Brooklyn and Spokane
Irwin Allan Rose was born in Brooklyn, New York, on July 16, 1926. His mother, Ella Greenwald, was American-born into a family whose other children had all been born in Hungary; his father, Harry Royze, came from a family from the Odessa region of the Russian Empire and ran a flooring business. In his Nobel autobiography Rose remembered the ethnic variety of his public school, P.S. 134, handball games played against the walls of the family’s apartment house, and neighbourhood boundaries set by unfriendly gangs.
When he was 13, in 1939, his younger brother developed rheumatic fever and doctors advised the family to move to a high, dry climate. His mother took the boys to Spokane, Washington, where her sister had a house big enough to take them in, while his father stayed behind in Brooklyn to run the business. Rose later wrote that he never understood the arrangement and felt conflicted about it; his father’s visits were rare. His mother did secretarial work at the Navy Supply Depot in Spokane, and the boys went through the city’s public schools. Summer jobs at a local hospital, mostly on the psychiatric ward, gave him his first idea of a career: he came to see himself solving medical problems, although no one in his family had ever done research and he had no one to ask for advice.
Becoming an enzyme chemist
Rose spent a year at Washington State College, where a zoology professor, Herbert Eastlick, urged students to set high standards for themselves, and then served briefly in the US Navy at the end of the Second World War. Afterwards he went to the University of Chicago, earning his bachelor’s degree in 1948 and his PhD in biochemistry in 1952. His first thesis project collapsed when it became clear that the DNA content of a cell does not change with diet, so he picked a new problem out of his freshman lecture notes and showed that the cell can turn a building block of RNA directly into one of DNA, sugar and all.
After postdoctoral work at Western Reserve University and with Severo Ochoa at New York University, he joined the biochemistry department at Yale School of Medicine in 1954. There he became known as one of the most careful enzymologists of his generation, a scientist who wanted to know exactly how an enzyme moved each atom during a reaction. He used radioactive and heavy isotopes to trace hydrogen atoms through sugar-converting enzymes, and with Kenneth Hanson he solved the long-standing problem of how enzymes tell apart chemically identical parts of the citric acid molecule. In his first year at Yale he also read a paper by Melvin Simpson showing that the breakdown of proteins in liver tissue seemed to require energy. It made no sense, since breaking things down usually releases energy. Rose kept the puzzle in mind, and worked on it on the side, for the next twenty years.
Fox Chase
In 1963 Rose moved to the Institute for Cancer Research at the Fox Chase Cancer Center in Philadelphia, where he would spend the rest of his career until he retired in the 1990s (his own Nobel account gives 1997; some obituaries say 1995). He was drawn by the institute’s founding idea that to understand cancer one needed a broad understanding of all of biology. Crystallographers, embryologists, chemists and medical biologists worked side by side without departmental walls and went to each other’s seminars. Rose thrived there. He studied how red blood cells control their sugar metabolism, how brain tissue responds to a loss of blood supply, and the step-by-step chemistry of enzymes that use ATP, the cell’s energy currency.
Colleagues described a quiet thinker who did not talk fast. Alfred Knudson, the institute’s director in those years, later recalled that Rose would never come to ask for something unless it was important.
The kiss of death
By the 1970s cell biologists had learned a great deal about how cells build proteins, but very little about how they get rid of them. It was known that cells constantly destroy their own proteins, and that this destruction, unlike the digestion of food, requires energy. In 1977 Alfred Goldberg’s group showed that an extract of immature red blood cells could break down abnormal proteins if ATP was added. The Israeli biochemist Avram Hershko and his graduate student Aaron Ciechanover, at the Technion in Haifa, took up that system and found that it could be split into two fractions that were inactive alone but worked together. The key ingredient of one fraction was a small, heat-stable protein they called APF-1.
Hershko had met Rose at a scientific conference and knew of his long interest in energy-dependent protein breakdown. From the late 1970s Hershko and Ciechanover spent a series of sabbaticals in Rose’s laboratory at Fox Chase. In 1979 Rose went to Knudson and asked for nearly $50,000 so that the Israeli scientists could extend their stay to a year; Knudson agreed and wrote in a memo that the whole problem of how protein breakdown is regulated now seemed accessible, with enormous implications. In two papers published in 1980, Ciechanover, Hershko and Rose showed that APF-1 becomes firmly bound to proteins that are about to be destroyed, and that many copies can be attached to the same target. APF-1 turned out to be ubiquitin, a small protein found in nearly every kind of cell. Keith Wilkinson, a postdoctoral fellow in Rose’s laboratory, was the first to identify APF-1 as ubiquitin.
Between 1981 and 1983 the three scientists and their students worked out the machinery: an enzyme called E1 uses ATP to activate ubiquitin, an E2 enzyme carries it, and an E3 enzyme recognises the specific protein to be destroyed and attaches the ubiquitin chain. The chain is a molecular label, which the Nobel committee later called a kiss of death, that sends the tagged protein to the proteasome, a barrel-shaped structure that chops it into small pieces for recycling. The energy requirement that had puzzled Rose for decades was the price the cell pays for precision: it lets the cell choose exactly which proteins to remove and when.
