Engineering Fellowships For Growth: Designing Feedback Control in Biology for Robustness and Scalability

合成生物学是“生物学工程”：它渴望使用工程设计周期来生产行为可预测和可靠的生物电路，通常考虑到特定的应用。合成生物学有潜力在几个领域创造新的产业和技术，从农业到环境，从能源到医疗保健。其中一些应用要求合成生物学设计是可扩展的，这样就可以组成小电路来形成更大的系统。然而，目前，即使是小型生物电路也很少能像预期的那样发挥作用，因为蜂窝环境的高度不确定性，特征不佳的部件组装在一起的方式，以及缺乏将部件集成到形成系统的系统框架。这是一个需要克服的重大挑战，以实现合成生物学的潜力，并使工业和社会获得回报。自然系统使用几种机制来克服这一重大挑战。最重要的一点是要谨慎使用反馈控制。这是在所有级别的组织中完成的--从遗传、代谢、细胞到系统级别。尽管存在高度的环境不确定性和内在和外在的噪声，但细胞内生化过程的调控是确保强大功能的关键。这项奖学金申请将使用系统和控制工程方法，基于建模、抽象、标准化和开发新的生物反馈模块来针对细胞中的特定不确定性。我将创建一个跨学科的研究团队，该团队将证明，通过仔细设计和实施反馈控制组件，可以使其余设计电路的功能变得健壮并允许可扩展性。反馈设计将在多个组织规模和相互作用(遗传、信号和细胞-细胞)上进行，并将在实验室实施，以证明该方法的有效性。

Synthetic Biology is the "Engineering of Biology": it aspires to use the Engineering design cycle to produce bio-circuits that behave predictably and reliably, usually with specific applications in mind. Synthetic Biology has the potential to create new industries and technologies in several sectors, from agriculture to the environment, and from energy to healthcare. Some of these applications require Synthetic Biology designs to be scalable, so that small circuits can be composed to form larger systems. Currently, however, even small bio-circuits seldom function as expected because of the high level of uncertainty in the cellular environment, the way poorly-characterized parts are assembled together and the lack of a systematic framework for integrating parts to form systems. This is a major challenge that needs to be overcome in order for the potential of Synthetic Biology to be fulfilled and for industry and society to reap the rewards.Natural systems use several mechanisms to overcome this major challenge. The most important one involves careful use of feedback control. This is done at all levels of organization - from the genetic, metabolic, cellular to the systems level. The regulation of biochemical processes inside a cell is key for ensuring robust functionality despite the high levels of environmental uncertainty and intrinsic and extrinsic noise.This Fellowship application will use a systems and control engineering approach, based on modelling, abstraction, standardization and the development of new bio-feedback modules to target specific uncertainties in the cell. I will create an interdisciplinary research team which will demonstrate that through careful design and implementation of feedback control components, the functionality of the rest of the designed circuitry can be made robust and allow scalability. The feedback designs will be done at multiple organizational scales and interactions (genetic, signalling and cell-cell), which will be implemented in the laboratory, demonstrating the effectiveness of the approach.