"Do what's important, not what's fashionable"

Avram Hershko  photo: Vincent Ma

Israeli Nobel laureate in chemistry Avram Hershko talks forthrightly about peace, democracy, academic independence, and how to do science.

In the middle of our conversation, Prof. Avram Hershko, Nobel laureate in chemistry, apologizes: we have to take a short break because the clock shows that a stage in an experiment he is conducting in the laboratory next to his office has finished, and he needs to go and transfer the proteins to the next stage. He invites me to accompany him to the seemingly simple laboratory, and explains to me what he is doing. It's a little hard to stifle the excitement at the situation: being present at an experiment by a Nobel prizewinner. Hershko, with precise movements, transfers his proteins to the next stage of the experiment, and remarks as he does so: "I try to do an experiment every day. It excites me."

He still gets excited, as though it were the first time, as he describes the discovery that brought him and his colleagues Aaron Ciechanover and Irwin Rose to the ceremony in Stockholm in 2004: the process of the degradation of proteins within cells, a fascinating deciphering odyssey that he spoke of at November's "Science without Borders" event held jointly by the Israel Academy of Sciences and Humanities and the Institut de France, Academie des Sciences, and attended by Israeli and French Nobel laureates.

Hershko's office is at the end of a laboratories corridor in the Technion Israel Institute of Technology Faculty of Medicine, where young researchers pore over their research projects. It's a modest room, with shelves laden with uniform-looking black files. These are research diaries, about 90 of them, mostly handwritten. "I can't read them anymore, but my students can," Hershko jokes. The walls are full of photos of children and grandchildren, and paintings they have painted over the years. One that catches the eye is a painting by one of his children at the time of the visit to Israel by Egyptian president Anwar Sadat in 1979, a painting expressing hope and peace.

The idyllic appearance and the tranquility are misleading. Prof. Hershko is a very worried man these days. For years, he has refrained from speaking out, "because I thought that it wasn't fair, that I'm not an expert on politics." Now, however, he feels he can no longer ignore the way the wind is blowing outside his modest, almost Spartan, ivory tower, and most of all the approach of Minister of Education Naftali Bennett, who greeted the universities at the start of the current academic year with a declaration that he had "broken their cartel," and that he was striving to reduce their power in favor of the academic colleges. In the background is the minister's desire to promote Ariel University and also to help the Interdisciplinary Center, Herzliya.

"I think that this remark, 'We have broken the universities' cartel' is revolting," Hershko says. "A minister of education shouldn't talk that way, and shouldn't think that way. He is not worthy of being minister of education. It's terrible to let a person like that become minister of education. The universities are the glory of Israeli science. The colleges are important too, but there's no reason to set the colleges against the universities. If he strangles the universities and sees it as a personal achievement - that's extremely bad.

"Politics must not be introduced into the academy. If research and teaching at the universities are to be at a high standard, the universities must be supported, and certainly not strangled. It's important to allow academic freedom. I'm head of the department (biochemistry), but each of the researchers researches what he or she wants. By the same token, the Ministry of Education should support the universities, but at the same time give them freedom. That's how it ought to be, and that's how it always was. Politics in the academy is a terrible thing. The ethical code he adopted (which, among other things, restricts lecturers in expressing political views) harms academic freedom, and I'm very angry about it."

Hershko's hard feelings about the situation in Israel caused him to break his longstanding custom of keeping his opinions to himself, which he maintained because he felt that even though he was a scientist of international renown, that did not give him any advantage in political understanding. A few months ago all that changed, and Prof. Hershko joined the Labor Party, with the intention that his joining should represent a kind of statement. As far as he is concerned, the breaking point has been reached. "I thought that it was no longer moral to keep silent," he explains.

Why now?

"Because the situation has become worse. Extremism is taking over everywhere, in the shape of the anti-democratic laws they want to pass. I think that democracy is in danger, that the Supreme Court, which was part of the State of Israel's resilience, is in danger, that education is in danger, and that our future with our neighbors is in danger. I'm very concerned at the fact that there is no dialogue. I don’t say it's easy to make peace. I don’t even say it's possible. But we have to try, we have to talk. And the leadership here evades this, it acts completely irresponsibly. I'm not thinking of myself, I'm at the end of my career, but I have children and grandchildren who live here, and I think about them. I'm not naive. I know that if we don't defend ourselves, they'll kill us all. But look, we made peace with Egypt. It worries me that we'll live by the sword for ever and ever."

