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Abstract Failure of modularity remains a significant challenge for assembling synthetic gene circuits with tested modules as they often do not function as expected. Competition over shared limited gene expression resources is a crucial underlying reason. It was reported that resource competition makes two seemingly separate genes connect in a graded linear manner. Here we unveil nonlinear resource competition within synthetic gene circuits. We first build a synthetic cascading bistable switches (Syn-CBS) circuit in a single strain with two coupled self-activation modules to achieve two successive cell fate transitions. Interestingly, we find that the in vivo transition path was redirected as the activation of one switch always prevails against the other, contrary to the theoretically expected coactivation. This qualitatively different type of resource competition between the two modules follows a ‘winner-takes-all’ rule, where the winner is determined by the relative connection strength between the modules. To decouple the resource competition, we construct a two-strain circuit, which achieves successive activation and stable coactivation of the two switches. These results illustrate that a highly nonlinear hidden interaction between the circuit modules due to resource competition may cause counterintuitive consequences on circuit functions, which can be controlled with a division of labor strategy. 

Abstract Interdependent critical infrastructures in coastal regions, including transportation, electrical grid, and emergency services, are continually threatened by storm-induced flooding. This has been demonstrated a number of times, most recently by hurricanes such as Harvey and Maria, as well as Sandy and Katrina. The need to protect these infrastructures with robust protection mechanisms is critical for our continued existence along the world’s coastlines. Planning these protections is non-trivial given the rare-event nature of strong storms and climate change manifested through sea level rise. This article proposes a framework for a methodology that combines multiple computational models, stakeholder interviews, and optimization to find an optimal protective strategy over time for critical coastal infrastructure while being constrained by budgetary considerations. 

Growth-mediated feedback between synthetic gene circuits and host organisms leads to diverse emerged behaviors, including growth bistability and enhanced ultrasensitivity. However, the range of possible impacts of growth feedback on gene circuits remains underexplored. Here we mathematically and experimentally demonstrated that growth feedback affects the functions of memory circuits in a network topology-dependent way. Specifically, the memory of the self-activation switch is quickly lost due to the growth-mediated dilution of the circuit products. Decoupling of growth feedback reveals its memory, manifested by its hysteresis property across a broad range of inducer concentration. On the contrary, the toggle switch is more refractory to growth-mediated dilution and can retrieve its memory after the fast-growth phase. The underlying principle lies in the different dependence of active and repressive regulations in these circuits on the growth-mediated dilution. Our results unveil the topology-dependent mechanism on how growth-mediated feedback influences the behaviors of gene circuits.