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

合成生物学是生物学的工程学。本着这一精神，该奖学金旨在将控制工程方法和专业知识与合成生物学的当前知识相结合，以解决具有高度工业和社会重要性的重要现实世界问题。合成生物学的预期高影响应用范围从用于治疗人类疾病的基于细胞的诊断和治疗，到有效地将原料转化为燃料或生物化学品，到生物传感、生物修复或生产先进的生物材料。解决这些问题的核心是开发细胞内自动反馈控制机制，以确保需要在不确定和不断变化的环境中运行的工程细胞的强大功能和性能。设计和实现反馈控制机制以产生更好的稳健性、效率和性能的方法的可用性是交通、工业生产和能源等工程领域巨大进步背后的关键因素之一。正如在这些和其他工程学科中一样，系统和控制工程将加速发展具有社会、商业和工业重要性的高影响力合成生物学应用。特别是，通过这一奖学金，我提出了一种全面的工程方法，以推动合成生物学的稳健性前沿向可靠的基于细胞的生物技术和生物医学迈进。这一雄心勃勃的目标要求：(1)开发反馈机制，以减少工程代谢途径在细胞“底盘”上的足迹；(2)开发系统级反馈机制，以在全细胞健康的背景下稳健而高效地管理一个或多个合成设备；以及(3)开发基于合成细胞的系统，旨在恢复和维持某些生物分子在严格的体内平衡范围内的胞外浓度。这三个方面定义了我的研究员的三个工作包。每个工作包各自解决现实世界应用程序中重要的合成生物学挑战，而它们在WP4中的组合旨在实现强大的基于细胞的生物技术和生物医学。相应的工作包是：*WP1*：自动管理稳健而有效的代谢途径的通量(通过遗传-代谢反馈控制)*WP2*：自动管理细胞负担，以实现稳健和有效的全细胞行为(通过主机电路反馈控制)*WP3*：自动管理细胞外浓度，以实现对环境条件的稳健的动态平衡调节(通过细胞-环境反馈控制)*WP4*：系统集成和结合WP 1-3中开发的反馈控制机制前两个工作包解决设备对细胞环境的稳健性，而第三个工作包解决对不断变化的环境条件的稳健适应和控制。WP4将使用和进一步发展在WP 1-3中开发的系统和控制工程框架，以探索建议的反馈控制机制的协同组合。通过提供赋予工程生物系统强大功能的系统工程解决方案，我们将能够增强现有的生物技术过程和工业应用的可靠发展，以改善健康和生活质量。通过上述，该奖学金将在英国和全球范围内培养强大和持久的经济和社会影响，并促进以知识为基础的英国领导力。

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.