Hershko chose the Labor Party not because he identifies with it down to the last detail, but because it seemed to him "a sane, centrist party." The choice did not come easily. "I was at a political circle in someone's home, and I stated that I wasn't happy with Avi Gabbay, because he wouldn't declare his intentions about dialogue with the Palestinians. They said fine, Avi Gabbay will come to you at your home. I asked him if he would make such a declaration, and he said yes, he would, so I said alright, I'll join."

Post-Nobel crisis

Although he has turned eighty, Prof. Hershko continues to work as usual, comes every day to the cluster of laboratories and to see the students he supervises, and to the almost daily experiments that he carries out. At the Technion, he explains, there are five-six professors who are called research professors, who have special achievements to their names, and who are not obliged to retire. Each year they have to apply for a year's extension, "so I have been applying for an extension for fifteen years, and I mean to continue doing so," Hershko says with humor. Hershko's co-winner of the Nobel prize Aaron Ciechanover (along with Irwin Rose of Philadelphia) enjoys the same status. Hershko, it should be mentioned, received this status before the three men were awarded the Nobel Prize in 2004.

What research are you currently working on?

"It's a continuation of my previous work, in a new direction. After the Nobel Prize, there's a crisis of course. What do I do now? How to carry on with life, particularly from the point of view of work and research. There are those who stop doing research and start making appearances, and there's no lack of invitations. There are those who go into academic administration and become heads of institutes and that kind of thing. Some continue with research, but in a completely new direction, like Francis Crick, a molecular biologist (who, with James Watson, won a Nobel Prize for the discovery of the structure of DNA in the 1950s) who wanted to do brain research, but didn’t succeed. It was too big a leap. Some continue with the work they have been doing, which is a little boring. And there are those like me, who continue to work and do research in a different direction, but based on what I know."

To understand the new direction, it is necessary to understand the discovery for which Hershko and his colleagues were awarded the Nobel Prize, and Hershko will shortly pull out one of his black files and show me history as it happened. First, though, we shall ask how winning a Nobel Prize affects not just life in research, but one's personal life as well. "Personal life? In the first year I received dozens of invitations to be a guest speaker and open conferences. At first I accepted them, but then I saw that basically they were inviting me as decoration, and I got sick of being a decoration. I come to a conference, open it, and welcome the participants. And what conference is it? A conference of gynecologists. What do I know about gynecology?"

And has the prize made any difference financially?

Hershko laughs. "The prize is a million dollars, and three winners shared it. So each one received $330,000, and I have three sons to buy homes for. So each son received a third, which is a small part of the cost of an apartment. We didn't make our fortunes from that."

You won't hear bombastic declarations from Prof. Hershko about how he always wanted to be a scientist and a researcher, or fine phrases about a sense of mission. He was born in late December 1937 in Karcag in Hungary. At age six, he was incarcerated with his mother and brother in the ghetto that was set up in the suburbs of the city - his father had previously been taken away for forced labor in the Hungarian army and fell into Soviet captivity. Of this period, Hershko says, "I remember only pictures here and there." When he was twelve, the family immigrated to Israel and settled in Jerusalem. His elder brother, Chaim Hershko (who eventually became a professor of hematology), pushed him towards medical studies. "When I was a student in high school, I didn't know what I wanted to do. I thought of becoming an archeologist or an engineer, but my brother knew from age five that he wanted to be a doctor, and when I shared my vacillations with him, he said, why not study medicine? I already have books for you. So in my case the whole choice was happenstance."

During his studies, he found that what particularly attracted him in medicine was the scientific part, and he decided to go into medical research, although he did finish his medical studies, and even did an internship and served as a doctor in the army for a certain period, as he studied in the framework of the academic reserve. "I think that medical studies are a good basis for anyone who wants to do research in biology," he says. "You take just one creature, the human being, but you learn it very thoroughly, how it works and what can happen when this machine doesn't work."

When the Technion was a village

After the army, he returned to the Hebrew University for research under Prof. Yaakov Magar, did a further doctorate, and then, "as usual, you leave for post-doctoral work." Hershko did this at the University of California, San Francisco, with a well-known researcher, Gordon Tomkins. Tomkins worked on mechanisms of protein synthesis. "When I arrived, I saw that there was a huge group, 25 post-doctoral researchers all working on protein synthesis using slightly different methods. I told him that I didn't want to do what everyone else was doing. So he said, 'Fine. Work on the reverse.' And it turned out well, because I started to become interested in protein degradation, and there were very few people interested in protein degradation at that stage."

