Born with the state
Aaron Ciechanover was born in Haifa on October 1, 1947, a month before the United Nations voted to partition Palestine and some seven months before the State of Israel was declared. His parents, Bluma, née Lubashevsky, and Yitzhak Ciechanover, had come from Poland with their families as teenagers in the mid-1920s. Both came from religious homes, and he believes their move was driven by Zionist idealism and by the ancient Jewish dream of returning to the land. Relatives who stayed behind in Poland were murdered in the Holocaust.
His father worked as a clerk in a law firm in the Arab section of Haifa and later qualified as a lawyer; he also served in the Haganah, the pre-state Jewish defence force. His mother was an English teacher. Aaron’s brother, Joseph, known as Yossi, was fourteen years older. The family gave the boys what Ciechanover calls a liberal modern Orthodox education: synagogue every Saturday and on holidays, a kosher kitchen, and a home full of books, from the Talmud to modern law and classic literature, along with a large collection of classical records. His father spoke Hebrew, Polish, Arabic, French, English, German and Yiddish.
Loss, and a love of biology
From early childhood Ciechanover was drawn to living things. He collected flowers on Mount Carmel and pressed them in his brother’s heavy volumes of the Babylonian Talmud, to his brother’s fury. When he was eleven, Yossi brought him a microscope from England, and with it he saw cells in onion skin for the first time and did his first experiment in osmosis. He went on to keep a collection of animal skeletons and to major in biology at high school in Haifa.
Those years were also marked by grief. His mother died in 1958, and his father died a few years later, leaving Aaron an orphan at sixteen. His mother’s sister, Miriam, took him into her home in Haifa so he could finish school with his classmates, while he spent weekends and holidays with his brother and sister-in-law, Atara, in Tel Aviv. He later wrote that their help was a true miracle, and that without it he could easily have gone astray.
From medicine to biochemistry
Under an army programme that let promising students postpone military service to study fields useful to the military, Ciechanover entered the medical school of the Hebrew University and Hadassah in Jerusalem in 1965. Medicine seemed a practical compromise between his fascination with biology and the security of a profession. But as he began to see patients he became frustrated by how little was understood about the mechanisms of disease, and how many treatments only eased symptoms. He took a year off to do research in biochemistry, studying how a toxic chemical causes fatty liver in rats, and earned a master’s degree in 1971. He had found, he said, a new love.
Keeping a promise to his brother, he finished his clinical studies and qualified as a doctor. In October 1972 he began working with a young biochemist, Avram Hershko, at the new medical faculty of the Technion, Israel’s institute of technology in Haifa, a partnership that would last more than three decades. From 1973 to 1976 he served as an army doctor, first aboard the missile boat Reshef as it sailed from Haifa around Africa to the Red Sea after the Yom Kippur War, and then in the Medical Corps’ research and development unit. In 1975 he married Menucha, a physician.
The kiss of death
In 1976 Ciechanover began doctoral studies in Hershko’s laboratory. At the time, biologists understood a great deal about how cells build proteins but very little about how they break them down. It was known that destroying proteins inside cells mysteriously required energy, which made no chemical sense for a simple demolition job. Hershko’s group studied the question in immature red blood cells, which destroy most of their own machinery as they mature. When Ciechanover separated an extract of these cells into two fractions, neither could break down proteins alone; only together did they work. In 1977 and 1978, with the help of his colleague Michael Fry, he found that the active ingredient in the first fraction was a small, heat-stable protein, which they called APF-1.
During summer visits from 1978 to 1981 to the laboratory of Irwin Rose at the Fox Chase Cancer Center in Philadelphia, Ciechanover, Hershko and Rose made the decisive discovery. APF-1 was being attached, several copies at a time, to the proteins that were about to be destroyed: a molecular tag marking them for disposal. Their papers of 1980 described this tagging as the signal for degradation. Colleagues in Rose’s laboratory then showed that APF-1 was a known protein called ubiquitin. Over the next years Ciechanover, Hershko and their colleagues identified the three enzymes, E1, E2 and E3, that work in sequence to attach ubiquitin to its targets, while other researchers identified the proteasome, the cellular machine that shreds the tagged proteins. The Nobel committee later called the ubiquitin tag a molecular “kiss of death”.
