Interview with the 1996 Nobel Laureate in Physiology or Medicine Rolf M. Zinkernagel, at the 57th Meeting of Nobel Laureates in Lindau, Germany, July 2007. The interviewer is Adam Smith, Editor-in-Chief of Nobelprize.org.
Rolf Zinkernagel talks about the importance of good teaching and communication in the laboratory, how chance led him to work with co-Laureate Peter Doherty (14:24), the difficulties in creating a new vaccine for tuberculosis and HIV (22:24), and why informing the general public about controversial scientific topics relies on improving cooperation between scientists and the media (31:30).
Rolf Zinkernagel, welcome to this interview. You were the co-recipient of the 1996 Nobel Prize in Physiology or Medicine with Peter Doherty. I’d like to start by exploring a few general themes. If I say the word mentorship, what does that conjure up for you?
Rolf Zinkernagel: I get the whole process of being taught and educated in whatever field. For me it’s medicine and biology. And as always is the case, you have a few key figures on your way into a certain area and I think that applies to everybody. In my case, teachers in Switzerland like Jean Lindenmann who discovered Interferon, together with [Alick] Isaacs, a long time ago, 50 years in fact this year. Then Henry Isliker, a complement researcher in Lausanne, played a major role. Then in Canberra, I’d say Bob Blanden, Gordon Ada, Frank Fenner would be amongst them. And in the US, Frank Dixon would be one of these persons.
And is there anything that you particularly carry over from them in your mentorship of people?
Rolf Zinkernagel: Yes, for example we always used what we call the Bible Allah in our teaching for post docs and doctoral students in Zurich. And this is an idea I took over from two persons, one at the Basel University where I grew up, his name is Adolph Portmann, he is a human physiologist in the broader sense. And he had a course which I attended during medical school which was called Classical papers in zoology and biology. We read classical papers of Lamarque or Darwin and so on, and he put that into connection of time. And Gordon Ada had a similar project where we went through certain papers in immunology, and I sort of combined this and taught a class every two or three years about very important papers over the first 100 or 120 years of immunology.
Incredibly useful but quite a rare thing to do now I imagine.
Rolf Zinkernagel: I guess so because Medline stops I think at, for most things now, at about 1970 or 1965. And many of these older types of studies have been incredibly ingenious.
So that’s primarily what you’re teaching. You’re teaching ingenuity through …
Rolf Zinkernagel: Through that course, yes absolutely. And just for youngsters getting a perspective of that immunology didn’t start in 1997; it started much, much earlier. And I think this is true for most areas of medicine and biology. And I think it’s good to get a sort of perspective of both history, but also to make us all more humble because other people have been probably much more clever than we have.
When you choose students to come and work with you, what do you look for in the student?
Rolf Zinkernagel: We look mostly for performance, are they good? And the second is we always have them visit at least twice the lab to talk with people. And thirdly, we ask their mentors or whoever knows about them personally.
So having them visit the lab is a way of finding out whether they’ll fit in.
Rolf Zinkernagel: Correct. And I think particularly in a relatively small lab like ours, I think the personalities and characters are usually the limiting factors. It’s not the brains.
That leads me onto the next question I was going to ask you, what sort of lab environment do you like to create?
Rolf Zinkernagel: What we have done over the past 30 years, and this is also largely influenced by my experience in Lausanne at the Biochemistry and Henry Isliker’s lab, but also in Canberra. There you have a very open, flat hierarchical type of structure, where the only thing that really counts is what your competence is and how good you are, and how intelligent in combining things together, advising people, and have them accept you as a character.
Is that easy to do? Because I imagine that hierarchies are sort of inbuilt for students.
Rolf Zinkernagel: Yes, but I think as long as the hierarchy is linked to knowledge or expertise, it’s easy. Because I think you cannot fool yourself nor the others very easily.
That’s true. But you need to bring students’ confidence up to a level where they’ll start to …
Rolf Zinkernagel: Yes, but I think if you are confident in the students, they are usually confident in you as a teacher. And I think if you basically behave like a decent person towards them, they will also in very general terms be a decent counterpart. So, I think it’s easy.
As well as having an open communication, do you also have an open lab structure? Do you have people working together next door to each other, bumping into each other?
Rolf Zinkernagel: Absolutely. We have this in Zurich, but this basically has been my experience in all other places I’ve been. You’re very much limited in space. People cannot avoid bumping into each other. I think that also makes the priority clear that they have to fit somehow, otherwise this is not possible to be living together on the very small amount of space.
I’ve sometimes wondered whether some of the problems of the drug industry might be put down to the fact they have too much money when they build their labs and they create too much space between people.
