The Initial Genentech Years

During this founding era, the lab helped establish the core philosophy that proteins could be rationally engineered. Using subtilisin as a model in collaboration with Dave Estell’s group the team pioneered some of the fundamental tools of mutagenesis and protein engineering, proving that enzymes could be engineered for improved stability and novel functions. Co-founded the Protein Engineering Department with Tony Kossiakoff

• Lab Members: Paul Carter, Brian Cunningham, Dave Powers

Key Achievements

• Subtilisin Engineering: Pioneered the cloning, expression, and characterization of autoproteolysis of the first bacterial serine protease, subtilisin.
• The Toolkit (DMS): Developed cassette and site-saturation mutagenesis—the direct precursors to modern Deep Mutational Scanning.
• Gain-of-Function: Rational engineering of subtilisin for oxidative stability, altered specificity, introduction of disulfide (S-S) bonds, and enhanced stability.

Commercial Impact

• Genencor: These engineered enzymes formed the technological foundation of Genencor.
• Detergent Proteases: Seeded the development of the industrial enzymes used in laundry detergents worldwide.

Phage Display & The Hot Spot Theory

The lab shifted focus to protein-protein interfaces, using Human Growth Hormone (hGH) to define fundamental rules of binding energy between proteins. This period introduced the concept of "Hot Spots"—discovering that binding energy is concentrated in a few key residues—and Phage Display technologies for protein display and optimization.

• Lab Members: Lars Abrahmsen, Steve Bass, Scott Braxton, Henry Lowman, Colin Mitchinson, Brian Cunningham, Germaine Fuh, Lei Jin

Key Achievements

• The 1:2 Dimerization Mechanism: Discovered in conjunction with Tony Kossikoff’s lab the mechanism where one hGH molecule dimerizes two receptors to activate signaling.
• Hot Spots: Demonstrated via Alanine-scanning that binding energy is concentrated in specific "hot spot" residues.
• Phage Display: Developed protein phage display, monovalent display, and methods for affinity optimization.
• Catalytic Engineering: Engineered the catalytic triad of subtilisin and demonstrated substrate-assisted catalysis.
• Receptor Engineering: Engineered prolactin to bind the hGH receptor (hGHr) and created receptor-specific variants.

Translating structural insights into therapeutics, the lab utilized rational design and phage display to create antagonists for hGH and to "humanize" antibodies. These studies were important for engineered biologics discovery that produced two approved therapeutics still in use today.

• Lab Members: Dave Matthews, Tom Chang, Dave Jackson, Tim Clackson, Marcus Ballinger, Ken Pearce, Manuel Baca, Andrew Jameson, Brian Cunningham, Germaine Fuh, Shane Atwell, Warren DeLano

Key Achievements

• Rational Antagonists: Designed antagonists for hGH and hPRL.
• Avastin: "Humanization" of the anti-VEGF antibody (Avastin) using mono-valent phage display.
• Subtiligase Utility: Applied Subtiligase for protein assembly and peptide cyclization.
• Advanced Phage Display: Developed Substrate Phage and Zinc Finger Phage display methods.
• Subtilisin Specificity: Engineered di-basic substrate specificity into subtilisin.

Commercial Impact

• Somavert (Pegvisomant): Engineered the long-acting hGH antagonist that became the approved drug for Acromegaly.
• Avastin (Bevacizumab): Provided the humanization technology for one of the world's most successful cancer therapies.

Fragment-Based Discovery & The Sunesis Years

Moving beyond biologicals, the lab invented "Tethering"—a technology to discover small molecule fragments that bind to "undruggable" protein interfaces. This work bridged the gap between protein engineering and medicinal chemistry.

• Lab Members: Greg Weiss, Dev Sidhu, Michelle Arkin, Dan Erlanson, Shane Atwell, Warren DeLano

Key Achievements

• Tethering: Invented the disulfide-trapping technology to screen small molecule fragments against protein targets considered undruggable. First use of covalent libraries for discovery.
• Convergent Evolution: Demonstrated that small molecules and proteins can evolve convergent binding solutions to a single hot-spot.
• Expanded Ala-scanning: Developed "Shot-gun Ala-scan" for high-throughput mapping of interfaces (Heregulin, VEGF, TPO).
• Enzyme Display: Developed enzyme phage display for Subtiligase.

Commercial Impact

• Sunesis Pharmaceuticals: Co-Founded Sunesis based on Tethering technology; two drugs eventually emerged from these discovery efforts including lifitegrast, an LFA-1 inhibitor (a PPI) for dry-eye disease sold today by Takeda, and a BRAF inhibitor, tovorafinib for gliomas approved in 2024 by Day One Biopharmaceuticals.

The Move from Sunesis to UCSF, SMDC & Cell Death Signaling

Upon moving to UCSF, the focus shifted to the "Demolition Crew" of the cell: Caspases. The lab mapped the allosteric networks that regulate cell death and applied Tethering to new target classes like GPCRs.

• Lab Members: Jack Nguyen, Chris Thanos, Liz Buck, Jeanne Hardy, Justin Scheer, Hikari Yoshihara, Debajyoti Datta

Key Achievements

• Caspase Allostery: Discovered hidden allosteric regulatory sites on Caspases using Tethering.
• Hot-Spot Mimicry: Structural analysis of small molecules binding IL-2 revealed atomic-level convergence to the natural receptor.
• GPCR Tethering: Applied Tethering to a GPCR (C5aR) to discover both agonists and antagonists.

