A MAN OF GOOD INTENTION

For Bill Kaelin—Duke’s first undergraduate alumnus to win a NOBEL—"solving puzzles" has paid off.

BY SCOTT HULER

BILL KAELIN LIKES A PUZZLE.

Not a crossword, not a Sudoku. You won’t find Kaelin playing Words With Friends, and Board Game Night was never a staple in the Kaelin household. A puzzle demands concentration. It demands focus; it requires you to pay attention to one thing at a time.

And William Kaelin Jr. ’79, M.D. ’83 and Duke trustee likes to do one thing at a time. In a multitasking world, where you’re checking your e-mail while doing your work, scanning social media while talking to your spouse, making dinner and listening to the radio and entertaining the pets and looking at your kids’ homework, Bill Kaelin chooses what he’s going to do. Then he does what he’s doing, that one thing, with all his awareness. Bill Kaelin pays attention.

It’s more even than attention. It’s a kind of intention: a fierce focus on what he’s dealing with, a powerful presence in the task or conversation at hand, the choice to not be anywhere else. If Kaelin is talking to you, he’s talking to you. If he’s writing a paper, he’s writing a paper. If he’s checking in on the research his postdocs are running in his lab, he’s doing that.

If you’re looking for the source, the spring from which Kaelin’s 2019 Nobel Prize in Physiology or Medicine emerged, the fierceness of that concentration may be a place to start. Kaelin, Sidney Farber Professor of medicine at the Dana-Farber Cancer Institute (DFCI) and the Brigham and Women’s Hospital, Harvard Medical School, and an investigator at Howard Hughes Medical Institute, capped a lifetime of awards by winning the Nobel for work he’s done over a long career as a physician-scientist. The work is all related to the method by which cells perceive how much oxygen their environment contains and then respond to that perception. Given that oxygen is fundamental to virtually all life and all cells, so, too, is understanding how cells become aware of oxygen.

“Scientists often toss around the phrase ‘a textbook discovery,’ ” says Nobel Prize committee member Randall Johnson, professor of molecular physiology and pathology at the University of Cambridge. “This is essentially a textbook discovery…. This is something basic biology students will be learning about when they study, at age twelve or thirteen or younger, and learn the fundamental ways cells work.”

Kaelin has advanced understanding of a basic life process. He got there by taking small steps, by doing one thing at a time. By, as he likes to say, solving puzzles.

“THE PUZZLE THAT BROUGHT ME TO STOCKHOLM,” Kaelin says, “was ‘What is the function of the VHL gene, and why do losses of the VHL gene cause these particular tumors that have these curious clinical features?’ ” That’s a mouthful, but in essence Kaelin helped figure out how a particular gene turns on and off the ability of tumors to create new blood vessels and otherwise behave like cells that want to increase their access to oxygen.

He can explain it better, but before he does that, take a look around. Despite the wall of awards, medals, and diplomas (the Nobel is still in a little box that he will open up to show, if you ask), Kaelin’s office will not make you think of science. It will not make you think of medicine, either. It’s just an office, with a big corner desk and a monitor. Shelves full of binders and reference books, pictures on the walls, file cabinets. He could be a middle manager.

Kaelin was admitted to Duke and MIT. His father, a Duke alumnus, said, "If you go to MIT, you'll pay your tuition, and if you go to Duke, I'll pay your tuition."

Dana-Farber Cancer Institute

In fact, in some ways he is. He works with postdocs in his lab to design and run experiments. “Unfortunately, I stopped doing experiments at the bench many years ago,” he says. He now leads the fifteen or so postdocs in his lab, thinking through experiments, helping them solve problems.

This was itself one of those one-thing-at-a-time conscious decisions. To effectively inhabit his role as principal investigator of his lab and thus as mentor to his postdocs, he needed to focus. “I found that when I was doing experiments at the bench, I didn’t necessarily want to be distracted,” he says.

“And I realized that was not fair to my trainees, who were entrusting their training to me.” So, he stepped away from the bench itself and fully into his role as lead scientist.

“I can say I get almost as much satisfaction seeing someone else do the experiment if I had a role in guiding them.”

