Christian de Duve

Interview

Interview, June 2000

Interview with Christian de Duve by Sten Orrenius at the meeting of Nobel Laureates in Lindau, Germany, June 2000.

Christian de Duve talks about becoming a biochemist; the difference between laboratories in the United States and Europe (7:43); the discovery of lysosomes and peroxisomes (10:49); running two laboratories in different parts of the world (19:32); how to create and foster a culture of creativity (23:47); and about the Nobel Prize and its influence on science (26:17).

Interview transcript

Why don’t we start and say that this interview is in the Insel Halle during the Lindau meeting and I’m Sten Orrenius. And I have the pleasure of carrying out this discussion with Professor Christian de Duve who received the Nobel Prize in 1974 for discoveries concerning the structural and functional organisation of the cell together with Albert Claude and George Palade. And my first question is perhaps a banal one, but I would like you to comment briefly on how it all started.

Christian de Duve: I won’t give you the whole history of my life, but basically when I entered university I wanted to become a physician. That was my goal. But then when I was in medical school I had some free time and spent it in a physiology laboratory doing some research under a professor there and I was so enthusiastic about research that I found it difficult to finish my medical studies, because I didn’t want to waste time getting a clinical training, but anyway, I finished. By that time the war had started in Belgium and I was interested at that time in insulin, the mechanism and action of insulin. I decided that I could not solve this problem with the kind of techniques that I was using in this rather traditional physiology laboratory. I decided I needed biochemistry. Since I had time on my hands, I went back to school and studied chemistry and got a degree in chemistry, doing many other things at the same time, including being an assistant in a cancer hospital, at least to get the food and lodging.

Anyway, the war was ended and then I decided now I know medicine and biology, I know chemistry, it’s time to become a biochemist. There were really not very good biochemists in my university, and also I want to take advantage of newly gained freedom, get out of the country and find the training I needed elsewhere. I had been, before the war already, I had been to Sweden and to Norway, I knew the countries and I loved them very much, and since Sweden had not known occupation, I thought well let me try and find something in Sweden. I had known a Swedish girl, she was really Hungarian, who was a chemist, and she worked with Hans von Euler and I decided I would go and work with von Euler. I wrote to her, I hadn’t seen her for five years of course, and I wrote to her and she said Hans von Euler is passé, you should go to Hugo Theorell, he is the coming man in Stockholm. I wrote to Theorell, I wrote a letter in which I explained all this. I said I don’t know anything about biochemistry. I want to become a biochemist. I would work on any problem you give me.

Amazingly, he accepted me. I still don’t understand why he accepted me because, I had a thesis, but on insulin. So anyway, that’s how I spent 18 months at the Medicinska Nobelinstitutet, Hantverkargatan 3 in Stockholm. Those were fantastic months, I really enjoyed them. But when I came there, I will tell you, I said to Theorell: I know nothing about biochemistry, you’ll just have to give me a problem, any problem, which was crystallising human myoglobin, that’s the problem he gave me, so that I can learn the techniques. He sent me to a fantastic man, who’s dead now, you may have known him, Åkesson, who was his first technician, but who eventually became a PhD and a professor at the end of his years. Åke Åkesson was a fantastic teacher, he really taught me to pipette, to measure pH, to precipitate proteins with amino, and so on and so on. I learned the trade from Åke Åkesson. I learned many other things from Theo, as we all called him, Hugo Theorell, who was a wonderful man. Also I met a number of very interesting people because that laboratory had become world famous, and so by the time I was there, after I arrived, I was about the first one to come, there were a number of Americans, Breton Charles arrived, and John Buchanan, there was Ralph Holman, there Chris Athenson arrived the day I left, so it had become a major laboratory. And I will always remember those times which were really wonderful and of course I got to learn the Sweden and there are many other stories, including Nobel stories, that I could tell, but there isn’t time and it’s not important here.

