Study of Cell Breakdown Captures Nobel
By KENNETH CHANG
Published: October 7, 2004
Like most fields, modern biology focuses most of its attention on how things are built and created: how a cell reads the blueprints encoded in DNA and how it takes that information to manufacture proteins in molecular factories.
Two Israelis and one American won this year's Nobel Prize in Chemistry yesterday for their work on the opposite, less glamorous function of a cell: how it breaks down proteins that are damaged or have outlived their usefulness.
The winners are Dr. Aaron Ciechanover, 57, and Dr. Avram Hershko, 67, both professors of biochemistry at the Technion-Israel Institute of Technology in Haifa, and Dr. Irwin A. Rose, 78, a scientist at the University of California, Irvine. They will each get one-third of the $1.3 million prize.
The cell's custodial duties have turned out to be much more than just taking out the trash. Rather, they act like a sophisticated inventory control program. The quick removal of specific proteins tells the cell when to divide, when to turn on or turn off various functions, when to die.
Understanding these processes also helps in understanding diseases that occur when they go awry, including cystic fibrosis, Parkinson's disease and many types of cancer.
The disposal of proteins is ''crucial to almost any cellular process that anybody has studied,'' said Dr. Mark Hochstrasser, a professor of molecular biophysics and biochemistry at Yale. Until about a decade ago, though, few realized the importance, he said.
''The focus at that time was on how proteins were made,'' Dr. Hochstrasser said, ''and in some quarters it was believed protein degradation was of little or no consequence. It was rather risky to work on it.''
Dr. Hershko and Dr. Rose, however, each had had a long interest in the cell's disposal system. ''I realized this was an important problem and a few other people in the world were working on it at that time,'' Dr. Rose said.
Experiments in the 1950's had yielded a puzzle. Most enzymes that break down proteins, including those that allow the body to digest food, do not need energy to work. But whatever was breaking down the cell's own proteins did consume energy. Scientists had no idea why energy was needed.
In 1975 came a second, seemingly unrelated mystery. In the sweetbread glands of calves, scientists discovered a small protein consisting of just 76 amino acids. Subsequently, scientists found the exact same protein in every tissue of every organism higher than bacteria, from fungi to yeast to frogs to people. They gave an obvious name to the ubiquitous protein: ubiquitin. They had no idea what it did.
In the late 1970's, Dr. Rose and Dr. Hershko met at a scientific conference and realized they were working on the same problem. They began collaborating, and Dr. Hershko visited Fox Chase Cancer Center in Philadelphia, where Dr. Rose then worked. Dr. Ciechanover was a graduate student of Dr. Hershko's at the time.
In the early 1980's the scientists figured out that ubiquitin was a molecular ''kiss of death'' that the cell attaches to proteins it wants destroyed. The process of attaching ubiquitin takes energy, solving the earlier puzzle of why the process consumed energy. The tagged proteins are taken to barrel-shaped chambers floating in the cell cytoplasm called proteasomes, which slice the proteins into bits that are then recycled into new proteins.
For example, the protein-destroying process plays an important role when a cell divides, because of proteins called cyclins that change at each step of the process. ''These are proteins that sort of tell the cell what stage they are at in the cell cycle,'' said Dr. Daniel Finley, a professor of cell biology at Harvard. ''To go from one stage to the next, you need to get rid of these cyclins very suddenly.''
In people, about 1,000 of the genome's 35,000 genes appear to take part in the ubiquitin system. ''A large fraction of the genome is dedicated to this pathway,'' Dr. Finley said.
In addition, some genes that were initially identified as tumor suppressors now appear to be involved with ubiquitin, he said.
Last year, the Food and Drug Administration approved a drug called Velcade, which interferes with the workings of the proteasomes as a treatment for multiple myeloma, a cancer of the bone marrow.
Dr. Rose said he got a phone call at 2 a.m. yesterday from Sweden informing him of the prize. ''It's been interesting, I have to say that,'' he said. ''I guess the main problem is the phone has been ringing off the hook and we've been trying to get calls from our children, et cetera, but we haven't been able to do that.''
Dr. Hershko, meanwhile, never received the official phone call. Because yesterday was a holiday in Israel, he and his family were at a swimming pool. ''We had a day out with my four granddaughters,'' he said. ''There I got a call from a cousin who heard it on the radio.''
Photos: Dr. Avram Hershko, left, and Dr. Aaron Ciechanover, professors of biochemistry at the Technion-Israel Institute of Technology in Haifa. (Photo by Roni Schutzer/Agence France-Presse -- Getty Images); Dr. Irwin A. Rose of the University of California, Irvine. (Photo by Fox Chase Cancer Center)
Chart/Diagram: ''Cells Cleaning House''
The Nobel Prize in Chemistry was awarded to three scientists for their discovery of an elaborate dance of enzymes that identifies, tags and shreds unwanted proteins in cells.
UBIQUITIN (TAG FOR DISPOSAL)
The first enzyme is prompted to grab a tag.
It transfers the tag to a second enzyme.
TARGET PROTEIN (TO BE DISPOSED OF)
A third enzyme recognizes the protein to be destroyed and transfers the tag from the second enzyme to the target protein.
The process is repeated, creating a chain of tags.
The chain is recognized by a structure called a proteasome. The protein is threaded through its barrelshaped chamber and chopped into pieces that are recycled for new proteins.
Diagram illustrating the cell breakdown process.
(Sources by Dr. Mark Hochstrasser, Yale University; Nobel Foundation)