James A. Wells
Professor James A. Wells pioneered protein engineering methods that transformed both basic research and therapeutic development. His work at Genentech established fundamental principles for modifying enzymes and hormones, produced widely used technologies including alanine scanning and protein phage display, and yielded multiple products now in clinical use. His subsequent academic research has advanced understanding of cell surface proteomics and caspase biology.
Wells was born on April 28, 1950. He earned dual B.A. degrees in biochemistry and psychology from the University of California, Berkeley, in 1973 and a Ph.D. in biochemistry from Washington State University with Ralph Yount in 1979. He completed postdoctoral training at Stanford University School of Medicine with George Stark in 1982.
In 1982 Wells joined Genentech as a co-founding member of the Protein Engineering Department, where he remained for 16 years. His group pioneered gain-of-function engineering of enzymes, hormones and antibodies through site-directed mutagenesis and phage display. Working with subtilisin, they demonstrated that enzymes could be engineered for improved industrial performance, producing variants now used in laundry detergents worldwide. The group developed cassette mutagenesis for systematic exploration of sequence space and invented alanine scanning to identify energetically important residues in protein interfaces, revealing the concept of hot spots in protein-protein interactions.
Wells and colleagues elucidated the activation mechanism of human growth hormone, demonstrating with Anthony Bhusuki Kossiakoff and Bart de Vos that one hormone molecule binds two receptor molecules sequentially to trigger dimerization and signaling. This paradigm applies broadly to cytokine receptor activation. Building on this insight, his group engineered a human growth hormone antagonist by introducing mutations that preserved binding to the first receptor site while blocking the second. The resulting drug pegvisomant, marketed as Somavert by Pfizer, became a first-line treatment for acromegaly. Wells also contributed to the humanization of the anti-VEGF antibody bevacizumab, sold as Avastin by Genentech for treating multiple cancers.
In 1998 Wells co-founded Sunesis Pharmaceuticals, serving as Chief Scientific Officer and President. There his group developed Tethering, a site-directed fragment-based approach for discovering small molecules that bind cryptic allosteric sites and protein-protein interfaces previously considered undruggable. This work produced lifitegrast, an anti-inflammatory drug approved for dry eye syndrome, along with clinical candidates for cancer.
Wells joined the University of California, San Francisco, in 2005 as Harry W. and Diana Hind Distinguished Professor in Pharmaceutical Sciences, with joint appointments in Pharmaceutical Chemistry and Cellular and Molecular Pharmacology. He founded the Small Molecule Discovery Center and served as Chair of Pharmaceutical Chemistry for eight years. His laboratory developed subtiligase and related engineered enzymes for N-terminomics, enabling proteome-wide identification of caspase substrates and revealing nearly 2,000 cellular targets. In 2012 he founded the Antibiome Center to generate recombinant antibodies at proteome scale using automated phage display.
His honors include the Pfizer Award from the American Chemical Society for achievements in enzyme chemistry in 1990, the Vincent du Vigneaud Award in 1998 and the Distinguished Alumni Award from Washington State University in 1997. He was elected to the National Academy of Sciences.
