Sentinels: A plug-and-play RNA sensing technology platform for surveillance and response to emerging viral diseases

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Cells can be programmed to sense infectious agents and, in response, actuate biomolecular programs to alert, protect the host, or destroy the pathogenic target. Engineering cells in this manner would provide a transformative approach to address the threat of emerging viral diseases. The goal of this project is to develop a novel pathogen detection platform that can be easily reprogrammed to sense new threats, and in response, produce any protein output. This technology will forward our ability to engineer sentinel cells for diverse diagnostics and therapeutic applications. This project will also provide educational and training opportunities aimed at increasing the number and diversity of high school students and undergraduates pursuing careers in biomolecular and cellular engineering, and related STEM fields. As part of this project open-source web-based design tools for designing sentinel cells will be created through a student-led initiative.RNA-based sensors present a particularly attractive option for programming cells to detect pathogens because they rely on designable RNA base pairing interactions and enable detection of RNA encoded genomes (genotypes) and mRNAs (phenotypes) of both the pathogen and host, allowing for potentially more accurate readouts of the infection status. However, there is currently a lack of genetically-encoded RNA detection platforms that can interface RNA inputs to biomolecular outputs, precluding the design of cellular devices that execute sentinel programs in response to specific RNA signatures. To address this, biomolecular and synthetic biology strategies to create plug-and-play RNA sense-and-respond platforms will be explored. Devices will be created that detect different virus associated RNA molecules, and, in response, activate diverse biomolecular programs to alert and destroy viruses. This will find direct applications for sentinel cell design and could be easily utilized for other applications in basic science, synthetic biology, and metabolic engineering.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.