Layered feedback control overcomes performance trade-off in synthetic biomolecular networks.

Layered feedback is an optimization strategy in feedback control designs widely used in engineering. Control theory suggests that layering multiple feedbacks could overcome the robustness-speed performance trade-off limit. In natural biological networks, genes are often regulated in layers to adapt to environmental perturbations. It is hypothesized layering architecture could also overcome the robustness-speed performance trade-off in genetic networks. In this work, we validate this hypothesis with a synthetic biomolecular network in living E. coli cells. We start with system dynamics analysis using models of various complexities to guide the design of a layered control architecture in living cells. Experimentally, we interrogate system dynamics under three groups of perturbations. We consistently observe that the layered control improves system performance in the robustness-speed domain. This work confirms that layered control could be adopted in synthetic biomolecular networks for performance optimization. It also provides insights into understanding genetic feedback control architectures in nature.