Rolf Zinkernagel: I don’t think this is the problem really. I think their problem is more that they are under a certain pressure to deliver. I think that’s one problem. The other problem is that, and this is a positive problem, what you say, you have more money available once you are on the subject of interest to the company. But the disadvantage, nothing is black and white, so I think the cost point is that if the company or the firm decides after three years that’s not going to gel out and you have to change your subject, that’s very difficult because you have invested a lot of time in developing your baby. And then suddenly you have to jump from x to y. And I think you can do that once, maybe twice, but the third time it already gets at your very innermost desires. And I think that is, with time, a huge problem.
You say that the pressure to deliver is a problem in the industry. Why do you think that that pressure to produce is …?
Rolf Zinkernagel: It’s very simple. If the industry or the company cannot develop products that deliver the goods, that are active and relieve certain symptoms or disease, improve certain disease states, then the company’s out. This is very much Darwinian type of evolution.
But the pressure to deliver could have a positive effect on the people who are actually doing it?
Rolf Zinkernagel: It always has. But it’s just more drastic. In academia, if you don’t deliver next year, you are usually given a chance to come up with the goods two or three years later, because you’re granting period is usually 3-5 years. Or the university backs you up for a certain period. I think that’s a big difference to industry.
Turning to your own development, you took some time to decide what you wanted to be when you were young, I gather from your autobiography. And eventually settled on medicine initially, how did that path come about?
Rolf Zinkernagel: My choices were pre-history, ethnology, chemistry, organic chemistry or medicine. It’s difficult really to rationalise why, but I just had to make up my mind at some time. And I think this is probably true for everybody and is also true for a scientist’s life because every day you have many more questions than you can attack or solve. So you have to reduce your choices. I think that’s what I did.
But a lot of people say that it’s important to capture scientists when they’re in their early teens, you have to get them young and there needs to be a huge focus on education at that point. But for you, there were lots of things going on.
Rolf Zinkernagel: That’s right, maybe too many. Then to make choices is more difficult. But I have no regrets. I think the choices were ok.
It seems that quite an important event was attending the experimental medicine course in Zurich, which was 40 years ago or so almost, and that seems to be quite precocious in a way because now experimental medicine is much talked of and people are really investing in it. For Zurich to have a department of experimental medicine at that point seems to be ahead of its time.
Rolf Zinkernagel: It was quite unique actually and what happened at the time, during the 1960s, was that a reasonable number of young Swiss spent their post-doc time in the US or in England or somewhere else. And came back home developing new departments. That was the time when science and science endeavours had only upsides and everything went up. And at that time, it became apparent that, and this is a general trend I think it applies to the US and the UK, that the number of MDs, of doctors actually choosing to do clinical research or basic research dwindled. And this had of course many reasons, amongst them I guess the bread baskets hanging lower or higher. That there was perhaps not quite the open culture in clinical medicine as let’s say in the Anglo-Saxon countries. So that was basically what a group of physicians tried to change and they created the course. I think the first course was about in 1967 or so. And a number of very good people actually, because it was highly selective from all of Switzerland only 10 people could attend the course per year. You got a reasonable bunch of youngsters and it was very good.
Would it be fair to say that it turned you towards basic research from medicine or were you already heading that way which is why you joined the course?
Rolf Zinkernagel: I was still seeking or looking for something because initially I wanted to become a surgeon, which I thought was the most honest way to practice medicine. But somehow this didn’t really preoccupy my mind, so I was looking around, then just got onto that course and from there things went in a bended way, but still relatively straight forward for the next 40 years.
What focused you on immunology? You quite quickly found that was your path.
Rolf Zinkernagel: Infectious disease is still I think the biggest problem in medicine. To relate infectious disease, to understand host/infectious agent relationships and so on, was in a way logical for an MD.
And your second post-doc was in Canberra where you found yourself at the Australian National University. And working with Peter Doherty you had very rapid results and came up with MHC restriction as an idea within a year of joining together.
Rolf Zinkernagel: Even less. This I think is a good example how chance really operates because the original plan was not to work with Peter but to work with Bob Blanden on the faculties of intracellular bacteria, such as listeria or salmonella or TB. And then the lab sizes at the ANU in micro are very small. In each so-called lab there actually were two heads and one pair of hands. And the heads could be PhD students or post-docs or a professor and the technician basically. And the only open space in the whole floor was actually in Peter Doherty’s lab. So I started doing some experiments with Bob Blanden, but by co-infiltration and co-adaptation, we started to simply work on a problem he was interested in, which was at the time information in the brain. And I came from an institution where so-called cytotoxicity, I say is namely that T-lymphocytes or cell mediated immune effected cells were measured by their capacity to liaise or destroy in-vitro cultured cells with some abnormalities or additions. And since I had learned that test in Lausanne that fitted nicely to the problem of information in the brain. And then we started to combine our expertise and that was the beginning of the end.
In your banquet speech at the Nobel ceremony you talked about the combination of Peter the mystic and Rolf the collector. It was obviously a great combination of talents and complementarity, what was special about that relationship?
