Coordinating Cell Killing by Communication: Biological Control and Cancer Therapy

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DESCRIPTION (provided by applicant): Cancer treatment requires development of diverse therapeutic strategies. To this end, engineered bacteria offer promise for efficiently delivering and expressing genes with therapeutic effects and for selective tumor targeting. To fully realize bacteria's therapeutic potential, we need to overcome technological hurdles at multiple levels. These include development of a toolbox of genetic elements that can be pieced together to carry out therapeutic functions and a better understanding of design principles that will enable precise control of bacterial dynamics in the complex micro-environments of solid tumors. To address these challenges, the objective of this application is to use bacterial "quorum sensing" modules to coordinate bacterial behavior (life, death, spatial aggregation) in diverse settings. Quorum sensing is a mechanism by which bacteria sense and respond to changes in their population density. Built upon strong preliminary data, the proposed research will focus on design, modeling, implementation, and characterization of two synthetic bacterial multicellular systems in Escherichia coli. The first system (Aim 1. a predator-prey system) will attempt to program the interaction of two bacterial populations that mutually regulate their gene expression; the circuit logic and dynamics resemble well-studied predator-prey ecosystems. The second (Aim 2. a targeted consensus circuit) will program bacteria to target tumor cells with high specificity through coordinated decision making by two communicating bacterial populations. The proposed research is innovative, because it extends basic concepts and design methods of synthetic biology to address the pressing issue of cancer therapy. Its outcome will have significant impact by setting a solid foundation for engineering bacteria with highly reliable behavior for therapeutic applications. In particular, expected outcomes include (1) a repertoire of well-characterized genetic elements, modules, and systems, (2) insights into fundamental design laws for robust control of cellular dynamics in complex environments such as solid tumors, and (3) thoroughly tested modeling tools and methods. All of these can be applied in systems beyond the proposed ones and will be shared with the biomedical research community. Relevance to Public Health: The proposed research will fill the important gap that limits the application of engineering design strategies to the development of cancer-targeting bacteria. This approach will offer the extremely high targeting selectivity and bacterial containment efficiency needed for effective and safe cancer therapy.