Then after Theorell, I went for six months to work with Carl and Gerty Cori in Washington University in St Louis because I wanted to get back to my main problem which was insulin, and of course they worked on that. There I was able to work for five months with Earl Sutherland, in fact, together we established that glucagon is made by the alpha cells of the pancreatic islet. Finally at the beginning of 1948 I came back to Belgium to start my own laboratory. You can see I’ve been very, very lucky because Hugo Theorell got the Nobel Prize in Medicine in 1955, Carl and Gerty Cori got it in 1947, just while I was there, and Earl Sutherland got it in 1971, so chance has it that all my mentors were … Even my Belgian mentors were not Nobel Laureates but had worked with Nobel Laureates. They always ask whether the Nobel Prizes are hereditary and not genetically I think, although there are a couple of father and son pairs. But I think science, and this is really a rather important message, I think science, especially the art, the craft of scientific research, is not learned in books. The only way you can learn to do good science is to work under a good or several good scientists.

I wondered because we have just heard a panel discussion on creative milieus in science and certain things were brought up there, among those differences between Europe and America. I would like to come back to this and ask you the question: if you compare the creativity and the milieus in the Theorell laboratory when you came as a post-doc, with the Cori laboratory and your time in America, at that time were there obvious differences? Was one more European and the other more American? Or were they pretty similar would you say?

Christian de Duve: The Cori’s came from Europe, and their laboratory was much more the hierarch kind of, European, they were very autocratic. We all did what we wanted but it was all very, you know, their door was not open all the time. Whereas Hugo Theorell, Theo, he was available all the time. He would be in the lab, he would talk with people, he would sing, he would walk on his hands, because he had polio and had a problem walking on his legs, so he would be walking on his hands, singing. I would have lunch with him every day. That was a privilege, I don’t know why. Anyway we would try to talk French, he liked to use me to speak French. We never spoke of science. Mostly we spoke of music because Theo, as you know, was a very good violinist and Margit, his wife, she was a concert pianist and a harpsichord player. We spoke of music, we spoke of many things but rarely of science.

Would you say that from that aspect that the Theorell laboratory at the time was a pretty unusual or uncommon European laboratory?

Christian de Duve: I’ve never known in my life a laboratory that had a very strong boss and a hierarchical organisation. Wherever I went there was a tremendous conviviality and collaboration and lack of formalism between professor and students. I think perhaps the better scientists are probably less … insist less of being on top of the mountain and looking down on those students and so on, because I think you have to feel insecure to want to put this distance between you and the other people. But good scientists are not insecure.

There are several other interesting aspects I would like to bring up in this interview, and that is when you returned to Belgium from the United States, you returned to go back to your work, maybe you had gone back to your insulin work already at the time, and you had pursued that very actively for a long period of time. You went back to Belgium and then during the late 1950s you changed your direction of research.

Christian de Duve: No, it started much earlier. To try to make it very short, all these 12 years that I had devoted to my personal training had as a final goal to elucidate the mechanism of action of insulin on liver, that’s what I wanted to do. As soon as I had my own lab and a small group of collaborators, I decided that I would study some of the biochemical aspects, enzymatic aspects of liver to try and find out what made it so difficult to demonstrate this action of insulin in vitro on liver. Then I chose an enzyme that had in fact been discovered by the Cori’s, but not characterised by them, because I thought it might be a very critical enzyme in this whole mechanism because it exists in liver and not in muscle and that may be a big difference. That was glucose 6-phosphatase.

Our first work was to characterise, trying to purify glucose 6-phosphatase. Now it turned out that, I’ll try not to go into details, but when we tried to purify this enzyme by standard techniques we came to the conclusion that it must be bound to some structure. The main conclusion was that at pH5 the enzyme would be precipitated and then it would remain precipitated, even at the external, so it was not isoelectric precipitation, it was some kind of agglutination. Claude had just described his techniques for fractionation and so I said – it was a difficult decision – let’s find out what structure by using Claude’s technique. We did that first, we developed our first system for centrifugal fractionation following published techniques and quickly demonstrated that glucose 6-phosphatase is basically a microsomal enzyme. It’s bound to microsomes, now we know it’s bound to membranes of the endoplasmic reticulum. That was that. We knew about that and at the same time we had proved something, namely that microsomes correspond to a special cell, but which was not yet clear at that time. It so happened that at the same time we had been studying another phosphatase, acid phosphatase. Not because we were interested in it, but because when we purified the glucose 6-phosphatase we had to separate it from the acid phosphatase. We also measured the acid phosphatase on the fractions. And run into this – now it’s a well-known observation, at that time it was very surprising – namely that in our fractions the enzyme had disappeared. We could not find it or very small amounts. I thought at first that we’d made a mistake and five days later, we kept the fractions in the refrigerator, and we re-assayed them and there the enzyme was. One thing leading to another, I thought that was a mystery, the missing enzyme and so on, why is it missing, why is it not?

