Engineering Synthetic Multicellular Systems

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。这些前瞻性的工程努力将帮助我们理解发育过程，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采取重要的第一步，以工程细胞间通信途径和协调基因表达和细胞群体之间的行为。这些合成通信系统利用细菌“群体感应”系统的天然成分，但以新的方式组装它们，使人类能够控制种群的发展以及最终的行为。许多细胞的协调活动通常是复杂的生物行为所必需的，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进行交互，这些交互共同产生所需的全局时空动作。这项工作的最终目标是建立一个具有这种能力的合成细菌系统，完全在合成电路中编程。为了实现这一目标，该研究还将建立工程细胞间通信网络的框架，包括信号扩散和细胞反应的适当数学描述，以及允许细胞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组件和子电路预计将转移到其他生物体，包括哺乳动物细胞。这个合作项目是独一无二的，它将从几十年的计算机工程和生物研究中收集到的“理性”设计原则与实验室进化相结合，可以微调粗糙的人类设计，并制造功能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.