Avram Hershko during the interview.

Transcript from an interview with Avram Hershko, 2004 Nobel Laureate in Chemistry, at the 57th Meeting of Nobel Laureates in Lindau, Germany, July 2007. The interviewer is Adam Smith, Editor-in-Chief of Nobelprize.org.

Avram Hershko, it is a great pleasure to meet you.

Avram Hershko: Same here.

You were the co-recipient of the 2004 Nobel Prize in Chemistry for your part in the discovery of the ubiquitin-mediated protein degradation pathway. I would like to start by asking you some general questions.

Avram Hershko: Yes.

When I say the word mentorship, what does that conjure up?

Avram Hershko: Mentorship is important in science. You learn from reading, you learn from experience, you are creative but there is something that you have to learn from some other people. So it can be your supervisor for your PhD, it can be your colleagues, but it is important that you have some people to talk to and some people that you really appreciate. I personally was very fortunate with two mentors who kind of complemented each other. I had a very good biochemist as a supervisor for my PhD, after I did my MD I did a PhD, Jacob Mager who was an excellent biochemist and also a vigorous man., I learned from him to do controlled experiments which are very important.

… in science you need both imagination and to control yourself …

And then I had another mentor in my post-doctoral fellowship, Gordon Tomkins, who had a very broad horizon, a great imagination. On the other hand he was not so strong in controls. So these two kind of complemented each other because in science you need both imagination and to control yourself. So I think I was very fortunate with my mentors.

A nice balance.

Avram Hershko: And then I was a mentor for Aaron Ciechanover but that is history.

So the two mentors you mentioned had very different profiles, Tomkins is very well known, Mager is less known.

Avram Hershko: He is less known. He is very well known in Israel but he was a scientist of the old kind in that he was interested in too many things. So he worked at the same time on about five or six different projects. And because of that he could not of course concentrate on one field and nowadays we have to. But as a student it was very useful for me because I had experience in many fields. So each project was in a completely different field so I got quite a broad education. But because of this he did not make an imprint in the scientific world, I do think he made an imprint through his students. I was his student and Aharon Razin who is very well known in DNA methylation was his student and a couple of others.

So he left a legacy for sure?

Avram Hershko: Left a legacy for definitely.

And as a student were you able to identify that he was too dissipated?

Avram Hershko: Yes, I identified it and I learned from it, so I was not dissipated. I did concentrate on one topic later on. But you know it is fun to be dissipated, it is not so useful.

I fear I know that to my own cost.

Avram Hershko: Yes.

When you choose students what do you look for?

Avram Hershko: I look for somebody who has a genuine interest in science, because that is the only reason to go into science. It is enthusiasm and the interest and being really enthusiastic about it. So I look for that, is he really interested in science? Of course I am trying to see whether he or she is intelligent. Some are very enthusiastic but in a kind of a non … They do not really understand what they are enthusiastic about. And the rest is I think is up to me, that is not having skills with their own hands and that I can teach them so I am not worried about that.

And how do you organise your lab environment? What is your perfect lab environment?

… I think it is our duty to teach the graduate students …

Avram Hershko: I like to have a small lab, I have always had a small lab. I have three to four graduate students and a technician and myself, it was always like that. And I purposefully kept it small because first of all I like to work myself, that is my hobby, bench work and I still do. So if I want to do bench work I can’t have a big group because then I would be busy with so many people. Also, the few students that I have, three or four students I want to give them sufficient attention. So because of that I always kept a small lab all my life and continue today. Also, I did not have too many post docs it was mostly graduate students. I think it is our duty to teach the graduate students.

That is very honourable but at the same time you have trained people in your way of thinking to become very useful around the lab and then you let them go.

Avram Hershko: Well, you have one example, Aaron Ciechanover who shared the Nobel Prize with me for his PhD. It is sufficient time.

It works.

Avram Hershko: It works.

And do you have any other physical principles by which you put the lab together which helps it work? Is there anything in particular?

