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A Knight's Discovery of Oxygen Sensing System Results in Nobel Prize

2019; Wolters Kluwer; Volume: 41; Issue: 22 Linguagem: Inglês

10.1097/01.cot.0000615164.16409.87

1548-4688

Valerie Neff Newitt,

Renal function and acid-base balance

Sir Peter J. Ratcliffe, MD: Sir Peter J. Ratcliffe, MD“Sir Peter J. Ratcliffe, MD, Nobel Laureate” has an impressive ring to it. But the fact that this British knight is one of three joint recipients of the 2019 Nobel Prize in Physiology or Medicine does little to sway his course. A member of the Oxford Branch of the Ludwig Institute for Cancer Research in England, Sir Peter shows up daily with one thing on his mind—scientific discovery. During an autumn telephone interview, he summarized the complex research that has earned him the Nobel honor. “I think it's always possible to be concise,” he said with chivalrous willingness to provide an explanation that even a lay person might understand. “I'd draw out two main aspects of discovery,” he began. “One, we found out that there was a system in all cells in the human body that senses levels of oxygen. Previously it was not thought that a system was present in all cells; we successfully showed there is. And the second thing we found out was how it worked. Oxygen sensing, in a lay analogy, is like a thermostat that senses heat. This system senses the level of oxygen and it causes the cells to act accordingly to regulate metabolism, or to restrict use of oxygen, or to do things that might bring more oxygen to them, or to move to a place where there might be more oxygen. All sorts of things. Quite simply, the discovery and elucidation of an oxygen sensing system is the sum of my work. In the Q&A that follows, Sir Peter graciously explained more about his work, which is already beginning to impact clinical treatment, named his favorite food, and joked about the advantages of being a knight. But in the end, he made clear that it is science that fans his intellectual passion and sets the course of his life. On the Personal Side How, exactly, does one correctly address a knight who is also a doctor? Is it Sir Peter? Well it's really just plain Peter, as far as I'm concerned. But in relation to the title of sir, that is the one you should use—Sir Peter. Anything else is an insult to Her Majesty. (Chuckle). That's the strict position. I don't think Her Majesty will be too concerned, actually, and I think she will forgive whatever you call me. How does being dubbed a knight change your life? It doesn't change it very much. I probably shouldn't say that in front of Her Majesty, but the truth is it doesn't. It might have a certain cachet when going for opera tickets, or getting a table at a restaurant, or maybe even getting an upgrade on British Airways. But I'm not even too sure about that. (Laughter.) So mainly my life is just the same. Where are you from originally and what was your childhood like? I'm from Carnforth, Lancashire, a small railway junction town of maybe 4,000 people. It's a rural farming area. I had a delightful childhood playing around in trees and quarries. Possibly there was some hint of a scientist in the making, because I really enjoyed making explosions. I enjoyed inventing catapults that would enable stones to be thrown for longer distances, playing around with fires, trying to melt lead. All of these important scientific issues were part of my early childhood. I was just on-and-off studious. To be honest, I don't know how I got to be in a position to be important enough for an interview.Prof. Alain F. Carpentier, Gregg L. Semenza, MD, PhD, William G. Kaelin Jr., MD, and Sir Peter J. Ratcliffe, MD: Receiving the Grand Prix of the Institute de France from Prof. Alain F. Carpentier, far left, President of the Scientific Council of the Lefloulon-Delalande Foundation, are the joint winners of the 2019 Nobel Prize in Physiology or Medicine, (second from left) Gregg L. Semenza, MD, PhD, William G. Kaelin Jr., MD, and Sir Peter J. Ratcliffe, MD.What directed you into science and medicine? Well, as you probably recognize from what I've just said, I didn't initially intend to study medicine; I intended to study chemistry because I enjoyed chemical reactions. I can remember making the decision to study medicine rather clearly. I was in the chemistry laboratory at Lancaster Royal Grammar and the head master came into the classroom. He was a rather glacial figure who wore a gown. He said, “Ratcliffe, could I have a word with you?” And, of course, I said “Yes, sir.” I followed him out of the room. And at that point he said, “Ratcliffe, I think you should study medicine.” And I again said, “Yes, sir.” And we struck out the word “chemistry” on the university application form and wrote in the word “medicine.” Just like that the decision was made. To this day, I don't really know whether he felt I would be a good doctor or a bad chemist. Are you married? Do you have children? Yes, I'm married with four very nice adult children. My elder daughter is a doctor; she's an anesthetist