Plenary Keynote Program

Join 1,300 of your colleagues for the Discovery on Target Plenary Keynote Program. Bridging both halves of the event, it's the only time our whole community of drug discovery professionals assembles in one room to learn about big-picture perspectives, innovative technologies, and thought-provoking trends from luminaries in the field.

WEDNESDAY, SEPTEMBER 18 | 12:20 - 2:00 PM

12:20 pm Event Chairperson’s Opening Remarks

An-Dinh Nguyen, Team Lead, Discovery on Target 2019, Cambridge Healthtech Institute

12:30 Plenary Keynote Introduction

12:40 Base Editing: Chemistry on a Target Nucleotide in the Genome of Living Cells

David R. Liu, PhD, Howard Hughes Medical Institute Investigator, Professor of Chemistry & Chemical Biology, Harvard University

Point mutations represent most known human genetic variants associated with disease but are difficult to correct cleanly and efficiently using standard nuclease-based genome editing methods. In this lecture I will describe the development, application, and evolution of base editing, a new approach to genome editing that directly converts a target base pair to another base pair in living cells without requiring double-stranded DNA breaks or donor DNA templates. Through a combination of protein engineering and protein evolution, we recently developed two classes of base editors (BE4 and ABE) that together enable all four types of transition mutations (C to T, T to C, A to G, and G to A) to be efficiently and cleanly installed or corrected at target positions in genomic DNA. The four transition mutations collectively account for most known human pathogenic point mutations. Base editing has been widely used by many laboratories around the world in a wide range of organisms including bacteria, fungi, plants, fish, mammals, and even human embryos. We have recently expanded the scope of base editing by enhancing its efficiency, product purity, targeting scope, and DNA specificity. By optimizing base editor expression, we developed “max” versions of cytosine and adenine base editors with greatly increased editing efficiency in mammalian cells. We also show that base editing can function in vivo in post-mitotic somatic cells that do not support homology-directed repair. To improve the targeting scope of base editing, we used our phage-assisted continuous evolution (PACE) system to rapidly evolve Cas9 and base editor variants with broadened PAM compatibility, higher DNA specificity, and enhanced editing capabilities. Finally, we integrated several of these developments to address cell and animal models of human genetic disease. Base editing can be used to correct pathogenic point mutations, introduce disease-suppressing mutations, and create new models of genetic diseases.

1:20 PROTACs: Past, Present, and Future

Craig M. Crews, PhD, Professor, Chemistry; Pharmacology; Molecular, Cellular & Developmental Biology; Yale University

The ability to control protein levels using PROTACs is changing how drugs are being developed and is expanding our concept of the druggable target space. Moreover, PROTACs offer the advantages of siRNA but with more favorable pharmaceutical properties (ADME, biodistribution, routes of administration). For the past 18 years, Professor Crews has pioneered the development of this new modality from concept to clinical trials. Here he will describe the current and future trends in this fast-paced, exciting new therapeutic field.

2:00 Close of Plenary Keynote Program

Plenary Keynote Biographies

David R. Liu, PhD

Howard Hughes Medical Institute Investigator, Professor of Chemistry & Chemical Biology, Harvard University

David R. Liu is the Richard Merkin Professor, Director of the Merkin Institute of Transformative Technologies in Healthcare, and Vice-Chair of the Faculty at the Broad Institute of Harvard and MIT; Thomas Dudley Cabot Professor of the Natural Sciences and Professor of Chemistry and Chemical Biology at Harvard University; and Howard Hughes Medical Institute Investigator. Liu graduated first in his class at Harvard in 1994. He performed organic and bioorganic chemistry research on sterol biosynthesis under Professor E. J. Corey’s guidance as an undergraduate. During his PhD research with Professor Peter Schultz at UC Berkeley, Liu initiated the first general effort to expand the genetic code in living cells. He earned his PhD in 1999 and became Assistant Professor of Chemistry and Chemical Biology at Harvard University in the same year. He was promoted to Associate Professor in 2003 and to Full Professor in 2005. Liu became a Howard Hughes Medical Institute Investigator in 2005 and joined the JASONs, academic science advisors to the U.S. government, in 2009. Liu has earned several university-wide distinctions for teaching at Harvard, including the Joseph R. Levenson Memorial Teaching Prize, the Roslyn Abramson Award, and a Harvard College Professorship. Liu has published ≥170 papers and is the inventor of ≥65 issued U.S. patents. His research accomplishments have earned distinctions including the Ronald Breslow Award for Biomimetic Chemistry, the American Chemical Society Pure Chemistry Award, the Arthur C. Cope Young Scholar Award, and awards from the Sloan Foundation, Beckman Foundation, NSF CAREER Program, and Searle Scholars Program. In 2016 he was named one of the Top 20 Translational Researchers in the world by Nature Biotechnology, and in 2017 was named to the “Nature’s 10” researchers in the world and to the Foreign Policy Leading Global Thinkers. Professor Liu’s research integrates chemistry and evolution to illuminate biology and enable next-generation therapeutics. His major research interests include the engineering, evolution, and in vivo delivery of genome editing proteins such as base editors to study and treat genetic diseases; the evolution of proteins with novel therapeutic potential using phage-assisted continuous evolution (PACE); and the discovery of bioactive synthetic small molecules and synthetic polymers using DNA-templated organic synthesis and DNA-encoded libraries. Base editing (named one of four 2017 Breakthrough of the Year finalists by Science), PACE, and DNA-templated synthesis are three examples of technologies pioneered in his laboratory. He is the scientific founder or co-founder of six biotechnology and therapeutics companies, including Editas Medicine, Pairwise Plants, Exo Therapeutics, and Beam Therapeutics.

Craig M. Crews, PhD

Professor, Chemistry; Pharmacology; Molecular, Cellular & Developmental Biology; Yale University

Dr. Crews is the American Cancer Society Professor of Molecular, Cellular and Developmental Biology and holds joint appointments in the departments of Chemistry and Pharmacology at Yale University. He graduated from the University of Virginia with a BA in Chemistry and received his PhD from Harvard University in Biochemistry. Dr. Crews has a foothold in both the academic and biotech arenas; on the faculty at Yale since 1995, his laboratory pioneered the use of small molecules to control intracellular protein levels. His first company, Proteolix, developed the proteasome inhibitor, Kyprolis™ for the treatment of multiple myeloma. His second venture, Arvinas, applies his lab’s PROTAC ‘induced protein degradation’ technology to drug development. He has received numerous awards and honors, including the CURE Entrepreneur of the Year Award (2013), Ehrlich Award for Medicinal Chemistry (2014), Yale Cancer Center Translational Research Prize (2015), a NIH R35 Outstanding Investigator Award (2015), the AACR Award for Outstanding Achievement in Chemistry in Cancer Research (2017), the Khorana Prize from the Royal Society of Chemistry (2018), the Pierre Fabre Award for Therapeutic Innovation (2018), the Pharmacia-ASPET Award for Experimental Therapeutics (2019) and was named an American Cancer Society Professor in 2018.