Natural Host Feedback Simplifies the Design of Metabolic Switches

The performance of microbial chemical production can be improved by incorporating inducible synthetic gene circuits which ‘switch’ the microbial cell factories from growth to production. Here, we consider the design of an inducible switch, implemented as a small-scale gene regulatory network, in the context of host processes. We show that by accounting for the non-regulatory interactions which arise between host and circuit processes due to natural metabolic and ribosomal constraints the design of the gene circuit can be simplified with little cost to performance. We show that whilst optimal performance is achieved by engineering the full three-gene controller, a partial system composed of fewer regulated genes can still achieve near optimal performance. This may allow for engineering controllers in living cells with fewer time consuming and expensive experimental steps.