Although there has been considerable progress in the development of engineering principles for synthetic biology, a substantial challenge is the construction of robust circuits in a noisy cellular environment. Such an environment leads to considerable intercellular variability in circuit behaviour, which can hinder functionality at the colony level. Here we engineer the synchronization of thousands of oscillating colony ‘biopixels’ over centimetre-length scales through the use of synergistic intercellular coupling involving quorum sensing within a colony and gas-phase redox signalling between colonies. We use this platform to construct a liquid crystal display (LCD)-like macroscopic clock that can be used to sense arsenic via modulation of the oscillatory period. Given the repertoire of sensing capabilities of bacteria such as Escherichia coli, the ability to coordinate their behaviour over large length scales sets the stage for the construction of low cost genetic biosensors that are capable of detecting heavy metals and pathogens in the field.
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This work was supported by the National Institutes of Health and General Medicine (R01GM69811), the San Diego Center for Systems Biology (P50GM085764), the DoD NDSEG (A.P.) and NSF Graduate Research (P.S.) Fellowship Programs. L.T. was supported, in part, by the Office of Naval Research (MURI N00014-07-0741). We would like to thank J. Imlay, S. Ali and J. Collins for helpful discussions and J. Hickman, B. Taylor and K. Lomax for their help with illustrations.
The movie shows timelapse fluorescence microscopy of a 200 trap sensor array displaying NDH-2 engineered synchronization. An EMCCD camera was used to keep exposure times extremely low (4X magnification, 20ms, 95% attenuation) to ensure no fluorescence interaction, hence the appearance of lower signal.
The movie shows timelapse fluorescence microscopy of the 500 trap biosensor array showing the onset of synchronization from disparate initial conditions using period modulator circuit. Flashes indicate changes in arsenite concentration which result in changes in the oscillatory period.
The movie shows timelapse fluorescence microscopy of a sensor array containing thresholding circuit. Red color indicates addition of 0.25 mM arsenite that initiates oscillations in blue.
The movie shows timelapse fluorescence microscopy of a modified 500 trap sensor array in which traps are farther apart. This increased separation results in anti phase oscillations, where a biopixel and its nearest neighbors alternate bursts.
The movie shows timelapse fluorescence microscopy of the 12,000 trap scaled up array showing oscillation and synchronization maintained over a maximum distance of 27 mm.
The movie shows Real time microscopy depicting the loading of our microfluidic device. Cells flow in from the cell port and fill the trapping regions.
The movie shows Timelapse fluorescence microscopy of a modified 500 trap sensor array in which traps of 2 sizes are present. This results in 2:1 resonant oscillations where larger traps oscillate at twice the frequency of smaller traps.
The movie shows timelapse fluorescence microscopy of a 500 trap sensor array showing unsynchronized oscillations when NDH-2 is not present and high-intensity fluorescence bursts are not used.
About this article
Nature Microbiology (2017)