Bistable State Switch Enables Ultrasensitive Feedback Control in Heterogeneous Microbial Populations

Molecular feedback control circuits can improve robustness of gene expression at the single cell-level. This achievement can be offset by requirements of rapid protein expression, that may induce cellular stress, known as burden, that reduces colony growth. To begin to address this challenge we take inspiration by ‘division-of-labor’ in heterogeneous cell populations: we propose to combine bistable switches and quorum sensing systems to coordinate gene expression at the population-level. We show that bistable switches in individual cells operating in parallel yield an ultrasensitive response, while cells maintain heterogeneous levels of gene expression to avoid burden across all cells. Within a feedback loop, these switches can achieve robust reference tracking and adaptation to disturbances at the population-level. We also demonstrate that molecular sequestration enables tunable hysteresis in individual switches, making it possible to obtain a wide range of stable population-level expressions.