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Rock-paper-scissors: Engineered population dynamics increase genetic stability

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Science  06 Sep 2019:
Vol. 365, Issue 6457, pp. 1045-1049
DOI: 10.1126/science.aaw0542

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Stabilizing synthetic gene circuits

Making synthetic gene circuits in bacteria is one thing, but making them stable under selective pressure with high mutation rates is another. Liao et al. addressed this problem with an ecological strategy in which they created three strains of bacteria, each of which could kill or be killed by one of the other strains (see the Perspective by Johnston and Collins). Once the first strain of bacteria hosting the engineered circuit underwent mutations that decreased function, the system could be “rebooted” by addition of another strain that killed the first but also contained the desired synthetic circuit, allowing its function to proceed unperturbed. This strategy provides a way to control synthetic ecosystems and maintain synthetic gene circuits without using traditional selection to maintain plasmids with antibiotics.

Science, this issue p. 1045; see also p. 986

Abstract

Advances in synthetic biology have led to an arsenal of proof-of-principle bacterial circuits that can be leveraged for applications ranging from therapeutics to bioproduction. A unifying challenge for most applications is the presence of selective pressures that lead to high mutation rates for engineered bacteria. A common strategy is to develop cloning technologies aimed at increasing the fixation time for deleterious mutations in single cells. We adopt a complementary approach that is guided by ecological interactions, whereby cyclical population control is engineered to stabilize the functionality of intracellular gene circuits. Three strains of Escherichia coli were designed such that each strain could kill or be killed by one of the other two strains. The resulting “rock-paper-scissors” dynamic demonstrates rapid cycling of strains in microfluidic devices and leads to an increase in the stability of gene circuit functionality in cell culture.

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