Ultrasensitive Negative Feedback Control: A Natural Approach for the Design of Synthetic Controllers

Abstract

Many of the most important potential applications of Synthetic Biology will require the ability to design and implement high performance feedback control systems that can accurately regulate the dynamics of multiple molecular species within the cell. Here, we argue that the use of design strategies based on combining ultrasensitive response dynamics with negative feedback represents a natural approach to this problem that fully exploits the strongly nonlinear nature of cellular information processing. We propose that such feedback mechanisms can explain the adaptive responses observed in one of the most widely studied biomolecular feedback systems—the yeast osmoregulatory response network. Based on our analysis of such system, we identify strong links with a well-known branch of mathematical systems theory from the field of Control Engineering, known as Sliding Mode Control. These insights allow us to develop design guidelines that can inform the construction of feedback controllers for synthetic biological systems.

Novel Influences of IL-10 on CNS Inflammation Revealed by Integrated Analyses of Cytokine Networks and Microglial Morphology

“…Adaptation is an important emergent property of engineered feedback control systems and components of the immune system operating inside and out of the CNS (Brudecki et al, 2013 ; Anderson et al, 2015 ; Montefusco et al, 2016 ). Our previous study showed that IL-10 restrained the adaptation of the TNFα response to LPS in vitro .…”

Ultrasensitive molecular controllers for quasi-integral feedback

“…High-gain negative feedback is known to improve the reliability of systems that are uncertain: operational amplifiers are a classical example that illustrate how the output of a high-gain device can precisely track the input, despite uncertainty in the gain, as long as negative feedback is present. Potential disadvantages of high-gain controllers include instability (which in our case could introduce oscillations), and chattering, a phenomenon where the controller rapidly switches between its on and off states and often occurs in sliding mode controllers [78]. Instability can be prevented by imposing suitable limitations on the closed-loop gain; if the process gain is fixed, this gain reduction would fall on the controller and possibly reduce its ultrasensitivity.…”

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