Interview, June 2000
Interview with Edmond Fischer by Hans Jörnvall at the meeting of Nobel Laureates in Lindau, Germany, June 2000.
Edmond Fischer talks about how he came into the field of biochemistry; receiving the Nobel Prize (2:04); how he made his key discoveries (4:53); problems with present day support of science (13:43); and his thoughts about future breakthroughs in scientific research (15:25).
We are now at the Lindau meeting for Nobel Prize laureates and we have just met Professor Edmond Fischer from the department of biochemistry at Washington University in Seattle and he has promised to participate in a discussion and perhaps we start by wishing you welcome here, and we are happy to see you here.
Edmond Fischer: I’m delighted to be here.
Then the first question. How did you come into your research field and what were your initial steps in the field that lead you to your future career?
Edmond Fischer: How I went into science, that came very early when I was about 15 years old, I had read books on Louis Pasteur and I decided I wanted to become a microbiologist, and I remember for my 16th birthday I asked, as a present, for a microscope and my brother who was at the Polytechnical school in Zürich bought in a second hand store, beautiful in fact, lights, the old lights microscope with a emersion objective. I wanted to solve all the problems of the world and this is how I went in fact into that field. Then when, before I went to the university, I went to see the professor in microbiology and he said: you know, there’s no money in microbiology. If you want to become a microbiologist you have to get a diploma of something, pharmacy or chemistry, pharmacy didn’t interest me so I went into chemistry and this is how I ended up.
You finally came into the Nobel Prize laureate field and you did this 1992 in physiology or medicine for reversible protein phosphorylation. How did that feel?
Edmond Fischer: It came as a big surprise. In fact I, I got a phone call in the middle of the night, my wife was a little bit ill so she was sleeping in another room and the phone rang and I grabbed it and somebody said ‘Dr Fischer’. The first idea was somebody wants to sell me a new roof on the house. I said ‘Yes’, he said ‘Are you Dr Fischer from the University Washington? I said ‘Yes, why does he’ … and he said ‘Congratulations, you just got the Nobel Prize’ and it had no reality. I said ‘I don’t believe it’, he said ‘Oh yes, believe it, you and Dr Krebs are sharing’, and the moment he mentioned Ed Krebs’ name since we had been working together for 40 years, it put everything in the right ball park, so that woke me up. I put the light on and it was 3.45 in the morning. It was CBS New York.
That’s the usual time, because there is a time difference and this time difference from the decision to reaching the West Coast, US, makes that early in the morning for you. But I meant how did you come into exactly that field, because it must have been a long story before that too.
Edmond Fischer: It came from the fact that Ed Krebs, my colleague, had been working with Carl Cori, the Cori’s in St Louis, on phosphorylase, muscle. We in Geneva, my mentor was Kurt Meyer and we had been working on potato phosphorylase and the muscle enzyme is activated as you well know by compound called AMP, adenylic acid, but not the potato one. The Cori’s thought it was a form of co-enzyme and I thought it can’t be because co-enzymes are preserved through evolution as you know better than anybody else. We decided to investigate the system and we started working, we thought we would be working for a few months on that and very rapidly we found that the enzyme was activated by a totally different mechanism. That’s how we entered the field of phosphorylation.
And then you had a long series of discoveries, would you like to describe some of them you think are crucial?
Edmond Fischer: That was the first, that the protein could be activated and inhibited by phosphorylase and dephosphorylation. When we worked in crude muscle extract there was an absolute requirement for calcium, but when we purified the enzyme there was no involvement of calcium and the question is why do we need calcium in the crude extract? There were a lot of our enzyme, phosphorylase, there was a lot of magnesium ATP required, why do we need calcium? The only possibility is that the enzyme, we knew it had to be an enzymatic reaction, we knew it had to be what we call a kinase, the only possibility was that kinase also existed in inactive and active form and calcium was involved in that and that turned out to be correct. That was the beginning of a cascade system, activation of an enzyme that activated another enzyme that breaks down glycogen.