Avram Hershko: Physical principles, I mean the basic equipment to be close by. Because Israel is a small country so we have to be careful about our equipment. So I teach each student how to use the equipment carefully in a considerate way so that others can use it and in a way that will preserve the equipment. So the lab is not a big lab but we have all the basic equipment and then we are quite careful about maintaining it. If that is what you meant.

That is one of the things I meant yes. Thank you. So let us turn a bit more to your history. You were born in 1937 in Hungary, and you and your family were caught up in the war and swept up in the deportations in the holocaust. It may be a foolish question but can you identify ways in which that shaped your future development as a scientist?

Avram Hershko: I am not sure that it shaped my career as a scientist. It definitely shaped my personality. The way I look at things, what is important, but I am not so sure about science. It was an experience, experience with the Nazis and over this period whether it shaped my career as a scientist … Actually I was interested in many things and I became interested in science only during my medical studies so it was a later event. I went to medicine and then during medical studies I got interested in basic sciences. But I am not sure that my personal experiences in the war shaped that. They do shape my outlook on the world and things like that of course.

What made you choose medicine as a subject?

Avram Hershko: It is a funny story and actually I wrote it up in my autobiography. I was interested in many things. I was interested in history, literature and when I finished high school it was a hard thing for me to decide what to choose. I have an older brother who went to medicine, who was a medical student and he said Why don’t you come to medicine, I already have books for you. So that is how I got to my medical sciences. But when I studied I got interested in the basic aspects of medicine. I finished medicine, I have an MD degree but I never practiced it much.

And you always planned to be a biochemist as soon as you …?

Avram Hershko: Yes, I took off one year, we did not have a formal MD-PhD programme at that time, but I took off one year during my medical studies and I went to a lab and then I knew that I was interested in biochemistry, that was actually already in the lab of Jacob Mager. So I finished medical studies, I finished internship. I think it is a good education, I think, to study medicine, if you want to be a biologist it is not a bad way to do it, study medicine, because you get a deep understanding of one organism, the human body. You learn much more than you can for example in biology, because you learn disciples such as pharmacology /- – -/ pathology, different diseases and then you see patients so you know what are the problems of bio-medical sciences today. I think it was a good way, a good biological education. That is how I look at it.

Interesting, so even if you are not going to practice medicine and you are never even going to apply yourself to clinical problems it is worth having that background?

Avram Hershko: I feel so, yes. I think so. At least for me it worked. Yes, this way, yes.

And bio-chemical approaches, classical bio-chemical approaches have characterised your life time’s work. Jumping ahead, was it a pleasure to you when you were awarded the Nobel Prize in Chemistry rather than in Physiology or Medicine? In a way of recognising that there is a link between chemistry and biology.

Avram Hershko: It was a pleasure. I realise that the Nobel Prize always regarded biochemistry as a part of chemistry, and so it is chemical processes in our body so even though the impact is in medicine, but the discovery was about chemical processes in our body, of protein cell labelled for destruction. As for using our classic bio-chemical techniques I always say that you have do in science what you have to do. So even though there was in the 1970’s, 1980’s a big revolution in technology in molecular biology but I saw that we would not be able to get there without physical biochemistry so that is why I continue to do biochemistry, that was the only way to find out how a completely new system works.

And it is still the case. There are still many genes without function.

… in the beginning the only way to go was by biochemistry …

Avram Hershko: Yes, yes. But now you have a very broad molecular genetic knowledge about the ubiquitin system. So it is very wise now to use also complementation, molecular genetic methods but of course you will need biochemistry in order to find out all the certain ubiquitin /- – -/ or it is regulated, so it is a combination now of biochemistry and molecular genetics. But in the beginning the only way to go was by biochemistry.

Do you still find sufficient numbers of people coming into biochemistry as a field?

Avram Hershko: Well it is more difficult than micro biology. You can not do everything with kits. But I think that people are beginning to realise there are limits to where you can go with genetics. Even with the most sophisticated techniques because we have the human genome but 60% of the human genome is genes of unknown function. And without biochemistry you will never know their function. So I think that people are realising that they have to use biochemistry, not only biochemistry, but in conjunction with other technologies to find out new functions of genes of unknown function.

