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Nobel Laureate Avram Hershko: The Orchestra in the Cell

Nobel laureate Avram Hershko, who determined cellular mechanisms for breaking down proteins, talks about his research in a conversation recorded at the Lindau Nobel Laureate Meeting in Lindau, Germany. And Scientific American Editor in Chief Mariette DiChristina discusses the recent inaugural Google Science Fair

Nobel laureate Avram Hershko, who determined cellular mechanisms for breaking down proteins, talks about his research in a conversation recorded at the Lindau Nobel Laureate Meeting in Lindau, Germany. And Scientific American Editor in Chief Mariette DiChristina discusses the recent inaugural Google Science Fair

Podcast Transcription

Steve:          Welcome to the Scientific American podcast, Science Talk, posted on July 27th, 2011. I'm Steve Mirsky. This week on the podcast:

Hershko:          So you turn on a machine by making a protein and then you have to turn it off, so I liken it to an orchestra. In the symphony you have, this side is a huge orchestra with thousands of players—they are the proteins.

Steve:          That's Avram Hershko, who won the Nobel Prize in Chemistry in 2004. If you have listened last week you know that I was recently in Lindau, Germany for the 61st annual Lindau Nobel laureate meeting, which this year featured laureates in Physiology or Medicine and in Chemistry. Twenty-three Nobel winners lectured and schmoozed with more than 550 graduate students or post doctoral fellows at the beginning of their scientific careers. And I had a chance to catch up to a few of the laureates between events—interviews I'll be rolling out over the next few weeks. Later in this episode, Scientific American Editor in Chief Mariette DiChristina talks about the Google Science Fair, but first up is Avram Hershko. He shared the Nobel for the discovery of the systems whereby cells break down proteins. We spoke, as you'll easily be able to tell, in the restaurant next to the Inselhalle, the site of the Lindau meeting.

Steve:          When you were doing your work for which you were awarded the Nobel Prize, everybody was looking at the synthesis of proteins, and you went with very few other people in a different direction to look at the degradation of proteins. Is that your nature to go in a place where no one else is or was it something specific about this problem that caught your attention?

Hershko:          Well, it's not my nature, but in science I think that you should find unique problems, and you should find a niche, which is not in the mainstream. I believe in that especially for young investigators. Because to go with the mainstream, it's not so great, you know; people are already interested in that and if you want to make a discovery, you should find something unique which is not yet in the mainstream. It will be later on, but it is not yet in the mainstream. So proteins were important. It was known they are the so called machines of the cells, if you know about DNA. DNA is the genetic information. It is really the blueprint, but it is a blueprint for making proteins. So proteins are well known to be important. And of course, it's very important to know how proteins are made based on their genetic information. But it was already known that some proteins are degraded, and it was clear that you can have important control mechanisms, right; so it was an important problem, but not yet in the interests of the mainstream of science. I thought it was a good problem. It's not in my nature, but I think it's a good idea for young investigators to look for unique problems which are important but not yet in the mainstream.

Steve:          Now, the reason why it's important that proteins can not only be assembled but be taken apart is there's machinery in the cells that should not be there except under special circumstances.

Hershko:          Yes, that's correct. So there are two main reasons. One is to get rid of bad proteins. So proteins have to, after they're made, they have to fold in a certain shape, and the shape is actually important for their functions. When they're defective they have to be removed because they can get in the way of good proteins. So, abnormal proteins have to be removed. So that's one important function, to remove damaged proteins. But protein degradation is not just waste disposal to remove damaged proteins; it's also like a switch. So you turn on a machine by making a protein and then you have to turn it off. So I liken it to an orchestra in the symphony, you have, this side is a huge orchestra with thousands of players—they are the proteins. A certain player has to play a tune at a certain time, then it has to stop; if he doesn't stop, he ruins the symphony. So the stopping is very important also. That is the regulation part of the functions of protein degradation.

Steve:          So, examples of the kinds of cellular apparatus that have to be turned off would be, for example, during mitosis: You don't want mitotic machinery around all the time.

Hershko:          Yes, actually, I worked on this problem after we found out the basic machinery, how does it work? As an example, I looked at an important role of protein regulation in cell division and some regulators of cell division are made before mitosis, before the cell divides. But then they have to be turned off, in order to get out of mitosis and that turning off of some proteins called cyclins, that were discovered by another Nobel Prize laureate, Tim Hunt; so the turning off of these regulators is done by the degradation exactly at the time, the right time of the cell cycle when it has to be degraded.

