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FISCHER, EDMOND H.April 6, 1920 – August 27, 2021
The American biochemist Edmond Fischer was born in Shanghai, China, in April 6, 1920, the third son of Oscar and Renée (Tapernoux) Fischer. Fischer’s father had come to Shanghai from Vienna, Austria, after studying law and business. His mother had come by way of Hanoi with her parents from France. His grandfather, a prominent figure in Shanghai, helped to established the first French newspaper in China, Courrier de Chine, and established the first school that Fischer attended. At the age of seven, Fischer, along with his two older brothers, Raoul and Georges, moved to Switzerland to attend the Swiss Federal Polytechnical Institute, in Zürich. He began his study of chemistry at the University of Geneva in 1939, and he was awarded his Ph.D. in 1947, after completing his doc- toral thesis, entitled “Purification and Crystallization of Hog Pancreas Amylase.” From 1948-1950 he was a fellow of the Swiss National Foundation, and from 1950-1953 he was a fellow of the Rockefeller Foundation.
Fischer came to the United States in 1953, first spending a year at the California Institute of Technology as a research associate in the division of biology. He then joined the faculty of the University of Washington in 1954. It was there that he met his research partner, the American physiologist EDWIN G. KREBS. In the autobiography Fischer wrote for Les Prix Nobel, he recollected his first days at the University of Washington: “Within six months of my arrival, Ed Krebs and I started to work together on glycogen phosphorylase. He had been a student of [CARL F. CORI and GERTY T. CORI] in St. Louis. They believed that AMP [adeno- sine monophosphate] had to serve some kind of cofactor function for that enzyme. In Geneva, on the other hand, we had purified potato phosphorylase, for which there was no AMP requirement. Even though essentially no information existed at that time on the evolutionary relationship of proteins, we knew that enzymes, whatever their origin, used the same coen- zymes to catalyse identical reactions. It seemed unlikely, therefore, that muscle phosphorylase would require AMP as a cofactor but not potato phosphorylase. We decided to try to elucidate the role of this nucleotide in the phosphorylase reaction. Of course, we never found out what AMP was doing: that problem was solved 6-7 years later when Jacques Monod proposed his allosteric model for the regulation of enzymes. But what we stumbled on was another quite unexpected reaction: i.e. that muscle phosphorylase was regulated by phosphorylation-dephosphorylation. This is yet an- other example of what makes fundamental research so attractive: one knows where one takes off but one never knows where one will end up.
“These were very exciting years, when just about every experiment revealed something new and unexpected. At first we worked alone in a small, single laboratory with stone sinks. Experiments were planned the night before and carried out the next day. We worked so closely together that whenever one of us had to leave the laboratory in the middle of an experiment, the other would carry on without a word of explanation. Ed Krebs had a small group that continued his original work: determining the structure and function of DPNH-X, a derivative of NADH. I was still studying the amylases with Eric Stein. In collaboration with Bert Vallee, we were able to demonstrate that these enzymes were in reality calcium-containing metalloproteins.”
In 1992, more than 40 years later, Fischer and Krebs were awarded the Nobel Prize for this work, which led to the accidental discovery of a basic process in human cells that regulates most of the biochemical processes of life. The process of reversible protein phosphorylation controls how chemical reactions within cells are turned on and off. It is now known to be a prominent player in most, if not all, normal cellular phenomena. It also may play a major role in the treatment of most diseases, including cancer and AIDS.
Fischer and Krebs began this work with a grant from the National Institutes of Health to study the problem of how adrenalin causes the breakdown of glycogen, giving muscles the energy to contract in the “fight or flight” response. They were concentrating on an enzyme called phosphorylase, which Fischer had previously worked with in plant studies at the University of Geneva. It was known that both active and inactive forms of the enzyme were present in muscle cells, but how the two forms differed was not understood.