Do all the new nomenclatures that are coined for subject surrounding if you like, the search for biological principles, systems, biology, functional genomics, these sorts of things? Do you think they confuse the picture a bit? Do you think they make it more difficult for students to know which way they should be heading?

Avram Hershko: Yes and no. To have systems in biology is a good idea, you know, you have to integrate things. I think it might be a bit too early yet you know, because you need to know more to put up with more depths. You can put up more depths when you have got a lot of knowns but when you have a lot of unknowns sometimes /- – -/ do not help you a lot. But in some cases they do. So I think system biology is now being fashionable because it is dangerous and it is good for some purposes and for some other purposes it is a slow /- – -/ which may actually hinder progress. That is my own thought about that.

If we turn to those extremely productive years of 1977 to 1981 when you were sorting out the basics of the ubiquitin pathway, there were really, it turns out, there were a team of three of you and what was it that, was there something special about that combination of personalities which led to the success of the project?

Avram Hershko: Yes, there was definitely a complementation. I was helped a lot by the collaboration with Ernie Rose. Ernie Rose was not in the field at all but I liked him so went to him for a sabbatical. His main work was enzyme mechanisms, that is what he was known for, how enzyme’s work. He has a very critical and sharp mind and I am kind of more intuitive, going by my nose. So I usually did an experiment which was kind of unexpected and he criticised me and that combination of intuitivness and criticism worked very well. And Aaron is a person of boundless energy, Aaron Ciechanover. He helped a lot with his huge energy and enthusiasm as a graduate student. So we all three are different people, three different generations, three different personalities but I think as a team we complemented each other very well.

It seems to have been a very wise choice to go to Ernie’s lab, particularly if he was not in the field, that is quite brave. It is a lovely idea that you go and work with a friend that who is outside the field, but it is novel.

Avram Hershko: Yes, but you know it was, I sometimes make such decisions.

It seems right.

Avram Hershko: I was in the Technion for seven years already and you know, we have a sabbatical every seventh year. And there was a small community of people who were interested in protein degradation and the field was quite awful at that time. Everybody had a pet theory without any basis or experimental evidence. So I did not feel like going to one of the people who were in the field of protein degradation. And I happened to meet Ernie Rose in a meeting a year before my sabbatical and we began to talk and I knew him, he was working on enzyme mechanisms, and I asked What else are you interested in? And he said that he was interested in protein degradation. I asked him How come you have never published anything in protein degradation? He said that “There is nothing worth publishing on protein degradation!”

He was interested because he was with a young investigator, he sat right next to Mel Simpson at Yale University, and Mel Simpson found, made the initial observation that when you add inhibitors of energy production to liver slices the degradation of protein stops so that integration was energy dependent. And then Mel Simpson went down to other things, protein synthesis and Ernie went down to enzyme mechanisms but he kind of, from time to time, he did some experiments on why energy is needed for protein degradation. He did not get anywhere so he did not publish. And he also saw that the field is not so good so that is why he say nothing is worth publishing on protein degradation. I like that. I like that he is a character and I thought to ask him Can I spend a sabbatical in your lab? and when I got there we already had the initial fractionations, fraction one, fraction two, and by the end of the sabbatical I asked him Can I bring my student over? and I brought over Aaron and that is when we made the breakthrough.

And was it counter intuitive finding that protein degradation required energy that had drawn you into the field? Was that what attracted you?

Avram Hershko: Yes, that is what attracted me … I would not think it is counter intuitive, it is counter what was known about the properties of protein, so it is giving you a clue that it is some kind a completely new mechanism. That I found with Gordon Tomkins, when I was a postdoc with Gordon Tomkins. And when I found it I actually found it earlier, similar observations were made by Mel Simpson so I was quite ignorant when I did my experiment. Energy inhibitors to liver cell cultures and found that the degradation of a certain enzyme tyrosine aminotransferase requires energy I was quite surprised because I thought it would be the opposite. But then I read up the literature and found that Simpson had found it.

