Design trade-offs and robust architectures for combined transcriptional and translational resource allocation controllers

Recent work on engineering synthetic cellular circuitry has shown that non-regulatory interactions brought about through competition for shared gene expression resources, such as RNA polymerase and ribosomes, can result in degraded performance or even circuit failure. Transcriptional and translational resource allocation controllers based on orthogonal ‘circuit-specific’ gene expression machineries have previously been separately designed to enforce modularity and improve circuit performance. Here we investigate the potential advantages, challenges, and design trade-offs involved in combining transcriptional and translational resource allocation into one overarching centralised control system. We design a number of biologically feasible controllers that reduce coupling at both the transcriptional and translational levels simultaneously, and identify some key performance tradeoffs. We apply tools from robust control theory to rigorously quantify the impact of uncertainty/variability arising due to experimental implementations on the operation of such controllers. Based on these results, we identify promising architectures for the construction of robust dual transcriptional–translational resource allocation controllers.