The Hungarian-American biochemist Albert von Szent-Györgyi (1893-1986) was awarded the Nobel Prize in Physiology or Medicine for his discoveries relating to cell respiration and to the composition of vitamin C. He also did important work on the chemistry of muscle contraction.
The son of a landed proprietor, Albert von Szent-Györgyi was born in Budapest on Sept. 16, 1893. He became a medical student at the University of Budapest in 1911. His studies were interrupted by World War I, when he joined the military and was wounded in battle. Upon discharge from the army he resumed his studies and graduated in 1917 as a doctor of medicine. After further study at Prague, Berlin, and Hamburg and a post in pharmacology at Leiden, he worked from 1922 to 1926 as an assistant in the Institute of Physiology of the University of Groningen.
By 1920 there was great interest in the method whereby the energy of the foodstuff molecule was released and utilized by the living cell. It was realized that the process could not be one of "slow combustion" with molecular oxygen, as the heat produced in such a process would have destroyed the living cell. Otto Warburg held that the liberation of the foodstuff's energy was the result of oxidation of the foodstuff molecule by activated oxygen. Heinrich Wieland argued that the release of energy was due to loss of hydrogen by the foodstuff molecule. Chemically, the two processes are equivalent. In 1924 Warburg isolated his "respiratory enzyme, " which activated oxygen and allowed it to be taken up by the foodstuff molecule. This discovery strongly favored Warburg's theory.
At Groningen, Szent-Györgyi studied biological oxidation in the animal cell. Warburg had studied the inhibition of cell respiration—that is, oxidation by activated oxygen— by cyanide. It was known that methylene blue acts as an artificial hydrogen acceptor (H-acceptor). In minced tissue Szent-Györgyi now inhibited oxygen activation by cyanide and then added methylene blue. The dye lost its blue color, showing that it had acted as an H-acceptor and that respiration had been restored. He thus clearly demonstrated that in cell respiration the two processes of oxygen activation and hydrogen activation were both active.
While at Groningen, Szent-Györgyi became interested in the bronze pigmentation of the skin in Addison's disease, the cause of which was unknown. He decided to study the brown discoloration produced by injury in the catechol group of plants, and he clarified the method of its production. Nothing was known of the oxidative system of the peroxidase group of plants, which do not show this discoloration, except that they contain an active peroxidase which activates peroxide and that they can oxidize various pigments. He found that if peroxide was added to a mixture of peroxidase and benzidine an intense blue color appeared immediately. But if he repeated this reaction, using juice squeezed from a peroxidase plant instead of purified peroxidase, the blue color appeared only after a second or so. He concluded that the plant juice must also have contained a powerful reducing agent which reduced the oxidized benzidine until it had itself been used up. Arguing on these lines, he found that the adrenal cortex contained a similar reducing substance. The adrenal was a very rich source, but he later found that it was merely a storehouse for the substance.
At the invitation of Sir F. Gowland Hopkins, Szent-Györgyi spent the year 1927 at Cambridge University, where he isolated the reducing substance from adrenal glands, orange juice, and cabbage. With a thesis on this work he graduated as a doctor of philosophy. He found that the reducing agent had the empirical composition C6H8O6, and he called it provisionally hexuronic acid. As the enormous quantities of adrenals required for his further analysis were not available in Great Britain, he spent the year 1928 at the Mayo Clinic in Rochester, Minn., where supplies of adrenal were available from the St. Paul slaughterhouses. In 1929 he returned to Cambridge with 25 grams of hexuronic acid. Most of this he gave to (Sir) Norman Haworth of the University of Birmingham and to other specialists in carbohydrate analysis.
In 1930 Szent-Györgyi became professor of medical chemistry at the University of Szeged in Hungary. He had long thought that hexuronic acid was vitamin C, and he was now joined by J. Svirbely, who was experienced in the necessary animal tests. In April 1932 they announced that they had, by the administration of one milligram of hexuronic acid daily, protected guinea pigs from scurvy for 56 days. Three weeks later they claimed the identity of hexuronic acid and vitamin C. Simultaneously Charles G. King and W. A. Waugh announced their isolation of crystalline vitamin C and its apparent identity with hexuronic acid. On the basis of these results Szent-Györgyi and Haworth changed the name hexuronic acid to ascorbic acid.
Szent-Györgyi's supply of ascorbic acid was now exhausted, but Szeged was the center of the paprika industry. He now, for the first time, tested paprika for the presence of ascorbic acid and found that it was a very rich source. He soon prepared several hundred grams for distribution to chemists. The structural formula of ascorbic acid was determined by Haworth in 1932, and by Paul Karrer in 1933. It was synthesized by Haworth, and independently by Tadeus Reichstein in 1933. Synthetic ascorbic acid was soon available commercially.
