We are developing a basis by which cells can be programmed like robots to perform complex, coordinated tasks for pharmaceutical and industrial applications. We are engineering new sensors that give bacteria the senses of touch, sight, and smell. Genetic circuits — analogous to their electronic counterparts — are built to integrate the signals from the various sensors. Finally, the output of the gene circuits is used to control cellular processes. We are also developing theoretical tools from statistical mechanics and non-linear dynamics to understand how to combine genetic devices and predict their collective behavior. Specific projects:
1. Engineering Two-Component Systems. Bacteria respond to their environment using membrane-bound sensors, which interact with intracellular response regulators to control gene expression. These systems are remarkably modular and new sensors can be built using in vitro recombination to swap protein domains. We demonstrated this process by fusing the light sensing domain from a cyanobacterium with a signal transduction domain from E. coli to create a strain that can respond to light. We are refining this strategy to create new sensors as well as studying the downstream signal processing events that occur once a sensor is activated.
2. Construction of Synthetic Genetic Circuits. Foundational genetic circuits are being built that can perform a variety of signal processing functions. These include logic gates, time delays, inverters, and amplifiers. Promoters are also being designed that can integrate information from multiple transcription factors.
3. System Design. Model systems are used to explore the design of programs that enable bacteria to perform a complex series of tasks. For example, we are designing a bacterium that can identify malignant cells within the body and deliver a therapeutic. This involves the construction of sensors that can identify an in situ microenvironment and genetic circuits to integrate this information. The circuit outputs are linked to the control of cellular processes, such as the adhesion of the bacterium to malignant cells and the selective delivery of a therapeutic protein.
4. Organelle Refactoring and Engineering. We are engineering multi-gene prokaryotic organelles for applications in biotechnology. Currently, we are focusing on the type III secretion system, which pumps proteins from the cytoplasm, through both membranes, to the extracellular environment. This system is being exploited to deliver heterologous proteins to the growth media. We are also interested in engineering photosynthetic systems to convert sunlight into energetic and specialty chemicals.