Peter Ratcliffe was jointly awarded a Nobel Prize in 2019 for his work on how cells sense and adapt to oxygen availability. Stepping down after a decade as the Crick’s Clinical Director, he shares 10 lessons from a life in science, spanning explosions, rejection letters and the phone call that changed everything.
Peter Ratcliffe. Credit: Paul Wilkinson.
I was interested in explosions, fire, heat and physical force. My inventive streak expressed itself in improving kilns for baking pots, building catapults to fire stones at other boys, melting metals and making increasingly large explosions from things a young boy could buy at the local newsagent. I learned that if one took 100 caps, supplied for toy guns, and compressed them between two bolts and a nut, then threw the lot against a wall, you had a near equivalent of a hand grenade. I wasn’t interested in working things out at all, but in pyrotechnics.
One day in the chemistry laboratory, John Lorraine Spencer, MA, the headmaster, strode in in his gown and said: “Ratcliffe, can I have a word?” I said, “Yes, sir.” We went to his study. I was nervous because the usual reason for going there was to be caned. There, he just said, “Ratcliffe, I think you should study medicine.” I replied “Yes, sir.” That was the decision. And we changed my application form for Cambridge. I never thought it through. I don’t think people do in early life. And I don’t think you should. What matters is how to deal with the consequences.
I’ve no idea whether he thought I wasn’t good enough at chemistry. I still don’t know. Rather to my own surprise, and greatly to that of some at the school, a telegram arrived announcing an open scholarship to Gonville & Caius College, Cambridge.
I had got the scholarship to Cambridge a year early and there was a little time to kill. I probably couldn’t make it as a first-class racing driver – that’s what I wanted to be. I took a job in the analytical laboratory of a local textile firm and earned enough money to buy a racing kart. It was great fun. While others did it full-time, I was doing it while preparing for Cambridge University and wasn’t good enough. But it did give me skills.
The important thing to remember in motor racing is that you have accidents and, until you’re dead, you’re not yet dead. Until you’ve crashed, you’ve not yet crashed. And if the machine’s out of control, it’s obviously going to go off the track, and it matters whether you hit the straw bales or an iron post. The point is, it is not over until it is over – don’t put your head down and give up. Manage the problems to completion and you’d be surprised what you can achieve.
If you get a good question, then you may answer it. And if it’s answered, it just might be important. And I also teach that you must have your own question, ideally an unfashionable one. If it’s not a crowded field with loads of people in it, you can be fairly incompetent, which I am, and still succeed. If there’s 1,000 people competing, you won’t. So, I picked this question as to the regulation of erythropoietin, EPO, the hormone that regulates your red blood cells that carry oxygen. I thought it had a clear physiological purpose and there would likely be an answer to that problem – that there would be a mechanism that accounted for the extraordinary sensitivity such that, if I take a unit of blood from you, you will replenish that blood with complete accuracy.
Now, some people said, “Peter, if you want to be an academic nephrologist”, which was the intention then, “you’ll have to do something more important than this EPO stuff.” At that time, in the late 1980s, the recombinant hormone was available for clinical use, and they asked, “why do we need to know how it’s regulated?” In my view, it doesn’t matter how important the question is perceived but it does matter whether you can solve it. And it turned out to be a much more important problem than just EPO. We set out to find a specialised oxygen-sensing system. What we discovered instead was a fundamental pathway regulating thousands of genes and biological processes.
We did face setbacks. I set about trying to measure erythropoietin messenger RNA by Northern blotting. I never got it to work. We had to change the method. So, the first six months we achieved absolutely nothing. You don’t have to be clever to do this kind of work. It might even be a hindrance. But you do have to be persistent and do experiments.
Eventually we got evidence that this system that we eventually unravelled did not just work on erythropoietin. When we put the essential DNA control element into other cells, linked to what’s called a reporter gene, it worked in every cell, and therefore, we deduced that it must be doing other things in other cells, and with that extraordinary sensitivity.
I was sad. We did actually keep the rejection letter from the journal, Nature, who said the field was very small, so it wasn’t sufficiently significant. The fact the referees rejected the paper had nothing to do with whether it was true or false. It was true. We just carried on. We kept the rejection letter for a certain purpose. You might see that as arrogant, but we were pretty sure that we were on something that was important. We did get into a secondary journal, but it didn’t create a buzz.
The excitement in the field came after all the discoveries were made, from 1989 to 2002. Those were the discoveries on which the Nobel Prize was based in 2019. It is an entirely subjective matter who wins the Nobel Prize, or who wins any prize, and it came our way for reasons I’m not clear about.
We have defined a biochemical signal which directs oxygen demand and supply. And that’s present in all animals, which means it’s probably been present for about 500 million years. And if the planet survives another 500 million, it will almost certainly still be the case. So that’s for me what’s satisfying – finding something out with rock-solid certainty.
There have been two classes of drug that have been developed on different components of the system, but that was not our work, and it was not our primary intention. Still, it is deeply satisfying to get letters from patients saying how grateful they are for the scientific work that took place.
We had got the Lasker Award. I had heard mention of the Nobel in discussions of the merits or otherwise of our work on oxygen sensing. I am not one of these people who keeps their mobile by their bedside. And in the frenzy of activity writing a grant application, I had quite forgotten the significance of the first Monday in October, when they make the announcement. My secretary Catherine hadn’t. She burst into a routine science meeting of the lab and said: “There’s a man from Sweden on the phone, he says it’s Thomas Perlmann [Secretary-General of the Nobel Committee for Physiology or Medicine].”
He took quite a long time to explain why he was ringing: “I’m calling you from… from Stockholm, which is in Sweden, which hosts the Nobel Assembly, which awards the Nobel Prize…” I was just hanging on trying to work out if it was one of my friends or enemies winding me up.
You also must be careful because I have had several calls where people say, “are you aware of prize X?” and, instead of being told you’ve got the prize, they ask you to fly half the way around the world to serve on the jury. But the call was indeed from Thomas Perlmann and, yes, they had awarded me the Nobel Prize. Catherine replaced my strong coffee with a calming mug of tea because I was a bit shaky when I returned to finish the meeting. I didn’t tell anyone until we got to the end. A great deal of champagne was subsequently consumed, and my colleagues were very gracious. But giving the award to one individual is unfair. It was the lab’s prize.
My poor wife, Fiona, had to bring up four children, more or less, on her own. Sometimes I took the children into the lab on a Saturday morning and put carbon dioxide into a beaker of water to make ‘hot ice’, as the children called it. I thought that was a reasonable contribution to paternity and their upbringing. But it wasn’t. So, I must be grateful.
I think teaching is really important and you can influence the life of others. So, it’s about people influenced, and things found out. You have to publish something, but the idea of having 1,000 publications – I am just not interested. I’ve had some great people through the lab, and they’ve gone on to do great things, and I fondly imagine that I might have helped them.
People ask, what’s a high moment of the Nobel Prize and, with all respect to the assembly, it was the day that we found the enzyme, the oxygen sensor that we were looking for. I’m less comfortable now in the post-Nobel period. I have had some odd lecturing invitations to speak on world affairs, to speak on climate change, and offers to fly me business class to wherever. Probably about 1,000 speaking invitations that, if you took them up, would destroy your life because you would only do that and nothing else. The danger after winning a Nobel Prize is people believing you understand everything. You don’t.
