UCSF

About

Research overview

We are keenly focused on how cells remodel their extracellular proteome in health and disease. We develop enabling technologies to understand and disrupt these human disease-associated signaling processes through protein and antibody engineering and site-directed small molecule discovery.

In the UC San Francisco (UCSF) lab of James Wells, PhD, research focuses on how the cell surface proteome is remodeled in health and disease. We seek to understand both the fundamental biology of this signalling hub, and to identify new biomarkers and therapeutic targets to prevent, mitigate, and cure disease. We use state-of-the-art proteomics and DNA-barcoded antibodies to define the changes in cellular remodeling events that occur when cells are transformed by oncogenes, differentiate, or are treated with drugs. We also employ gene perturbation screens to identify essential surface proteins in remodeling. Empowered by novel biological understanding of surface protein remodeling, we then generate new recombinant antibodies as tools for developing biomarkers and therapeutics to affect disease. We emphasize mechanism-based research in basic and therapeutic sciences. Our lab has a joint home in both the Department of Pharmaceutical Chemistry at the School of Pharmacy and the Department of Cellular and Molecular Pharmacology at the School of Medicine.

History

Jim Wells received his BA degrees in biochemistry and psychology from University of California, Berkeley and a PhD in biochemistry from Washington State University with Ralph Yount, PhD. He completed his postdoctoral studies at Stanford University School of Medicine with George Stark, PhD. He began his independent research career as a founding member of the Protein Engineering Department at Genentech, and then became founder, CSO, and president of Sunesis Pharmaceuticals, Inc.

At Genentech, his group pioneered:

  • gain-of-function engineering of enzymes (such as subtilisin), growth factors (hGH), and

  • antibodies by site-directed mutagenesis and protein phage display.

The group also:

  • discovered hot-spots in protein-protein interfaces by developing alanine-scanning, and with Kossiakoff Lab (University of Chicago) they revealed the first cytokine-receptor mechanism for dimerization

  • built a new antagonist for human growth hormone, now used for treating acromegaly (Somavert, sold by Pfizer)

  • helped humanize the anti-VEGF antibody for treating cancers (Avastin, sold by Genentech).

At Sunesis, the group developed a novel technology for site-directed fragment-based drug discovery, Tethering®, and applied it to cancer targets. Several of the compounds discovered with Tethering are now in clinical development. They also discovered the anti-inflammatory drug Lifitegrast, which was subsequently developed by SarCODE and is now sold by Shire for dry eye syndrome.

Joining UCSF

Wells joined UCSF in 2005 in both the Department of Pharmaceutical Chemistry at the School of Pharmacy and the Department of Cellular and Molecular Pharmacology at the School of Medicine.

The Wells Lab first focused on understanding the family of caspases, site-specific proteases best known for driving cell death. We developed an N-terminomics proteomics technology using an engineered peptide ligase, to tag the caspase products cleaved during apoptosis. These studies revealed nearly 2,000 cellular targets cleaved by caspases, and showed that each caspase had a preferred clientele. (See Degrabase.) We have further engineered a variety of split-enzymes to study proteolysis, kinase activity, and gene editing. We founded the Small Molecule Discovery Center (SMDC) at UCSF, now directed by Michelle Arkin, PhD, that offers UCSF researchers access to modern small molecule discovery technologies.

Today

We have shifted our focus to understand how cells remodel their surface proteomes when transformed with oncogenes, treated with drugs, undergoing differentiation, or in aging.

We use state-of-the-art surface proteomic methods and a new genetically encoded DNA-barcoded antibody technology called Phage-antibody Next Generation Sequencing (PhaNGS). This allows us to identify important new groups of proteins that then become targets for us to generate recombinant antibodies towards, using phage display. This work is fueled by the Antibiome Center at UCSF with Michael Hornsby, PhD, which uses an automated phage display robot for generation of renewable recombinant antibodies to the proteome. We have constructed new protein-directed or motif-directed phage antibody libraries to produce high quality synthetic monoclonal antibodies specific to target proteins or phosphorylation sites in proteins. We use these to generate detection probes and immunomodulators such as antibody drug conjugates, bi-specific T-cell engagers (BiTEs), or CAR-T cells for cancer, which drives us to understand cell surface remodeling and how that can lead to new biomarkers and therapeutics in cancer and immunology.

Wells is passionate about mentoring graduate students and postdocs and is proud that all have gone on to highly productive careers in science in industry and academia.


Tethering is a registered trademark of Sunesis Pharmaceuticals, Inc.