Interview with the 2019 laureate in physiology or medicine Sir Peter J. Ratcliffe, 6 December 2019.

Did you always plan on studying medicine? 

Sir Peter J. Ratcliffe: I can remember the day of choosing medicine. The headmaster, rather austere figure, came into the chemistry classroom and said Ratcliffe, could I have a word? And I followed him out of the classroom. He said, Ratcliffe, I think you should study medicine. He wasn’t the sort of guy you challenged. So I said ‘yes, sir.’ That’s what we did. We struck out chemistry and wrote medicine on the university forms. That’s where I ended up in medicine. I’ve liked it, although we never quite knew whether he thought I would be a bad chemist, good chemist, or a bad doctor. And to be perfectly clear, I don’t think we know that now. 

What do you enjoy about medicine? 

Sir Peter J. Ratcliffe: I think medicine has so many facets. I’ve done several of them. I’ve worked in research in discovery science, as you know, that’s why I’m here today. But that wasn’t my medical part. I trained as a kidney specialist. I’ve done a lot of acute diagnostic medicine that’s quite fascinating, quite challenging. I enjoyed that bedside teaching of medical students. I think it’s the breadth of medicine that’s so fascinating. The science is quite a different way of life. I’ve had the great good fortune of being able to practice medicine and be a scientist. 

How do you deal with failures? 

Sir Peter J. Ratcliffe: We just carried on. People have asked me: ‘were there eureka moments in your work?’ There were several. They were not sheer brilliance. They were stumbling around and eventually recognising that something that had been actually almost obvious was there before you. I’m not talking about chemistry, physics, they’re quite different subjects, but biology is very complicated. You’re made by Darwin in evolution. You are not actually a logical way of doing what you do. You are fit for purpose. So it doesn’t help to be terribly clever, absolutely brilliant or terribly logical. You just have to do experiments and observe the results and draw your simple conclusions from those experiments. That’s what we do. 

Did anyone influence you? 

Sir Peter J. Ratcliffe: Someone who was very kind to me at the start of all this was Sir David Weatherall. I had a slightly unusual entry to this. I’m a physician. I trained as a physician and I had this idea to work on erythropoietin, which is a little bit unusual. That was very important because it’s a relatively small field. I needed an institute, an infrastructure which actually knew about molecular biology. David Weatherall and also John Bell, who had one of the labs in David’s institute, very kindly taught me the technology that was necessary for the molecular approach to erythropoietic regulation. They were very important people. 

The people that were helpful were those who built confidence. In some respects, a mentor is someone who might guide you to the right field or the right area. I didn’t think that’s very good because it almost certainly will guide you to feel this already occupied by others. They’re really helpful people, those that give you the confidence, but allow you the completely free choice. That was important to me, that people were kind to me in that way. 

What would you say to a young person going into science? 

Sir Peter J. Ratcliffe: I’ve had a terrific time in science and medicine, so I’d recommend it to anyone really. The accent is on finding your own question. You must do that. You have to acquire the technical knowledge, but the application is yours. You own your destiny. Do your own thing confidently. They’re often rather unreasonable people, you know that? Reasonable people don’t discover the North Pole. They don’t discover the South Pole. They don’t cross deserts, climb mountains, and they don’t discover, to a first approximation, things in science. Most of us scientists are in some way unreasonable people who don’t fit the mould. 

For the young people, it’s important to support them in their unreasonable behavior. Someone will always say, it’s not worth doing. It’s going to be done by other people. It can’t be done. All sorts of reasons for not doing research. It’s only the unreasonable people who really take it on. Since I have an experience in university management, I was head of department for a while. Heads of department have to know that often the most awkward people in their department are the most productive. 

How did you react to finding out you had been awarded the Nobel Prize?  

Sir Peter J. Ratcliffe: I was very careful. I’m a scientist. That’s why I’m here. We like to be sure of our facts. I was listening very carefully to make sure it really was Thomas Perlmann on the telephone before I was completely convinced. Of course, there was collateral evidence coming quite quickly in the announcement over the web and in all sorts of congratulatory notes from my friends and others very quickly. I then realised, probably true, I had in fact got it. 

Can you describe your Nobel Prize-awarded discovery? 

Sir Peter J. Ratcliffe: Oxygens essentially powers the fuel of metabolism, which the cells need to, to grow to make new molecules. You need it for the energy of movement. Practically everything the body does needs energy. And that energy comes from essentially the burning combustion of oxygen. That level of oxygen to support the energy needs, but not to cause trouble has to be precisely right. So we discovered a system akin to a thermostat for temperature, but for oxygen, by which the cells sends the level of oxygen and make hundreds or thousands of responses to adjust their metabolism, their behavior in many, many ways to the level of oxygen or to adjust the level of oxygen to what they need. Both types of adjustment. 

What practical uses are there for your discovery? 

Sir Peter J. Ratcliffe: We’ve been very fortunate. We didn’t anticipate that we would find as the oxygen sensor an enzyme. An enzyme is a biological catalyst. And these enzymes are often the targets of drugs. This enzyme, your oxygen sensing enzyme is a classical drug target. That means that we can alter that thermostat for oxygen with a drug mimic the body’s natural response, say to low oxygen, and improve the adaptation diseases, which involve low oxygen. Many, many diseases have low oxygen hypoxia, we call it, as a component. Anemia, for instance, can be improved by drugs which mimic hypoxia, make the body think it has less oxygen and move up the level of red blood cell production. 

Those drugs are undergoing what we call late stage trials in the US and Europe. They’re actually licensed for the treatment of the anemia complicating kidney disease which is due to low erythropoietin levels in Japan and China. Of course, with all new drugs, there are uncertainties and we’ll know over the next so many years whether this is a blockbuster cure for all sorts of low oxygen diseases or, or whether it’s difficult to do that safely. The indications have to be restricted. 

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

Sir Peter J. Ratcliffe: I think there’s a good balance. Research has to start with the basic facts. I actually would prefer to call it passion-driven research. I’ve heard a lot of terms for this curiosity-driven, bottom-up basic research. I don’t think they convey to the average person the reasons why we do this. We discover things. That’s what we like to do. We get passionate about doing it. This is an important principle, that people work in this way and they find things out. That knowledge, so long as it’s secure knowledge, other people build on in often quite unexpected ways.  

Our work was really unexpected. We started to work on erythropoietin. We found this general system, to our surprise. Also, it was an enzyme that could be targeted by drugs. Those are all examples of passion-driven research that turned out to have that utility, that societies are rightly seeking. But I, as you see, I believe things do begin with that basic principle. Get the knowledge right. And many people can build on it. 

Watch the interview