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

For the creativity of synthetic biologists to be unleashed, basic circuits must become truly interchangeable — that is, modular and scalable. Two papers in this week's Nature take steps towards that goal — one from the Escherichia coli camp and the other using yeast. Tamsir et al. harness bacterial 'quorum sensing' in E. coli and Regot et al. exploit yeast pheromone communication to achieve complex computation through communication between individual cells performing simple logic functions. Such extracellular 'chemical wiring' is one promising way to get around the difficulty of insulating different genetic circuits when these operate within a single cell. For synthetic biologists' creativity to be unleashed, basic circuits must become truly interchangeable, that is, modular and scalable. This study, one of two linked papers, has harnessed bacterial 'quorum sensing' to achieve complex computation through communication between individual cells performing simple logic functions. Such extracellular 'chemical wiring' is one promising way to get around intracellular noise when building more complex genetic circuitry. 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.