Steve:          We have certain compounds that are therapies today, certain medicines, that work by interfering with the breakdown of proteinaceous structures.

Hershko:          Yes, it usually happens in science, you know. Scientists are doing fundamental science or basic science. They're trying to understand how nature works, but eventually all this knowledge will help in the development, it will help mankind. So it's a lengthy process. In our case, it took more than 30 years, but eventually all this knowledge is now being converted to drugs that are effective. There is already one drug that inhibits a certain enzyme in the system—the proteasome—it is very effective against a certain cancer, a bone marrow cancer called multiple myeloma; and this drug actually changed the treatment. They revolutionized the treatment of multiple myeloma together with some other developments. So now many people can have many more years of good quality life, and they're very happy about it.

Steve:          Which drug is that?

Hershko:          The name, I don't want to advertise but the name is bortezomib or Velcade, and it's a proteasome inhibitor used for the treatment of multiple myeloma.

Steve:          Yesterday, when you were talking directly to the students, you talked about how research should be fun and exciting.

Hershko:          Yes, I believe in that. I think that discoveries, that the main motivation for discoveries, is curiosity. You should be curious like a child, and you should try to satisfy your curiosity. You should be excited about whatever you're doing, what you're doing. And I told it to the students, because there's also lot of chores I call them, you know, in science we have to publish papers, we have to fill grant applications and all these are very important, but we should not let—and they tell that again and again, because this is the daily life—we should not let our work be dominated by our chores. These have to be done, but our work should be directed by doing exciting work of trying to find out things that arouse our curiosity. That is the way discoveries are made.

Steve:          You mentioned grants. I want you to just briefly discuss the fact that you have at times been funded through what are called foreign grants from the United States National Institutes of Health, and I think some people might not know that the U.S. Government funds research in other countries. We have people in America who don't even want the NIH to fund Americans, so could you talk about what the NIH's funding of foreign researchers enables around the world?

Hershko:          Yes, I see that you did your homework because I actually, in my biography, I thank the NIH for the very generous help, you know. These are American taxpayers who helped me do this research, and I hope that now it is being given back to the American people, by for example, by using these new drugs that are based on our research. So the research grants usually are very small. Now they're about $40,000 a year; when I started it was $10,000 dollars a year, that is not much, not really enough to do work, so I was looking for other sources, and actually some American friends knew about this foreign research program of the NIH and advised me to apply for an NIH grant, which is not easy to get. Also, the foreign research grants are not as big as the grants for Americans, but they're sizeable. It was really significant, so even though I was kind of doubtful whether, why should American people, you know, support foreign scientists? I applied for it and I got it and I must say, I got it for five consecutive grant periods. So I crossed three years, another three years, another three, then it went on for 15 years, and I think that was crucial for the discoveries that I made—the help of the NIH. So I think the American taxpayers should know about it. It is not given out easily, it is given out only for things that the NIH thinks that there is some knowledge or there is some expertise that is outside of America; and in that case, I guess, it is what the committees decided. So I am very grateful for that. But it does help in certain cases, scientific work and basic research, in that case, outside of America. And I think that is not only very nice, I think it's very wise, because that is one way to help mankind, as it turned out in this case. So I am very grateful to the NIH and then very grateful to the American taxpayers for helping this work.

Steve:          As one of them, let me speak for everybody, which I shouldn't do, but let me speak for the taxpayers—we're grateful to you for your work as well.

Hershko:          Yeah, it is really thousands of people now who are treated with this drug and greatly benefited from them.

Steve:          That's great. I just want to wrap up. Your last line from your official Nobel biography, it's a bittersweet kind of understatement where you say, you talk about, you know, the wonderful life you have now and the research you did and the excitement of it and the sense of satisfaction, and then you say, "If only there was some peace in the world, I would be completely satisfied."

Hershko:          Yes. I think, you omitted three words there, as I remember, I wrote, it was including between Israel and its neighbors, yeah, yeah. So we are living in a very troubled world, you know. We have really grave problems, you know; we are facing crisis in the economy, in energy availability. All these are really nothing as compared to the animosities that there are that exists between different cultures, different natures. And we should do more about trying to decrease this animosity to bring about more peace now. How it is done that is beyond my control, but I'm definitely trying to join a different effort for making peace. So, yeah, I say that I was very lucky in my life, in my personal life, in my scientific life, but I would be even happier, if more was done for peace among nations.

