Growth-Aware Optogenetic Control for Cross-Scale Disturbance Rejection in Bacterial Batch Cultures

Population-level disturbances can disrupt molecular gene expression through growth-dependent host-circuit coupling, creating a cross-scale challenge for synthetic biology. Here, we use a multiscale model to develop growth-aware optogenetic control strategies that maintain a target molecular-scale gene expression signal following population-level dilution in bacterial batch cultures. Simulations predict distinct disturbance-response regimes within a model that couples population growth to intracellular dilution and expression capacity. At intermediate disturbance magnitudes, growth-dependent feedback gains reduce signal overshoot relative to the fixed-gain controller tested. At large disturbances, additional population-based feedforward compensation accelerates signal recovery. Mapping performance across disturbance magnitudes and times identifies when each architecture is beneficial, with the predicted rankings retained under tested parameter perturbations. These results establish model-guided design rules for cross-scale disturbance rejection, showing how population-level information can inform feedback and feedforward regulation of molecular gene expression.