Now Simpson saw that it means that protein synthesis is needed for protein degradation. But then I did an experiment, we had a good inhibitors of protein synthesis /- – -/ so then I saw that this was a completely new mechanism in which you need energy and it made sense because you need energy for selectivity and degradation of several proteins are highly selective. As opposed to the question of trypsin for example. So it was not counter intuitive it was a kind of a lead that gave me the thought that we had to look for a new system. And that is when I saw that I have to use biochemistry. So the original observation was actually made in culture cells.

And the selectivity of the system turns out to be much bigger than one ever would possibly have imagined. I assume that is the case? As the field has expanded and has come to take in lots of medical applications, have you moved with the field or have you stayed at the basic mechanism?

… I do not know if I moved with the field but I moved ahead …

Avram Hershko: I do not know if I moved with the field but I moved ahead. Before that I went to work on the basic mechanism, but in the last 50 years I am working on the roles of the ubiquitin system and cell division in the cell division cycle. Because I was impressed by the finding of Tim Hunt of cyclins, a protein that is degraded at the end of mitosis. And he thought, he called it a cyclin protease but I saw that it must be the ubiquitin system so I began to work on that again by biochemistry. I used extracts from clam ocytes that were found by Joan Ruderman to facefully reproduce programmed cyclin degradation and so I found that ubiquitin mediated and there is a ubiquitin /- – -/ and shortly afterwards similar findings were made in the laboratory of Marquez in Harvard. So it was discovered at the same time. But I definitely went on from the basic mechanisms to the roles of the system in the cell, division cycle and that is what I am still interested in.

And was it the combination of the fact that it was Tim Hunt’s observation that brought you into the cell division field and your need for clam eggs that took you to Woods Hole on a regular basis?

Avram Hershko: Yes, correct. Because at first I tried to do it, I was on another sabbatical in Fox Chase and I tried to bring the clams to Fox Chase and then I found out it is much easier to bring myself to Woods Hole because you need a big supply.

And you go there every summer, is that correct?

Avram Hershko: Every summer, yes. I work there. It is a wonderful place to work.

What does it give you? Apart from the raw materials, what else does it provide?

Avram Hershko: It has a very great environment, scientific environment. Also in the summer lots of activities, excellent summer courses. Sometimes I go and hear lectures in the course of the students, good lectures. Very peaceful environment and for me, coming out from that pressure cooker of Israel, to get away, to a peaceful place for two months it gives you lots of stimulation in the way to think, to work. Also it is very convenient as I said I love bench work and I have there a small lab and I do experiments. It is all very close so we give the students quarters and my wife and I, there is dormitories there and the lab is 100 yards away. So I just, after dinner, go back and finish an experiment and it is all very convenient.

Do you work alone there?

Avram Hershko: I work alone with my own hands and I usually bring a graduate student because I think it is a good exposure for a graduate student to see what is going on there. As I said there is great activity of summer courses and good lecturers that are brought in during the summer. So both for work, together with me because it is a small lab, I rent a lab and you pay by the square feet so it has to be small. And when it is small it has advantages because I sit right next to the student so I tell him you do not hold the pipette in the right way and things like that.

Marvellous training for the student I guess.

Avram Hershko: Yeah usually it works well yes. I think I already brought four students in the past 12 years. They are used to it.

And then come the autumn it is back to Technion and I wanted to ask a little bit about that because it was quite a brave move to take the position at Technion originally. What prompted your decision to go there where you had to set up your own department in an engineering based university? What decided you to choose Technion in particular? Rather, for instance, I do not know, Hebrew University which already had a department.

Avram Hershko: Well it was, the story was a miscommunication. That is Mager, my mentor told me that he has this position for me at Hebrew University but he hated to write letters, at that time there were no e-mails, it was only letters. So post doctorate periods at that time were two years, not five years or more than that, like now. So after a year and a half I wrote him a letter, do I have a position? I got no answer. I wrote him another letter, no answer.

He was too busy.

Avram Hershko: I got his offer from the Technion because they started a new medical school so I said Ok. And then I got a big letter from Mager and it turned out that they had a position and he prepared the lab and everything so it was a case of a miscommunication, I suppose he just thought that it was clear to me that there is a position for me at the Hebrew University, which there was. They had a 10 year position and everything was prepared actually, the lab too.