like her mother. But they haven't really followed in my science research footsteps. Do you have any hobbies or some way that you relieve the pressure of your work? No! That's certainly is cut-and-dried. So you carry work with you always—is it always in your mind? I suppose so, because in many ways it is a pleasure. Well, not always a pleasure. Many things in the lab don't work. But when they do, it's satisfying. The work carries its own variety. I can quite literally come into the laboratory in the morning and say, “I had an idea last night and I'd like someone to pursue it if you don't mind.” And almost certainly someone will pursue it. This freedom to delve into whatever I want is something that few people have. Even the environment of the laboratory has its own balance. I work with a lot of young, multicultural people, from many other countries. So, in all sorts of ways, my work intrinsically carries a variety that many people have to seek through other activities. So what do you eat after long hours in the lab? What do I eat? You want to know what I eat? Yes. (Laughter.) What does a genius eat? Salted crisps (potato chips). As a Brit, how many cups of tea do you drink in a day? It's mainly coffee, probably about six cups, maybe more, and a bit of tea. My secretary will say, “Will you have a cup of coffee?” And of course I say “yes” after a moment of trying to resist. I probably drink too much. On Winning the Nobel Prize Let's talk about that moment when you learned you won the Nobel Prize. How did that happen? It was on a Monday morning during a group laboratory meeting. My secretary burst in through the door looking a little bit shaken, and she said, “There's a man on the phone from Stockholm.” I answered the phone, and the voice on the other end said his name and that he was phoning from Stockholm, Sweden, where the Nobel Assembly, which he chaired, was convened at the Karolinska Institute. Of course. I have heard all sorts of stories of people being hoaxed, so I wanted to be sure this was real. I was constantly trying to detect some breakdown in the Scandinavian accent. But there wasn't one. And then the caller eventually got to the point. He said we'd won the Nobel Prize. Then we saw on the Web that indeed they'd made the announcement in Stockholm, so we knew it was true. During the week that followed, we got a thousand or more congratulatory notes. So that really proved the case that we really had won it. Will you be going to Stockholm to accept the prize? Oh yes, in December, we must. My understanding is that it will be rather a full week. So I'll be taking dancing classes, speaking classes, all sorts of things to make sure I do the right thing at the right time. On the Work Itself When you were working through the years, was it in concert with your fellow winners, William G. Kaelin, Jr., MD, and Gregg L. Semenza, MD, PhD? Or were you all working independently on hypotheses that mutually advanced each other? We were not working together. We all have independent groups. I think we take some pride in being friends, colleagues, and competitors. And sometimes, we were more of one than the other. Was there a specific breakthrough moment when you could see your work really coming together? Looking back, I think there were about five or six really substantial discoveries. Each one was incomplete and, interestingly, it was often pointed out by editors and journalists that this story was incomplete. But you know, most scientific discoveries are incomplete. The consequences and the implications only become evident after a discovery. It's very important to record accurate but still incomplete discovery. So, after our fifth discovery, we really did have “it.” We had the enzymes that consumed oxygen. That clearly was an answer. That's when it all came together for sure. Can you list those five discoveries in the order they happened? Indeed, I can. Here it goes. First, we found a DNA sequence—a piece of the genome close to the erythropoietin (EPO) gene, which could confer regulation by oxygen on an artificial gene. That was the starting point. And that was the first step in the journey from the EPO gene outward to oxygen sensing. That was number one. And rather nicely, it was very clear. Second, using gene transfer, we put that sequence into all sorts of cells that don't make EPO. And we watched its operation. To our great surprise, it worked in all the other cells. The implication was that the system was not just making erythropoietin in the kidney; instead, it was doing so in all of the cells in the body, and likely doing lots of other things, too. That is why we can now talk about this in relation to cancer and lots of other disease. That was a big transition. Third, we had to find another gene with the target of what Gregg Semenza had identified as hypoxia-inducible factor, or HIF. We had to find another gene control region that binds to that. And we found phosphoglycerate kinase. That's a metabolic enzyme—a glycolytic sugar-splitting enzyme—that is a classic feature of cancer. Next, we made the connection