Why it matters
The ubiquitin system turned out to govern much of life inside the cell. It controls when a cell divides, repairs damaged DNA, switches genes on and off, clears out faulty proteins (as many as 30 per cent of newly made proteins fail the cell’s quality control and are destroyed this way) and presents fragments of viruses to the immune system. When the system goes wrong, disease follows. The human papilloma virus causes cervical cancer partly by hijacking an E3 enzyme to destroy p53, the protein that normally guards the genome; in the most common form of cystic fibrosis, a misfolded chloride channel is tagged and destroyed before it can reach the cell surface.
Understanding the system opened a new route to medicines. The first was bortezomib (Velcade), which blocks the proteasome and so causes a toxic pile-up of proteins in cancer cells. It was approved in the United States in 2003 for multiple myeloma, a cancer of the bone marrow, and later for mantle cell lymphoma, and it is on the World Health Organization’s list of essential medicines. Other proteasome inhibitors followed, and drug companies now design molecules that steer the cell’s own E3 enzymes onto disease-causing proteins so that the body’s waste disposal removes them. The Boston Globe’s obituary noted that the discoveries also helped researchers understand cystic fibrosis, Parkinson’s disease and many types of cancer.
Nobel Prize
In October 2004 the Royal Swedish Academy of Sciences awarded the Nobel Prize in Chemistry jointly to Aaron Ciechanover, Avram Hershko and Irwin Rose for the discovery of ubiquitin-mediated protein degradation. The academy said the three had gone against the stream: while at least five Nobel Prizes had been given for understanding how cells make proteins, almost no one had been interested in how cells break them down. It noted that much of the decisive work had been done during the Israeli scientists’ sabbaticals in Rose’s laboratory at Fox Chase.
Rose was 78 and working in borrowed laboratory space at the University of California, Irvine, when the news came. James Nowick, an Irvine chemist who collaborated with him, recalled that by the time he got through on the phone hours later, Rose was fed up with it ringing; by the end of the day he was back in the laboratory.
A secular Jewish family
Rose described his background plainly in his Nobel autobiography: both the Greenwalds and the Roses were secular Jews, and the children more so. He and his younger brother spent some time in Hebrew school to please Grandfather Rose. His family history was a typical story of Jewish immigration to New York, with grandparents from Hungary and from the Odessa region, and a father whose surname, Royze, became Rose in the next generation.
His scientific life was also bound up with Israel. The Nobel-winning work was a collaboration between an American Jewish enzymologist and two Israeli scientists from the Technion in Haifa, Hershko, born in Hungary, and Ciechanover, born in Haifa, and it was carried out largely in Philadelphia. Rose is included in lists of Jewish Nobel laureates, including that of the Jewish Virtual Library.
Family and character
At Yale Rose met Zelda Budenstein, a graduate student in the biochemistry department; he called his proposal of marriage the crowning event of 1954 to 1955, adding that he caught up with her before she graduated. Zelda had a research career of her own, often running parallel to his, until 1987, when she retired to devote herself to peace and social causes. Her widowed mother lived with them and helped raise their four children. Their daughter Sarah died in 2005.
Friends knew him as Ernie. He was modest to the point of self-effacement, and in his autobiography he summed up fifty years of research as an eclectic journey, gratefully listing dozens of collaborators and regretting that he had never been clever enough to open the black box of enzyme structure. He trained postdoctoral fellows who became leaders of the ubiquitin field, among them Arthur Haas, the first to see ubiquitin chains, Keith Wilkinson and Cecile Pickart.
Later years and legacy
After retiring from Fox Chase, Rose and Zelda moved to Laguna Woods in Southern California. One morning he turned up unannounced at the office of an old friend, Ralph Bradshaw, a professor of physiology and biophysics at the University of California, Irvine, looking for laboratory space. Bradshaw shared his, the university soon gave Rose a research appointment, and he went on doing experiments into his eighties. He died in his sleep on June 2, 2015, at the home of his son Frederic in Deerfield, Massachusetts, at the age of 88.
Rose’s legacy is a basic piece of how life works. Before the ubiquitin discoveries, protein breakdown was treated as cellular garbage collection, too dull to study. Today it is recognised as one of the cell’s main control systems, as important as making proteins in the first place, and thousands of laboratories study it. Patients with multiple myeloma and other cancers are treated with drugs that target the system he helped uncover, and a new generation of medicines that harness the ubiquitin tag to destroy disease proteins is in development. It began with a puzzle that a patient, curious enzymologist refused to let go of for twenty years.
Sources & further reading
Irwin Rose, Biographical, NobelPrize.org · The Nobel Prize in Chemistry 2004, Popular information, NobelPrize.org · Irwin Rose, 88; Nobel-winning biochemist, The Boston Globe (New York Times obituary) · Bortezomib, Wikipedia · Irwin Rose, Wikipedia · Researched from the sources above and checked against them. Spotted an error? Tell us.
A life of tikkun olam. This is part of tikkun olam, the Jewish idea of repairing the world, and every one of us can add to it.