Cracking Down on Cancer: A Profile of Owen Witte

Witte’s idea that the Abelson murine leukemia virus (A-MuLV) protein should be a protein kinase stemmed primarily from work by molecular biologist Raymond Erikson, then at the University of Colorado, and his colleagues. They had shown that the oncogenic viral gene src was associated with protein kinases, and Witte expected to find something similar with A-MuLV. He followed the standard protocol for characterizing protein kinases by identifying their phosphorylated amino acid products, which involved adding the A-MuLV protein to an acidic solution, heating it, then waiting 24 hours for the enzyme to complete its action. But in the end, Witte could see only free phosphates—compounds that are transferred during a kinase reaction. 

Reed Hutchinson/UCLA

Exasperated, he tried something different. He analyzed his solutions at several time points during the reaction rather than only at the end. The new protocol worked. Finally, after several months of trying, he’d identified the elusive amino acid, which appeared within a few hours. To Witte’s surprise, the amino acid was neither phosphoserine nor phosphothreonine, which, at the time, were thought to be the primary phosphorylated amino acids produced by protein kinases in mammals. Instead, it turned out to be phosphotyrosine, which had never before been observed as the product of a protein kinase reaction. The A-MuLV protein was a newly discovered type of enzyme: a tyrosine kinase. 

Another team, led by Tony Hunter at the Salk Institute in California, nearly simultaneously reported tyrosine kinase activity associated with another virus that causes cancer in chickens. Witte, after setting up his own lab, demonstrated that a homolog of the A-MuLV tyrosine kinase, ABL1, was highly active in human leukemias—a discovery that contributed to the development of a lifesaving leukemia therapy called Gleevec (imatinib). The discovery of tyrosine kinases also revealed an entire class of enzymes that could be medical targets. It is “probably the single greatest discovery that I could ever imagine being associated with,” Witte says.

From suburbia to Stanford

Born in Brooklyn in May 1949, Witte started his life as a city boy, then spent much of his childhood and adolescence in Levittowns along the East Coast of the US. Levittowns were large housing developments that sprang up after World War II to house veterans and their families. Abraham Levitt and his two sons, William and Alfred, founded the company that constructed these developments, which became the prototypical American suburbs—sprawling neighborhoods with rows upon rows of nearly identical homes, situated on rectangular land plots with driveways and neatly trimmed lawns.

When Witte was in third grade, Levitt & Sons hired his father, and the family moved to one of the cookie-cutter suburbs in Pennsylvania. Witte credits his early interest in science to a fifth-grade teacher in the Pennsylvania Levittown. “She taught science not by reciting facts from a textbook, but with hands-on experiments,” Witte says, noting that one such experiment involved learning about the circulatory system by dissecting a cow’s heart. “That allowed us to learn what real science is about.”

Witte continued to do hands-on science as he got older, working at the Department of Health conducting bacterial counts in lakes, swimming pools, and restaurants. But at the time, he wasn’t dead set on a career in science. In high school he was drawn to the culinary arts, and later, in 1967, he went off to study at Cornell University in Ithaca, New York, with an undecided major. While he was there, he considered a career in hotel management, but was drawn back to science after taking classes in the university’s College of Agriculture, where he was exposed to various scientific disciplines, including food science and microbiology.

When Witte arrived at Stanford in the early 1970s, he initially planned to work with Henry Kaplan. Kaplan was a radiologist famous for groundbreaking work that transformed Hodgkin’s disease, a cancer that originates in the lymphatic system, from a fatal illness to a treatable one. But after being introduced to one of Kaplan’s former mentees, Irving Weissman—a young professor who would go on to become a leading scientist in the fields of immunology and cancer biology—Witte saw a better fit. He joined Weissman’s lab while maintaining a relationship with Kaplan as a co–thesis advisor. “I kind of got the best of both worlds,” Witte says. “The younger professor energy in the lab and the more senior professor with a lot of experience and great [connections].”

In Weissman’s lab, Witte studied retroviruses that cause cancers in mice. That research led to several important insights into the viruses’ morphology and the role of their proteins in processes such as replication and budding, where a virus exits a cell in an envelope derived from the host’s membrane. Some of this work contributed to crucial advances years later, when scientists studying human immunodeficiency virus (HIV) identified proteins that could inhibit proteases; the finding later served as the foundation for antiretroviral medications for HIV. “That’s the great beauty of science,” Witte says. “Doing work because the question is interesting and not necessarily being able to anticipate when it might actually be useful down the road.”

