CAREER: Engineering Biomolecules and Cells for Oral Protein Delivery

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Advances in biotechnology have made available recombinant forms of critically important therapeutic proteins. The idea of orally delivering such proteins is extremely attractive because this mode of administration is noninvasive, has higher patient compliance, and, in some cases, can more accurately mimic native physiology. However, due to major barriers encountered in the gastrointestinal tract - particularly harsh pH, rapid proteolytic degradation, and low intestinal permeability - proteins typically have very low bioavailability via oral delivery and are therefore routinely administered through an invasive method such as intravenous or subcutaneous injection. Here, a combined biomolecular and cellular engineering approach will be employed to overcome these bottlenecks and enhance oral protein delivery. This strategy will entail the development of general in vitro directed evolution approaches to enhance protein stability in the gastrointestinal tract as well as tunable synthetic biology approaches for engineering food-grade microorganisms to deliver these proteins orally. The specific application here is to create novel proteins and cells that can be used to orally regulate glucose levels in diabetic patients. These same protein engineering and synthetic biology approaches will also form the basis for a broadly reaching educational and training platform. Locally at the University of Pennsylvania, new educational modules will be incorporated into existing undergraduate and graduate courses, the first International Genetically Engineered Machine (iGEM) team will be created, and a new service learning course will be established to teach molecular biotechnology to inner-city high school students in Philadelphia. Nationally, high school teachers, undergraduates, and high school students will be recruited from underrepresented minority populations to carry out summer research projects. And internationally, impoverished street children in Mumbai, India will be introduced to principles of protein engineering and synthetic biology using examples that are of particular relevance to that population.