Interview with Gregg Semenza on 6 December 2019 during the Nobel Week in Stockholm, Sweden.

What was your childhood like?

Gregg Semenza: I have two brothers and two sisters, so we have a large family and especially when we were young of course that involved a lot of chaos, and we had a lot of freedom at that time. Children now seem to have very scripted lives and whereas we had a lot of freedom. Basically, we go out of the house in the morning, at say in the summertime and you come back in the evening for dinner and nobody is expecting to see you in between so, y it was a lot of fun to grow in that kind of an environment.

Was there a particular teacher that inspired you?

Gregg Semenza: For my carrier inspiration, I was very fortunate to have a high school biology teacher, a Dr Rose Nelson and she was a PhD, so she had done research, she had done post-doctoral training and she taught us biology, not as a series of sort of facts but she would teach us about discoveries and about scientist who made discoveries and sort of the excitement of learning something new in science. And that really excited me. She also recommended to me a summer programme at a research institute where I was able to experience research firsthand. All those experiences really, really excited me and developed a passion in science that I have had ever since, so I really owe that to her. It’s one of my regrets that she passed away before this time because she was a very, very positive person and very abluent, joyful, she always had a beatific smile on her face and she would be teaching us something and she would say,:“Now, I want you to remember that when you win your Nobel Prize that you learned that here”. And she said this, not to me, but to the class and she would say this as a statement of fact, so I don’t know how she knew, but she was really a remarkable teacher.

Why did you become interested in genetics?

Gregg Semenza: I guess the idea of hereditary passing down of traits and how this was determined by sequences within the DNA. It’s kind of a very amazing thing to go from these molecules to traits of living organisms and that really interested me. I was first interested in genetics, sort of basic genetics and thought I would do basic genetic research, but while I was in college, a family that we knew had a child born with Down syndrome and I became interested in medical genetics, and decided that I would try to get training both as a MD and a PhD, so that I could do both genetics research and medical genetics as a clinical specialty.

How do you deal with failure?

Gregg Semenza: When I was a college student I worked in a lab in Boston and the leader of the lab, he would always say: “Search and research”, because that’s the nature of science. There are always obstacles to be overcome, experimentally, and that’s a challenge and if that isn’t something that is enjoyable to you then probably science is not a good line of work because we are constantly faced with those kinds of obstacles and challenges. And part of the fun of the work is using our creativity to come up with solutions to those kinds of problems when they arise.

Persistence is a very critical attribute, absolutely, and then the other part of it that is very helpful, is to have colleagues who take orthogonal approaches to the science. They may look at the science in a slightly different way and may provide an avenue for circumventing various obstacles. When we were trying to isolate the DNA sequences that coded for the subunits of hypoxia-inducible factors we took one approach because we thought that there was only one protein that was involved, and we took an approach that involved screening human DNA sequences in bacteriophage and we screened millions and millions of these clones, and we got negative results. As a leader of the research project, it’s sort of my role to decide what to do. We could continue doing what we were doing – that didn’t seem like a very good idea. We could give up and let someone else do it – that didn’t seem like a very good idea either. Or we could take a completely different approach which was rather than a molecular genetic approach to take a biochemical approach and try to purify the protein through biochemistry. And this was not exactly our foretake, we owned none of the equipment that was required for purify proteins, did not really have the expertise to do that, but fortunately, across the street at Johns Hopkins was the lab of Tom Kelly and his lab was one of the first labs to purify a protein based on its binding to DNA. With the assistance of his lab, we were able to do that, to purify the protein from a hundred leaders of cells, growing in culture and to get just enough of the protein that we could obtain some protein sequence and then use that protein sequence to identify the DNA sequences of what turned out to be the two subunits of the protein. So, in fact the approach that we had been taking would never have worked because that approach only works if the protein has the single subunit and because our protein turned out to have two different subunits only through the purification, the biochemical purification, would we have been able to succeed.

How important in freedom in science?

Gregg Semenza: The freedom and the creativity, these are the really fun parts of the job that no one tells us how to do our work and as long as we are successful, we are left alone and we can do our thing. To have that freedom to, not only with regards to problem solving, but even more fundamentally, what questions do we ask, what are the really important questions that we would like to answer. That’s left entirely up to us and obviously that changes over time. So, we started with more basic, fundamental questions and then over time have shifted to more applied applications as the project has evolved. That’s been very satisfying over the course of thirty years, to be able to connect the dots to very molecular fundamental questions: how does the cell sense the oxygen concentration and respond to changes all the way to … can we develop new treatments for anaemia, for cancer, for cardiovascular disease. And as someone trained both in research and medicine, for me, I’ve always thought it’s my role to bridge between the basic science and the clinical translation and it has been very satisfying to reach that point where we see these translations occurring now as a result of these basic discoveries that were made 25 years ago.

