Our long term goal is to be able to engineer cells or cell-like molecular assemblies that perform """"""""smart"""""""" therapeutic functions: tasks such as tissue repair or """"""""search and deliver"""""""" actions to treat microscopic tumors or cardiovascular lesions. The ability to precisely engineer cell-based therapeutics would have revolutionary effects on healthcare. Our ability to engineer cells, however, is extremely primitive; achieving this vision will require an understanding of the design principles underlying biological regulatory systems, as well as establishment of a standardized, modular framework of molecular components that can be used to rapidly and reliably fabricate diverse control circuits and assemblies. Once established, such a framework could be used to generate a wide range of cellular behaviors. The goal of our Center is to establish a framework for engineering eukaryotic cells. We have chosen to initially focus on one testbed system: actin-based cell movement. Motility is a complex process driven by molecular self-organization. It is essential during development, wound healing, immune response, and many other processes. The ability to control the movement and targeting of cells would have many therapeutic applications. To lay the foundation for facile engineering of nanoscale motility systems we will develop three technology platforms: 1) a molecular toolkit of modular parts and devices, 2) quantitative assays for analysis of cell polarization, force generation, and movement, and 3) a theoretical frame-work for design of motility circuits. We will develop and refine these platforms by using them to solve four target engineering Grand Challenges: a) Replace or rewire the guidance system in a motile cell. b) Reprogram a non-motile cell to display directed movement. c) Build alternative force generating systems from non-actin polymers and/or nanoparticle assemblies. d) Build cell-like assemblies capable of induced shape change and/or movement. Members of the Center will be organized into integrated, interdisciplinary, interlab teams centered around each of these Grand Challenges. We expect three outcomes. First, cycles of design/fabrication/analysis will help uncover the basic design principles of cell motility circuits. Second, each of these increasingly difficult challenges is a stepping stone on the path toward the engineering of therapeutic cells. Third, the technologies and basic design principles that emerge by tackling these challenges can then be applied to the engineering of many other complex biological processes driven by dynamic self-organization.
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