Eventually, the mechanism he would discover with his partners would become the basis of, for example, Velcade for the treatment of myeloma blood cancer. But Hershko wasn't thinking about drugs and future uses. "Any great discovery in basic science eventually has a use. But if you think about the use from the beginning, it wrecks the research. There's a trend now called translational research, in which research doesn't start unless practical applications are envisaged. Mostly, it fails. You have to do research without thinking about applications. The applications will come."

So you didn’t think about usefulness, but you were confident that the world would know what to do with it?

"I didn’t even think about that. I thought it was terribly interesting, how proteins degrade."

The first clue in the deciphering process was the discovery that it takes energy to degrade proteins within the cell. "That was surprising, because it was known that protein degradation outside cells actually releases energy. I thought that perhaps the energy was needed for control, for order. In physical chemistry there is the concept of entropy, meaning that without an investment of energy, everything is in disorder. Order requires energy." And it was clear that there was some order that determined when to degrade which protein out of the 25,000 proteins in our cells. "I thought that the energy was a clue to how it happened."

With this discovery, he returned to Israel. "I was supposed to return to the medical school in Jerusalem, but my teacher, Magar, didn't like answering letters. I wrote to him, 'How are things? Is there an appointment for me?', and he didn’t answer. I wrote a second time; still no answer. Meanwhile, they opened a new medical school here (at the Technion), and invited me to run the biochemistry department. Later it turned out that Magar had organized a job and laboratories for me; he just didn't like writing letters."

And are you sorry or glad about that?

"Looking back, it was good, because sometimes isolation is good for originality. In Jerusalem and at the Weizmann Institute there was serious medical and bio-medical research, and here it was a sort of village. And precisely because I was stuck here and didn't talk to anyone apart from my students, I worked on things that there they might perhaps have said weren't worth working on."

At a certain stage, he met Irwin Rose, then a researcher at the Fox Chase Cancer Center in Philadelphia. Rose was doing research on enzyme mechanisms, but one day, at a conference, he and Hershko shared a table at breakfast, and Hershko asked him, "Tell me, is there anything else you're interested in?" and Rose said, "Yes, protein degradation." "I asked him, 'Then how come I've never read any article of yours on the subject?', and he said, 'There's still nothing worthy of publication on protein degradation.' I liked that, and I said to him, 'Perhaps I can work with you.'"

Hershko traveled to the US to work alongside Rose, bringing with him his student Ciechanover, and they worked as a team. In 1979, "came the breakthrough in which we understood how the system worked." They discovered that a certain substance called ubiquitin - which they already knew played a part in the degradation process, but not how - attaches to the proteins and signals to them to degrade. That is to say, this substance is responsible for all the order in the process, "and we also understood why this process requires energy."

It took ten years to go from this discovery to a general understanding of how the process works. After that, Hershko took this understanding and went on to the next stage, on which he has been working "for about 30 years" - the part played by this system of protein degradation in the division of body cells. "This is a process that has to be under control, because if there is no control, and cells divide uncontrollably, we have a disease (cancer). I'm not a cancer researcher, but I research the mechanisms in a healthy person that determine whether a cell divides or not. For example, brain cells do not divide, but bone marrow cells do. And how is the ubiquitin system involved in this? Because in order for a cell to divide, certain proteins have to degrade with very precise timing."

The millions didn't reach me

Hershko and Ciechanover's discovery formed the basis of one of the most important cancer treatments, Velcade, for treating multiple myeloma (a cancer of the plasma cells), which became something of a blockbuster for its developers. One of these developers is Julian Adams, whose background is in the US biopharmaceutical industry and who is currently CEO of Israeli company Gamida Cell. Adams related in an interview with "Globes" magazine "G" how this drug was born out of a conversation with Hershko, or, more precisely, how the understanding dawned that the right use for it was for cancer patients. Hershko, Adams said, was just then working on an experiment to examine how cell division is inhibited through the mechanism he had already recognized.

Do you remember that conversation?

