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10/10 - Student-Invited Lecture (chem bio): David Liu, Harvard University

David Liu - speaker's website
Department of Chemistry & Chemical Biology
Harvard University

Integrating Chemistry and Evolution to Illuminate and Program Biology

In this lecture I will describe two efforts in our laboratory to address fundamental challenges facing the discovery of molecules, both small and large, with tailor-made activities. These efforts are (i) the application of the powerful principles underlying biological evolution to the discovery of bioactive synthetic small molecules, and (ii) the development of a new form of directed evolution that can very rapidly generate macromolecules with desired novel activities. The first effort has resulted in DNA-templated synthesis, a method to translate DNA sequences into corresponding synthetic molecules. DNA-templated synthesis coupled with in vitro selections resulted in the discovery of new kinase and protease inhibitors, including a macrocycle that has revealed new in vivo functions and the therapeutic potential of an important mammalian regulator of glucose homeostasis. The second effort has resulted in phage-assisted continuous evolution (PACE), the first method that enables proteins to evolve continuously in the laboratory. We applied PACE to characterize the reproducibility and path dependence of long protein evolutionary trajectories, and revealed the molecular basis of evolutionary stochasticity and path dependence for T7 RNA polymerase.