In-Silico Analysis and Implementation of a Multicellular Feedback Control Strategy in a Synthetic Bacterial Consortium

Abstract

Living organisms employ endogenous negative feedback loops to maintain homeostasis despite environmental fluctuations. A pressing open challenge in Synthetic Biology * To whom correspondence should be addressed † Department of Engineering Mathematics, University of Bristol ‡ BrisSynBio, University of Bristol ¶ School of Biochemistry, University of Bristol § School of Biological Sciences, University of Bristol Department of Electrical Engineering and Information Technology, University of Naples ⊥ Contributed equally to this work as first authors # Contributed equally to this work 1 is to design and implement synthetic circuits to control host cells' behavior, in order to regulate and maintain desired conditions. To cope with the high degree of circuit complexity required to accomplish this task and the intrinsic modularity of classical control schemes, we suggest the implementation of synthetic endogenous feedback loops across more than one cell population. The distribution of the sensing, computation and actuation functions required to achieve regulation across different cell populations within a consortium allows the genetic engineering in a particular cell to be reduced, increases the robustness, and makes it possible to reuse the synthesized modules for different control applications. Here, we analyze, in-silico, the design of a synthetic feedback controller implemented across two cell populations in a consortium. We study the effects of distributing the various functions required to build a control system across two populations, prove the robustness and modularity of the strategy described and provide a computational proof-of-concept of its feasibility.

Multicellular feedback control of a genetic toggle-switch in microbial consortia

“…However, since the reference molecule R and signaling molecule Q y have inverted roles, the biochemical reactions describing the Activator and Deactivator cells are in general different. For the sake of brevity, we next describe only the biological implementation of the Deactivator cells in Figure 2, which is directly taken from [10].…”

“…In this letter we present a radically new solution to the problem of controlling a cell population endowed with a toggle-switch. Namely, we take a multicellular control approach [10] and synthesize a microbial consortium comprising three cellular populations communicating with each other via orthogonal quorum sensing molecules. In such a consortium, the state of the toggle-switch endowed in one of the populations, the Targets, can be controlled by providing or removing a reference input to the other two, the Controllers.…”

Design of a multicellular feedback control strategy in a synthetic bacterial consortium

“…Further in-silico studies tackling the stochasticity of biochemical processes and experimental work towards the implementation of the proposed strategy are currently being carried out and will be reported elsewhere [30].…”

A low cost, open source Turbidostat design for in-vivo control experiments in Synthetic Biology

“…This modularity allows for customisable experiment set up. Our design has the potential to be adapted and expanded for multicellular control experiments [see Fiore et al (2017)], for which currently there are very limited options both commercially and otherwise. Our base model can be produced for less than $200, with the cost of additional components being low.…”