between HIF and VHL [von Hippel-Lindau disease gene]. The connection to hypoxia signaling had been made by Bill Kaelin [MD] and Rick Klausner [MD]. We made the mechanistic connection to HIF itself. We could show that VHL, the tumor suppressor that's mutated in kidney cancer, actually physically touches HIF and is necessary for its regulation by oxygen. That was another eureka moment. Fifth, this raised the question of what controlled that association. It turned out to be prolyl hydroxylation, just the addition of an oxygen atom by an enzyme to the amino acid residue proline. That was yet another eureka moment. And finally, we tested a group of enzymes (identified by chemist Christopher Schofield) known to do this hydroxylation reaction. One of them turned out to be the correct one. So now we've got the enzyme, which is the oxygen sensor. And that's the main story in a nutshell. How does this relate to cancer? Well, broadly speaking, the relation to cancer is very tricky. Cancer, almost more than any other disease, is a perturbation of the way normal cells behave. However, in broad terms, cancer needs an oxygen supply to keep it going. Cancer entrains blood vessels and things to do that, just as do normal tissues. And again just as normal tissues are supported by HIF, cancer tissues are, at least to some extent, supported by this system as well. Can we draw the conclusion that, if an oxygen system could be cut off, it could potentially have impact on cancer treatment and patient survival? Yes, if you were able to turn the system off completely, it would be very difficult for large, massive cells to grow properly under those conditions. So that would be an anticancer effect for sure. Where does this work take you next? Well, we have really two things. First, there's quite a bit of value in finding an oxygen sensor, because of the relation of low oxygen to human disease. So I think it's reasonable to go looking for other sensors, and there is pretty clear evidence that there are some. That's one of our main programs now. Consider that, if you put your head in a gas oven, you're going to be in trouble in 2 minutes and you're going to be dead in 5 minutes. But this sensor system doesn't work on a 5-minute timeescale. The body has to adjust and get its oxygen deliveries correct on a timescale of seconds-to-minutes. But those important mechanisms are not yet discovered and properly understood. So we believe there must be a lot of other systems that in some way affect oxygen homeostasis. That's one side of our lab's work; it's a rather pure discovery program. Second, we want to know what the implications of this are for cancer, which as I've said, are extremely complicated. How long do you expect it to take for the discoveries you've made to make clinical impact? The first drugs resulting from our work are already on the market in China for the treatment of anemia. And we're expecting to hear the outcome of trials in Europe, the U.S., and Japan later this year or 2020 that will determine whether it's possible to treat the anemia of kidney disease safely. We already know it's effective; what is at issue is the long-term consequences of doing this. So that's the first off the blocks. There also are some anticancer treatments which are looking quite promising. They're in trial now. These compounds work to prevent the action of one particular type of HIF—HIF2. The two proteins have to dimerize—come together—to work; these compounds block that dimerization and they prevent HIF from working. Cancer needs at least some sort of oxygen circuitry to get by, to grow. So if you block it, then that can block the tumor growth. It's this particular isoform HIF2, which is highly expressed in the most common form of kidney cancer. That's one of the targets that people are attacking with this drug. Glioblastoma, also is very dependent on HIF2, is another target. Is there any message you would want to send directly to our readers about your work? Beware the complexity of cancer. We're very interested in the implications of enormous interconnected pathways for cancer. We think this is very important. When cancer makes a mutation, it makes a switch. Then all of these highly interconnected pathways are perturbed. We think that cancer having to learn to live with that unphysiological pathway switch is a fundamental issue that is restricting the early stages of cancer. Does this mean that if those cancer cells are adequately perturbed they may not be able to make the switch necessary to thrive? That's right. They die off. They don't cause cancer. It's really, really difficult to make a cancer and many of the cells that have this switch just don't get there. Sadly, a few of them accommodate the switch and those are the ones that pick up and cause trouble. It's fascinating. Thank you for the work that you've done and continue to do which will certainly benefit all of mankind. Well, that's very kind. But to be clear, it's mainly been a pleasure. Yes, it's mainly been a great pleasure in my life. Valerie Neff Newitt is a contributing writer.