RoL: FELS: RAISE: Principles of Modular Organization in Resource-Limited Biological Circuits

从微生物到哺乳动物，生物回路控制着细胞感知和响应环境的方式。尽管这些电路共享和交换共同的蜂窝资源，但令人惊讶的是，它们能够保持独立的(高度分离的)功能。生物回路如何既能连接又能解耦呢？这个项目试图解决这个令人困惑的问题。这项研究将提高我们目前对自然系统的理解，并帮助创造新的生物电路，控制细胞在能源、环境和医疗应用中的行为。目前，人类工程的生物电路是不可预测的，对于实际使用来说也不够可靠。该项目的生物学发现可能有助于开发工程解决方案，将合成生物电路彼此分离，以实现可预测和可靠的行为。在该项目下进行的研究需要理论和实验之间以及生物学和工程学之间的协同。因此，将培训具有跨学科专业知识的新一代跨学科研究人员。该项目将开发跨部门边界的新教育课程。研究人员将在国内和国际会议上就该项目涉及的问题组织讲习班和应邀举行的会议，并将在剑桥科学节及其卫星活动“街上的科学”上介绍研究成果。教材将通过麻省理工学院的OpenCourseWare和edX进一步传播到更广泛的社区。模块化规定了系统的输入/输出行为实际上与其上下文无关，从而允许自下而上的组合方法来预测复杂系统的行为。今天，创建生物电路的一个关键挑战是，当模块处于不同的环境中时，模块的输入/输出属性会发生不可预测的变化。虽然许多元素导致模块对上下文的依赖，但共享有限的细胞资源，如基因表达所需的资源，仍然是缺乏模块化的主要未解决原因。这个项目将阐明从预期的监管链接的组成和资源共享产生的间接追溯性来预测电路紧急行为的一般规则。这将导致将模块化的崩溃表述为减弱间接追溯力的控制论问题，该问题将通过受自然启发的分散反馈控制解决方案来解决。这一解决方案的试验性实施将阐明自然反馈基序如何在协调工作的同时保持动态平衡，并可能大大增强我们在合成生物学中创建可预测系统的能力。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Biological circuits control the way in which cells sense and respond to their environment, from microbes to mammals. Despite the fact that these circuits share and trade common cellular resources, they are surprisingly able to maintain separate (highly decoupled) functionalities. How can biological circuits be connected yet be decoupled? This project seeks to address this puzzling question. This research will improve our current understanding of natural systems and help create new biological circuits that control cellular behavior for energy, environment, and medical applications. Currently, human-engineered biological circuits are unpredictable and not sufficiently reliable for practical use. The biological discoveries of this project may serve to develop engineering solutions that decouple synthetic biological circuits from each other for predictable and reliable behavior. The research conducted under this project requires synergy between theory and experiments and between biology and engineering. As such, a new generation of interdisciplinary researchers will be trained, with cross-disciplinary expertise. This project will develop new educational curricula that cross department boundaries. The researchers will organize workshops and invited sessions at national and international conferences on the problems addressed in this project and will present the research at the Cambridge Science Festival and at its satellite event "Science on the Street". Teaching materials will be further disseminated to the broader community through MIT's OpenCourseWare and edX.Modularity dictates that the input/output behavior of a system is practically independent of its context, thus allowing a bottom-up compositional approach to predict the behavior of complex systems. Today, a key challenge when creating biological circuits is that the input/output properties of a module changes unpredictably when the module is in a different context. While many elements contribute to dependence of modules on context, sharing limited cellular resources such as those required for gene expression remains a major unresolved cause of lack of modularity. This project will elucidate general rules to predict the emergent behavior of a circuit from the composition of intended regulatory links and indirect retroactivity arising from resource sharing. This will lead to formulate the breakdown of modularity as the control-theoretic problem of attenuating indirect retroactivity, which will be addressed with a decentralized feedback control solution inspired from nature. The experimental implementation of this solution will elucidate how natural feedback motifs keep homeostasis while working in orchestration and may substantially enhance our ability to create predictable systems in synthetic biology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.