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Robust multicellular computing using genetically encoded NOR gates and chemical ‘wires’

Abstract

Computation underlies the organization of cells into higher-order structures, for example during development or the spatial association of bacteria in a biofilm1,2,3. Each cell performs a simple computational operation, but when combined with cell–cell communication, intricate patterns emerge. Here we study this process by combining a simple genetic circuit with quorum sensing to produce more complex computations in space. We construct a simple NOR logic gate in Escherichia coli by arranging two tandem promoters that function as inputs to drive the transcription of a repressor. The repressor inactivates a promoter that serves as the output. Individual colonies of E. coli carry the same NOR gate, but the inputs and outputs are wired to different orthogonal quorum-sensing ‘sender’ and ‘receiver’ devices4,5. The quorum molecules form the wires between gates. By arranging the colonies in different spatial configurations, all possible two-input gates are produced, including the difficult XOR and EQUALS functions. The response is strong and robust, with 5- to >300-fold changes between the ‘on’ and ‘off’ states. This work helps elucidate the design rules by which simple logic can be harnessed to produce diverse and complex calculations by rewiring communication between cells.

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Figure 1: The genetic NOR gate.
Figure 2: Input modularity of the gates.
Figure 3: Construction of an XOR gate by programming communication between colonies on a plate.
Figure 4: Construction of all 16 two-input Boolean logic gates.

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Acknowledgements

We thank W. Mulyasasmita and K. Temme for critical discussions. This work was supported by the National Science Foundation (SynBERC, NSF#0943385 and NSF Sandpit CCF-0943385) and the Office of Naval Research.

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Contributions

A.T. designed and performed the experiments, analysed the data and wrote the manuscript. J.J.T. designed experiments and edited the manuscript. C.A.V. designed experiments, analysed the data and wrote the manuscript.

Corresponding author

Correspondence to Christopher A. Voigt.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures S1-S11 with legends, Supplementary Table S1-S5, Supplementary Discussions, a List of Strains, Plasmid Maps, and Supplementary References. (PDF 1665 kb)

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Tamsir, A., Tabor, J. & Voigt, C. Robust multicellular computing using genetically encoded NOR gates and chemical ‘wires’. Nature 469, 212–215 (2011). https://doi.org/10.1038/nature09565

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