From a tiny group of chairs in his office, Kaelin speaks rapidly, sometimes looking off into the distance. Not thinking of something else: thinking of exactly what to say. That intensity increases when he explains the science behind his award. Starting as a postdoctoral fellow, Kaelin profited from the greater and greater understanding of the human genome. In the lab of David Livingston, Charles A. Dana Chair in human cancer genetics at DFCI, Kaelin worked on understanding a gene that, when lost or altered, causes a childhood eye tumor called retinoblastoma (RB). Genes contain instructions for making proteins, and Kaelin identified the minimal fragment of the RB protein that allowed it to suppress tumor growth.

He then identified proteins that bound to this fragment, including E2F, critical for cancer cell proliferation. That protein fit into a region of RB that seemed to function as a pocket. “They’re now called pocket proteins,” Livingston says, “thanks to Bill Kaelin.”

Kaelin remained at DFCI and started his own lab, and he chose as his focus von Hippel-Lindau disease, a genetic disease that causes tumors as a result of trouble in a tumor-suppressing gene called VHL. Kaelin noticed that VHL-related tumors seemed to have a large amount of new blood vessels: The tumors seemed to create blood vessels and stimulate red blood cell production, much like tissues do when they’re starved of oxygen. Kaelin suspected that meant VHL was somehow involved in cells’ fundamental method for sensing oxygen.

“I think I made a nonobvious conclusion that VHL gene had to play a critical role in oxygen sensing,” Kaelin says. “Therefore, if you could understand the biochemical functions of the VHL protein, that would be a good way to understand how cells adapt to changes in oxygen.” His lab did experiments with kidney cancer cells that proved that the VHL protein was required for oxygen sensing. Other researchers had identified a protein called HIF (hypoxia-inducible factor) known to regulate certain genes involved in hypoxia. Kaelin’s lab showed that if oxygen is present VHL binds directly to HIF and destroys it, preventing the new blood vessels and other responses to lack of oxygen.

Kaelin at rest near Boston's Charles River

David Binder/Contact Press Images

As he explains, Kaelin picks up a little blue model of the VHL protein, with the HIF region marked in yellow. He goes into detail about mapping the region of HIF recognized by the VHL protein, getting down to a small region of HIF called a peptide, and even down within this peptide to specific amino acids (the building blocks used to make proteins), including one particular amino acid in the peptide called proline. A chemical flag appears on this particular HIF proline when oxygen is present. This chemical flag includes an oxygen atom and can’t be made when oxygen is too low. “Now we knew in chemical detail what the oxygen-sensing mechanism was. We did some further corroborating experiments, but that was basically the eureka moment.”

He describes this model as “surprisingly simple and surprisingly elegant.” Elsewhere he has used a metaphor. Among the 20,000 or so genes for making proteins in your genome, several hundred are devoted to helping you respond to low-oxygen environments. He posits those several hundred genes as an orchestra, and HIF is the conductor, telling them to play when oxygen is low. When oxygen is present, HIF has the little flag described, and VHL destroys HIF, but when oxygen is missing there’s no chemical flag, and HIF is left alone, raises its baton, and a professor who promised him that the the low-oxygen orchestra plays its tune. When there’s trouble in the VHL gene, the orchestra plays even when oxygen is present, and you get those vessel-filled tumors. More important, by understanding that flag and where it fits, we now understand how cells sense oxygen in the most foundational way.

“I’M SURE I WAS THE KIND OF STUDENT MOST PROFESSORS SORT OF HATED. IT WAS A GAME TO ME: I JUST WANTED TO SEE IF I COULD GET THE HIGHEST GRADE AND PARLAY THAT INTO ADMISSION INTO MEDICAL SCHOOL.”

ONCE HE’S COMMUNICATED this startlingly understandable lesson in biochemistry, Kaelin sits back in his chair. His attention in explaining this work has been almost palpable. That focus—that intensity—did not come to him, he says, perhaps until medical school. Always smart, always interested in school, he liked math and science better than the humanities. “I liked things that were objectifiable. I liked things where you got the right answer or the wrong answer.” He was intrigued by nature and as a child had the usual chemistry sets and microscopes (he donated his childhood microscope to the Nobel museum, along with his doctor bag), but he describes himself as an indifferent student, even at Duke.

“I’m sure I was the kind of student most professors sort of hated. It was a game to me: I just wanted to see if I could get the highest grade and parlay that into admission into medical school.”