One thing leading to another, I left insulin on the back burner to find out why acid phosphatase did not show its normal activity. When you know the answer it was because it was inside a little bag and as long as the membrane of that bag was intact, the enzyme would not be able to act on an external substrate. You open the membrane, it comes out. it acts on the substrate, that was a fascinating observation. I left insulin on the back burner for a little longer and went after that, because there were a couple of other enzymes that were possible candidates for this kind of behaviour, beta-glucuronidase and cathepsin D, indeed they did behave in the same way. Then two others were found to behave in the same way, acid ribonuclease and acid dioxygenase, and by 1955 we had published already six tissue fractionation papers. And the number six has in it the word lysosol, that’s when the word lysosome was invented, so you see by 1955 I was already very much immersed in this kind of work. Although in the lab many people were still working, and are still working today, on carbohydrate metabolism. And so peroxysomes followed lysosomes in fractionation and so we discovered the peroxysomes. And that is basically how I became a cell biologist. I never used an electron microscope in my life. In fact, we did not even have a microscope when we did all this work. All this work was strictly biochemical. I discovered, if you like, tried isolated those two new cell paths, lysosomes and peroxysomes using strictly the approachable biochemist when he purifies a protein using fractionation techniques of one sort of another, chemical measurements to follow my enzyme.

The latency of the acid phosphatase led to the work on lysosomes and the discovery and characterisation of the lysosome. Was there a similar observation that led to the peroxysomes?

Christian de Duve: No, it turned out that when you fractionate using the classical technique then the lysosomal enzymes sediment about two thirds with the mitochondrial fraction, one third with the microsomal fraction. We devised a technique with an additional very small intermediate fraction between the mitochondria and the microsomes in which those enzymes were highly concentrated so that they are associated with particles that are a little smaller than mitochondria but bigger than microsomes and so they sediment in between. From working the literature in particular, some work that was done by Alex Novikoff, who became as you know the electron microscopist most interested in lysosomes and peroxysomes. I included in our measurements an enzyme that might be a candidate for the lysosomes and that was urate oxidase, uricase. It behaved the same way but it was not latent. It had an alkaline pH optimum where all the others have an acid pH optimum. We said, well that looks like maybe something different, and so we followed, we found other enzymes, diamino acid oxidase, catalase, lactic acid oxidase, behaving in the same way and not being latent, except catalase for some special reason. We developed new techniques based on density gradient centrifugation, in which we were able to separate those two groups, lysosomes on one hand and the non-hydrolytic enzymes which were mostly oxydasers plus catalase. And that was the peroxysomes, which we now know of course to be very complex organelles in some plants and in some lower animals and so on.

When you had gone back to Belgium and developed your career and became professor at the University of Louvain you continued to build the group and to do your research. Then, a bit later you also were recruited as a professor to the Rockefeller University as it was at the time, and from my early time in research, I remember you having passes to major research institutions or research groups, both contributing enormously to the cell biology field. How did that come about and how important were these two appointments, the two milieus?

Christian de Duve: That is one of the many lucky accidents in my life. Belgium, I had a wonderful group, you know their names: Berthet, Beaufay … They were really excellent people, but it was a very, very hard job for me because I had to do all the teaching of biochemistry for the medical students, to take all of the examinations which took me two months. I had administration, I had to find funds for this group and so on, and to direct a group that was getting bigger and bigger. It was a very, very big load and I found it a little difficult. And one day I visited George Palade, I was travelling in the United States and I was in his office and I said, My God, you are really fortunate, I wish I could work here. Just like that. George looked at me and he said, Do you mean this? I said, Yes George, I mean it. Six months later Detlev Bronk, the President of the Rockefeller University offered me a job.