Steve:          Let's also, there's a great story you tell about meeting your wife. You literally bumped into your wife, who was working in a hospital for a year.

Hershko:          Yes. That is one of my lucks. I was a medical student, and I needed some sample of blood for my research, the research I did as a medical student. So, I went over to the hematology lab, and it turned out, Judy, my wife of 47 years now, came over from Switzerland for a year to work and live in Israel for a while. She wanted it to be just a visit, and then she held a tray, okay, and I bumped up the tray, not intentionally, but then I helped her to pick it up you know, like in some old movies, and that was the beginning of the lifetime association, and of having a wonderful family of three children and six grandchildren.

Music

Steve:          Next up, Mariette DiChristina, she's the editor in chief of Scientific American. She was recently a judge at the first Google Science Fair.

DiChristina:          This is the first year Google had a science fair. And they did a virtual science fair, of course, because it's Google. And it was launched in January of this year, and it was a world open to every student around the globe, 13 to 18. So, three age categories: 13 to 14, 15 to 16 and 17 to 18. And Google drew 7,500 applications from 91 countries, which is really excellent for a first year out.

Steve:          And you were one of the judges?

DiChristina:                  I was one of the judges. The idea here was that students could enter their science fair projects and you know, many students would like to participate in science fairs, but they don't do them in their schools; or in many countries, it's not such a tradition as it is here in the U.S. too. So it sort of opens new doors for people to be able to display their things using free Google tools. So the students could, you know, Google set it up so they could put the information about their projects all online. They could do a video, they could do a slide show, once they had done their experiments and it was an easy way for everybody to be able to see and enjoy them.

Steve:          And did Google bring the finalists out to California?

DiChristina:                  Yeah. So the launch event was in New York, at the Google offices there, and the finalist event was on Monday, July 11th. And actually, it started on July 10th for the finalists. There were 15 finalists, five in each of those three categories. The students were flown in from all over the world. There was a student from Singapore, a student from India, one from South Africa, and students from the U.S. and Canada, as well, among those 15 finalists.

Steve:          And the winners turned out to be all young women.

DiChristina:                  Yeah, as it turned out. So the 13-to-14-year-old age category, the winner was Lauren Hodge. And Lauren's project which was, you know, a fascinating, simple idea, where she had been learning about proteins in school in her biology classes and she noticed that when her mom marinated chicken in lemon juice, the chicken edges turned white. So she noticed something was going on with the proteins in the chicken. She learned what was happening there. Near the same time that she noticed that with her mom cooking, she also had learned of a lawsuit against some fast food companies about carcinogens from the grilling of chicken. So, you know, as we know, this is not new news for folks who were listening—when you barbecue things, the charred pieces that end up on your chicken or your beef or whatever have some carcinogenic compounds in them, and you know, just a small amount, but they are there.

Steve:          The delicious part.

DiChristina:                  The delicious part—that's exactly the case. So Lauren, I remember in her project, put a piece of fried chicken and a piece of grilled chicken on the first slide and said, "Which one is healthier?" Which was kind of a provocative way to lead into it. So she had the law suit in mind about, you know, certain fast food companies that had been, you know, that were being sued for potential carcinogens under, I believe, the California regulation and she noticed this happening in her kitchen, and she wondered what if it makes a difference, what kind of marinades you put on the food? And why don't I check that? And when she looked into it, she actually found nobody had tested that specifically. So she tested a lemon juice, soy sauce, salt water, brown sugar and olive oil; and she tested how many carcinogenic compounds were then produced on the meat itself as a result of the marinades. And I keep mentioning lemon juice because that one was the best, as far as being the most healthful. Now, of course, Lauren would be the first one to tell anybody that this needs to be replicated and so on. But what a creative and a very simple idea. So that was in the 13-to-14-year-old age category.

Steve:          And Lauren is from the U.S.?