Rolf Zinkernagel: I think that the most important part is really that Peter and I had a very similar sense of humour which was very good. And in terms of character, him being a vet, myself being an MD, I think we had complementary types of views on certain things and doing certain things and thinking about things. You cannot plan these things they just happen or don’t happen. We got along extremely well. And I think very important if you work in two’s or three’s, I think we both had an extremely open discussional relationship which meant at the end none of us were afraid of the other. In contrast we really had a very easy relationship.
Open and giving – no secrets.
Rolf Zinkernagel: Yes.
The work you did basically appeared in two nature papers and as very often happens, the Nobel Prize was awarded sometime after that, it was actually about 22 years gap. Did it take that long for the importance of the work to be recognised do you think?
Rolf Zinkernagel: I think in our case it’s a combination of several factors. I think the repetition and the confirmation of the work happened fairly quickly, within two years or so. But then what remained unclear is how? How does it? Why? How does it happen? This then took a fair amount of time. So that’s my interpretation, that perhaps Stockholm waited for a certain molecular explanation of the initial observation. Which then came along, there’s a number of people involved, Emily /- – -/ who described how antigens, foreign stuff taken up by macrophages or similar cells and then being digested and re-presented on the surface in the connection of these major transmutation antigens of the class 2 type came about. And there were several people around that. Then Alan Townsend, who did the same for the MAC class 1, which was a big splash at the time because it simply wasn’t understood how this combination of this presenting molecule and the virus antigens, how this should happen. And then I think the second general finding was the crystal structure of the major transmutation molecules, of class 1 and class 2. That put the corner stone into the pot. And I think that happened roughly 1996 or -97. And then came the T-cell receptor, also 1984-87, the crystal structure was done. And this then convinced everybody that maybe the original observation triggered all this evolution of science and we probably were very lucky that we got the prize and not the others. That’s how it is.
As the mechanism was worked out did the applicability of the discovery become much broader as well? Was it realised that it could be of much more benefit if you like?
Rolf Zinkernagel: Yes and no, like always. I think the detailed understanding is very satisfying because if you understand something, but the practicability, the hope was that once we understood everything, we could just take peptides, which are sort of localised in this presenting molecule and immunise easily and tumours and all sorts of things, and that hasn’t happened. It’s the biology at the end of the day that shows where the limitations are and in a way I find this very satisfying being an MD, a physiologist basically, that physiology counts. That understanding counts as well of course, it’s very important and satisfying. But to have function and improve disease states or prevent death is usually much more complicated than see the molecule.
You need to see the basic mechanism operating within the system.
Rolf M. Zinkernagel: You need both.
We’re here at the Lindau meeting where Nobel Laureates mix with a large number of students and your lecture here was entitled ‘Why don’t we yet have a vaccine against TB or HIV?’ So we seem to have found our way into that question. What answer did you provide to the students
Rolf Zinkernagel: Despite the fact that we know all these details, where T-cells recognise how cell mediating immunity functions, how it’s getting triggered, theoretically you would have thought, put things together, express things, make the molecules, should go. It doesn’t. And I think what I try to do is to show some commonalities between the problems we have solved like the acute childhood infections, what they have in common, versus all the infections where we haven’t succeeded in making a vaccine. What are their commonalities? And to put it in very simple terms, the commonality is that for the acute /- – -/ killing types of infections, the only thing you need is a high enough antibody level, because in a way evolution has chosen that pathway as a successful pathway because the mother can give these antibodies to you when you are born. Whereas the other group of infections, including malaria, schistosomiasis, TB, leprosy, HIV and …
Which come later in life, yes?
Rolf Zinkernagel: No they don’t come in fact, they also come very early. But in most of these cases it’s not sufficient to have just maternal antibodies. You need an excellent immune response that actually keeps on being driven by low level infection that you cannot get rid of. And I think that part, namely to have a vaccine that imitates, starts a very low level of infection, to actually maintain and boost the immune response all the time. That is what we haven’t succeeded. Take TB, there is a so-called vaccine against TB, it’s called BCG, the bug that has been selected and developed at Pasteur in the 1920’s. Now interestingly, BCG can reduce the chances of very small kids, between 0-2 years, to catch what is called an overwhelming type of TB infection. But it cannot change TB disease after that period of time. And this correlates virtually to the month with the persistence of the BCG bug in the small kid, because the BCG is so much attenuated that after one or maximum of two years, the bacterium has been eliminated from the host. And once that has happened protection decays, is finished. And I use this example to explain that in my view, and this is not a popular view, that what we call memory, immunological memory, that is having seen an antigen or infection once, protects you for the rest of life, is not true. It’s an academic idea which is nice and interesting but doesn’t correlate with the experience we have in clinical medicine.
Although it’s the basis for all vaccination programmes, is it not?
