On Oct. 7, at about 3:45 a.m., Gregg L. Semenza slept through a life-altering phone call.
“I was in a deep sleep,” he says.
The phone rang again a few minutes later. “I was a little quicker the second time around,” he says. “If you’re going to get woken up in the middle of the night, it’s good to have that call come from Stockholm.”
Semenza, a physician-scientist at Johns Hopkins University, had won the Nobel Prize in Physiology or Medicine. Along with colleagues William G. Kaelin Jr. of the Dana-Farber Cancer Institute and Sir Peter J. Ratcliffe of Oxford University and the Francis Crick Institute, Semenza had unraveled a fine-tuned mechanism of how cells sense oxygen levels.
When oxygen levels are normal, cellular enzymes called prolyl hydroxylases use that available O2 to hydroxylate a protein called HIF-1α. These hydroxyl groups act as a signal that spurs the cells’ machinery, including a protein called VHL, to whisk HIF-1α off to be destroyed. But when oxygen levels are low, such as at high altitudes or when tumors are growing nearby and using up everything around them as fuel, HIF-1α doesn’t get hydroxylated.
Instead, the protein moves into the nucleus, pairs up with another protein, and turns on a gene that spurs the production of erythropoietin, a hormone that triggers red blood cell formation. Cancers use this process to get as much oxygen as they can, and it makes HIF-1, and all the proteins it interacts with, possible targets for cancer drug development. Indeed, there are nearly 2,500 patents in late-stage clinical trials of small molecules targeting HIF-1 and prolyl hydroxlases.
It’s been a year of highs and lows for Semenza. During a press conference on Oct. 7, he revealed that earlier in the year, he had fallen down the stairs and broken his neck. Then came the Nobel. C&EN chatted with Semenza on the day he found out about the prize. This interview has been edited for length and clarity.
When you got into the office the morning of the Nobel announcement, what was the mood like?
Everybody was ecstatic. They had champagne and we had a toast. It was fun for me to see how excited they were.
Why is research on oxygen sensing so fundamentally important?
Oxygen is the ultimate small molecule. It’s the basis of life of on Earth. You can look at oxygen as the organizing principle of evolution, from single-celled organisms to blue-green algae and photosynthesis to the respiratory chain to the development of metazoans and progressively larger body mass. This is associated with the evolution of progressively more complex systems of oxygen delivery. Also, oxygen is critical to chemistry because it’s required to make all the adenosine triphosphate that fuels so many biochemical reactions.
What drew you to this field of research?
It really started with studying the erythropoietin gene. I was interested in studying its tissue-specific regulation. After we worked that out, I was interested in this other major aspect of its regulation—regulation by oxygen.
You were toiling away at this for a while. At what point do you think people realized this mechanism was important?
Some people realized it a lot sooner than others. I have colleagues who are pulmonary physicians, and they deal with oxygen all the time, and they immediately recognized the potential importance. Whereas the basic molecular biology types, they had no perspective to appreciate the significance of the results. In terms of mainstream biology, it took quite a while.
Is oxygen sensing a possible drug target?
EPO (recombinant erythropoietin) was one of the first recombinant DNA blockbuster drugs. That was an important backdrop to our work. There are prolyl hydroxylase inhibitors that are in phase III trials for anemia and chronic kidney disease. There’s a drug that targets HIF-2 in kidney cancer that looks promising for cancer therapy.
Awards like the Nobel prize sometimes uphold the myth of the lone scientist toiling away to make breakthroughs. Tell us about your team and teamwork.
All science is a collaborative effort. I have all these hardworking postdocs and graduate and undergraduate students in the lab. Everybody works together as a team. I have a really fine group of people who work in the lab. My major criterion for picking people is that they’re really nice to work with because we spend a lot of time together.
And then of course, science is iterative. You publish something, and someone else builds on that, and the field moves forward.
So, you have two types of legacy: the papers you publish, because they’ll be there forever, and the people you train and the work that they do.
What’s changed the most in the years since you discovered what HIF does?
The power of the tools we used back then was so much less than it is now. For my PhD thesis, I sequenced 4 kilobases of DNA at the globin locus, and today you can do that in a day. It’s just been tremendous, the improvement in the power of the techniques that are available to do research.