Why it matters for medicine
The ubiquitin system turned out to be one of the cell’s most important control mechanisms, with more than a thousand components. By destroying particular proteins at particular moments, cells regulate cell division, repair damaged DNA, remove faulty proteins and run key parts of the immune response. When the system goes wrong, people fall ill: the Nobel committee pointed to cervical cancer and cystic fibrosis as examples, and errors in protein disposal are also involved in neurodegenerative diseases. Ciechanover’s own laboratory showed that important cancer-related proteins, including the tumour suppressor p53 and the growth promoter c-Myc, are targeted by the ubiquitin system.
This knowledge has been turned into medicines. Bortezomib, sold as Velcade, blocks the proteasome, the end point of the ubiquitin pathway, and causes cancer cells that depend on it to die. Approved in the United States in 2003, it became a mainstay of treatment for multiple myeloma, a blood cancer, and is also used for mantle cell lymphoma; it is on the World Health Organization’s List of Essential Medicines. Other proteasome inhibitors have followed, and researchers are now designing drugs that deliberately steer disease-causing proteins to the cell’s own disposal system, an approach built directly on the pathway Ciechanover helped uncover.
MIT and a laboratory of his own
After completing his doctorate at the Technion in 1981, Ciechanover spent three years as a postdoctoral fellow with Harvey Lodish at the Massachusetts Institute of Technology. There, with Alan Schwartz and Alice Dautry-Varsat, he worked out how iron is delivered into cells by the transferrin receptor, a cycle that became a classic of cell biology. With Alexander Varshavsky and Daniel Finley he showed that a mouse cell line which stopped dividing at high temperature had a faulty E1 enzyme, the first link between the ubiquitin system and the control of the cell cycle.
Despite attractive offers to stay in the United States, he returned to Israel at the end of 1984 to set up his own laboratory at the Technion, where he became a Distinguished Research Professor. His group went on to discover new ways in which proteins are marked for destruction, including a role for transfer RNA and tagging at the very start of a protein chain. He has written candidly that this work was done in difficult conditions, at an institution long dominated by engineering, and sustained by a worldwide network of collaborators.
A Jewish and Israeli scientist
Ciechanover’s Jewish identity runs through his own account of his life. He describes being raised to be a proud Israeli Jew in an independent state that his parents saw as a direct historical answer to the Holocaust. He inherited his father’s love of Jewish learning: for years he has studied with a rabbinical scholar, alongside other physicians and scientists, how Jewish law views moral and ethical questions in modern medicine and science. Jewish cantorial music is his favourite, and he hunts for old recordings in flea markets, record shops and auctions around the world; Judaica decorates his study.
With Avram Hershko, he became one of Israel’s first Nobel laureates in science, and he has since been a tireless public speaker for science and for Israel, lecturing to students and scientists around the world, from Taiwan and China to Armenia. He has received the Albert Lasker Award for Basic Medical Research in 2000, the Israel Prize in 2003 and membership of academies around the world, including as a foreign associate of the United States National Academy of Sciences.
Nobel Prize and legacy
On October 6, 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 to discover one of the cell’s most important cyclical processes, showing that the cell is a highly efficient checking station where proteins are built up and broken down at a furious rate.
Ciechanover lives in Haifa with his wife Menucha; their son, Tzachi, is named for his late father. He credits his aunt, his brother and sister-in-law, his wife and his mentors with carrying him through, and he tells students what his teachers taught him: choose an important, unfashionable problem, stick with it, and be stubborn and critical. The pathway he helped uncover as a graduate student in Haifa is now a central topic in biology textbooks and a source of medicines for people with cancer.
Sources & further reading
Aaron Ciechanover, Biographical, NobelPrize.org · Press release: The Nobel Prize in Chemistry 2004, NobelPrize.org · Bortezomib, Wikipedia · Aaron Ciechanover, 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.