Then came the complications because I wanted to work there and at the same time when the opportunity came, there was the problem of family, I could’ve taken my family with me, I had four children by that time, but there was also the problem of what would happen to my Belgian lab and so on. Bronk came to Louvain, talked to the director and finally they agreed, because suddenly the director of Louvain had discovered some qualities in me. I was relieved of most of my academic duties in Louvain and I was accepted by both, to share about 50% of my time between the two, that’s how I was able to start a new lab at Rockefeller. But this was supposed to be for five years and I’m still commuting today. It became permanent. But it was a crazy business, I mean to run two labs on each side of the Atlantic, nobody would say that’s a good way of doing science. But I had so many good co-workers that it was possible. I would always take one of my Belgian co-workers with me to New York. When I went back to Belgium he would keep on. We were able to do in New York, thanks to the Rockefeller, a large amount of work that I would not ever have been able to do. Now perhaps since you were talking about my career, perhaps I should add one more thing, if you don’t mind. Namely that I changed again, I’ve changed my field twice since. In 1975 I opened this new institute in Brussels, the ICP, which is a small biomedical research institute more or less copied on Rockefeller but on a much smaller scale. I went back to medicine, finally to medical research through that institute. Then in the last 10-15 years I have found new interest with origin of life and evolution.

I think it’s very important that you say so. I was going to more or less end my questioning by coming back to your fantastic career and that you have developed world renowned laboratories, at least three of them, and also recruited so many internationally very well-known scientists and followers. Would you have some final comment on creativity or how as a teacher and a mentor should you be in order to achieve what you have achieved?

Christian de Duve: I think it’s been said today already, namely that it’s extremely important to collaborate, to communicate, to be open to the ideas of others. I think it’s extremely important to give young people freedom. I think they should be allowed freedom. The important thing in life is to recruit the best, that’s the most difficult thing, find the best. Give them an environment in which they are able to develop their own potential, the best that is. Not only the instruments, the techniques, but the colleagues, the atmosphere, there must be some kind of environment in which creativity is fostered, in which freedom is fostered. I think basically that is the important thing. The secret of creativity, I would not know, it’s a very complex cocktail. Certainly to be a first class scientist, it is not sufficient to be intelligent. In fact, I’ve known some of my co-workers who were very much, and I’m not being modest, much more intelligent than I am, but they never achieved perhaps the same kind of science that I achieved because they lacked something which is I think extremely important for this cocktail, and that’s imagination. And that is where science and art get together. Namely, imagination is a quality common to both and essential to both.

Has the Nobel Prize changed your career in some way to the better or the worse?

Christian de Duve: I would be completely dishonest if I said it had not changed my career. First of all, it was a tremendous pleasure when I got it, a tremendous encouragement. We all like recognition and we all know that we’ve done some good work and that we may be candidates, but as you know very well, there’s a big distance between being a candidate and being a laureate. And there is an element of chance there also. Sometimes I tell people, I think I won the big lottery. They say no, you’re being much too modest. I say but the tickets are very expensive. Anyway, to get back to your question, it has changed my life in many ways. I think it has made a number of things easier, at least in Belgium it has made it easier for me to get some funding and support for my new institute which was opened just the day I came back from Stockholm, so that was very helpful. It certainly has given me personally a certain amount of visibility which one may or may not enjoy. Certainly it has given me opportunities to do things, like being invited to conferences and symposium and so on. All that I would say was rather positive.

The negative aspects, in the United States for instance, I had a feeling it was more difficult to get financial support for some wild reasons that I don’t know, but anyway I had some problems. Maybe my science was not so good anymore. Then of course one wastes a lot of time because of all these things like being interviewed for television, things like that. I would say that perhaps what I would consider the most negative aspect about Nobel Prizes, and now I’m being really very serious, is that within the scientific community it establishes a distance between individuals that is not deserved. Within the scientific community there are many scientists who I consider just as good, if not better than me. I know many who could’ve shared the prize with me and did not share it. As you know some of the people, the unlucky candidates, who do not become laureates can suffer very much. I think it’s a pity within the scientific community to create this kind of super class of scientists who have this little Nobel badge and are greeted everywhere like being very special, although they are just the same as all the others. I think that’s dangerous. Since we’re talking about the Nobel Foundation here, I think there is a redeeming aspect to this. Namely, within the scientific community, maybe it’s a pity that something like the Nobel Prize exists, but for the relationship of the scientific community in the outside world, I think the Nobel Prizes have been tremendous because somehow they have caught the collective imagination of the world. The respect for Nobel Prize winners, which is not deserved, anyway becomes translated in the general public into some kind of respect for science. I think in this way the Nobel Foundation, by giving those high prestige prizes, have probably done an enormous amount of good for the visibility of science within the general community, for the appreciation by every people, not enough perhaps, but to some extent of the importance and the significance of science.

Thank you very much.

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