He cites one of his best memories as being a member of “a fairly infamous frat, Beta Phi Zeta, affectionally or otherwise known as the Bozos.” People expect someone as intellectually powerful as he to have been a student aesthete, a New Yorker magazine’s Eustace Tilley of a college student. But “I was more of the study hard, play hard mindset,” he says. “I wasn’t going to be sipping tea and reading Virginia Woolf in my spare time. I needed some down time.” He describes the Bozos, suspended in 1982 and ultimately disbanded, as a place where he could be utterly relaxed; his brother, Michael Kaelin ’81, J.D. ’84, describes it as being like home, like a family. With the Bozos he was the hard-partying friend.

Before his senior year, Kaelin took an independent study in a Duke lab, with a professor who promised him that the previous seven students who had worked on the research had all got into medical school. “I thought I had the golden ticket,” Kaelin says. The research turned out to be complex, the mentorship lacking, and the study itself, a visiting professor eventually told Kaelin, misguided. The result was a C-minus, which Kaelin likens to “a wooden stake driven through your heart” if medical school is your goal.

An assessment came, too. “He actually wrote: ‘Mr. Kaelin appears to be a bright young man whose future lies outside the laboratory.’ So that was my introduction to laboratory science.” The bright young man ended up graduating summa cum laude—and staying at Duke for medical school.

FOR THE SCIENTIST IN KAELIN, things improved there. For his third-year research project, he latched onto Randy Jirtle, then-assistant professor of radiation oncology. Instead of choosing a full professor with the power to help him in his career, Kaelin chose a project and a professor that interested him. Jirtle was working on tumor blood flow, and that intrigued Kaelin. The therapeutic aspect of Jirtle’s work addressed chemotherapy: Tumors with low blood flow aren’t reached well by chemotherapy drugs, and they’re also resistant to radiation. Jirtle was looking for ways to increase flow to tumors, making therapy more helpful. This was the beginning of Kaelin’s interest in tumors and blood flow, and in the way cells respond to the oxygen in their environment.

What Jirtle remembers about Kaelin is his creativity. They were working with the standard drugs of the day to affect blood flow, until one day Kaelin, noticing that his grandfather had been put on different drugs to alter blood flow, suggested they experiment with those. The new drugs worked well, and Kaelin and Jirtle published two papers as a result. “And he was the one who came up with the idea,” Jirtle says. “I had not heard of these compounds at that time.”

Along with that whatever-works thinking, Kaelin was “unbelievably hard-working,” Jirtle says. “He just never stopped.” But what Jirtle remembers above all is Kaelin’s choosing Jirtle to work with based not on what Jirtle could do for Kaelin’s career but on shared interest in the science. “Bill seemed to pick projects he wanted to work on because he was truly interested,” he says. “And I think that’s the only way you can truly succeed in science, is to work on a project that you love.”

KAELIN AGREES. “Even by the time I was a resident,” he says, “I knew there was something special about these VHL-associated tumors.”

He became chief resident at Johns Hopkins medical center, which meant he had a gaggle of residents to keep in line, he says, “and there are two ways that chief residents establish they are the alpha dog.” One is keeping available knowledge of rare diseases. “So if someone steps out of line on rounds you start asking questions about Von Hippel-Lindau disease,” and they’d back off. The other thing is differential diagnoses: lists of different diseases that can cause a particular symptom. “It turns out there are a lot of causes of excess red blood cell production,” including Von Hippel-Lindau disease, which again popped up. Lots of angiogenesis and lots of red blood cells both indicated connection with oxygen. “So again, just how my clinical training as well as my training with Randy set the stage. It was just fortunate.”

As a resident at Johns Hopkins, he loved the challenge of explaining what was causing a set of symptoms. But “there are a lot of puzzles that are interesting the first or second time you see them, but not as interesting the fiftieth time.” He noticed that even more when he came to DFCI as a fellow to learn about cancer as a physician-scientist. At a place so specialized, most of the diagnoses were done long before patients arrived. “And that’s the puzzle I used to like to solve.” Fortunately, at the same time, revolutionary advances in molecular biology were revolutionizing the study of human disease.

