Host-circuit interactions explain unexpected behavior of a gene circuit

Mathematical models are powerful tools for the design of gene circuits in synthetic biology. Models can predict circuit behavior and guide the selection of suitable circuit components and implementations. The increasing complexity synthetic circuits typically requires model approximations that are amenable for analysis and parameter estimation. However, these simpler models may not reflect the actual behavior of a synthetic circuit once implemented in a host of interest. The experimental implementation of a circuit may show dynamics that cannot be accounted by simplified models. Potential sources for unexpected circuit behavior are host-circuit interactions through competition for shared cellular resources. The allocation of cellular resources to circuit expression inevitably reduces those resources available to other cellular functions such as growth and biosynthesis. Yet the balance between circuit function and host physiology is often overlooked at the design stage. Here we integrate a model of a synthetic circuit, the incoherent feedforward loop, with a mechanistic model for cell growth. We show how the integrated model explains measured circuit responses that the circuit-only model was unable to predict. Our results provide evidence that anomalous circuit dynamics can be traced back to host-circuit interactions.