CPS: Frontier: Collaborative Research: BioCPS for Engineering Living Cells

纳米技术和合成生物学的最新发展为生物工程提供了一个新的方向：合成多细胞细菌和哺乳动物系统的集体行为和时空模式。这将在诸如非晶计算、纳米制造，特别是组织工程等领域产生巨大影响，在这些领域中，模式可以用来将干细胞分化成组织和器官。虽然最近的技术，如组织和类器官芯片，有可能在组织工程和药物开发中产生范式转变，但在细胞群体中合成用户指定的紧急行为是释放这一潜力的关键一步，但仍然是一个具有挑战性的未解决问题。该项目将合成生物学和微米级移动机器人技术结合在一起，以定义下一代网络物理系统（CPS）的基础，称为生物CPS （bioCPS）。利用生物设计自动化（BDA）工作流自动合成用于细胞间决策和局部通信的合成基因电路。作为该项目的一部分，设计和建造了一个用于蜂窝网络通信、传感和控制的机器人助手，用于在工程细胞网络中生成所需的模式。在RA中，工程细胞与一组微型机器人相互作用，这些微型机器人实现控制、传感和远程通信策略，以实现所需的全局行为。微型机器人包括生物和非生物物质（附着在无机基质上的工程细胞，可以使用外部应用电场进行控制）。该技术被用于检测活细胞中各种图案的形成。该项目有丰富的教育和推广计划，其中包括针对高中生的全国CPS教育活动、针对高中生和本科生的实验室参观和竞赛、针对研究生的讲习班、研讨会和课程，以及针对代表性不足群体的具体举措。该项目的核心是理论和计算工具的发展，这将大大提高CPS的技术水平。提出了一种新颖的形式化方法，用于综合大量局部相互作用代理的紧急全局行为。特别地，提出了一种新的逻辑，其公式可以有效地从分割图像的四叉树表示中学习。逻辑的定量语义将局部控制和通信协议的综合映射为一个优化问题。该项目通过开发一种机器学习方法从大量数据中学习时间逻辑分类器，为时间逻辑推理的新兴领域做出了贡献。定义了一种新的随机动力系统抽象和验证技术，并将其用于验证BDA工作流中基因电路的正确性。

Recent developments in nanotechnology and synthetic biology have enabled a new direction in biological engineering: synthesis of collective behaviors and spatio-temporal patterns in multi-cellular bacterial and mammalian systems. This will have a dramatic impact in such areas as amorphous computing, nano-fabrication, and, in particular, tissue engineering, where patterns can be used to differentiate stem cells into tissues and organs. While recent technologies such as tissue- and organoid on-a-chip have the potential to produce a paradigm shift in tissue engineering and drug development, the synthesis of user-specified, emergent behaviors in cell populations is a key step to unlock this potential and remains a challenging, unsolved problem. This project brings together synthetic biology and micron-scale mobile robotics to define the basis of a next-generation cyber-physical system (CPS) called biological CPS (bioCPS). Synthetic gene circuits for decision making and local communication among the cells are automatically synthesized using a Bio-Design Automation (BDA) workflow. A Robot Assistant for Communication, Sensing, and Control in Cellular Networks (RA), which is designed and built as part of this project, is used to generate desired patterns in networks of engineered cells. In RA, the engineered cells interact with a set of micro-robots that implement control, sensing, and long-range communication strategies needed to achieve the desired global behavior. The micro-robots include both living and non-living matter (engineered cells attached to inorganic substrates that can be controlled using externally applied fields). This technology is applied to test the formation of various patterns in living cells. The project has a rich education and outreach plan, which includes nationwide activities for CPS education of high-school students, lab tours and competitions for high-school and undergraduate students, workshops, seminars, and courses for graduate students, as well as specific initiatives for under-represented groups. Central to the project is the development of theory and computational tools that will significantly advance that state of the art in CPS at large. A novel, formal methods approach is proposed for synthesis of emergent, global behaviors in large collections of locally interacting agents. In particular, a new logic whose formulas can be efficiently learned from quad-tree representations of partitioned images is developed. The quantitative semantics of the logic maps the synthesis of local control and communication protocols to an optimization problem. The project contributes to the nascent area of temporal logic inference by developing a machine learning method to learn temporal logic classifiers from large amounts of data. Novel abstraction and verification techniques for stochastic dynamical systems are defined and used to verify the correctness of the gene circuits in the BDA workflow.