Engineering Fellowships for Growth: Systems and control engineering framework for robust and efficient synthetic biology

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Synthetic Biology is the engineering of biology. In this spirit, this Fellowship aims at combining control engineering methodology and expertise with synthetic biology current know-how to solve important real-world problems of high industrial and societal importance. Anticipated high-impact applications of synthetic biology range from cell-based diagnostics and therapies for treating human diseases, to efficiently transforming feedstocks into fuels or biochemicals, to biosensing, bioremediation or production of advanced biomaterials. Central to tackling these problems is the development of in-cell automatic feedback control mechanisms ensuring robust functionality and performance of engineered cells that need to operate under uncertain and changing environments. The availability of methods for designing and implementing feedback control mechanisms that yield improved robustness, efficiency and performance is one of the key factors behind the tremendous advances in engineering fields such as transportation, industrial production and energy. As in these and other engineering disciplines, systems and control engineering will accelerate the development of high-impact synthetic biology applications of societal, commercial and industrial importance.In particular, through this Fellowship, I propose a comprehensive engineering approach to push forward the robustness frontier in synthetic biology towards reliable cell-based biotechnology and biomedicine. This ambitious goal requires: (1) the development of feedback mechanisms to reduce the footprint of engineered metabolic pathways on their cell "chassis", (2) the development of system-level feedback mechanisms to robustly and efficiently manage one or more synthetic devices in the context of whole-cell fitness, and (3) the development of synthetic cell-based systems designed to restore and maintain the extra-cellular concentration of some biomolecules within tight homeostatic bounds.These three aspects define three work packages in my Fellowship. Each work package on its own tackles important synthetic biology challenges for real-world applications, while their combination in WP4 aims towards robust cell-based biotechnology and biomedicine. The corresponding work packages are:*WP1*: Automatic management of fluxes for robust and efficient metabolic pathways (through genetic-metabolic feedback control)*WP2*: Automatic management of cellular burden for robust and efficient whole-cell behaviour (through host-circuit feedback control)*WP3*: Automatic management of extra-cellular concentrations for robust homeostatic regulation of environmental conditions (through cell-environment feedback control)*WP4*: System integration and combination of the feedback control mechanisms developed in WP 1-3The first two work packages address device robustness to cellular context, while the third addresses robust adaptation to and control of changing environmental conditions. WP4 will use and further develop the systems and control engineering framework developed in WP 1-3 to explore the synergistic combination of the proposed feedback control mechanisms.By providing systematic engineering solutions that endow engineered biosystems with robust functionalities, we will enable the enhancement of existing biotechnological processes and the reliable development of industrial applications to improve health and quality of life. Through the above, this Fellowship will foster strong and long-lasting economic and societal impact in the UK and globally and promote knowledge-based UK leadership.