How do you feel now with something like 10% or whatever of all protein being regulated by phosphorylation? It must be a wonderful feeling to have found this first and then know that everything depends on it.
Edmond Fischer: This is really serendipity. You know where you start in research and you never know where you will end up. This is the beauty of basic research and yes, now there’s an explosion of kinases and the very very big development in the field was the discovery just 20 years ago that a very important carcinogenic virus, Rous sarcoma virus, brings about tyrosine phosphorylation and involve tyrosine phosphorylation in transformation and oncogenesis. The field developed, at first people thought: Oh, it’s a nice system, but they are working on it why. Then when we found that calcium was involved that got all the muscle physiologists interested because muscle contraction is triggered. Then it was found that nerve conduction, phosphorylation, that got all the neurologists excited and then when it was found a transformation is brought about by tyrosine so that was the explosion.
You feel that you have an incapacity to follow all the different fields?
Edmond Fischer: Absolutely not. This is the importance of going to meetings, the importance of friends who call you. I’m retired now, in fact since seven years, but I closed my laboratory about three years ago and I’m delighted I have because now I can read science for the beauty of it without saying: Oh, I have to tell Al he should do that, I have to remember that. Now I just read science and follow science for the pleasure of it.
That’s very good. This matter with sociology on science, did the Nobel Prize change your life? Did you come into lots of committees, you’ve got other commitments?
Edmond Fischer: In many little ways, nice ways, I certainly can’t bitch about it. It has been an extraordinary experience, not only for me, but we have always been very very close friends with Ed Krebs, but more than that. The two families went to Stockholm, they have become close friends. Within my family they have become much closer, you know we are bound by this sort of a confrerie, brotherhood, if you want. It has been a really extraordinary experience. A little bit disturbing too. Disturbing because – and I was wondering why – you wonder you know why? Why were we selected? Somebody this morning spoke about that, science, you never do science alone. You do science with collaborators; the whole field is carried out by many many groups. We would have never been able to do what we did without very very bright collaborators. There is a difference between the Nobel Prize for instance and the gold medal in the Olympic games. For the Olympics you train like crazy for several years with one goal in mind, you compete, you beat all the other guys and by golly when they give you the gold medal you know why you got it. Not with the Nobel Prize.
But in some cases perhaps it may be different, in different fields. How much do you rate … I mean first there is experience, science has long tradition and lots of previous results and then you work hard and you have lots of collaborators but you also need that push, the creative environment and the creative realisation of yourself. How do you think first, what did you consider about that in your case and how can we promote it in general?
Edmond Fischer: For me, I can tell you it was the love of science. Really that. The enormous pleasure, working in a lab, never knowing what you’ll get, getting extraordinary results that will prove wrong within a week, others that hold, it’s like reading a detective book, you try to follow some clues and try to build a story. I like the approach of making hypothesis and either trying to destroy them or to prove them and go this way, I like this approach.
I liked your lecture, there was an NPSA meeting in Seattle and I was listening to you then, before you got the prize. I liked your models and theories already then, so that was great. It must be great fun for you.
Edmond Fischer: It has been, so if I had to do it again which I have no desire whatsoever and I’m very happy of what I have done, I feel very very lucky in what I have done. I wouldn’t do it differently.
But most people have something they might wish to have changed, anything you would have changed?
Edmond Fischer: No, when I went into science, I was at the conservatory in Geneva, playing the piano, and maybe there was some hesitation whether or not I should go into music. I would have never been able to become a concert pianist, you have to be a virtuoso at age 12, you know, like tennis players, and I was not, I didn’t have the virtue, but I would have probably become a conductor. I like music more than piano, but I don’t know, I felt that music, I should keep that for the garden, for the pleasure of it.
Do you see any connection between the music and science because you had this connection. The previous person I interviewed here had the same, Manfred Eigen, and my mentor Hugo Theorell had the same. Do you see any reason for this?
