UC Irvine Researcher Shares the Nobel Prize in Chemistry
A UC Irvine researcher and two Israeli scientists Wednesday were awarded the 2004 Nobel Prize in chemistry for their discovery of the cellular system that, like a miniature Mafia don, gives the “kiss of death” to proteins marked for destruction.
The system was initially thought to be used only for getting rid of defective proteins or those that had outlived their usefulness to the cell, but 25 years of research have shown that it is intimately involved in a variety of processes that includes cellular replication, cystic fibrosis and other diseases, the immunological response and even cancer.
Irwin A. Rose, 78, an emeritus professor at UC Irvine, and Aaron Ciechanover, 56, and Avram Hershko, 70, of the Technion-Israel Institute of Technology in Haifa will share the $1.35-million prize. It is the first Nobel awarded to Israeli scientists and the third to a faculty member at UC Irvine.
The team’s research “has given us an important close-up view of the regulatory processes taking place inside human cells and what happens when these processes don’t work correctly,” said Charles P. Casey of the University of Wisconsin-Madison, president of the American Chemical Society. It “provides a cornerstone for the development of new drugs” against cancer and other diseases.
One cancer drug based on inhibiting this system, Velcade, is already on the market, and several others for cancer and degenerative diseases are in development, experts said.
“The practical applications are too numerous to mention,” Rose said.
The award is a case study for the benefits of going against the conventional wisdom.
When Rose and Hershko met at a conference in 1979, the majority of protein researchers were interested in tracing the mechanisms by which the 100,000 or so proteins in each individual cell were produced. In fact, five Nobel prizes have been presented for studies of those mechanisms.
Researchers knew that proteins had to be broken down in the cell, Rose said, but “nobody had a clue as to how it worked.”
That chance meeting led to a decades-long collaboration between Rose and Hershko and, soon thereafter, Ciechanover, who was a graduate student in Hershko’s lab in Israel.
Both Israelis took sabbaticals in Rose’s lab at the Fox Chase Cancer Center in Philadelphia, and Hershko came to work in the lab virtually every summer for 19 years.
What they found was a protein called ubiquitin, so named because it is ubiquitous, occurring in every cell of the body. Through a series of clever studies, they found that cells marked proteins destined for destruction by attaching one or more ubiquitin molecules to them. The Nobel citation characterized this marking as a “kiss of death.”
Proteins thus marked are then shuttled into specialized cellular structures called proteasomes, where they are broken down into small groups of amino acids that can be recycled for the cell’s further use.
As many as 30% of the proteins produced in the cell are defective and must be destroyed before they can subvert normal cellular operation. Virtually all proteins eventually become defective with age and must be replaced with new ones. Functioning proteins must often be destroyed as the cell moves toward carrying out new functions, such as in multiplying. The ubiquitin system plays a major role in all of those cases.
Studies of the system “began to explode” about 10 years ago, Hershko said. There have now been tens of thousands of papers published on the subject, he said.
Hershko was not at home when the Swedish Academy called Wednesday to notify him of the award. Because it was the last day of the harvest festival of Sukkot, he and his wife were out on a picnic with their grandchildren, and he did not hear the news until an aunt called later in the day.
“I really did not expect it,” he said.
At a news conference in his apartment, Hershko said he was happy for himself and his family and for his country, noting that such recognition did not come easily.
“We’re a small country ... so we don’t have all the infrastructure that big laboratories have in the U.S. or in other places,” he said.
Ciechanover said he was “overwhelmed, excited, exhausted. Our house is flooded with flowers and cakes. Friends are coming in and out all the time. It’s beyond the digestion of a sane, normal human being.”
With some disappointment in his voice, he noted in a telephone interview late Wednesday that “the prime minister or the president hasn’t called. But that’s OK. The people in the street are happy.”
Rose, who came to UC Irvine in 1997 after retiring from Fox Chase, said he had long been confident that Hershko would win the Nobel Prize, but was less confident about his own prospects.
“There is no question that he did the major work in this field,” said Rose, known to friends and colleagues as Ernie. “I was a contributor. I never felt that I was really the key person.”
He noted that the call from Sweden came at 2 a.m. and that “the phone has been ringing off the hook ever since. The main problem is that we are trying to get calls from our children but haven’t been able to do that.... I don’t want to go through this again.”
The two previous winners at UC Irvine, both in 1995, were F. Sherwood Rowland in chemistry and Frederick Reines in physics.
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Staff writer Laura King in Jerusalem contributed to this report.
