The body’s protein cleaning machine

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 travelling 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 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.

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 a US 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. 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 per cent of the people who take it get excellent remissions. It’s not a cure. They get several more years of good quality life.

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.