From Shanghai to Lake Geneva
Edmond Henri Fischer, known to everyone as Eddy, was born on April 6, 1920, in Shanghai, China. His father, Oscar Fischer, had come from Vienna with doctorates in law and business and worked in Shanghai as a lawyer and in the import-export trade; he had taken Italian citizenship for business reasons, so Eddy was born an Italian citizen. His mother, Renée Tapernoux, was French. Her father had been a journalist for L’Aurore, the Paris newspaper that published Émile Zola’s J’accuse in defence of Alfred Dreyfus, and he later founded the Courrier de Chine, the first French-language newspaper in China. Eddy began school at the French municipal school in Shanghai that his grandfather had helped to establish.
The family was prosperous, with a large house and annual holidays in Japan. In 1927 they travelled to Europe on the Trans-Siberian Railway, and Eddy, then seven, and his two older brothers, Raoul and Georges, were placed at La Châtaigneraie, a boarding school above Lake Geneva. From then on he was largely separated from his parents. His father later died of tuberculosis, and the loss made the microbiologist Louis Pasteur a childhood hero; for his sixteenth birthday Eddy asked for a microscope, and a brother bought him a professional one.
Music or science
At the Collège Calvin in Geneva he heard the pianist Johnny Aubert play Beethoven and asked the next day to become his student. Aubert accepted him at the Geneva Conservatory after an audition, and Fischer studied with him for seven years and seriously considered a career as a concert pianist before deciding to keep music, as he put it, purely for pleasure. With a school friend he made a pact: one would become a scientist and the other a doctor, so that between them they could cure all the ills of the world.
When Mussolini allied with Hitler in 1939, Fischer burned his Italian passport on the steps of the Italian consulate in Geneva and took Swiss nationality. He spent the Second World War in neutral Switzerland studying chemistry and biology at the University of Geneva, and in 1947 earned his doctorate under the polymer chemist Kurt Meyer, purifying and crystallising amylase, the enzyme that breaks down starch. In 1950 he taught the University of Geneva’s first course in enzymology.
Seattle and Ed Krebs
After Meyer’s sudden death, Fischer left for the United States in 1953, planning a postdoctoral fellowship at the California Institute of Technology. On arrival he found a letter from Hans Neurath offering him a post at the brand-new medical school of the University of Washington in Seattle. He and his wife Nelly visited, found that the mountains, forests and lakes reminded them of Switzerland, and stayed for the rest of his life. He became a full professor in 1961.
Within six months he had teamed up with a colleague, Edwin Krebs, who had trained with Carl and Gerty Cori in St Louis. Both had worked on glycogen phosphorylase, the enzyme that releases sugar from glycogen to fuel muscle. The Coris had found that the muscle enzyme exists in an inactive and an active form, but not what the difference was. Fischer, who had studied the potato version of the enzyme, doubted their explanation. The two men worked side by side at one bench, so closely that either could finish the other’s experiment without a word.
The switch inside every cell
Within eighteen months, in 1955, they had the answer, partly thanks to an accident. The Coris had filtered their muscle extracts through paper; Fischer and Krebs used a centrifuge and got only the inactive enzyme. When they tried filter paper, the enzyme switched on, because calcium leaching out of the paper was activating it. They found that the switch also needed ATP, the cell’s energy currency, and showed that another enzyme, which they named phosphorylase kinase, turns the enzyme on by attaching a phosphate group to it. A second enzyme, a phosphatase, turns it off again by taking the phosphate away. They later traced the hormone adrenaline’s effect on muscle to this switch, and the Krebs laboratory found the first cascade in which one kinase switches on another.
For years this looked like a special trick of sugar metabolism. Then, in the 1970s and 1980s, it emerged that reversible phosphorylation controls almost everything a cell does: how it grows, divides, responds to hormones and dies. The human genome contains hundreds of kinases. Many cancer-causing genes turned out to be kinases stuck in the on position, and the receptors for insulin and for growth factors turned out to be kinases too. Fischer and Krebs shared the 1992 Nobel Prize in Physiology or Medicine, thirty-seven years after their discovery. At the banquet Fischer joked that two Eds are better than one.
