EFRI-MKS: Harnessing Intercellular Signaling to Engineer Pattern Formation

这项由新兴前沿研究与创新办公室颁发的国家科学基金会奖，支持莱斯大学和华盛顿大学的研究人员合作，设计细菌干细胞，使其生长并分裂成各种各样的多细胞模式和结构。在生物学中，多细胞组织和生物体是由未分化的干细胞通过复杂的胚胎发生和发育过程产生的。大量嘈杂和易出错的生物细胞如何在空间和时间上精确地协调它们的行动，仍然是一个开放和具有挑战性的问题。在这里，研究人员将采用工程方法来解决这个问题，通过在大肠杆菌中构建一个多细胞“发育”系统模型。人们对大肠杆菌的遗传学很了解，因此这种生物很容易被改造。此外，由于大肠杆菌不会自然形成模式，它是一张白纸，任何形成的模式都可以更容易地归因于工程基因程序。该研究项目将直接的实际影响与概念深度相结合。这项工作将使一种潜在的变革性技术成为可能，通过工程细胞-细胞通信来控制组织和高阶细胞结构的生长。该方法结合了生物模式形成的关键特征，例如(i)在细胞外信号梯度内编码的位置信息的使用，（ii）细胞间通信，（iii）反馈和信号处理以及（iv）状态的表观遗传。研究人员将开发并定量表征实现这些核心功能的分子器件，然后将这些元件模块化地组合成越来越复杂的模式形成电路。实验工作将以数学建模为指导，并将利用定制的编程形式来指定所需的形状和模式。这组研究人员在信号处理、细胞-细胞信号、分布式计算和合成生物学方面具有高度互补的专业知识。这将使研究人员能够产生一个结合实验和计算的设计周期，从而加快这一具有挑战性和重要研究领域的进展速度。这项技术将产生巨大的科学、经济和社会影响。在过去的十年里，合成生物学在细胞传感和信号转导工程以及大规模合成DNA方面取得了一系列重大进展。利用这些进步来协调多细胞行为的工程，最好的例子是模式形成，现在是该领域的一个主要目标。这项合作将通过开发一个严格的框架来设计单个干细胞生长和分化成任意模式，从而显著推进程序化模式形成的当前艺术状态。这项工作的成果将影响发育生物学、组织工程、再生医学、代谢工程和生物材料的研究。这项工作与一个有两个主要目标的外展计划紧密结合。第一个目标是制定一个教育计划，教授学生在合成生物学领域取得成功所必需的跨学科技能。为了实现这一目标，pi正在开发一个由赖斯大学和华盛顿大学的几个部门协调的三门课程。第二个目标是增加女性和未被充分代表的少数民族在工程学科中的参与。这将通过针对高中教师、即将入学的新生、未被充分代表的少数民族和妇女的既定外展项目来实现。特别是，pi将开发新的生物教学工具，利用这里构建的视觉上引人注目的实验系统。

This NSF award by the Office of Emerging Frontiers in Research and Innovation supports a collaboration between investigators at Rice University and the University of Washington to engineer bacterial stem cells to grow and divide into a wide variety of multicellular patterns and structures. In biology, multicellular tissues and organisms arise from undifferentiated stem cells via complex processes of embryogenesis and development. How large numbers of noisy and error-prone biological cells precisely coordinate their actions over space and time remains an open and challenging question. Here the investigators will take an engineering approach to this problem, by constructing a model multicellular "developmental" system in the bacterium E. coli. The genetics of E. coli are well understood and the organism is therefore very amenable to engineering. Moreover, because E. coli does not naturally form patterns, it is a blank slate where any pattern formed can be more easily attributed to the engineered genetic program.This research program combines immediate practical impact with conceptual depth. The proposed work will enable a potentially transformative technology for controlling the growth of tissues and higher order cellular structures through engineered cell-cell communication. The approach incorporates key features of biological pattern formation, such as (i) the use of positional information encoded within gradients of extracellular signals, (ii) intercellular communication, (iii) feedback and signal processing and (iv) epigenetic inheritance of states. The investigators will develop and quantitatively characterize molecular devices for implementing each of these core functionalities and will then modularly combine those elements into increasingly complex pattern-forming circuits. Experimental work will be guided by mathematical modeling and will take advantage of a custom-made programming formalism for specifying desired shapes and patterns. This group of investigators has highly complementary expertise in signal processing, cell-cell signaling, distributed computing and synthetic biology. This will allow the investigators to produce a combined experimental-computational design cycle that will accelerate the rate of progress in this challenging and important research area.This technology will have great scientific, economic and societal impact. The last decade of synthetic biology boasted a series of significant advances in engineering cellular sensing and signal transduction and constructing synthetic DNA at large scale. Harnessing these advances for the engineering of coordinated multicellular behaviors, best exemplified in pattern formation, is now a major goal in the field. This collaborative effort will significantly advance the current state of the art in programmed pattern formation by developing a rigorous framework to engineer a single stem cell to grow and differentiate into any arbitrary pattern. The outcomes of this work will impact developmental biology, tissue engineering, regenerative medicine, metabolic engineering and biomaterials research.This work is tightly integrated with an outreach program that has two main goals. The first goal is to develop an educational program to teach students the interdisciplinary skills necessary to be successful in synthetic biology. To achieve this goal, the PIs are developing a three course curriculum that is coordinated between several departments at Rice University and the University of Washington. The second goal is to increase the participation of women and underrepresented minorities in engineering disciplines. This will be achieved through established outreach programs aimed at high school teachers, incoming freshmen, underrepresented minorities and women. In particular, the PIs will develop new biological teaching tools that take advantage of the visually compelling experimental systems constructed here.