After earning his medical degree, Witte moved to Boston to become a medical intern. But it wasn’t long before he decided to abandon a career as a doctor and head back to the lab. “I just did not like it,” he says. Not only was the medical internship an imperfect fit, a family illness made this a particularly trying time in his life. 

Witte decided to return to Stanford, but Weissman suggested that before he packed his bags and crossed the country again, he reach out to David Baltimore, who was then a professor of microbiology at MIT. “I kind of laughed because David Baltimore had won the Nobel Prize about two years prior, and I was sure that the lineup of people trying to get into his lab was quite long,” Witte recalls.

Fortunately for Witte, Weissman knew Baltimore and called to put in a recommendation for his former mentee. “Irv said such wonderful things about him that I thought I would be missing out on a terrific person if I didn’t take him,” Baltimore recalls. “And of course, it worked out terrifically well.” 

At the time, a focus of Baltimore’s lab was the Abelson murine leukemia virus, a retrovirus that causes cancer in mice. As a postdoc, Witte worked diligently to characterize a protein encoded within the virus’s genome, which eventually led to the discovery that it was a tyrosine kinase. “My graduate work and my postdoc were the most enjoyable times during my [scientific career], because all I had to do was be in the lab and do the work that I love,” Witte says.

Exploring new frontiers 

Witte left Boston in 1980 and headed west again to set up his own lab at the University of California, Los Angeles. Within the first few days of arriving, Witte met Jami McLaughlin, a research assistant in the department. The two started dating shortly after and got married in May 1984. A few months later, McLaughlin joined Witte’s lab, where, alongside Witte’s graduate students, she helped clone and sequence BCR-ABL, an oncogene that causes human leukemias. “It’s really been a partnership over many years, with her doing some of the really critical experiments that led to these important results,” Witte says. 

His team later identified Bruton’s tyrosine kinase (BTK), a protein produced by a mutated gene in X-linked agammaglobulinemia, a human immune deficiency marked by a loss of B cells. Further investigations of BTK’s expression and kinase activity eventually led to the develop of ibrutinib (Imbruvica), a drug used to treat B cell–associated leukemias and lymphomas. 

For almost three decades, Witte’s research centered on leukemias and lymphomas. Then, in the mid-1990s, he started hearing from relatives who had been diagnosed with prostate cancer. “They would call me asking, ‘What should we do?’” he recalls. After digging through the literature, Witte discovered that there had been little change in the treatment of prostate cancer for several decades. The paucity of advances in this field led him to a radical decision: to shift his focus from blood cancers to prostate cancer. “That wasn’t easy at that stage of my career,” Witte says. “I had a very well-established reputation in one area, and no reputation whatsoever in this new area.”

I’m 70 years old and I’m still really jazzed up about this new finding.

—Owen Witte, UCLA

But just as he had persevered with his groundbreaking experiments in the 1970s, he pushed himself to work through any roadblocks that popped up as he started down a new research path. This work has led to, among other things, pinpointing the population of stem cells that gives rise to human prostate cancers. Another realm where Witte’s perseverance paid off was in his participation in industry, particularly with companies developing cancer drugs. “One of the important things about Owen was that he has been unafraid to get involved in companies,” Baltimore says. “Many researchers are comfortable working both with industry and as academics, but that was not true 20 years ago when Owen was first doing that.” It allowed him to have an even greater scientific impact, Baltimore explains.

Witte has also had an impact on his students with his scientific curiosity and warmth. Witte was incredibly knowledgeable and was an insightful mentor with high expectations for his students, says Charles Sawyers, now a physician-scientist at Memorial Sloan Kettering Cancer Center. “I found [his lab] to be the most intellectually stimulating community of people,” he says. “I was like a sponge, soaking up everything, because I was so new to the area.” 

Prostate cancer researcher John Lee of Fred Hutchinson Cancer Research Center recalls Witte’s softer side. During his graduate work in Witte’s lab, Lee’s mother was diagnosed with metastatic bladder cancer and passed away a year after starting treatment. “Owen was very supportive during that period,” Lee says. “But the other really important thing that he told me was that [when it comes to cancer research], there’s a lot of work yet to be done.” 

Witte’s lab continues to contribute important discoveries to cancer research. One of the most recent was demonstrating that epithelial cancers starting in different organs, such as the prostate and lung, develop into highly aggressive, lethal late-stage tumors by a nearly identical mechanism. The discovery suggests that targeting a set of “master” gene regulators could potentially help treat a wide range of cancers, Witte says. “I’m 70 years old and I’m still really jazzed up about this new finding.”

Diana Kwon is a Berlin-based freelance journalist. Follow her on Twitter @DianaMKwon.