Rolf Zinkernagel: Yes, but you see the key point is that for all the cases where the classical vaccines protect and work, the only thing you need to have is a high enough antibody level. If that is fulfilled, and there are many ways to fulfil that, then you are ok. But in all other cases where you apparently cannot inject something and then be protected for the next 40 years of your life, there is no reasonable explanation.
So what’s the approach?
Rolf Zinkernagel: It’s in a way to create infectious agents that fulfil the requirement of persistence without causing disease.
So sufficiently stimulating throughout.
Rolf Zinkernagel: Correct. For many, many years. But the experience just shows that evolution or co-evolution between let’s say TB or leprosy or malaria, has done an excellent job. Because over many, many years, millions probably, the adaptation has reached such an elegance and minimal entropy level that you virtually cannot improve. Or you have to be extremely optimistic to think you can do better. But it’s not impossible. But it’s just very difficult.
As well as theorising about it are you working on this precise problem?
Rolf Zinkernagel: Yes, we try. We follow certain possibilities, for example, in the virus we use which is called lymphocytic choriomeningitis virus, LCMV, in mice, it has exactly those characteristics. Usually, it’s controlled very well in mice, but then persists at a very low level and keeps up the immune response. We’ve found an unexpected way how virus actually seem, this is an RNA virus, but isn’t a so-called rhetoral virus. It’s not like HIV, nevertheless we find in mice footprints of this virus, but not in RNA form. We also found RNA’s of the virus. But in some cases we find a DNA form of certain viral antigens, which is completely unexpected. So we now try to understand what is going on. And the interesting part of that is that LCMV is highly adapted, like in a way HIV to higher primates is highly adapted to the mouse. HIV in the mouse is completely different from HIV in a rat. And rats and mice are fairly close. And in rats this does not happen. In rats the virus cannot create DNA, in mice it can. It must be highly species specific.
So the problem you’re really battling is co-evolution of …
Rolf Zinkernagel: Yes, in a way. Because at the end of the day both have to survive. And the virus is not interested in killing the host.
You returned to the ETH …
Rolf Zinkernagel: I am actually at the university.
You returned to the university in 1979 and have been there ever since. It obviously provides an environment that suits you well. Is there anything special about it?
Rolf Zinkernagel: I guess it’s a combination of many factors. Both my wife and myself come from Basel, which is about 50 miles away from Zurich. Our kids basically grew up in Canberra, in La Jolla for five years and have now grown up in Zurich, we feel very comfortable. It’s a very interesting, culturally rich university life, small city, it only has about 400,000 inhabitants. But you have two excellent universities. So if you can’t solve or attack a problem, you find somebody to do it with you or for you. So it’s a very good environment. But I think La Jolla was an excellent environment, Canberra …
Wherever you can do good work.
Rolf Zinkernagel: Yes, in a way.
In parallel to your research work you’ve become, especially in recent years, quite a spokesperson for the animal experimentation movement. And also, you’ve spoken out in favour of gene technology. What do you think needs to be done from the research community’s point of view for those causes?
Rolf Zinkernagel: I think there are two major aspects. One is the media, the public opinion side and the other is the research side. I think researchers have to make all reasonable efforts to report and talk about what they do and how they do it. I think some people do that fairly well and others have an intellectual arrogance that is not very conducing to these efforts. So, on the other side you have the media and it’s not a secret, I think this is a worldwide phenomenon that the of course media in very general terms, there are exceptions, but are leaning towards a red/green type of tingeing of their glasses. So basically because of the atom bomb, physics and chemistry is very bad for you because of infections. Science is bad because of …
Chemicals can’t be good etc.
Rolf Zinkernagel: But this of course is over simplified and is not correct in this, but it’s a brave form of formulating the concerns. So, I think that’s one part, and the other part is to report on scandals in science is very attractive to the media, because I think that’s the major justification for media. And the second part is that to report that science is very hard work, very difficult, requires an enormous dedication because in fact 99% of the experiments go down the drain and are unsuccessful. The media are not interested in all that part. They simply pick the few raisons or cherries out of the cake that are enormous. And some of these picked cherries turn out to be rotten cherries. This gives a very strange atmosphere. But I think the sports is the same. As long as somebody jumps eight metres he’s ok, but if he’s doping, of course he is not ok. So I think the same happens with science. And this makes the business very difficult because the third aspect is I think as scientists we must not create hopes that are unjustified. Because that is very dangerous. And I think that happens too often.
Yes, there’s a lot of claim of potential cure.
Rolf Zinkernagel: And this has happened with HIV vaccines for example for many years. And I think we should be much more careful. But then I think we need the honest cooperation of the media because I think it’s, in a way, as much in the interests of the media to make a big splash about some hope. We need some co-evolution I’d guess.
That’s a nice rounding off of things. Thank you very much indeed for speaking to us.
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