Abstract
The control of microbes and microbial consortia to achieve specific functions requires synthetic circuits that can reliably cope with internal and external perturbations. Circuits that naturally evolved to regulate biological functions are frequently robust to alterations in their parameters. As the complexity of synthetic circuits increases, synthetic biologists need to implement such robust control “by design”. This is especially true for intercellular signaling circuits for synthetic consortia, where robustness is highly desirable, but its mechanisms remain unclear. Cybergenetics, the interface between synthetic biology and control theory, offers two approaches to this challenge: external (computer-aided) and internal (autonomous) control. Here, we review natural and synthetic microbial systems with robustness, and outline experimental approaches to implement such robust control in microbial consortia through population-level cybergenetics. We propose that harnessing natural intercellular circuit topologies with robust evolved functions can help to achieve similar robust control in synthetic intercellular circuits. A “hybrid biology” approach, where robust synthetic microbes interact with natural consortia and—additionally—with external computers, could become a useful tool for health and environmental applications.
Highlights
Homeostasis is the ability to maintain physiological parameters at steady levels, for example, body temperature or blood salt concentration in an organism and turgor pressure or macromolecular crowding in cells [1,2]
Robustness has been observed in a variety of molecular systems, including the pathways that control gene expression, metabolism and cellular signaling [4], with negative feedback being at the core of the operation of such circuits
Electronic and biological circuits can both be seen as information processing flows and share conceptual similarities regarding the description of their dynamics and sensitivity to external perturbations
Summary
Homeostasis is the ability to maintain physiological parameters at steady levels, for example, body temperature or blood salt concentration in an organism and turgor pressure or macromolecular crowding in cells [1,2]. Robustness can be generally defined as the property that allows a system to maintain its functions, at least partially, in the presence of internal and external perturbations [3]. Advances towards a quantitative definition of biological robustness have emerged from the similarity between negative feedback in electronic circuits and negative autoregulation in genetic circuits [5]. Synthetic biologists have already proposed theoretically and produced experimentally such robust genetic circuits. These advances pave the way towards the construction of more complex cellular networks with predictable and useful functions, which could enable desired complex cellular behaviors to be engineered from the bottom-up. We introduce robust control in natural intra- and intercellular circuits, focusing on examples with well-described derived biological functions. We explore how such interventions may help to achieve robust control of natural populations for biomedical applications
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