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

Fiore, Davide; Salzano, Davide; Cristòbal-Cóppulo, Enric; Olm, Josep M.; Bernardo, Mario di

doi:10.1101/2020.03.05.979138

Cited by 12 publications

(21 citation statements)

References 26 publications

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“…We used both agent-based and lattice modeling to show that reducing average cell division-length in a two-strain consortium confers a "mechanical fitness" advantage to the shorter-length strain. This is in contrast to previous approaches to strain fraction control achieved primarily via exogenous signals [19,25], or induced cell lysis [40,61].…”

Section: Discussionmentioning

confidence: 74%

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Emergent Spatiotemporal Population Dynamics with Cell-Length Control of Synthetic Microbial Consortia

Winkle

Karamched

Bennett

et al. 2021

Preprint

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Increased complexity of engineered microbial biocircuits highlights the need for distributed cell functionality due to concomitant increases of metabolic and regulatory burdens imposed on single-strain topologies. Distributed systems, however, introduce additional challenges since consortium composition and spatiotemporal dynamics of constituent strains must be robustly controlled to achieve desired circuit behaviors. Here, we address these challenges with a modeling-based investigation of emergent spatiotemporal population dynamics that result from cell-length control of monolayer, two-strain bacterial consortia. We demonstrate that with dynamic control of a strain's division length, nematic cell alignment in close-packed monolayers can be destabilized. We found this destabilization conferred an emergent, competitive advantage on smaller-length strains---but by mechanisms that differed depending on the spatial patterns of the population. We used complementary modeling approaches to elucidate underlying mechanisms: an agent-based model to simulate detailed mechanical and signaling interactions between the competing strains and a reductive, stochastic lattice model to represent cell-cell interactions with a single rotational parameter. Our modeling suggests that spatial strain-fraction oscillations can be generated when cell-length control is coupled to quorum-sensing signaling in negative feedback topologies. Our research employs novel methods of population control and points the way to programming strain fraction dynamics in consortial synthetic biology.

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Section: Discussionmentioning

confidence: 74%

“…We suggest that desired strain fractions could be robustly generated under a wide range of initial population distributions. Such control of consortium composition is a fundamental problem in synthetic biology [10,52], and earlier solutions relied primarily on the use of exogenous control [19,25].…”

Section: Discussionmentioning

confidence: 99%

Emergent Spatiotemporal Population Dynamics with Cell-Length Control of Synthetic Microbial Consortia

Winkle

Karamched

Bennett

et al. 2021

Preprint

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show abstract

“…We suggest that desired strain fractions could be robustly generated under a wide range of initial population distributions. Such control of consortium composition is a fundamental problem in synthetic biology [ 10 , 20 ], and our simulations suggest a method to relax dependence on necessary exogenous control [ 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

“…Assigning different functions to genetically distinct strains in a bacterial consortium reduces the metabolic load on each strain and thus allows for more complex functionality and greater robustness [ 8 – 12 ]. Synthetic gene circuits previously engineered in single strains, such as feedback oscillators and toggle switches [ 13 , 14 ], have recently been implemented in consortia [ 10 , 12 , 15 , 16 ]. However, we still lack the mathematical and computational tools that would allow us to engineer such systems in a principled way.…”

Section: Introductionmentioning

confidence: 99%

Emergent spatiotemporal population dynamics with cell-length control of synthetic microbial consortia

et al. 2021

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The increased complexity of synthetic microbial biocircuits highlights the need for distributed cell functionality due to concomitant increases in metabolic and regulatory burdens imposed on single-strain topologies. Distributed systems, however, introduce additional challenges since consortium composition and spatiotemporal dynamics of constituent strains must be robustly controlled to achieve desired circuit behaviors. Here, we address these challenges with a modeling-based investigation of emergent spatiotemporal population dynamics using cell-length control in monolayer, two-strain bacterial consortia. We demonstrate that with dynamic control of a strain’s division length, nematic cell alignment in close-packed monolayers can be destabilized. We find that this destabilization confers an emergent, competitive advantage to smaller-length strains—but by mechanisms that differ depending on the spatial patterns of the population. We used complementary modeling approaches to elucidate underlying mechanisms: an agent-based model to simulate detailed mechanical and signaling interactions between the competing strains, and a reductive, stochastic lattice model to represent cell-cell interactions with a single rotational parameter. Our modeling suggests that spatial strain-fraction oscillations can be generated when cell-length control is coupled to quorum-sensing signaling in negative feedback topologies. Our research employs novel methods of population control and points the way to programming strain fraction dynamics in consortial synthetic biology.

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“…To overcome these limitations, a promising strategy is to distribute the required functionalities among multiple cell populations forming a microbial consortium, so that each cell strain embeds a smaller subset of engineered gene networks. [6][7][8][9]. In this way, each cell population carries out a specialized function and, by dividing labor with the others in the consortium, contributes more efficiently to the achievement of the overall final goal.…”

Section: Introductionmentioning

confidence: 99%

Controlling reversible cell differentiation for labor division in microbial consortia

Salzano

Fiore

Bernardo

2021

Preprint

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We address the problem of regulating and keeping at a desired balance the relative numbers between cells exhibiting a different phenotype within a monostrain microbial consortium. We propose a strategy based on the use of external control inputs, assuming each cell in the community is endowed with a reversible, bistable memory mechanism. Specifically, we provide a general analytical framework to guide the design of external feedback control strategies aimed at balancing the ratio between cells whose memory is stabilized at either one of two equilibria associated to different cell phenotypes. We demonstrate the stability and robustness properties of the control laws proposed and validate them in silico implementing the memory element via a genetic toggle-switch. The proposed control framework may be used to allow long term coexistence of different populations, with both industrial and biotechnological applications. Examples include consortia where each population produces a compound of interest or where one population supports the growth of the other which has the role of producing a desired molecule. As a representative example we consider the realistic agent-based implementation of our control strategy to enable cooperative bioproduction in microbial consortia.

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

Cited by 12 publications

References 26 publications

Emergent Spatiotemporal Population Dynamics with Cell-Length Control of Synthetic Microbial Consortia

Emergent Spatiotemporal Population Dynamics with Cell-Length Control of Synthetic Microbial Consortia

Emergent spatiotemporal population dynamics with cell-length control of synthetic microbial consortia

Controlling reversible cell differentiation for labor division in microbial consortia

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