2016 Smissman Memorial Lecturer

James Wells, Ph.D. 

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PhD, Biochemistry, Washington State University, 1979
BA, Biochemistry, University of California, Berkeley, 1973

Public Lecture and Award Presentation

  • "Challenges and Opportunities for Discovering New Drugs"
    4:30 p.m., Thursday, May 18
    Room 3020, School of Pharmacy Building, 2010 Becker Drive

Scientific Lectures

  • "Drug Discovery at Challenging Interfaces"
    9:30 a.m., Thursday, May 18
    Room 3020, School of Pharmacy Building, 2010 Becker Drive
  • "Engineering Proteins for Signaling and Therapy"
    10 a.m., Friday, May 19
    Room 3020, School of Pharmacy Building, 2010 Becker Drive

Biosketch

James Wells grew up in Palo Alto, California. He completed a B.A. degree in Biochemistry and Psychology from the University of California, Berkeley in 1973. He took a year off to work as a scrub nurse in a Berkeley hospital allowing him to make the important decision to pursue a PhD to do science, as opposed to pursue an MD for routine patient care. He completed his PhD in Biochemistry with Professor Ralph Yount at Washington State University in 1979. There they discovered a specific and reversible thiol cross-linking reagent that trapped nucleotide in the binding site of myosin allowing them to correlate conformation changes with nucleotide binding and label the active site specifically for the first time using ATP-based photo-affinity probes. He obtained a Daymon Runyon Walter Winchell post-doctoral fellowship in 1980 to work with Professor George Stark at Stanford. He was able to purify and characterize 2-5A synthetase from human cells which was known to set off antiviral emergency signals through the synthesis of short 2’-5’-linked oligo-adenylates 5-9 long. 

In 1982 he took his first independent position as a founding scientist in the Protein Engineering Department at Genentech. There he pioneered the use of site-directed mutagenesis for gain-of-function design for enzymes, hormones, and antibodies as well as developing new technologies for engineering and probing protein function. These included the development of cassette mutagenesis to saturate small coding regions in proteins to find optimal substitutions. His group engineered subtilisin, a bacterial serine protease for improved thermal and oxidative stability, altered substrate specificity. Subtilisin is the largest industrial enzyme market and many of these recombinant variants are sold today in laundry detergents and other cleaning products through Genencor a company founded on these engineered proteases. His group further probed the enzyme mechanism to understand the role of catalytic groups in catalysis, and designed a peptide ligase useful today for complete protein synthesis, semi-synthesis and bioconjugation and for N-terminomics to study protease signaling. At Genentech his group also developed new technologies for probing and engineering protein-protein interactions. The developed homolog and alanine-scanning to probe how human growth hormone (hGH) bound and activated its receptor. One of the key findings was that not all residues at a protein interface were critical for binding but rather there were smaller “hot-spots” that drove the interaction, which was good news for those interested in making small molecule mimics. They developed protein phage display to optimize the affinity of these hot spot interactions 400x for binding of hGH to its receptor. Such work was embodied in the development and eventual FDA approval of a potent antagonist of hGH, Somavert,  sold by Pfizer for treatment of acromegaly. They further expanded the use of phage display for humanization of antibodies one of which is the anti-VEGF antibody, Avastin, used for treating cancers and macular degeneration.  

In 1998 Dr. Wells left Genentech to found Sunesis Pharmaceuticals where he served as President and Chief Scientific Officer. Sunesis developed a novel fragment discovery technology known as disulfide trapping or Tethering. Tethering is a site-directed drug discovery technology where thiol containing fragments are discovered at pre-determined sites by thiol-disulfide exchange with engineered or natural cysteines. They applied this technology and understanding of hot-spots to many protein-protein targets and were the first to show successful discovery of a nM affinity compound for a protein-protein target, the 60nM inhibitor that binds IL-2. This was expanded to enzyme targets, including many kinases, which served to seed partnerships with Jansen, Biogen and Merck among others. The company is currently publically traded on NASDAQ and continuing to develop cancer drugs.

In 2005, Dr. Wells joined UCSF as the Harry W. and Diana Hind Distinguished Professor in Pharmaceutical Sciences. He is a joint Professor in the Departments of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology. He served as Chair from 2008-2016. His current research uses a combination of protein design and small molecule drug discovery to study and modulate cellular processes involved in apoptosis, inflammation and cancer. Using Tethering and small molecule screeing his group identifies and probes allosteric sites in enzymes and proteins including proteases (caspases),  kinases (PDK1), and phosphatases (PTP1B). The Wells group developed an N-terminomics technology for studying protease signaling using the engineered subtiligase to identify the largest set of the cellular substrates that are cleaved by caspases during apoptosis (nearly 2000). They engineered a number of new enzymes for probing signaling and cellular engineering including: a split-TEV protease called the SNIPer for site-specific proteolysis, the NEDDylator for proximity tagging of protein and small molecule interactors, a split-Cas9 for inducible gene silencing or editing, and split-kinases to determine immediate substrates for activated kinases. More recently his group has developed a high through-put robotic technology for antibody discovery using Phage display. His group is part of the Recombinant Antibody Network whose long range goal is to develop recombinant antibodies to the entire proteome. They are currently focused on extracellular targets engaged in immunology and oncology.

His societal awards include: the Hans Neurath and Aviv Awards given by the Protein Society, the Pfizer,  Smissman, and Perlman Awards given by the American Chemical Society, the du Vignead Award given by the Peptide Society, the 2010 Merck Award given by the ASBMB. In 1999 was elected member of the National Academy of Sciences and 2015 elected member in the American Association of Arts and Sciences, and 2016 the National Academy of Inventors. See www.wellslab.ucsf.edu for more details.


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