Alumnus Irwin Rose receives 2004 Nobel Prize in chemistry
Irwin Rose, 78, who earned his B.S in 1948 and his Ph.D. in 1952 in biochemistry from the University of Chicago, will share the 2004 Nobel Prize for Chemistry with Aaron Ciechanover and Avram Hershko of Technion (Israel Institute of Technology), Haifa, Israel, "for the discovery of ubiquitin-mediated protein degradation," according to the press release from the Stockholm-based Nobel Foundation. Rose is now a professor emeritus of physiology and biophysics, at the College of Medicine, University of California, Irvine.
All three scientists will share this year's $1.36 million award.
At Chicago, Rose, known at the time as "Ernie," worked in professor Birgit Vennesland's laboratory, where he wrote his dissertation on the biochemical synthesis of nucleic acids.
After graduation, he spent most of his career at Fox Chase Cancer Center in Philadelphia. Many of the studies that led to the Prize were done when Hershko and Ciechanover took sabbatical leave and worked with Rose in Philadelphia, the Foundation said in a statement.
The three researchers discovered one of the cell's most important cyclical processes, regulated protein degradation. All living things -- plants, animals and humans -- are built of proteins. In the late 1970s, biochemists knew a good deal about how the cell produces proteins. Rose, Ciechanover and Hershko "went against the stream," according to the press release, and discovered how cells break proteins down.
Beginning in 1978, they began to show that the cell functions as a "highly-efficient checking station where proteins are built up and broken down at a furious rate," according to the release. "The degradation is not indiscriminate but takes place through a process that is controlled in detail so that the proteins to be broken down at any given moment are given a molecular label, a 'kiss of death.'"
The labeled proteins are then funneled into proteasomes -- the cell's waste disposers -- large, cylindrical cellular machines that slice proteins into short pieces and thereby destroy them.
The researchers showed that the kiss-of-death label was a protein called ubiquitin, which cells tag onto doomed proteins. Once fastened onto a protein slated for destruction, the ubiquitin accompanies it to the proteasome, where it conveys the message that this protein has been selected for disassembly. Shortly before the protein is fed into the proteasome, its ubiquitin label is disconnected for re-use.
Thanks to the work of the three Laureates, "it is now possible to understand at a molecular level how the cell controls a number of central processes," the announcement continues, "by breaking down certain proteins and not others."
This research solved "a fundamental puzzle," said ubiquitin researcher Mark Hochstrasser, Ph.D., professor of molecular biophysics & biochemistry at Yale, who taught at the University of Chicago from 1990 to 2000. Before this, the process was completely obscure. The series of biochemical reactions discovered by Rose and colleagues was "both unprecedented and complex," he added. "It required someone who really knew enzymology."
Examples of processes governed by ubiquitin-mediated protein degradation include cell division, DNA repair, quality control of newly produced proteins, and regulation of the immune defense. More recently, evidence for at least a dozen similar systems has come to light.
When degradation does not work correctly, it can result in disease. Inflammation, cancer and neurodegenerative disease like Alzheimer's or Parkinson's disease are examples. Knowledge of ubiquitin-mediated protein degradation offers an opportunity to develop drugs against these diseases and others. The first such drug, known as Velcade (bortezomib), a proteasome inhibitor, was approved by the Food and Drug Administration in May 2003 to treat a type of cancer called multiple myeloma. Velcade blocks the activity of proteasomes, which can lead to death of cancer cells.
The ubiquitin-proteasome pathway, however, is involved in nearly every cellular process, points out Hochstrasser. "So you would expect a lot of side effects." The next step is to find more narrowly targeted interventions.