DiChristina:                  Lauren is from the U.S. And then the next winner was Naomi Shah, and Naomi's idea—which also had the virtue of never having been really tried or at least not that we know of—was she noticed the increasing rates of asthma in the developed world, in particular, but everywhere also and wondered whether, given that people spend a lot of time indoors, where in theory anyway, you could manage your exposures to things a little bit better, you know, how did that look, what happens? So she measured a couple of pollutants that are very common in indoor air, and maybe people all know this already but, we spent something like 90 percent of our days indoors, a typical person. So this is obviously a big exposure area and she checked a kind of a particulate of a certain size and volatile organic compounds. These are the gases that are released by new things, like when you unroll a new carpet or when you just had new kitchen cabinets installed, things like that, that make a little smell; it's also responsible for that new car smell that everybody likes, right. And she found that indeed these two indoor air pollutants in particular reduce the ability of asthmatics to inhale and exhale, you know; the way that's measured is something called "exhalatory rate", and she couldn't, you know, when she measured with actual patients, I think, slightly more than 100 of them, she found that these influenced their, you know, their lung capacity. The interesting finding there is, of course, there are medicines that you can use, but then why medicate if you can remove the pollutants from the indoor environment? And her approach, you know, she's now gone on, she's on a mayor's advisory board where she lives, and she's trying to get people to remove the offending materials from houses. You know, this is very ambitious of course—the Clean Air Act addresses many such things—but in principle, what an interesting idea. Remove the things that are causing the problem rather than actually giving the patient medicines and drugs—maybe you don't have to, if you can remove certain things and you're spending most of your time indoors.

Steve:          And Naomi is also from the U.S.?

DiChristina:                  Yes, Naomi is as it turned out, also from the U.S.. And the 17-to-18 year-old category winner was Shree Bose, also a U.S. student. What Shree did was, she was trying to explore a particular kind of ovarian cancer therapy, a drug called cisplatin. And the problem with cisplatin is it's very effective for the 21,000 women or so that are diagnosed with ovarian cancer every year, but then the cancer cells, over the course of the disease, develop resistance to the cisplatin. And she wondered what could be the mechanisms behind that. And so she decided to explore AMP kinase, which is an energy protein of the cell, and she wondered whether it had some role in the cancer resistance that was developed. And she discovered that indeed it did, and then she, if you altered the drugs that were given or the compounds that were given along with the cisplatin, you could avoid the resistance. So it suggests a potential new therapy.

Steve:          Right.

DiChristina:                  A new course of therapy.

Steve:           This was in cell culture, so it's not, it can't be rushed into any kind of clinical application yet.

DiChristina:                  Right, of course, you can't rush this right into use in patients, and Shree would be first person to say so; this was done in cell cultures. But it suggests an intriguing potential therapy in a regimen adjustment, and also it gives us a little bit more insight into the mechanism of the cancer itself, which is always useful for a variety of reasons.

Steve:          So, all three of the winners were young women. Is there anything to be, to take away from that? Or you know, I don't know what the applicant pool was like. Is it just, you know, if all three were young men, we probably wouldn't even be commenting on it, but does it mean anything? Is Larry Summers upset? Does it, is there a take-home message or just are young women getting more interested in science and doing higher quality work? As a young woman yourself…

DiChristina:                  (laughs) So, yeah I mean, as Vint Cerf, the co-inventor of the Internet, who was also one of the judges and the Google—I guess the title is Google's Chief Evangelist, an Internet Evangelist—Vint Cerf said he was secretly pleased by this. And you're right, you know, people wouldn't be commenting on it if it were three boys. And indeed of the 15 finalists, six of them were young ladies, so there were the majority of boys in that pool as well. But the thing about this, and the judges—there were several quite, you know, science luminaries in our judge pool, quite apart from me, I might add. We did not know who the winners would be until we had done the judging on the criteria that Google gave us. So one of them was impact and we just talked about three things that have, I think everybody can agree, pretty high impact. Another was originality—was it a novel idea? And these all very novel ideas. Another one was excellence of scientific method; all things being equal, how well that these students do with their scientific process? And last was their communication skills, how well did they bring the science they did out to, you know, to us as judges and indeed to the public at large because the materials they submitted were publicly available and have been publicly available for some months now. So those were the four criteria we were paying attention to, and we literally did not know who the winners would be until we had gone through the process, and then we looked at the wall—and I remember being in the judging room saying, "Wow, three girls, neat," you know, but it was by no particular design. We were instructed sternly to, you know, make sure merit was considered above all else, because really with science, we consider merit above all else.

(music)

Steve:          More Noble Prize winners from Lindau soon. In the meantime, get your science news at our Web site, http://www.ScientificAmerican.com, where you can check out the slide show about the construction of the New York City Second Avenue subway, which has been under construction for so long that all the usual giant lizards, demonic entities and other monsters that such massive projects usually free from imprisonment to wreak havoc on the city died of old age. Hey, follow us on Twitter, where you'll get a tweet each time a new article hits the Web site. Our Twitter name is @SciAm. For Science Talk, I am Steve Mirsky. Thanks for clicking on us.

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