N-Terminomics & Apoptosis

The era of "Global Proteolysis." The lab developed the Degrabase to map cuts a protease makes at a proteome-wide level, revealing the wiring of cell death and inflammation, and engineered tools to find state-specific antibodies.

• Lab Members: Sami Mahrus, Dennis Wolan, Junjun Gao, Yingfeng Qiao, Jack Sadowski, Pete Wildes, Nick Agard, Huy Nguyen, JT Koerber, Jason Porter, Gerald Hsu, Min Zhuang, Kazutaka Shimbo, Julie Zorn, Emily Crawford, Chris McClendon, Dan Gray

Key Achievements

• The Degrabase: Applied N-terminomics to identify caspase substrates in cells and serum using Subtiligase.
• Allosteric  Circuitry: Defined the allosteric circuitry in caspases and kinases (PDK1).
• SNIPer: Engineered SNIPer for site-specific proteolysis using engineered TEV protease.
• Apoptosis Activators: Identified small molecule activators of apoptosis that spontaneously formed nano-fibrils mimicking amyloids.
• State-Specific Antibodies: Developed two-state selections to find conformation-specific antibodies (activators and inhibitors).

Commercial Impact

• Calithera Biosciences: Co-founded to translate caspase and metabolic expertise into cancer therapies.

Warp Drive, Soteria & The Antibiome Center

The lab scaled up its technologies with the Recombinant Antibody Network to "industrialize" phage selection, and combined chemical biology with surface proteomics to attack difficult targets like KRAS and E3 ligases.

• Lab Members: Nathan Thomsen, Arun Wiita, Olivier Julien, Paul Marinec, Zach Hill, Sean Hudson, Amy Weeks, Duy Nguyen, Peter Lee, Kurt Mou, Kevin Leung, Charlie Morgan, Justin Rettenmaier, Hai Tran, Julia Seaman, Ashley Smart, Ben Spangler, Alex Martinko

Key Achievements

• The Antibot: Industrialized phage selection for Transcription Factors.
• NEDDylator: Developed contact-dependent proximity labeling for E3 ligases.
• Warp Drive Bio: focused on natural products and RAS drugs (via Tethering-like approach).
• Surfaceomics: Initiated work on RAS-induced membrane proteins.
• AbCID: Selection of small molecule-induced drug-target antibody binders.

Commercial Impact

• Soteria Biotherapeutics: Co-Founded to develop switchable biologics using AbCIDs.
• Warp Drive Bio: Contributioned to the company's RAS tethering strategy.

Expanded surfaceomics to target neoepitopes and extracellular targeted protein degradation (eTPD). 

The lab expanded and developed new approaches for unbiased analysis of the surface proteome comparing healthy and diseased cells including changes in expression, proteolysis, glycosylation and immunopeptidome to discover neoepitopes.  The Lab developed "Proximity Pharmacology" for eTPD like AbTACs and KineTACs.

• Lab Members: Wentao Chen, Jeff Glasgow, Xin Zhou, Jie Zhou, Jamie Byrnes, Shion Lim, Joseph Gramespacher, Sam Pollock, Emily Kang, Nick Rettko, Susanna Elledge, Lisa Kirkemo, Cole Bracken, Adam Cotton, Paige Solomon, Kata Pance

Key Achievements

• Oncogene Surfaceomics: Profiling oncogene-induced surfaceomes (Myc, AZA-treated AML).
• Neo-N-termini: Mapping proteolytic neo-N-termini of cell surface proteins using cell targeted Subtiligase for novel cleaved form antibodies
• PhaNGS: Developed Phage Antibody NGS for global Surfaceomics.
• AbTACs & KineTACs: Pioneered Antibody-based PROTACs and Cytokine-targeting Chimeras for eTPD.
• COVID-19 Response: Rapidly engineered ACE2 Traps, bi-paratopic binders, and biosensors for SARS-CoV-2 antibodies.

Commercial Impact

• EpiBiologics: Founded to expand and commercialize the AbTAC and KineTAC to build EpiTAC platform for eTPD.

Inversion, Multi-Map & eTPD

In the current era, the Wells Lab is expanding the toolkit of eTPD and using spatial biology we for Molecular Photography to map and rewire surface biology circuits.

• Lab Members: Kaitlin Schaefer, Corleone, Delaveris, Zi Yao, Fangzhu Zhao, Brandon Holmes, Thomas Bartholow, Lindsey Lin, Ines Folger, Kun Mao, Yan Wu, Angel Vasquez-Maldonado, Sophie Kong, Kaan Kumru, Paul Burroughs, Madison Seto, Rita Loudermilk, Kamyar Yazdani, Sruthi Rugaveer, Yifei Chen, Oleks Zginniyk

Key Achievements

• eTPD Toolbox: Comprehensive engineering of KineTACs and degrader drug conjugates.
• Multi-Map: Mapping cell surface neighbors and distances (HER2, EGFR) with high precision.
• GT-Subtiligase: Direct cell surface N-terminomics of living cancer cells to identify new proteolytic neo-epitopes.
• Tumor Surfaceomics: Deep profiling of hypoxic cancer, T-cells, and microglial cells.
• SweepR: Tools for soluble protein degradation.

Commercial Impact

• Inversion: Co-Founded Inversion Therapeutics to target new surface targets.