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      An Allee-based distributed algorithm for microbial whole-cell sensors

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          Abstract

          Reliable detection of substances present at potentially low concentrations is a problem common to many biomedical applications. Complementary to well-established enzyme-, antibody-antigen-, and sequencing-based approaches, so-called microbial whole-cell sensors, i.e., synthetically engineered microbial cells that sense and report substances, have been proposed as alternatives. Typically these cells operate independently: a cell reports an analyte upon local detection.

          In this work, we analyze a distributed algorithm for microbial whole-cell sensors, where cells communicate to coordinate if an analyte has been detected. The algorithm, inspired by the Allee effect in biological populations, causes cells to alternate between a logical 0 and 1 state in response to reacting with the particle of interest. When the cells in the logical 1 state exceed a threshold, the algorithm converts the remaining cells to the logical 1 state, representing an easily-detectable output signal. We validate the algorithm through mathematical analysis and simulations, demonstrating that it works correctly even in noisy cellular environments.

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          Most cited references25

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          Quorum sensing in bacteria.

          Quorum sensing is the regulation of gene expression in response to fluctuations in cell-population density. Quorum sensing bacteria produce and release chemical signal molecules called autoinducers that increase in concentration as a function of cell density. The detection of a minimal threshold stimulatory concentration of an autoinducer leads to an alteration in gene expression. Gram-positive and Gram-negative bacteria use quorum sensing communication circuits to regulate a diverse array of physiological activities. These processes include symbiosis, virulence, competence, conjugation, antibiotic production, motility, sporulation, and biofilm formation. In general, Gram-negative bacteria use acylated homoserine lactones as autoinducers, and Gram-positive bacteria use processed oligo-peptides to communicate. Recent advances in the field indicate that cell-cell communication via autoinducers occurs both within and between bacterial species. Furthermore, there is mounting data suggesting that bacterial autoinducers elicit specific responses from host organisms. Although the nature of the chemical signals, the signal relay mechanisms, and the target genes controlled by bacterial quorum sensing systems differ, in every case the ability to communicate with one another allows bacteria to coordinate the gene expression, and therefore the behavior, of the entire community. Presumably, this process bestows upon bacteria some of the qualities of higher organisms. The evolution of quorum sensing systems in bacteria could, therefore, have been one of the early steps in the development of multicellularity.
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            Synchronized cycles of bacterial lysis for in vivo delivery

            The pervasive view of bacteria as strictly pathogenic has given way to an appreciation of the widespread prevalence of beneficial microbes within the human body 1–3 . Given this milieu, it is perhaps inevitable that some bacteria would evolve to preferentially grow in environments that harbor disease and thus provide a natural platform for the development of engineered therapies 4–6 . Such therapies could benefit from bacteria that are programmed to limit bacterial growth while continually producing and releasing cytotoxic agents in situ 7–10 . Here, we engineer a clinically relevant bacterium to lyse synchronously at a threshold population density and to release genetically encoded cargo. Following quorum lysis, a small number of surviving bacteria reseed the growing population, thus leading to pulsatile delivery cycles. We use microfluidic devices to characterize the engineered lysis strain and we demonstrate its potential as a drug delivery platform via co-culture with human cancer cells in vitro. As a proof of principle, we track the bacterial population dynamics in ectopic syngeneic colorectal tumors in mice. The lysis strain exhibits pulsatile population dynamics in vivo, with mean bacterial luminescence that remained two orders of magnitude lower than an unmodified strain. Finally, guided by previous findings that certain bacteria can enhance the efficacy of standard therapies 11 , we orally administer the lysis strain, alone or in combination with a clinical chemotherapeutic, to a syngeneic transplantation model of hepatic colorectal metastases. We find that the combination of both circuit-engineered bacteria and chemotherapy leads to a notable reduction of tumor activity along with a marked survival benefit over either therapy alone. Our approach establishes a methodology for leveraging the tools of synthetic biology to exploit the natural propensity for certain bacteria to colonize disease sites.
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              Predation, group size and mortality in a cooperative mongoose, Suricata suricatta

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                Author and article information

                Contributors
                mfuegger@lmf.cnrs.fr
                thomas@thomasnowak.net
                Journal
                NPJ Syst Biol Appl
                NPJ Syst Biol Appl
                NPJ Systems Biology and Applications
                Nature Publishing Group UK (London )
                2056-7189
                22 April 2024
                22 April 2024
                2024
                : 10
                : 43
                Affiliations
                [1 ]LMF, Université Paris-Saclay, CNRS, ENS Paris-Saclay, ( https://ror.org/03xjwb503) Gif-sur-Yvette, France
                [2 ]LISN, Université Paris-Saclay, CNRS, ( https://ror.org/03xjwb503) Gif-sur-Yvette, France
                [3 ]Institut Universitaire de France, ( https://ror.org/055khg266) Paris, France
                Author information
                http://orcid.org/0000-0001-5765-0301
                http://orcid.org/0000-0003-1690-9342
                Article
                363
                10.1038/s41540-024-00363-3
                11035582
                38649364
                2d2b1997-7f86-4caa-a264-0a18643ece71
                © The Author(s) 2024

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 25 September 2023
                : 27 March 2024
                Funding
                Funded by: FundRef 501100001665, Agence Nationale de la Recherche (French National Research Agency);
                Award ID: ANR-21-CE48-0003
                Funded by: FundRef 501100001665, Agence Nationale de la Recherche (French National Research Agency);
                Award ID: ANR-21-CE48-0003
                Funded by: FundRef 501100001665, Agence Nationale de la Recherche (French National Research Agency);
                Award ID: ANR-21-CE48-0003
                Categories
                Article
                Custom metadata
                © Springer Nature Limited 2024

                synthetic biology,population dynamics
                synthetic biology, population dynamics

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