Leveraging Next-Generation Directed Evolution Platforms and Chemical Control of Proteostasis to Deliver Robust Biotechnologies and Illuminate Roles of Chaperone Networks in Protein Evolution

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Directed evolution mimics and accelerates natural evolution in the laboratory in order to create useful new biomolecules and to study evolutionary processes. Although methodologies for directed evolution are well- established in test tubes and in simple organisms like Escherichia coli and yeast, there is still a major chal- lenge. Specifically, novel biomolecules derived from directed evolution campaigns in these platforms often fail to function when transferred to more complex cellular environments, such as that of human cells. To address this critical issue, our laboratory recently pioneered a directed evolution platform that can be used to repeatedly generate massive libraries of mutant biomolecules while continuously selecting and enriching the most func- tional variants directly in the human cell environment. From a chemical biology perspective, we are also deeply engaged in studying functions of the proteostasis network – a vital and unique aspect of the human cellular environment that ensures proteins are correctly folded, processed and trafficked. We have developed an array of chemical genetic tools to modulate proteostasis, and we are now primed to integrate these tools with our directed evolution platform to both evolve previously inaccessible biomolecule functions and gain a deeper un- derstanding of how cells solve protein folding problems. This supplement request seeks support to provide a post-baccalaureate training experience for Mr. Ra’Mal Harris, within the auspices of the parent R35 grant described above. The goal is to provide focused training and scientific exposure that will prepare Ra’Mal Harris for admission to and success at leading biomed- ical PhD programs around the country.