Dichotomous feedback: a signal sequestration-based feedback mechanism for biocontroller design

Abstract

We introduce a new design framework for implementing negative feedback regulation in synthetic biology, which we term ‘dichotomous feedback’. Our approach is different from current methods, in that it sequesters existing fluxes in the process to be controlled, and in this way takes advantage of the process’s architecture to design the control law. This signal sequestration mechanism appears in many natural biological systems and can potentially be easier to realize than ‘molecular sequestration’ and other comparison motifs that are nowadays common in biomolecular feedback control design. The loop is closed by linking the strength of signal sequestration to the process output. Our feedback regulation mechanism is motivated by two-component signalling systems, where a second response regulator could be competing with the natural response regulator thus sequestering kinase activity. Here, dichotomous feedback is established by increasing the concentration of the second response regulator as the level of the output of the natural process increases. Extensive analysis demonstrates how this type of feedback shapes the signal response, attenuates intrinsic noise while increasing robustness and reducing crosstalk.

Sequestration of histidine kinases by non-cognate response regulators establishes a threshold level of stimulation for bacterial two-component signaling

“…For instance, positive autoregulation has been argued to drive cells infected by HIV into latent or virus-producing states 47 . Sequestration is often viewed as a motif for achieving negative feedback and control 20 , 48 . For instance, in a recent computational study, non-cognate RRs, rather than the classical cognate HK-RR pairs, placed downstream of the cognate signaling pathway have been proposed as a negative feedback mechanism to achieve control by increasing sequestration in proportion to the stimulus strength and thus regulating the response 48 .…”

“…Sequestration is often viewed as a motif for achieving negative feedback and control 20 , 48 . For instance, in a recent computational study, non-cognate RRs, rather than the classical cognate HK-RR pairs, placed downstream of the cognate signaling pathway have been proposed as a negative feedback mechanism to achieve control by increasing sequestration in proportion to the stimulus strength and thus regulating the response 48 . Here, by combining sequestration with positive autoregulation, we identify a new (naturally occurring) motif that enables finer control of signal transduction.…”

Regulation strategies for two-output biomolecular networks

“…It is therefore a requirement for them to be resilient to context-dependent effects and adapt to external environmental perturbations. Several control approaches inspired by both natural and technological systems have recently been proposed allowing for effective and robust regulation of biological networks in vivo and/or in vitro [14][15][16][17][18][19][20]. Despite some conceptual differences, all of these studies focus on biomolecular systems with one output of interest, such as the expression of a single protein.…”