A teacher’s son in Karcag
Avram Hershko was born Herskó Ferenc on December 31, 1937, in Karcag, a small town of about 25,000 people some 150 kilometres east of Budapest, Hungary. Karcag had a Jewish community of nearly a thousand. His father, Moshe Hershko, taught at the town’s Jewish elementary school, and most of the Jewish children of Karcag passed through his classroom; former pupils in Hungary and later in Israel remembered him as an inspiring teacher. His mother, Shoshana, known as Margit or “Manci,” was an educated, musical woman who gave English and piano lessons. His older brother, Chaim, was born in 1936.
Hershko remembered his earliest years as happy ones, in a house with a beautiful garden that his father tended. But Hitler’s voice could already be heard on the radio, and his parents, he wrote, grew so apprehensive about the future that they decided not to have more children.
Surviving the Holocaust
Hungary joined the war as an ally of Nazi Germany. In 1942 his father was taken by the Hungarian army as a Jewish forced labourer and sent to the Russian front, where most of the men in his unit perished. He survived only because the Soviet army captured him, and he was then held as a forced labourer by the Soviets until 1946. For four years the family did not know whether he was alive.
In the spring of 1944 Germany occupied Hungary, and the deportation of Hungarian Jews began. Six-year-old Avram, his mother and brother were held for a couple of weeks in a ghetto on the outskirts of Karcag and then in a terribly crowded ghetto in Szolnok. From there most trains went to Auschwitz. By what he called a random event, his family was put on one of the few trains that went instead to Austria, where Jews were used for labour. Together with his paternal grandparents and three aunts, they worked in and near a small village outside Vienna until the Soviet army liberated them in the spring of 1945. His maternal grandparents were murdered, along with some 360,000 Hungarian Jews and almost two-thirds of the Jews of Karcag.
A new life in Jerusalem
After the family was reunited in 1946, they lived for three years in Budapest, where his father again taught school. In 1950 they emigrated to Israel and settled in Jerusalem, where the boy took the Hebrew name Avram. The family was poor, but education remained his parents’ highest priority, and they sent both sons to a private school, probably spending most of his father’s salary on fees. Moshe Hershko went on to teach at a teachers’ seminary and to write mathematics textbooks that became very popular in Israel.
Avram was a strong student in everything from mathematics and physics to literature, history and Talmud, which made it hard to choose a path. He chose medicine, he joked, partly because his brother was already a medical student and he could inherit his books for free. In 1956 he entered the Hebrew University–Hadassah Medical School in Jerusalem, then Israel’s only medical school.
Learning to do science
In medical school Hershko fell in love with biochemistry, taught by remarkable teachers including the philosopher-scientist Yeshayahu Leibowitz. In 1960 he began research in the laboratory of Jacob Mager, a shy man of encyclopaedic knowledge and an exacting experimentalist who insisted on every possible control and on repeating every important finding. Hershko completed his medical degree in 1965, served as a physician in the Israel Defense Forces from 1965 to 1967, and returned to Mager’s laboratory to finish his PhD in 1969.
In 1963 he met Judith Leibowitz, a Swiss-born biologist working in a Hadassah hematology laboratory; they literally bumped into each other when he went to collect a blood sample, and they married at the end of that year. They have three sons. For more than fifteen years Judy also worked in his laboratory. From 1969 to 1971 Hershko was a postdoctoral fellow with Gordon Tomkins at the University of California, San Francisco, and it was there that he became fascinated by a neglected question: how and why do cells destroy their own proteins?
The kiss of death
In 1971 Hershko became head of biochemistry at the new Faculty of Medicine of the Technion in Haifa, housed for more than fifteen years in an old two-storey monastery. For years his small team tried and failed to reproduce, in a test tube, the energy-hungry process by which cells break down proteins. A visiting colleague told him he should not have most of his laboratory working on a hopeless subject. He persisted, and in 1977 switched to an extract of immature red blood cells. When he and his graduate student Aaron Ciechanover separated the extract into two fractions, neither worked alone, but together they did. In 1978 they reported that the key ingredient in the first fraction was a small, heat-stable protein they called APF-1. A protein expert assured them it could not be a protein. It was: the molecule later identified as ubiquitin. “Maybe the lesson from this story,” Hershko wrote, “is that it is dangerous to consult experts.”