Proteins have a defined three-dimensional structure that dictates molecular interactions. An enzyme’s ability to act on other proteins depends on an elaborate “lock and key” mechanism by which the enzyme and the protein upon which it acts fit together perfectly; thus each has the ability to act only on specific molecules. Fischer and Krebs’s research proved that a phosphate molecule attached to the inactive form of phosphorylase at a key location activated the enzyme. The removal of the phosphate group rendered the enzyme inactive. The scientists thus discovered that proteins could be regulated by having their structure modified in a reversible way.
The process by which a phosphate group is added an enzyme is called phosphorylation. The enzymes that carry it out are called protein kinases. The reverse process, called dephosphorylation, is carried out by enzymes called phosphatases. The overall process is referred to as reversible protein phosphorylation.
“We stumbled on it,” said Fischer. “We had no idea how widespread this reaction would be.” The process turned out to be responsible for regulating a huge variety of metabolic processes, including the action of hormones in the body, muscle contraction, immune responses, cell growth and division, blood pressure, inflammatory reactions, and signals in the brain. The Nobel Academy’s statement on the prize states that an estimated 1 percent of the genes in human DNA are devoted to blueprints for the production of phosphorylating enzymes. Fischer was modest on the subject of the prize. “So much superb work has been carried out by so many investigators… you wonder why we were selected,” he said. “You can think of literally dozens of other people who would deserve it.”
One of the most important applications for the study of phosphorylation is oncology. More than half of the cancer-causing cells are known to encode protein kinases. Some biologists have theorized that blocking phosphorylation in cancer cells could halt tumor growth. Continued study of the phosphorylation pro- cess in cancer cells may lead to the development of new and different types of anticancer drugs.
Some immunosuppressant drugs, such as cyclosporine, utilize the reverse process of dephosphorylation to block the activation of white blood cells that would attack transplanted organs. Researchers are currently working on a possible role for dephosphorylation in the fight against diabetes. Since the original discovery, further research has shown that many phosphorylation reactions are considerably more complicated than they first appeared. Some kinases phosphorylate other kinases, which in turn phosphorylate still other kinases, producing a biochemical cascade. A corresponding number of phosphatases work against the cascade, creating a regulatory mechanism that is more like a dimmer than a mere on/off switch. Each time enzymes act upon each other in sequence, their effect is amplified one millionfold to 20 millionfold. The cascade effect in hormone reactions, for instance, allows a tiny amount of hormone to exert an enormous influence and yet still be very closely regulated.
Initially, the discovery of reversible protein phosphorylation by Fischer and Krebs gathered little attention in the scientific community. It was not until the mid-1970s that the wide application of the process was appreciated and research in the area blossomed. A whole new field of research has been initiated concerning the signalling processes that control cellular events; a particularly large area in recent years is the role of kinases and phosphatases in growth control. Unofficial estimates have suggested that up to 10 percent of articles published in the field of biochemistry deal with this topic.
As of 1996, Fischer was a senior researcher and professor emeritus at the University of Washington, where he continued to carry out research in the field he helped to found almost 40 years earlier. Around the time he was awarded the Nobel Prize, his research in- volved studying the process of cell transformation in cancer.
Fischer has two sons, FranDcois and Henri, from his first wife, Nelly Gagnaux, who died in 1961. He married Beverley Bullock in 1963. Fischer also has two grandsons. Edmond H. Fischer Nobel Prize in Physiology or Medicine 1992
In addition to the Nobel Prize, Fischer has received numerous awards from various institutions including the Swiss Chemical Society, the Guggenheim Foundation, the University of Geneva, and the University of Washington. He is the recipient of honorary doctorates from both the University of Montpellier in France and Switzerland’s University of Basel. Additionally, he is a member of the American Academy of Arts and Sciences, the National Academy of Sciences, and the Ven- ice Academy of Sciences, Arts and Letters, and a foreign associate of the Spanish Royal Academy of Sciences. Edmond H. Fischer died on 27 August 2021.
