From C− to Nobel Prize for ACP Member

ACP Member William G. Kaelin Jr., MD, tackled his first lab project. It didn't go smoothly: Dr. Kaelin struggled aimlessly on a project that seven previous undergraduates had been unable to complete. He questioned the very premise of the research, concerned that the project might be based on an artifact, and approached his advisor about it.

“He rewarded me with a C− for my first lab work,” Dr. Kaelin said. “And he wrote on my transcript, ‘Mr. Kaelin appears to be a bright young man whose future lies outside the laboratory.’”

That couldn't have been further from the truth. In 2019, research by Dr. Kaelin and two colleagues into how cells sense and adapt to oxygen availability won them the Nobel Prize in Physiology or Medicine.

Dr. Kaelin, a Howard Hughes Medical Institute Investigator and the Sidney Farber Professor of Medicine at Dana-Farber Cancer Institute and Harvard University in Boston, focused his line of work on von Hippel-Lindau (VHL) syndrome, which increases risk for kidney cancer. When Dr. Kaelin began his research, it was known that a mutation in the VHL gene causes kidney tumors and that kidney tumors churn out large amounts of vascular endothelial growth factor (VEGF), providing them with an extra blood supply to grow. This, and the ability of these tumors to occasionally secrete erythropoietin (EPO), indicated to Dr. Kaelin that the VHL protein was likely critical for oxygen sensing, since VEGF and EPO are normally induced by hypoxia. VEGF and EPO are controlled by the HIF transcription factor.

Dr. Kaelin and his fellow laureates ultimately showed that VHL protein, in the presence of oxygen, targets the HIF transcription factor for destruction and identified the chemical modification (prolyl hydroxylation) on HIF that tells the VHL protein whether oxygen is present, and hence whether to engage HIF. This work on the VHL protein motivated the successful clinical testing of VEGF inhibitors for kidney cancer and has also spurred the development of new HIF agonists and antagonists, Dr. Kaelin said. The agonists are being developed for anemia and ischemic diseases, while the antagonists are being developed mainly for cancer.

Dr. Kaelin describes himself as a late bloomer who didn't really find his way academically until he was a high school senior. His one saving grace, he said, was that mathematics (and later computer science) came easily to him, so he could get good grades in those subjects without really studying. He excelled academically in college (the C− not withstanding) but didn't see an attractive career for himself in either academic mathematics or the still nascent field of computer science. He entered Duke University School of Medicine in Durham, N.C., with the idea of becoming a practicing physician.

His first year, he recalled hating all the rote memorization involved in medical school. But in his second year, he and his fellow students were introduced onto the wards. “That brought medicine to life for me, and I could also see why I did all that rote memorization during my first year and how it came into play. So that sort of got me recharged to become a clinical doctor,” he said.

He did lab work again during his third year on an elective, and while it was a good experience, he said, it wasn't enough to convince him that he was going to be a research scientist. Fortuitously, the project related to tumor blood flow and tumor angiogenesis. It was during that time, Dr. Kaelin said, that he began to read about the highly angiogenic tumors associated with VHL syndrome.

After medical school, Dr. Kaelin did his internal medicine residency at The Johns Hopkins University in Baltimore and stayed an extra year as assistant chief of service, effectively a chief medical resident. In that role, Dr. Kaelin said, he further honed his knowledge of rare eponymous syndromes such as the VHL syndrome and also memorized the potential causes (differential diagnoses) for various signs and symptoms, including the causes for excess red blood cell production. He said he was struck by the fact that the various tumors seen in the VHL syndrome can cause polycythemia.

What new blood vessel formation and red blood cell formation have in common is that they're normally induced when tissues are not getting enough oxygen, he said. “So I always thought that the VHL gene must be important for oxygen sensing because it seemed like oxygen sensing was broken in these tumors, that the switch has been stuck in the ‘on’ position where the tumors were acting like they were profoundly starved of oxygen,” he said.