Have you ever doubted yourself?

Gregg Semenza: That’s a good question. I guess I doubt myself often. I often doubt, you know, am I taking the best approach? Am I running the lab most efficiently? Am I mentoring my students well enough, could I be doing a better job with that? I guess I have those kind of doubts or self-criticism on a fairy regular basis.

How did you discover you had been awarded the Nobel Prize?

Gregg Semenza: I think the word is dumbfounded. It was of course in the US and it was in the middle of the night and I was sleeping very soundly, and the phone rang and when I finally was awoken out of the sleep and got to the phone in the hallway it had stopped ringing. I was not even really awake yet and I figured, well, maybe this is somebodies’ idea of a bad joke, because I did know what day it was. So I went back to sleep and actually quite a while later the phone rang again, I said: “Perhaps I‘d better be quicker this time”. So I got to the phone and Thomas Perlmann apologized for waking me up and then gave the good news and I was sort of on the phone and my jaw just dropped and I didn’t really … words weren’t coming out. Of course, my wife was there, and she could hear what was being said on the phone and her jaw dropped and she couldn’t say much either, we were just kind of mute. It was a very one-sided conversation.

Can you explain your Nobel Prize-awarded discovery?

Gregg Semenza: Everybody appreciates the importance of oxygen. You just have to hold your breath and you’ll start feeling uncomfortable very soon, because you have a hundred trillion cells in your body, and they all need oxygen on a continuous basis. Principally to make energy, which allows us to … for this complex organism to function. The body uses glucose and oxygen in order to generate energy. By the same token, oxygen at too higher levels causes damage to cells, so there has to be a very tight coordination between supply and demand. The amount of oxygen that each cell requires, has to be matched by the delivery of oxygen which is of course carried by red blood cells through the blood vessels to each cell. There is a beautiful physiological system that maintains the balance between consumption and delivery of oxygen in every one of the hundred trillion cells in your body under normal healthy conditions and if that balance is disturbed by many common diseases, including cardiovascular diseases and cancer.

What practical applications does your work have?

Gregg Semenza: The first translation of the discovery of this system to the clinic is the development of new drugs for the treatment of anemia. We started by studying the hormone that controls red blood cell production, called erythropoietin, or EPO. Patients who have a chronic kidney disease, their kidneys stop making EPO and they become anemic. The discovery of EPO was a revolution because it enabled the patients to receive a recombinant EPO protein as an injection, to stimulate red blood cell production. Of course it’s a recombinant protein and it has to be injected and now there are in development drugs that induce the activity of the factors that we identified, the hypoxia-inducible factors that control EPO production, and these drugs can be given as pills by mouth. The treatment of anemia can be made much more convenient for patients, both with kidney disease and other causes of anemia. And there are four different drugs that are all in advanced clinical trials now, over 25,000 patients are being studied in these trials and one of the drugs has already been proved for use in China and Japan and will probably be approved in the US and in Europe within the next year, if everything goes well. That will be the first application of our discoveries to the clinic.

Another area in that context, the hypoxia-inducible factors are, as I said, play an important role in physiology and when they are not produced in sufficient amounts, we want to stimulate that. But in cancer, the factors are produced at very high amounts because oxygen becomes very limiting in cancers because the cells grows so rapidly that they basically outgrow their blood supply and become very hypoxic. And this can lead in fact to the cancer cells dying because they don’t have enough oxygen, which, of course, you can say what is bad about that, that’s what we like cancer cells to do, to die, but of course, the cells that are very far away die, but those that are closer, they can survive but their exposure to low oxygen changes them, makes them more invasive and metastatic, more difficult to kill. We believe these cells are really cells that are very dangerous in terms of the risks of the cancer spreading through the body and resisting therapy and pretty much all of the cancer therapies are targeted to cells around blood vessels that have lots of oxygen that are rapidly dividing, whereas the hypoxic cells are not really targeted by any therapy and we think that if we can inhibit the activity of the hypoxic inducible factors in the hypoxic area of the cancers, that will complement the existing therapies and lead to a better outcome for patients with advanced cancer. There is a HIF inhibitor that is now on clinical trials for kidney cancer, so, we’ve already started down that road as well. When I say we I mean the scientific community, the pharmaceutical industry, recognizing the importance of this area for targeting in different diseases.

Is there a good balance between basic and applied research in medicine today?

Gregg Semenza: Most applied research comes from a foundation of basic research and what I mean by that is that the basic studies are all often done just trying to understand the system and the properties of that system without directly saying, we want to target this particular disease, because that tends to be less effective than to say, let’s just learn about this system and by doing so, over time it will become apparent how we might target the system therapeutically. That’s how we started, just with very basic fundamental research, and it’s lead now, I think, to many applications. Being apparent that that again will take time to unfold but we’ll hopefully resolve in new treatments for a number of different diseases.

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