It was time for a decision. “I never wanted people to say, ‘He’s a good scientist for a physician,’ ” he says. “There were enough scientists who were B’s that if I were just going to be a B scientist, I should try to be an A clinician.” Things had gone well for him in Livingston’s lab; Livingston recalls Kaelin facing one of the RB1 gene questions, which “he managed to crack open with a precision that I hadn’t seen quite so ably practiced before,” Livingston says. “I said to myself, ‘This fellow is on a track to success that is pretty powerful.’ ” Kaelin chose science. He no longer even has a license to see patients.

“THE SATISFACTION OF SOLVING A REALLY INTERESTING PUZZLE, OR SERIES OF PUZZLES, ALONG THE WAY—IT SEEMED TO ME THAT WAS THE PRIZE.”

LIVINGSTON AND KAELIN ARE FRIENDS as well as colleagues now, and Livingston brings up a central challenge that Kaelin faced not long ago. Kaelin met his wife, Carolyn, at Johns Hopkins. She was a breast cancer surgeon at DFCI until she herself got breast cancer in 2003. She recovered, but died in 2015 of an unrelated cancer. He mentions her in most interviews, talking about their lifelong partnership and suggesting that wherever she is, she’s happy for him now.

“I watched him come to work every day,” Livingston says, “do the most he possibly could physically to help his wife. I watched him keep track of his work here, the same as he always had, and he was the bulwark of that family.” The personal tragedy did not affect his work; neither did he take his work home.

Kaelin’s daughter, Kathryn, now studying for her Ph.D. in criminology at the University of Oxford, remembers that separation. “It was pretty remarkable,” she says. “The sense that he was so present for us. There was actually an amazing way in which his professional demeanor and sensibilities didn’t much filter into the house.” Certainly that intensity was always on display: “I think my friends from childhood would have described him as intimidating,” she says, laughing. But when the workday was done, when he was home being a dad, he was a dad. Both Kathryn and her brother are pursuing advanced degrees in the liberal arts, so Kaelin was out of his league, but he made them music playlists and shared movies. They traveled to ski, to the beach, to Long Island to visit family, “dragnetting for little critters, body surfing,” she says. “My dad becomes very alive in those moments, getting away from it all in childhood wonder.”

That closeness brought honest conversation. “My daughter asked me an interesting question, which was, would I have been disappointed if I never won the Nobel Prize,” Kaelin says. “And I think the answer was, after having made this discovery…a little. But I was perfectly content before having won the prize, and I hope I’ll be able, now that I’ve won the prize, to get back to my work.” He fears getting swept up in celebrity. He says the wall of diplomas and medals in his office is more for recruiting purposes than anything else—it impresses postdocs considering DFCI—and he says, and means, just what you’d expect.

Kaelin accepting his Nobel Prize

Nobelstiftelsen/The Nobel Foundation

“The satisfaction of solving a really interesting puzzle, or series of puzzles, along the way—it seemed to me that was the prize. To occasionally understand something that’s never been understood before, and it’s right there before you and to know that you’re the first person who actually understands how something works is actually a wonderful feeling.”

A feeling he wishes he could share with young scientists. He fights in his writing and speaking for the importance of doing basic science rather than science with an expected end result. In that uncertainty, scientists, he fears, stress too much the rarity of success. “It doesn’t happen every day, it doesn’t even happen every year, but when it happens it’s just a wonderful, wonderful feeling.” He did some good experiments of which he’s proud, and he knows he’s made a contribution, but as for which contribution wins a prize? “After that,” he says, “it becomes a bit of a beauty contest.”

“Because the fact of the matter is, this is why it’s helpful to be a physician-scientist.” Pure research is great, and that’s what he practices. But the road to his research came through the clinic, and he’s always hopeful that his research will lead to clinical methods and treatments that will save lives. Therapies for kidney cancer based on his discoveries are already making their way through testing. That’s wonderful, but it’s nothing like an endpoint.

“If we had cured kidney cancer, and people didn’t have to worry about it anymore, that would be a prize.” When the waiting rooms at Dana-Farber are empty, he says, “then we’ll have a big celebration and give ourselves a medal. But we’re not quite there yet.” He’s just not focused on prizes. “There’s just too much work to do.” He saw how easy it would be to be swept into the celebrity of being a Nobelist, but so far—as his brother says, he answers his e-mails and visits his old elementary school—he’s managed to treat life after the prize the way he treats everything.

He looks at the challenge, he thinks it through, and he focuses. One thing at a time.