Engineering Cellular Control Systems: Synthetic Signaling and Motility SystemsNanomedicine ChallengesOur long-term goal is to understand the fundamental design principles of cellular control systems and to apply these principles to engineer “smart” cells or cell-like devices with novel therapeutic functions. This goal is extremely challenging, as cells are built from large numbers of molecules that interact with one another to form complex, dynamically regulated, self-organizing systems. Our ability to engineer cells and their constituent molecular systems is extremely primitive. Our goal is to develop the foundation for precision cellular engineering, analogous to the foundations that already exist in other highly developed engineering disciplines. Goals and ApproachesTo achieve our goal, we are focusing on actin-based cell motility as a testbed system. Many cells have the remarkable ability to detect environmental cues and to precisely move or alter their shape through spatiotemporal regulation of the actin cytoskeleton. Our primary goal is to learn how to program molecular systems to achieve this type of precise morphological control. Development of a fundamental cellular engineering framework within this testbed will then allow expansion and application to engineering other cellular behaviors. To understand how cell motility systems are built, our team is focusing on three engineering Grand Challenges:
The overall approach of our center represents that of the emerging field of Synthetic Biology. Cells, like many complex natural and engineered systems, are built from modular hierarchies: simple molecular parts are used to build devices which in turn are used to build increasingly complex systems. A powerful way to understand the hierarchical logic of such systems is to start with simple, well-characterized molecular parts and to try to use them to build new or modified cellular systems, such as those targeted by the Grand Challenges. This type of bottom-up, synthetic approach represents a bold step towards the rational engineering of cellular behavior for useful medical applications. In addition, synthetic approaches will ultimately play a critical role in revealing many of the basic design principles underlying complex biological systems. One can enumerate alternative and minimal molecular systems that yield a particular cellular behavior. Moreover, the individual parameters of these minimal, engineered systems can be systematically perturbed in an incremental fashion, allowing for far more complete quantitative modeling of systems behavior than could be obtained by studying a complex natural circuit with poorly characterized parameters. Such engineering approaches, combined with computational modeling, could thus help lay the foundation for a predictive field of cellular engineering comparable to the field of electrical engineering. In the long-term, the ability to precisely manipulate cells or synthesize molecular assemblies with cell-like behaviors would have revolutionary therapeutic potential. Engineered therapeutic cells, much like endogenous immune cells, would be “smart” — they could diagnose a lesion or threat, move to that site, and respond with a precise, feedback controlled treatment. Smart cells could hunt and destroy microscopic cancers or cardiovascular lesions. Their responses could be complex: they might directly release a therapeutic agent, or they might act as intermediaries, mobilizing and redirecting the immune system. The designed cells could act as a network, with distinct cells carrying out specific steps in a complex therapeutic cascade. Engineered cells with sophisticated homeostatic control circuits could precisely readjust hormonal and metabolic imbalances. Engineered control of cell motility could be used for repair of nerve and other tissue damage. Modified cells could be from the patient, or from compatible matches, thus eliminating or alleviating problems of immune response. The range of therapeutic potential would be staggering. In the shorter-term, this center may attempt to generate cells that mimic the regulated shape change of platelets or cells that can move in response to heterologous inputs. Nanomedicine: Unique and DistinctThe approach of our center is unique in several ways. First, the approach of the center represents a departure from traditional approaches to understanding complex biological systems – we are not simply observing and dissecting natural systems, but instead are trying to use biological parts to build new systems with “biological-like” behavior. Second, the approach of the center represents a departure from traditional molecular biology and protein engineering. We are not attempting to engineer single proteins with specific functions, but instead are trying to learn how to engineer complex systems made of many interdependent, interacting molecules. To take on this difficult engineering challenge, we are building the fundamental infrastructure necessary for cellular engineering: a library of off-the-shelf plug-and-play molecular parts, and a theoretical framework for component and systems design. In addition this approach necessitates a range assays for quantitating systems behavior. Such assays include traditional micro-scale assays (molecular affinities, rate constants, etc.) and macro-scale (cell level) microscopy assays. However, this work will also require novel mesoscopic assays for measuring properties of self-organizing molecular systems. For example, we are developing TIRF based assays for measuring polarization and other membrane ordering processes, and AFM based assays for measuring force generation. These assays will be useful for other biological processes involving spatial organization and intracellular force. InvestigatorsPI: Wendell A. Lim (UCSF) Collaborators UCSFHenry Bourne UC Berkeley |
This page last reviewed: January 29, 2008
Division of Program Coordination, Planning, and Strategic Initiatives • National Institutes of Health • Bethesda, Maryland 20892
