synthetic oscillatory network of transcriptional regulators

Nature volume 403, pages 335338 (20 January 2000) | Download Citation

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Abstract

Networks of interacting biomolecules carry out many essential functions in living cells1, but the ‘design principles’ underlying the functioning of such intracellular networks remain poorly understood, despite intensive efforts including quantitative analysis of relatively simple systems2. Here we present a complementary approach to this problem: the design and construction of a synthetic network to implement a particular function. We used three transcriptional repressor systems that are not part of any natural biological clock3,4,5 to build an oscillating network, termed the repressilator, in Escherichia coli. The network periodically induces the synthesis of green fluorescent protein as a readout of its state in individual cells. The resulting oscillations, with typical periods of hours, are slower than the cell-division cycle, so the state of the oscillator has to be transmitted from generation to generation. This artificial clock displays noisy behaviour, possibly because of stochastic fluctuations of its components. Such ‘rational network design’ may lead both to the engineering of new cellular behaviours and to an improved understanding of naturally occurring networks.

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Acknowledgements

We thank H. Bujard, S. Freundlieb, A. Hochschild, R. Lutz and C. Sternberg for plasmids and advice; U. Alon, N. Barkai, P. Cluzel, L. Frisen, C. Guet, T. Hyman, R. Kishony, A. Jaedicke, P. Lopez, F. Nédélec, S. Pichler, R. Kishony, T. Silhavy, T. Surrey, J. Vilar, C. Wiggins and E. Winfree for discussions; M. Surette for advice and encouragement; L. Hartwell and C. Weitz for comments on the manuscript; and F. Kafatos and E. Karsenti for hospitality and support at the European Molecular Biology Laboratory (EMBL), where part of this work was done. This work was partly supported by the US National Institutes of Health and the von Humboldt Foundation.

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  1. Departments of Molecular Biology and Physics, Princeton University , Princeton, New Jersey 08544, USA

    • Michael B. Elowitz
    •  & Stanislas Leibler

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Correspondence to Michael B. Elowitz.

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https://doi.org/10.1038/35002125

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