The Body’s Protein Cleaning Machine

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When Dr. Avram Hershko, 74, a biochemist at the Technion-Israel Institute of Technology in Haifa and a winner of the 2004 Nobel Prize in Chemistry, was recently asked to name the most important fact of his life, he answered: “That I love my six grandchildren. For two, three days every week, I take them to dance class, sport and school. I am completely in their lives.”

Technion-Israel Institute of Technology

Avram Hershko, of the Technion-Israel Institute of Technology.

Among top scientists, responses to such a question might well focus on prizes they’ve won or the import of their research. For Dr. Hershko, whose family was separated and sent to forced labor in World War II, family life trumps worldly accomplishments.

Yet Dr. Hershko’s scientific contributions are remarkable. His discovery of how individual cells destroy and eliminate malfunctioning proteins is a crucial component of efforts to unlock the mysteries of cancer and neurodegenerative disease.

We spoke when he visited New York City this spring. A condensed and edited version of the conversation follows.

How did the way that proteins are broken down within cells — the topic for which you won the Nobel Prize — become your life’s work?

I bumped into it by accident in 1969. At the time, I was a young Israeli biochemist with a fellowship to do postdoctoral studies with Dr. Gordon Tomkins, at the University of California, San Francisco.

Before my traveling to the United States, I’d corresponded with Dr. Tomkins about working on how proteins are formed in cells. But when I arrived, I could see he already had 25 postdocs studying that. To me the field looked overcrowded. “Can I do something else?” I asked. He suggested, “Why don’t you study the opposite?”

So I ran to the library. There were hundreds of papers on protein formation and almost none on protein degradation. It was obvious that protein degradation was important. It was also obvious that nobody much cared about it. So here was perfect territory for a curious young scientist.

Why exactly is protein degradation important?

Because proteins are important. Proteins are the machines that carry out the directions of genes. They must be formed at a certain moment and destroyed when they are no longer needed, or when they go bad. Think of a cell as something like an orchestra, with thousands of players. These are the proteins. They must all work together in harmony and play their parts at the right moment.

Maybe you’ve heard of Parkinson’s disease and Alzheimer’s? There we have bad proteins accumulating in the brain and destroying brain cells. The reason we don’t get Alzheimer’s when we are 10 is that when we are young, the bad proteins are disposed of quickly. With age, the cell’s machinery may lose the ability to do that.

How does a cell know when to eliminate a protein?

There’s a tagging system. Every cell has within it a special protein that is everywhere: ubiquitin. Out of the thousands of proteins, this one tags damaged and bad proteins, binds to them and creates a molecular “kiss of death” until they are chopped up and degraded.

Did you discover ubiquitin?

Its existence was known. Its function was the mystery. Since the early 1970s, it’s been my focus. Much like watchmakers seeking to understand a clock’s mechanisms, my then-graduate student Aaron Ciechanover (who with an American researcher, Irwin Rose, shared in the Nobel Prize) and I cracked open cells and figured out how the various parts worked.

Understanding the ubiquitin system took us a while. By 1980, we could describe this tagging process. Once we’d done that, I became interested in how cells divide, because that’s important to understanding cancer.

It would turn out that one of ubiquitin’s functions is to serve as a brake within the cell. When you have cancer, cell division can be something like a car running amok because its brake pedal isn’t working. There are oncoproteins in the body that stimulate cell division. In a properly functioning cell, the ubiquitin tags the oncoproteins for degradation. When that doesn’t happen, the cells keep dividing uncontrollably — cancer.

It has long been thought that your research was likely to lead to a whole new class of drugs against cancer and neurodegenerative diseases. Has that happened yet?

Right now, we have only one drug based on our discovery, Velcade, which is very effective against a terrible disease, multiple myeloma. I would say 60 to 70 percent of the people who take it get excellent remissions. It’s not a cure. They get several more years of good quality life. And that’s quite significant in a disease that used to be fatal.

Do you come from a family of doctors?

Teachers. My parents were teachers in Karcag, in Hungary. When I was 6, most of the town’s Jews were sent to Auschwitz. Because of a series of random events, my mother, brother, paternal grandparents and I were put on a train to a labor camp in Austria. There we worked in the fields, but my mother always tried to make a microcosmos for us, like things were almost normal.

After the war, we walked almost all the way back to Karcag. We had no idea where my father was. One night in 1946, he reappeared. He’d been taken to forced labor, first by the Hungarian Nazis and then by the Soviets. He arrived late at night and knocked on the window of my grandfather, who lifted him through the window, crying, “They are alive! They are alive!” My father was eventually able to teach at the Jewish school in Budapest. Then the Communists came to power. In 1950, we immigrated to Jerusalem, where he became a beloved teacher, again.

Did your childhood mark you?

I cannot psychoanalyze myself. I definitely had a drive to do something with my life, to help others, to make the world better. It’s not a nothing; it’s a bad experience. I knew that I was lucky and knew that my family was lucky. Some parts of my family were not. I almost never talk about it. Even when my kids ask me, I don’t say much.

Let’s return to science. Is it true that you do a new experiment every day in your laboratory?

Yes, it’s true. I like bench work. And I deliberately keep my lab small because I want to have enough time for it. This is quite rare. When people become principal investigators, they leave that to graduate students.

And yet, the experiment you do yourself is much better than the one you tell a student to do. You can see all the little details.

What have you been working on since your Nobel Prize?

I’ve been continuing with the ubiquitin system and asking a very difficult question: How does it control how chromosomes divide during cell division? Each new cell gets 46 chromosomes, and the ubiquitin system is involved in that. If you don’t have the right number of chromosomes, that’s bad. Cancer cells usually don’t have the right number. With Down syndrome, there are 47. We have to understand how the machinery of that works.

You often give speeches to young scientists. What do you tell them?

I tell them not to go with the mainstream in picking a research topic. Also, if you have an unexpected finding, don’t ignore it. Serendipitous findings are sometimes the most important.

Another thing: If your mentor is not good, leave him. In these big labs, sometimes your mentor doesn’t know much about your activities. That’s not a mentor. For scientific research, you have to learn how to do it from a good researcher. I had that myself, and I try to pass it on to my own students.

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