Edmond Fischer: Manfred Eigen is a super pianist and a good friend. I don’t know, I did a lot /- – -/ with Jerry Edelman who is a very good violinist. I love chamber music, I love to accompany people who sings, lieder, but it sounded gross to me to make a living out of music, I view music as something that you don’t touch.
If we should switch to support a little, how do you see the natural present-day support of science and the discussion that we just had in the lecture.
Edmond Fischer: I have the same worries that were expressed. The fact that now more and more you go towards targeted research. There’s nothing basically wrong in targeted research, in fact many fundamental discoveries came through applied research as exemplified for instance by the work of Louis Pasteur. But nothing wrong as long as all the money doesn’t go towards targeted research. Unfortunately, many administrations have this erroneous feeling that you can solve a problem by throwing millions of dollar at it. They don’t understand what is creativity in science, they don’t understand that so many discoveries come from serendipity. Mendel didn’t know that he would find the laws of classical genetics by trying to solve why peas would grow white or pink or another colour. Or Röntgen, who was interested simply in looking at the properties of electrons bouncing on the cathode. He didn’t know he would make maybe the largest discovery ever made in the field of medicine. If either Mendel or Röntgen would have applied to, let’s say NIH if it existed at that time, there’s not a chance in a million that their work would have been approved.
Perhaps we can end up with a question about the future. I guess you must have got it several times before Now you have had a successful scientific life, full of science, for 50 years or more, if you now go 100 years ahead, what would you think happen and which of the present-day questions are not solved or are all solved. A difficult question.
Edmond Fischer: If you ask me what percentage I would go zero upon zero, zero, zero, zero, etc. A tremendous problem will have to be solved. To predict, even in 10 years, you cannot do that. As a friend of mine once said it’s like asking a general of cavalry in 1880 to plan for World War III. He would tell you: Give me ten thousand cavaliers and I’ll protect Washington. You cannot predict, you cannot guess what you cannot imagine. The big problems that will be solved rapidly is genetic therapy, therapeutics, because we begin to understand a little bit the regulation of genes, the tremendous problems. To say: Oh, we’ll solve that in 10 years, it’s nonsense, I don’t know when, but it will. I’m certain we will be able to regenerate nerves when nerves are cut. I am sure that we will be able to grow stem cells, in all cases aplastic anaemias and things like, replace that, so many therapeutic problems will be solved. In my field which is cell signalling, there are many pathways, we begin to know those pathways, we know all the enzymes that are involved but enzymes are words, we know bits and pieces of phrases, but we don’t know the language, a cell has to speak among pathways to co-ordinate all those reactions, we don’t know that language. More importantly we don’t know the language that the cell has to speak with another cell to co-ordinate the development of multi-cellular organisms where messages have to be sent back and forth from one cell to the other. This communication has been crucial to the establishment of the very complex networks of communication we have in embryonic morphogenesis in the immune system, in the brain where you have some more than a thousand million cells speaking with one another through something like 10 million billion synapses, ultimately leading to generation of thought, memory, consciousness. That’s one of the huge challenges that faces the biologists.
I think you gave a very good answer to this difficult question, and you did it so well you’ll have another difficult question after all, and that is there are many ways of treatment, one is the genetic therapy for the future like you just said, there’s also transplantation. I was recently at the lecture where we were told all the benefits from transplantation, and I saw this drug treatments like using inhibitors and receptor agonists and so on. How do you see the future between these three fields, do you think we will soon be overtaken with genetic therapy or soon overtaken with transplantation?
Edmond Fischer: I don’t think so. I think that we developed all three and you know you’ll use the one which is the more advanced at one particular time and have taken over. What is remarkable now is that we begin to understand some of the mechanics that control each of these, for drugs we begin to know how to model the drug, so the opportunity, the potential for advances in those three fields is immense. I think that the young people today have a marvellous future ahead of them in those fields.
That’s again a very good answer and that was a very good end because you give the positive view for the future. I think we should thank you very much for coming here and this is the end here in Lindau with this discussion.
Edmond Fischer: Hans, my pleasure.
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