A Boston doctor who was once advised that his “future lies outside the laboratory” was awarded the scientific community’s highest award for medical research Monday, joining two other physician-scientists in receiving the 2019 Nobel Prize for their work identifying how cells adapt to changes in oxygen levels.
Dr. William G. Kaelin Jr., a researcher at the Dana-Farber Cancer Institute, shares the prize for physiology or medicine with Sir Peter J. Ratcliffe and Dr. Gregg L. Semenza.
The three were honored for elucidating the molecular machinery that regulates how cells respond to varying levels of oxygen — a process that, when it goes awry, contributes to several illnesses, including anemia and cancer.
Kaelin, 61, said he went to bed Sunday night knowing, as every scientist does, that the Nobel Prize in medicine would be announced at 5 the next morning.
“I’m embarrassed to say I allowed myself to dream one day it could happen,” Kaelin said in an interview with the Globe Monday morning.
As Sunday became Monday, however, he dreamed that he had woken up at 5:30 a.m. and the call hadn’t come in. Then he woke up for real and saw that it was only 1:30 a.m.; he went back to sleep, only to be awakened from a deep slumber at 5 a.m. when a distinguished voice calling from across the ocean delivered the happy news.
Had this honor come a few years earlier, it might have been too painful to enjoy, Kaelin said, because he had often mused with his wife about how they would celebrate a Nobel win. Dr. Carolyn M. Kaelin, also a cancer researcher, died of cancer in 2015 at age 54. If the award had come within a couple of years after her death, “I’d be too crushed,” he said.
“I’d like to think she’d be smiling down on me. At least her children are able to celebrate with me,” he said. Their daughter, Kathryn, is pursuing a doctorate in law at Oxford University and their son, Tripp, is working on a master’s in education at Harvard.
Kaelin recalled that a medical school professor once predicted that his “future lies outside the laboratory.”
That was not intended as a compliment, he remarked. Still, Kaelin ended up back in the laboratory because he realized, after caring for cancer patients, that the disease could not be conquered until it was better understood.
Kaelin, Ratcliffe, and Semenza were also honored for their work by the Lasker Foundation in 2016.
In addition to running his own laboratory at Dana-Farber, Kaelin is a Harvard Medical School professor and senior physician at Brigham and Women’s Hospital.
Ratcliffe is a professor at the University of Oxford and director of clinical research at London’s Francis Crick Institute. Semenza, a professor at Johns Hopkins University, directs the Vascular Research Program at the Johns Hopkins Institute for Cell Engineering.
“It was actually surprisingly simple,’’ Kaelin said of the research findings during a press conference at Dana-Farber Monday. “If God was designing a system, this is the system he would have designed.”
Kaelin said the three never directly collaborated on the research but followed their own investigative paths, read each other’s scientific papers, and sometimes discussed their findings at bars while attending scientific gatherings.
“We set out to solve a puzzle we thought might be interesting and we hoped it might become important,” he said.
Cells lower or raise their oxygen levels as needed. For example, when a person exercises or travels to high altitudes, the cells pump up their oxygen content. But no one understood how the cells sense when oxygen gets too high or too low.
As Kaelin explained it, hundreds of genes are involved in the process, like instruments in an orchestra. The “conductor” is a protein known as HIF, which tells the orchestra to play — directing the genes that determine whether the cell will add or reduce oxygen. The mystery was what controlled HIF.
Kaelin’s contribution was finding that a protein called VHL is involved in the cell’s response to low oxygen levels, and, with Ratcliffe, showing that VHL destroys HIF (the “conductor”) when a certain chemical flag gets attached to HIF.
“There are many, many diseases, including anemia, heart attack, stroke cancer, etcetera,” Kaelin said, “where tissues are not getting enough oxygen.” Understanding the molecular circuit that allows cells to sense oxygen and respond allows scientists to identify ways to intervene when that process goes awry.
Drugs that activate HIF, so that more red blood cells will be produced, have been approved in China and Japan to treat people with anemia and are undergoing studies in the United States.
Conversely, certain cancers can’t survive without HIF, Kaelin said. The cancers co-opt the oxygen-regulating pathway to enable them to grow as solid tumors. That has led to work finding drugs that will “de-activate HIF or at least certain members of the ‘orchestra,’” Kaelin said.
It’s noteworthy, Kaelin said, that research in fighting cancer yielded a treatment for anemia. Great advances often emerge from “curiosity-driven” work that didn’t have a predetermined destination, he said. Too often, he said, research funders try to get scientists to put blinders on. “They tell scientists, ‘We’ll only fund you if you tell us how the work will impact patients. You have to promise us this will have some predictable outcome,’” he said.
But science follows unpredictable paths. The other two Nobel winners, Ratcliffe and Semenza, were studying a different question at first.
“The real magic happened when the two lines of investigation collided,” Kaelin said. “Things dramatically accelerated in 1999 when we realized we were studying the yin and yang of the same mechanism.”
The Karolinska Institute, which awards the Nobel Prizes, said in a statement the trio should share equally the $918,000 cash award.
Kaelin was born in New York in 1957 and earned his medical degree from Duke University. He did his specialist training in internal medicine and oncology at Johns Hopkins University in Baltimore and at the Dana-Farber Cancer Institute and then established his own research lab at the Dana-Farber.