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Engineering Cellular Control: Synthetic Signaling and Motility Systems

 
2008 Progress Report – Executive Summary

Understanding the Design Principles of Cellular Control Systems. Living cells are extremely sophisticated sensor-actuator devices that detect specific environmental cues, process this information, and generate specific responses such as growth, shape change, directed movement, or secretion of a specific product. These processes are controlled by networks of signal transduction and cytoskeletal proteins that form a dynamic, self-organizing system. Our long-term goal is to understand the fundamental engineering principles underlying these nanoscale molecular control systems. If we understand these principles, we may be able to alter these systems to “reprogram” cells such that they carry out new therapeutic functions. Alternatively, we may be able to build artificial, biologically-inspired cell-like nanoassemblies that can perform targeted therapeutic functions. In the long-term, the ability to precisely program cells or synthesize molecular assemblies with cell-like behaviors would have broad, revolutionary therapeutic potential.

As our primary testbed, our center is focusing on understanding how cells achieve signal-guided movement (chemotaxis). Many cells can detect specific extracellular signals, process this information, and use the information to activate complex mechanical programs, such as directional cell movement or morphing into a new shape. Such programs are critical in immune cell movement and phagocytosis; they are also used in developing cells like neurons as they send out their long axons over great distances towards specific targets.

Pathway to Medicine Goal: Programming or building “smart” therapeutic cells. The goal of our center (pathway to medicine) is to apply the understanding of cellular control systems to a specific therapeutic application: learning how to reprogram or build cells that can function as smart search and delivery vehicles. It would be extremely useful to have cells that could search the body for an elusive target, such as a microscopic tumor. Engineered smart cells could in principle be designed to detect and integrate a host of different information to pinpoint the tumor, including detection of generic environmental conditions (such as low oxygen, which is typical in tumors) and detection of tumor specific molecules. These could be integrated and linked to the cytoskeletal movement machinery to allow for efficient search of the tumor. Once at site, the cells could be used to deliver a number of payloads, ranging from dyes for imaging of the tumor, to chemotherapeutics that would kill the tumor. Another example is engineered smart cells that might detect inflammatory signals associated with an autoimmune response. Such cells could in principle be programmed to secrete antiinflammatory mediators as a specific countermeasure response to locally block autoimmune flare-ups. The engineering principles that emerge from efforts to reprogram or build “smart” cells could be applied to treat and diagnose a wide range of diseases and could revolutionize medicine.

Specific Aims. Our Center is pursuing the following specific aims:

Aim1. Understand the design principles underlying the natural molecular sensor-actuator systems used to generate directed cell motility. We are studying fundamental mechanisms of the signaling and actin cytoskeletal systems that are used to build cell movement and cell shape change circuits. We are interested in understanding how subtle gradients of signals are interpreted by the cell to yield polarized (directed, asymmetric) activation of the actin cytoskeleton.

Aim2. Develop methods and tools to relink and reprogram cellular signaling subsystem components. Cell signaling systems are built from receptors, kinases, phosphatases, GTPases, and other regulatory components. How are these components wired in specific ways, and how can we rewire them? A growing body of evidence suggests that many of these components are functionally linked via specific protein interaction modules. These modules can organize multiple proteins into physical complexes and can also allosteric gate the activity of signaling enzymes. Thus we are trying to use a toolkit of protein interaction domains to link signaling components in new ways. These new circuits may yield new cellular behaviors. We are also developing engineered protein-protein interaction modules that are optimized for cellular engineering (i.e. have minimal cross-talk with endogenous molecules).

Aim 3. Develop ways to regulate force generation systems. Ultimately to bring about a process like movement, the signaling systems must activate the actin cytoskeleton in a spatially precise manner, and in a way that yields force and protrusion of the membrane. We are investigating how regulated polymerization systems can be used to perform spatially directed work in a cell-like environment. We are investigating the use of non-actin polymers to perform work in a cell. We are also investigating whether hybrid materials made of nanomaterials linked to biological regulatory components could be used to generate nanostructures that assemble in a regulated manner to perform mechanical work at the nanometer to micron scale.

Aim 4. Pathway to Medicine: Apply our knowledge to build cells or cell-like particles with novel motility control that can be used for targeting within an animal. We are taking both a top-down and bottom up approach towards building minimal motile particles that can be used as search and delivery vehicles. In the top-down approach we are trying to reprogram motile cells such as neutrophils so that they move towards novel inputs. We are also trying to generate cytoplasts (cell fragments lacking nuclei) that can move towards specified targets. In the bottom-up approach, we are trying to reconstitute minimal cell-like molecular assemblies that can show regulated movement or shape change, from either biological molecules or from nanomaterial components that are regulated in a biologically-inspired manner. These cells, cellfragments, or assemblies could potentially be used as a flexible search-and-delivery vehicles in the body. We will test the particles engineered using both approaches for targeting functions within a mouse.

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