Improving orthogonality in two-component biological signalling systems using feedback control

In natural biological systems, cellular responses to changing growth and environmental conditions are governed by complex signalling and control networks. A common signalling motif is that of the two component signalling systems (TCSSs), dozens of which may operate simultaneously in a single cell. When synthetic biologists create new signalling networks in living cells, achieving orthogonality of signal transmission can be difficult. One challenge is overcoming the crosstalk between pathways that arises from off-target interactions between TCSS components. In this letter we analyze a simple signalling network consisting of two parallel TCSS, demonstrating that substantial crosstalk can occur depending on induction levels of each pathway. We then propose and analyse a feedback control architecture that reduces crosstalk by expressing additional substrates depending upon the state of each pathway. We analyse this control architecture’s stability, and demonstrate that it facilitates near-orthogonal transmission of signals through each pathway