Engineering Synthetic Multicellular Systems

合成生物学将从根本上改变分子医学的本质，正如人类工程师所了解的那样。 如何构建和编程单元。这些向前工程的努力将帮助我们理解发展 并将其应用于组织工程、生物制造、生物传感等领域。这个 然而，现实目前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 以及概念上的挑战。拟议的研究旨在迈出重要的第一步，以 设计细胞间通信途径并协调基因表达和行为 细胞群。这些合成通信系统利用细菌中的天然成分 “群体感应”系统，但以新的方式组装它们，以允许人类控制种群如何 以及最终它所做的事情。 复杂的生物行为通常需要许多细胞的协调活动，包括 发育、生物膜形成或群体行为。每个细胞与其邻居相互作用，根据 简单的局部规则，这些相互作用共同产生所需的全球时空动作。这个 这项拟议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，研究还将构建 设计蜂窝间通信网络，包括适当的数学描述 信号扩散和细胞反应，以及允许细胞感知和 对多种化学信号作出反应。中开发的特定通信组件和子电路 这项研究有望转移到其他生物，包括哺乳动物细胞。这 协作项目是独一无二的，它结合了从几十年来的计算机中收集的理性设计原则 具有实验室进化的工程和生物研究，可以微调粗略的人类设计 并建立起运转顺畅的综合通信网络。

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.