Layered Feedback Control Improves Robust Functionality across Heterogeneous Cell Populations

Realizing homeostatic control of metabolites or proteins is one of the key goals of synthetic circuits. However, if control is only implemented internally in individual cells, cell-cell heterogeneity may break the homeostasis on population level since cells do not contribute equally to the production or regulation. New control structures are needed to achieve robust functionality in heterogeneous cell populations. Quorum sensing (QS) serves as a collective mechanism by releasing and sensing small and diffusible signaling molecules for group decision-making. We propose a layered feedback control structure that includes a global controller using quorum sensing and a local controller via internal signal-receptor systems. We demonstrate with modeling and simulation that the global controller drives contributing cells to compensate for disturbances while the local controller governs the fail-mode performance in non-contributing cells. The layered controller can tolerate a higher portion of non-contributing cells or longer generations of mutant cells while maintaining metabolites or proteins level within a small error range, compared with only internal feedback control. We further discuss the potential of such layered structures in robust control of cell population size, population fraction and other population-dependent functions.