So I was kind of left with my own system and without input …

But there were no phone calls at that time, only letters, and he hated to write letters. So that was to my … Looking back and I wrote it in my autobiography, I think it was good for me because Technion was a centre of technology but not of medical sciences. So at first kind of isolated new medical school, Technion, and sometimes isolation is good for you. ‘Splendid isolation’ as the British call it maybe. Because you do your own work, you are not bothered by anything else. So I was kind of left with my own system and without input or without any disturbance from others.

A little Woods Hole in Haifa.

Avram Hershko: Yes, in Haifa. Actually it was kind of like this Gregor Mendel … it was even a monastery, because until they built the medical school they put us in an old monastery that was used by the Vatican as a Christian school for girls. But then they ran out of students and so they rented it out, in this case to Technion. They never sell anything, they rent. So the whole ubiquitin system was discovered in that monastery.

That is a nice connection to the peace and quiet.

Avram Hershko: So you do not always need big buildings to do discoveries. And sometimes I think isolation is good for you when you work on a new field.

And you have been able to develop …

Avram Hershko: Because whenever I went to Jerusalem or to Weizmann they told me Why do you do old fashioned biochemistry? And I think, I still think that “old fashioned biochemistry” is what really allow the breaks.

And so now your department at Technion is the centre of old fashioned biochemistry.

Avram Hershko: Now my department and Technion medical school is one of the centres of bio-medical sciences in Israel. So you do a lot and also many /- – -/ people came in and still continue to do biochemistry because they know how to do that and not many other people know how to do that and they believe that it is needed. Right now I am working on the cell cycle and working on a certain aspect of a check point that is how certain ubiquitin ligase is regulated by the state of the mitotic spindle it is called the mitotic spindle assembly checkpoint. Which is very … It is a field in which many people work but most people do genetics or cell biology and I think that we have to learn, use again biochemistry to know how the system works, how the attachment …

It is the system that monitors the attachment of the chromosomes to the mitotic spindle and only when the last chromosome is attached to the spindle then these ubiquitin ligase that are loose exits from mitosis are deactivated, a ubiquitin inhibitor. And it is a very intricate system and dozens of proteins have been identified by these genetics and by /- – -/ in experiments but it is really not knowing how it is working. So it is like you have a play, you have a Hamlet but you do not know you have the bad king, the bad queen and you have Ophelia, but we do not even know what they are doing. So you know all the players but in order to find out how do they act you need biochemistry. So I am again applying biochemistry to a biological programme.

So this is really putting together the nuts and bolts of the error correction mechanism?

Avram Hershko: Yes. And for that I believe we need biochemists so I am doing that.

So one final question, the state of Israeli science and your hopes for how that will continue. Do you feel that things, there has been an incredible increase, exponential growth in Israeli science, is that set to carry on?

I still think that the limiting factor in science is the brains and not the machinery and not huge grants …

Avram Hershko: I hope so. Of course you need the resources and Israel is a small country. But I do believe that you can do good work with less resources, cannot do good work without any resources, but if you think well you can design experiments without wasting too much money and then you can do with smaller grants and small resources you can do with science. And I still think that the limiting factor in science is the brains and not the machinery and not huge grants. And they believe that Israel can make more contributions with its limited resources. Even though it is a small country and has many other problems.

I suppose the only potential problem on the horizon is the brains are being attracted away to the big jobs elsewhere.

Avram Hershko: There is always a brain drain, we have a good system, it is called a long fellowship. It is given by, it was made by some very wise people who viewed their faculty positions to post-doctoral fellows who come back to Israel. And the faculty position is given for three years so the university does not have to pay the salary for three years, or so they get some start up money provided that the university guarantees that it is a ten year tech position. So about ten or twelve are given out each year. And they are so prestigious that universities will find, even though they are hard up, they will find a position for that. And because of that the best can come back if they want you know. The best, the very best.

That is important.

Avram Hershko: And it is important, yes.

Yes. Ok, well thank you very much indeed for speaking to us.

Avram Hershko: Ok.

And I hope to see you again.

Avram Hershko: It was a pleasure.

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