"Certainly. They wanted to develop a treatment for muscle atrophy, and they injected the drug into mice, and the mice died. This was a drug that prevented protein degradation, and I already knew that the protein degradation process played a part in cell division. So I said to Adams that perhaps he should test the drug for cancer. And that's what he did, and he made many millions of dollars. He didn't give me any - don't tell my wife that or I'll get into trouble - but I have to say that he remembers it and mentions it at every opportunity. And that's nice for me too. I know that my work, in which I researched things to satisfy my curiosity, in the end helped sick people."

Isn't it a bit of a shame that the drug you were involved in wasn't developed by an Israeli company?

"I publish my findings, and the moment I publish, they belong to all mankind. There was no Israeli company that could have used it, and I certainly wasn't going to found a company. Today it works a bit differently, today the institutions of higher education encourage registration of patents and form companies. But I have mixed feelings about this, that I'm not sure that Globes readers will like."

Try them

"I think that in the academy we should be doing academic research. If we start forming companies and commercializing the knowledge, and especially when it happens with young researchers who haven't yet established themselves, it harms basic research. Before a researcher starts on research, he or she is already looking for entrepreneurs and investors and checking where the money is. In my view, for the first ten or twenty years after a doctorate, people should focus on basic research, and only after that turn to commercialization. I don't think that just because I'm old. I think that because, still, the great advances in science are achieved in basic research. If basic research is smothered and people want to reap the practical fruits too early, science will not advance."

So what do you recommend to young researchers who want to do something significant?

"Not to get caught up by fashions. Just as there are fashions in clothes, there are also fashions in science. It's hard to swim against the tide, but you have to do not what's fashionable but what's very important."

And are you among those who claim that the universities in Israel are not producing the next generation of Israeli Nobel prizewinners?

"If you're asking whether we have enough talented young people - there are lots. There's no problem as far as talent is concerned. There is a problem with the environmental pressure on the hot topics, and there's a budgeting problem. In the past there were ups and downs in the budgets for higher education, and now we are again on a down. It's harmful. Research takes money, and a university is also something that requires money. You need a critical mass of researchers in the various disciplines. I have a friend who teaches history at the Hebrew University, and he told me that every time a history professor retires, no-one is appointed in their place, and it won't be long before there is no-one to talk to. Unless there's a critical mass for exchange of ideas, it's hard to make progress in research, in thought."

What are today's major trends in science?

"One of them is brain research. The brain is the most important and most complicated organ we have, and I've heard all sorts of promises that within ten years we'll know how the brain works. In my opinion, in another hundred years we'll know a little. I'm not saying we shouldn't research the brain, but the amount of noise around it and the resources allocated to it are overdone. There are some nice advances and there are certain things that can be discovered, but it's ambitious to aspire to see how the whole machine works. The approach has to be gradual. To break through one wall and clear up the debris, and only then to break through the next wall, and there are thousands of such walls until we understand how the brain works. A little modesty is in order.

"Another thing is systems biology (which examines relationships between the various biological systems, mostly using mathematical models). Here too, there's a desire to understand the entire system. People construct mathematical models are very pleased with them. But mathematical models can only be constructed when there's a small number of variables. It's hard to solve an equation with 150 unknowns. This is also beautiful territory, but here too we have to advance slowly.

"The classic approach of science was the reductionist approach. You understand one thing, take one step, and only then do you go to the next step, and in the end you put all the steps together. That's how we worked and that's how all the great biomedical discoveries were made. It exactly the opposite of the generalized approach they work with today in brain research and systems biology.

"So I always tell young researchers, choose a subject that you believe is important, and that is still not mainstream. So then they ask me, what about publishing and promotion? And I say it's tough, but possible. At least I hope so."

Why should originality hinder promotion?

"At present in our universities they use a method of evaluating researchers' publications (a rating of professional journals according to academic prestige and similar criteria). If they had done that to me when I was young, I wouldn't have received tenure, because I didn’t publish in amazing journals. I'm aware that this is done because the universities themselves are ranked in international rankings according to these criteria. But because the system is based so much on formulae and numbers, and not on the articles themselves, young researchers don't dare do original things that might not be accepted by the most respected journals."

Is there another method of evaluation for promotion?

"At one time you would simply read the articles, and get other senior researchers in the field to read them to see whether they were important and innovative or not."

The full version of this interview appeared in Hebrew in "G" magazine on December 7, 2018.

Published by Globes, Israel business news - en.globes.co.il - on January 8, 2019

© Copyright of Globes Publisher Itonut (1983) Ltd. 2019

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Avram Hershko  photo: Vincent Ma
Avram Hershko photo: Vincent Ma
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