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A synchronized quorum of genetic clocks


The engineering of genetic circuits with predictive functionality in living cells represents a defining focus of the expanding field of synthetic biology. This focus was elegantly set in motion a decade ago with the design and construction of a genetic toggle switch and an oscillator, with subsequent highlights that have included circuits capable of pattern generation, noise shaping, edge detection and event counting. Here we describe an engineered gene network with global intercellular coupling that is capable of generating synchronized oscillations in a growing population of cells. Using microfluidic devices tailored for cellular populations at differing length scales, we investigate the collective synchronization properties along with spatiotemporal waves occurring at millimetre scales. We use computational modelling to describe quantitatively the observed dependence of the period and amplitude of the bulk oscillations on the flow rate. The synchronized genetic clock sets the stage for the use of microbes in the creation of a macroscopic biosensor with an oscillatory output. Furthermore, it provides a specific model system for the generation of a mechanistic description of emergent coordinated behaviour at the colony level.

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Figure 1: Synchronized genetic clocks.
Figure 2: Dynamics of the synchronized oscillator under several microfluidic flow conditions.
Figure 3: Spatiotemporal dynamics of the synchronized oscillators.
Figure 4: Modelling of synchronized genetic clocks.

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We thank J. Stricker for helpful discussions on plasmid construction, and M. Bennett, K. Wiesenfeld and J. Collins for stimulating discussions during the preparation of the manuscript. This work was supported by the National Institutes of Health and General Medicine (GM69811), the DOE CSGF fellowship (to T.D.), and CONACyT (Mexico, grant 184646, to O.M.-P.).

Author Contributions All authors contributed extensively to the work presented in this paper. T.D. and O.M.-P. are equally contributing first authors, and L.T. and J.H. are equally contributing senior authors.

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Correspondence to Jeff Hasty.

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Supplementary information

Supplementary Information

This file contains Supplementary Methods, Supplementary Data, Supplementary Figures 1- 6 with Legends and Supplementary References. (PDF 621 kb)

Supplementary Movie 1

This movie shows time lapse fluorescence microscopy of TDQS1 cells at low flow rate in a 100x100μm trap. (MOV 4428 kb)

Supplementary Movie 2

This movie shows time lapse fluorescence microscopy of TDQS1 cells in a 2000x100x0.95μm open trap showing propagation of AHL at millimeter scale. (MOV 2066 kb)

Supplementary Movie 3

This movie shows time lapse microscopy of TDQS1 cells at high flow rate in a 100x100μm trap. (MOV 9496 kb)

Supplementary Movie 4

This movie shows zoomed time lapse fluorescence microscopy of TDQS1 cells in a 2000x100x0.95μm open trap showing close-up of cells and propagation of AHL. (MOV 16235 kb)

Supplementary Movie 5

This movie shows time lapse fluorescence microscopy of TDQS1 cells in a three dimensional 1000x400x4.0μm trap. (MOV 2448 kb)

Supplementary Movie 6

This movie shows simulation of the wave propagation within a uniform population of cells. (MOV 1268 kb)

Supplementary Movie 7

This movie shows simulation of the wave propagation within a growing dense cluster of cells. (MOV 288 kb)

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Danino, T., Mondragón-Palomino, O., Tsimring, L. et al. A synchronized quorum of genetic clocks. Nature 463, 326–330 (2010).

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