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Engineering Cellular Control: Synthetic Signaling and Motility Systems

 
2009 Progress Report – Executive Summary
 

Vision: Engineering Cells or Cell-Like Devices as Next Generation Therapeutic Agents

Our long-term goal is to engineer cells or artificial cell-like devices that can be flexibly programmed to carry out a wide range of specific therapeutic tasks. Such cellular “nanorobots” would in principle be able to carry out combined diagnostic (sensing) and therapeutic (delivery) functions in a patient – long a dream of medical research. As a testbed, we are focusing on understanding how cells achieve signal-guided movement (chemotaxis) and exploring how we can harness the cell’s intrinsic motility machinery to generate cellular search-and-delivery platforms. In principle the motility machinery could also be harnessed to guide neurons and stems cells to specific sites for regenerative medicine. We hope to demonstrate the broad application of synthetic biology approaches to reprogram complex cellular behaviors like motility, and to develop the resulting cells or cell-like devices as next generation therapeutic agents. Moreover, we also believe that through the cycles of design and refinement that will be required to achieve this goal, we will learn more deeply about the fundamental mechanisms and organizational principles of living cells and how they are able to integrate complex sensor-actuator functions.

Center Aims – Our Center is pursing this vision through the following aims.

Aim1. Understanding the design principles of the natural molecular control systems that mediate cell movement. We are studying the fundamental mechanisms of the signaling and cytoskeletal systems that are used to build cell movement and shape change control circuits. We are trying to understand how these systems are used to allow chemotactic cells to detect subtle input grandients and yield polarized, directed movements. We hope to understand how these control systems are organized in a modular hierarchy, and how they might be reconnected to yield novel cell shape change responses, either though evolution or engineering.

Aim 2. Develop general a toolkit of molecular parts and methods to relink and reprogram cellular signaling systems. Cell signaling systems that make up the guidance system of a chemotactic cell include receptors, kinases, phosphatases, GTPases, and other regulatory components. We are trying to understand how these components are wired together to form specific pathways, and testing whether we can exploit these mechanisms to rewire pathways. We have had success in rewiring kinase and GTPase pathways through the use of synthetic protein-interaction scaffolds. We hope to develop these methods as a general toolkit for use in synthetic cell biology.

Aim 3. Develop general toolkit of nanoscale molecular parts for regulating and generating force in the context of a cell or vesicle. Cell polarization and movement ultimately requires transforming regulatory signals into precise force generation. Cells often use cytoskeletal polymers like actin as a key step in force generation. We are studying actin and actin-related proteins to understand their mechanism of polymerization, how this is tightly regulated by upstream control elements, and how the resulting polymer network generates force. We are also investigating the use of hybrid abiotic/biotic polymer systems as both physical sensors or as systems to generate force. We hope to develop a general toolkit for performing controlled mechanical work at the nanoscale, in cells of vesicles.

Aim 4. Pathway to Medicine: We will apply our module-based platform of molecular parts and signaling control to build cells or cell-like devices with novel motility control that can be used for targeting and delivery functions in a living animal. We are taking both a top-down and bottom-up approach towards building motile assemblies that can be used as programmable, controlled, and specific search and delivery vehicles. In the top-down approach, we are attempting to reprogram cells (using neutrophils as a testbed system) so that they respond and chemotax towards novel inputs and specific disease targets. We are also developing methods to generate motile cytoplasts (cell fragments lacking nuclei) that can move towards novel signals and specific disease targets. In the bottom-up approach, we are attempting to reconstitute minimal cell-like molecular assemblies that can show regulated movement or shape change, from either biological molecules or from nanomaterials that are regulated in bio-inspired mechanisms. We will be testing the cells and cell-like devices that we engineer for their ability to target and carryout specified functions within a living mouse.

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