Fischer’s laboratory also solved a quieter puzzle. Glycogen phosphorylase carries a form of vitamin B6, pyridoxal phosphate, and because the enzyme is so abundant in muscle and liver, up to 80 percent of the body’s vitamin B6 is bound up in it. Fischer found that, unlike every other enzyme that uses the vitamin, phosphorylase keeps working even when the vitamin is chemically locked in place, showing that its role there was unique; later structural studies explained how its phosphate group helps the enzyme break down glycogen.
From a muscle enzyme to cancer medicine
Because so many diseases involve kinases switched on at the wrong time, the switch Fischer and Krebs found became one of the most important drug targets in medicine. The first potent and specific kinase inhibitors were described in the mid-1990s. In 2001 imatinib, sold as Gleevec, became the first kinase inhibitor approved for clinical use; it turned chronic myeloid leukaemia from a rapidly fatal disease into a manageable condition. According to Fischer’s National Academy of Sciences memoir, more than 75 kinase-inhibiting drugs have since been approved, transforming the treatment of many cancers, including forms of lung, breast and kidney cancer and melanoma.
The other half of the switch matters too. The immunosuppressant cyclosporin, which made widespread organ transplantation possible, works by blocking a phosphatase. Fischer’s later research, with his postdoctoral fellow Nicholas Tonks, purified the first protein tyrosine phosphatases, opening a family of about 100 enzymes. They showed that CD45, a molecule on white blood cells, is one of them, which helped reveal how immune T cells are activated, and they identified PTP1B, later shown to be important in insulin action and studied as a target for diabetes treatment.
Jewish heritage
Fischer’s Jewish heritage came through his father. Oscar Fischer, the Viennese lawyer, was Jewish, according to a Jewish Telegraphic Agency report cited by the JINFO list of Jewish Nobel laureates; his mother’s family was French and not Jewish. Fischer did not write about religion in his autobiography, and he grew up in Swiss boarding schools far from any particular community.
He did form a deep connection to Israeli science. He spent a sabbatical at the Weizmann Institute of Science in Rehovot in 1963, became a close friend of the biophysicist Ephraim Katzir, who later served as President of Israel, and joined the Weizmann Institute’s board of governors and its scientific advisory committee, becoming a life member of its international board in 2010.
A generous host
Former members of his laboratory remembered him as someone who treated his research team like family: he met newcomers at the airport, put them up at his house until they found an apartment, took them skiing in the Cascades and to his holiday home on Lopez Island. At sixty he bought a small plane and learned to fly so that he could get to the island faster, and he flew until he was eighty. He loved history and art, painted under his mother’s maiden name, Tapernoux, and played the piano daily until a few weeks before his death. In June 2021, aged 101, he played the opening of Beethoven’s Ode to Joy from memory for a virtual orchestra of the Lindau Nobel Laureate Meetings.
He compared science to detective work: every result raises new questions, every question suggests the next experiment, and no one can order a great discovery at will. He served as honorary president of the World Cultural Council from 2007 to 2014. His other honours included the Werner Prize of the Swiss Chemical Society in 1952, election to the US National Academy of Sciences in 1973 and, in 2010, foreign membership of the Royal Society.
Family and legacy
Fischer married Nelly Gagnaux in 1948; they had two sons, François and Henri, before her death in 1961. In 1963 he married Beverly Bullock, who brought a daughter, Paula, to the family; Beverly died in 2006. He retired in 1990 but kept going to seminars and faculty lunches at the University of Washington until the Covid-19 pandemic. He died peacefully in Seattle on August 27, 2021, aged 101, at the time the oldest living Nobel laureate. One of his grandchildren, Elyse Fischer, earned her doctorate in 2021 studying how phosphorylation regulates cell division.
His discovery is a reminder of how basic research pays off in unexpected places. Two young professors trying to understand why a muscle enzyme needed an odd ingredient found the master switch of the living cell, and half a century later that switch is the target of medicines that keep many people with cancer alive.
Sources & further reading
Edmond H. Fischer, Biographical, NobelPrize.org · Philip Cohen, Edmond H. Fischer 1920–2021, Biographical Memoir, National Academy of Sciences · In Memoriam: Nobel Laureate Edmond Fischer, UW Medicine Newsroom · In memoriam: Edmond Fischer, ASBMB Today · Jewish Nobel Prize Winners in Medicine, JINFO · Edmond H. Fischer, 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.