Much of the decisive work was done during sabbaticals with the American biochemist Irwin Rose at the Fox Chase Cancer Center in Philadelphia. In two papers published in 1980, Ciechanover, Hershko and Rose showed that ubiquitin is chemically attached to proteins that are about to be destroyed, often in chains of many ubiquitin molecules. Between 1981 and 1983 they identified the three kinds of enzymes, known as E1, E2 and E3, that attach the tag. The Nobel committee later described the tag as a molecular “kiss of death”: proteins marked with ubiquitin are fed into the cell’s waste disposers, the proteasomes, and chopped up.
From a basic discovery to cancer medicine
The ubiquitin system turned out to control a vast range of life processes, including cell division, DNA repair, quality control of new proteins and important parts of the immune defence. Hershko himself went on to show how it times the cell cycle, discovering with colleagues the cyclosome, or anaphase-promoting complex, which tells a dividing cell when to separate its chromosomes. When the system goes wrong, people fall ill. The Nobel committee pointed to cervical cancer, in which a virus hijacks the system to destroy the tumour-suppressing protein p53, and to cystic fibrosis, in which a misfolded but potentially useful protein is destroyed before it can reach the cell surface.
Understanding the system made it a target for drugs. Bortezomib (Velcade), a proteasome inhibitor, received accelerated approval in the United States in 2003 for the blood cancer multiple myeloma, a disease for which, according to the U.S. National Cancer Institute, there had been no effective treatment. The NCI credits drugs like it with helping turn myeloma from an acute illness into something closer to a chronic disease. Today, researchers worldwide are designing medicines that work by deliberately steering the ubiquitin system toward disease-causing proteins.
Recognition
Hershko received the Weizmann Prize for Sciences in 1987 and the Israel Prize in 1994. In 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.”
He has been generous in sharing credit. In his Nobel autobiography he describes Rose as a brilliant, unselfish collaborator who had to be forced to put his name on papers he had helped make possible, and he thanks Ciechanover for physically pushing him into a chair and ordering him to write the grant application to the U.S. National Institutes of Health that kept his Haifa laboratory alive at a critical time. That grant was renewed for four more periods.
Jewish identity and an Israeli life
Hershko’s life follows the arc of twentieth-century Hungarian Jewry: a provincial Jewish community, forced labour, ghettos and deportation, a narrow escape by chance, and emigration to the young State of Israel. He has written that his father’s former pupils from Karcag, many of whom also reached Israel, still spoke of him with admiration. Hershko studied Talmud at school in Jerusalem, built his career in Israel’s universities, and has said that his only remaining wish is for peace, including between Israel and its neighbours.
He has also described how much of his success depended on chance and on people: the train that went to Austria instead of Auschwitz, a demanding first mentor, a supportive wife who moved from peaceful Switzerland to a new and less comfortable country, and colleagues willing to share an unfashionable obsession.
The scientist at the bench
Hershko is a Distinguished Professor at the Technion’s Rappaport Faculty of Medicine in Haifa and has also held an adjunct professorship at New York University. Unusually for a laureate, he has kept doing experiments with his own hands, which he calls his great hobby, for both peace of mind and excitement. For many years he spent his summers at the Marine Biological Laboratory in Woods Hole, Massachusetts, where clam eggs provided an ideal test-tube system for studying the cell cycle.
His legacy is a whole field of biology. Before his work, protein destruction was considered a dull housekeeping chore. Today the ubiquitin system is known to be one of the cell’s central control mechanisms, studied in laboratories all over the world and exploited by medicines that help patients with cancer live longer.
Sources & further reading
Avram Hershko, Biographical, NobelPrize.org · Popular information: The Nobel Prize in Chemistry 2004, NobelPrize.org · Velcade: a breakthrough for multiple myeloma, National Cancer Institute · Avram Hershko, Jewish Virtual Library · Avram Hershko, 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.