Engineering Synthetic Multicellular Systems

描述(申请人提供)：合成生物学将从根本上改变分子医学的性质，因为人类工程师将学习如何构建和编程细胞。这些前沿工程工作将帮助我们了解发展过程，并将这种理解用于组织工程、生物制造、生物传感等。然而，现实并没有梦想那么令人兴奋：编程细胞行为带来了巨大的技术和概念挑战。这项拟议的研究旨在为设计细胞间通信途径和协调跨细胞群体的基因表达和行为迈出重要的第一步。这些合成通讯系统利用细菌“群体感应”系统中的天然成分，但将它们以新的方式组合在一起，使人类能够控制种群的发展，并最终控制种群的功能。复杂的生物学行为通常需要多个细胞的协同活动，包括发育、生物膜形成或群体行为。每个细胞根据简单的局部规则与其邻居相互作用，这些相互作用共同产生所需的全局时空动作。这项拟议工作的最终目标是建立一个完全在合成电路中编程的、具有这种能力的合成细菌系统。为了实现这一目标，这项研究还将建立设计细胞间通信网络的框架，包括对信号扩散和细胞反应的适当数学描述，以及使细胞能够感知和响应多种化学信号的新组件。在这项研究中开发的特定通信元件和子电路有望转移到其他生物，包括哺乳动物细胞。这个合作项目的独特之处在于，它将从数十年的计算机工程和生物研究中收集的理性设计原则与实验室进化结合在一起，可以微调粗略的人类设计，并制造出运行顺畅的合成通信网络。

DESCRIPTION (provided by applicant): Synthetic biology will fundamentally change the nature of molecular medicine, as human engineers learn how to build and program cells. These forward engineering efforts will help us understand developmental processes and use that understanding for tissue engineering, biofabrication, biosensing, and more. The reality, however, is currently less exciting than the dream: programming cell behavior poses huge technical and conceptual challenges. The proposed research is designed to take important first steps towards engineering intercellular communications pathways and coordinating gene expression and behavior across cell populations. These synthetic communications systems utilize natural components from bacterial 'quorum-sensing' systems, but assemble them in new ways to allow human control over how a population develops and eventually what it does. The coordinated activity of many cells is often required for complex biological behaviors, including development, biofilm formation, or swarm behaviors. Each cell interacts with its neighbors according to simple local rules, and collectively these interactions yield the desired global spatiotemporal actions. The ultimate aim of the proposed work is to build a synthetic bacterial system that exhibits such a capability, entirely programmed in a synthetic circuit. Towards this goal, the research will also build the framework for engineering intercellular communications networks, including appropriate mathematical descriptions of signal diffusion and cellular responses, as well as novel components that will allow cells to sense and respond to multiple chemical signals. Specific communications components and sub-circuits developed in this research are anticipated to be transferable to other organisms, including mammalian cells. This collaborative project is unique in combining 'rational' design principles gleaned from decades of computer engineering and biological research with laboratory evolution, which can fine-tune rough human designs and make smoothly-functioning synthetic communications networks.