At Johns Hopkins Dr. Kaelin also met his late wife, Carolyn, who at the time was a fourth-year medical student. She would go on to become a celebrated breast cancer surgeon in Boston.

Dr. Kaelin came to Dana-Farber Cancer Institute in 1987 as a medical oncology fellow with the intention of becoming a clinical oncologist. He decided to try the laboratory one more time, expecting to become board certified two years later and to eventually return to the clinic. “My first laboratory mentor abruptly left science six months into my training—another inauspicious sign—and I found myself a laboratory refugee,” he said. Fortunately, he next began working with David M. Livingston, MD, who had just started researching tumor suppressor genes.

“David was a terrific laboratory mentor. He's really the one who taught me how to become a scientist,” Dr. Kaelin said. “At the end of the day, a lot of becoming a clinician is taught by apprenticeship. The same is true of becoming a scientist. I needed to learn by apprenticeship from David.”

Dr. Kaelin, to his own surprise, was highly successful as a postdoctoral fellow. He said he “wasn't smart enough to know what shouldn't work and didn't always know the classical way to solve certain problems” but noted that this was actually a blessing, because it meant he was willing to try challenging experiments and also looked at things afresh, sometimes inventing his own solutions.

Dr. Kaelin said that what he liked best about clinical medicine was arriving at the correct diagnosis, which he likened to puzzle solving, and then applying an effective therapy. While still a postdoctoral fellow, however, he realized that most of the patients referred to a medical oncologist already have a diagnosis and that effective therapies didn't exist for many cancer patients. He said it became clear to him that the only path to more effective cancer therapies was to understand the disease better at the molecular level. Solving puzzles in the laboratory began to provide the same joy he had once found solving clinical puzzles, he said.

After four years with his mentor, Dr. Kaelin started his own lab down the hall, and in 1993 he learned that the VHL gene had been isolated by a group at the National Cancer Institute. “I thought this would be a great opportunity to understand the pathogenesis of tumors like kidney cancer, to understand the molecular control of angiogenesis, and to understand how cells sense and respond to changes in oxygen,” he said.

The rest is history.

Dr. Kaelin pointed out that the clinical practice of medicine requires qualities also needed in good research scientists. “Physicians are constantly getting bombarded with data and information. They often have to make decisions, sometimes quickly, based on that information, and sometimes the decisions are literally life or death. It's easy if every piece of data and every piece of information points in the same direction, but often that is not the case. In the laboratory you might have done a number of different experiments and maybe eight point in one direction, but maybe two are pointing in another direction,” he said. “Clinical medicine teaches you how to think critically. It teaches you how to deal with conflicting data and to still operate in a sea of sometimes conflicting data.”

Another quality shared by busy physicians is the ability to multitask, Dr. Kaelin said. “In my experience, the scientists who do best in the lab are the ones who can keep multiple lines of experimentation moving forward at the same time. So they work in parallel and not in series.”

Over time, Dr. Kaelin moved from picking up these characteristics to encouraging them in others. Having benefited from great mentorship, Dr. Kaelin has now become a mentor in turn. “I've just had a succession of incredibly talented young people in my laboratory who have actually done the work. I couldn't be more grateful for the terrific people who have worked for me and with me over the years. I still have a cadre of wonderful postdoctoral fellows and students in the lab,” he said.

In 2003, Dr. Kaelin's wife developed breast cancer. She underwent a mastectomy and chemotherapy but developed an unrelated glioblastoma in 2010. “We of course tried to assemble the best scientists and clinicians in the world to put together treatment plans for her. We did have her for four and a half years, which was probably longer than, you know, unfortunately, is the case for most glioblastoma patients. But we did lose her in 2015. So for that reason, winning the prize was bittersweet because she's not here to share it with me.”

The newfound fame has been overwhelming at times, Dr. Kaelin said. “I want to make sure that I'm judicious and use the celebrity part of it for hopefully good purposes,” he said. “But I don't want to get swept up in it either. The balancing act is coming to grips with the fact that this, this is changing, potentially, my life, and I just want to make sure it's for the good. This is a work in progress.”