Pirating proteins for biomedicine

On April 26, 2022, James Wells, PhD, faculty member in the UCSF School of Pharmacy’s Department of Pharmaceutical Chemistry, addressed an audience of friends, family, and colleagues at Byer’s auditorium in the UCSF Mission Bay campus. Speaking as the recipient of the UCSF 64th Faculty Research Lectureship in Basic Science, Wells detailed the long arc of a career spent pirating proteins from nature and altering them for therapeutic and industrial purposes.

“Building the ship while you’re sailing it was our experience,” he enthused during the honorary lecture, titled “Pirating Biology for New Inventions.”

In the early days of protein engineering, circa 1980, few protein scientists thought that proteins could be improved for use beyond what nature had provided. But Wells, then a scientist at Genentech, lead a team that showed that both enzymes and protein hormones could be engineered for commercial and health applications.

According to longtime colleague Michelle Arkin, PhD, and now his chair of the Department of Pharmaceutical Chemistry, Wells was willing to try things that others wished they had pursued in hindsight. Arkin, who introduced Wells at the lecture, nominated the world-class scientist for the award, which recognizes outstanding career achievements of UCSF research faculty.

While working for Genentech from 1982 to 1998, Wells co-founded the company’s trailblazing protein engineering department and was given free rein to develop new methods for engineering proteins. “I was like a kid in a candy store,” he said.

Wells’ group was the first to engineer a class of enzymes called subtilisins for industrial purposes—these enzymes are now a common ingredient in laundry detergents. The Genentech team next showed that human growth hormone could be tweaked to make an effective first-line treatment for pituitary cancers.

protein hot spot

Wells and colleagues pioneered the identification of “hot spots” on proteins.

In the process of developing these products, Wells realized that the physical contacts or “hot spots” that proteins make as they interact could be mimicked by small molecules—opening the door to new therapies based on “drugging” these protein-protein interactions (PPIs).

To pursue this new line of inquiry, Wells and a few of his colleagues founded Sunesis Pharmaceuticals and developed a technique called tethering, enabling them to test molecular fragments that could fit into these crucial hot spots they had discovered on proteins. Small molecule candidate drugs for cancer, inflammatory disease, and even dry eye would soon be on the way, all thanks to their groundbreaking work.

Arkin, previously a post-doc with Wells at Genentech, was instrumental in developing the covalent tethering approach, among others, with Wells at Sunesis. “We learned a lot [in industry],” Arkin said during her introduction. “And eventually we learned to leave and come to UCSF, and now I am his boss,” a quip the audience greeted with laughter.

“Once you get into [drug] development like we did at Sunesis, it is like watching grass grow,” Wells commented on the slow pace of bringing drugs to market. “I really wanted to get back to invention.” In 2005, the call to return to the discovery sciences drew him to UCSF’s Department of Pharmaceutical Chemistry, “the best place on the planet to do chemical biology.” There, he joined a stellar community of drug-hunting researchers and established the Small Molecule Discovery Center, which is now led by Arkin.

A little over a year after Wells started at UCSF, he became chair of the department and held the position for eight years. During his tenure, he grew the department but yearned to return to research, like a ship’s captain to sea.

Wells and Arkin standing with a more than a dozen people in blue shirts

Wells and Michelle Arkin, PhD, pose with a sea of friends, family, and colleagues wearing blue pirate t-shirts in honor of Wells’ award.

At UCSF, Wells and his team built a robot, dubbed the Antibot, to automate the screening of thousands of antibodies for those well suited for binding and targeting other proteins and protein fragments. To date, the Antibot has yielded hundreds of antibodies with potential for use in drug development.

In recent years, Wells developed a faster and cheaper technique for identifying proteins on the surface of cancer cells—and then adapted the approach to find molecules to disable the spike protein in SARS-CoV-2.

Wells wrapped up the lecture, offering a taste of where his scientific pirate ship is heading. Currently he is examining how the assortment of proteins on the cell surface changes in health and disease, with an eye for new therapeutic targets—and he continues to move these advances into industry, via collaborations and new companies. A pirate’s work is never done.


School of Pharmacy, Department of Pharmaceutical Chemistry, Department of Bioengineering and Therapeutic Sciences

About the School: The UCSF School of Pharmacy aims to solve the most pressing health care problems and strives to ensure that each patient receives the safest, most effective treatments. Our discoveries seed the development of novel therapies, and our researchers consistently lead the nation in NIH funding. The School’s doctor of pharmacy (PharmD) degree program, with its unique emphasis on scientific thinking, prepares students to be critical thinkers and leaders in their field.