Intermediate Stages in Cell Respiration
In 1925 David Keilin of Cambridge University rediscovered an intracellular pigment, which he called "cytochrome." In living cells it showed a reversible oxidoreduction. It was fundamentally important in the final reaction of cell respiration, by which activated oxygen combined with activated hydrogen. It was later realized that Warburg's respiratory enzyme oxidized cytochrome, and the enzyme is now called cytochrome oxidase.
About 1926 Szent-Györgyi was intrigued by the peculiarities of succino-dehydrogenase. It was already known that this dehydrogenase could be inhibited by malonic acid, and he now showed that when he added malonic acid to minced tissue, respiration ceased. He concluded that succinic acid was not an ordinary metabolite but that it had to have some catalytic function. Following this observation Szent-Györgyi elucidated in succeeding years the role of the C4-dicarboxylic acids—oxaloacetic, malic, fumaric, and succinic, in that order—in transmitting hydrogen molecules along the chain from the foodstuff molecule to cytochrome, resulting in its final oxidation to water. At each link in the chain a portion of the energy of the foodstuff was released.
In the early stages of these researches Szent-Györgyi was interested in a fluorescent yellow pigment which showed reversible oxidation. He called it provisionally "cytoflav." It was inactive when added to a test system. In 1932 Warburg described his "yellow enzyme" and showed that it consisted of two components—a specific protein and this yellow pigment; neither by itself had any catalytic action. This flavoprotein was later shown to be vitamin B2 (riboflavin). In 1937 Szent-Györgyi attempted to suggest its position in the cell respiratory system. For these researches he was awarded the Nobel Prize in 1937.
Biochemistry of Muscular Contraction
About 1860 Willi Kühne extracted from muscle a protein that he called "myosin." Little further was done until 1939, when it was found that purified myosin showed the properties of adenosine triphosphatase, an enzyme that splits off the terminal phosphate group of adenosine triphosphate (ATP), thus releasing energy. In 1939, at Szeged, Szent-Györgyi repeated Kühne's work, and in 1941, with L. Banga, he showed that two types of protein could be extracted from muscle, depending on the length of the extraction period. Extraction for 20 minutes yielded a protein of low viscosity, further lowered on addition of ATP. They called this protein "myosin." Extraction overnight yielded a second protein which formed a loose complex with myosin, and it was this complex that constituted the "myosin" of Kühne. Banga and Szent-Györgyi called this second protein "actin, " and they showed that, if solutions of myosin and actin are mixed, the result is a solution of the loose complex which they called "actomyosin." In 1941 Szent-Györgyi made threads of actomyosin by squirting a solution of this complex through a fine extruder into water. He then added ATP to the water and found that the threads contracted to about ten percent of their original length. In 1942 actin was isolated and characterized by Szent-Györgyi's pupil F. B. Straub, and in 1943 Szent-Györgyi prepared crystalline myosin and worked out a method for its purification.
In 1949 Szent-Györgyi introduced the glycerinated fiber bundle; a strip of muscle treated with glycerol can be kept to study the effects of ATP. In 1952-1953 he studied the "staircase effect" in heart muscle and the action of drugs on it.
During World War II Hungarian leaders asked Szent-Görgyi to try to rescue Hungary from the Nazi stranglehold. He made an adventurous journey to Istanbul to consult with British and American diplomats. On his return he found that Hitler had personally demanded his delivery. Smuggled by friends out of Budapest, he hid near the Soviet lines. Rescued on Molotov's personal order, he was taken to Moscow and treated as a distinguished scientist. After the war Szent-Györgyi accepted the chair of medical chemistry at Budapest, and he tried to help Hungary through political activity. But it was impossible to counteract communist influence. In 1947 he emigrated to the United States, where he founded the Institute for Muscle Research at Woods Hole Marine Laboratory, Mass.
Szent-Györgyi received many honors, including the Cameron Prize of Edinburgh University (1946) and the Lasker Award (1954), and he was a member of many scientific societies in several countries. Among his most important books are On Oxidation, Fermentation, Vitamins, Health and Disease (1939), Chemistry of Muscular Contraction (1947), Chemical Physiology of Contraction in Body and Heart Muscle (1953), and Bioenergetics (1957).
Szent-Györgyi died on October 22, 1986 of kidney failure at his home in Woods Hole, Mass. He was in his eighties when he founded the National Foundation for Cancer Research. Through this organization, his work continues to help individuals throughout the world.
Further Reading on Albert von Szent-Györgyi
There is a biography of Szent-Györgyi in Nobel Lectures, Physiology or Medicine, 1922-1941 (1965), which also includes his Nobel Lecture. For the history of ascorbic acid see F. Bicknell and F. Prescott, The Vitamins in Medicine (1953). For biological oxidation see C. W. Carter, R. V. Coxon, D. S. Parsons, and R. H. S. Thompson, Biochemistry in Relation to Medicine (1959). For muscle biochemistry see G. H. Bourne, ed., The Structure and Function of Muscle, vol. 2 (1960), and Dorothy M. Needham, Machina Carnis (1971).