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      Synchronized cycles of bacterial lysis for in vivo delivery

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          Abstract

          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 13 . 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 46 . Such therapies could benefit from bacteria that are programmed to limit bacterial growth while continually producing and releasing cytotoxic agents in situ 710 . 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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          Most cited references25

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          The human microbiome: at the interface of health and disease.

          Interest in the role of the microbiome in human health has burgeoned over the past decade with the advent of new technologies for interrogating complex microbial communities. The large-scale dynamics of the microbiome can be described by many of the tools and observations used in the study of population ecology. Deciphering the metagenome and its aggregate genetic information can also be used to understand the functional properties of the microbial community. Both the microbiome and metagenome probably have important functions in health and disease; their exploration is a frontier in human genetics.
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            Combination bacteriolytic therapy for the treatment of experimental tumors.

            Current chemotherapeutic approaches for cancer are in part limited by the inability of drugs to destroy neoplastic cells within poorly vascularized compartments of tumors. We have here systematically assessed anaerobic bacteria for their capacity to grow expansively within avascular compartments of transplanted tumors. Among 26 different strains tested, one (Clostridium novyi) appeared particularly promising. We created a strain of C. novyi devoid of its lethal toxin (C. novyi-NT) and showed that intravenously injected C. novyi-NT spores germinated within the avascular regions of tumors in mice and destroyed surrounding viable tumor cells. When C. novyi-NT spores were administered together with conventional chemotherapeutic drugs, extensive hemorrhagic necrosis of tumors often developed within 24 h, resulting in significant and prolonged antitumor effects. This strategy, called combination bacteriolytic therapy (COBALT), has the potential to add a new dimension to the treatment of cancer.
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              Cell-based therapeutics: the next pillar of medicine.

              Two decades ago, the pharmaceutical industry-long dominated by small-molecule drugs-was revolutionized by the the advent of biologics. Today, biomedicine sits on the cusp of a new revolution: the use of microbial and human cells as versatile therapeutic engines. Here, we discuss the promise of this "third pillar" of therapeutics in the context of current scientific, regulatory, economic, and perceptual challenges. History suggests that the advent of cellular medicines will require the development of a foundational cellular engineering science that provides a systematic framework for safely and predictably altering and regulating cellular behaviors.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                22 July 2016
                4 August 2016
                04 February 2017
                : 536
                : 7614
                : 81-85
                Affiliations
                [1 ]Department of Bioengineering, University of California, San Diego, La Jolla, California, USA
                [2 ]Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA
                [3 ]BioCircuits Institute, University of California, San Diego, La Jolla, California, USA
                [4 ]Broad Institute of Harvard and MIT, Cambridge, MA
                [5 ]Department of Medicine, Brigham and Women's Hospital, Boston, MA
                [6 ]Electrical Engineering and Computer Science and David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA
                [7 ]Howard Hughes Medical Institute, Chevy Chase, MD
                [8 ]Molecular Biology Section, Division of Biological Science, University of California, San Diego, La Jolla, CA 92093, USA
                Author notes
                [9]

                Co-senior authors

                [†]

                Present address: Department of Biomedical Engineering, Columbia University, New York, NY 10027

                Correspondence and requests for materials should be addressed to J.H. ( hasty@ 123456bioeng.ucsd.edu ).
                Article
                NIHMS795279
                10.1038/nature18930
                5048415
                27437587
                3f9e1011-50e3-4d38-a094-bd8c26460386

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