Free Radical: Albert Szent-Györgyi and the Battle over Vitamin C
In Praise of Imperfection: My Life and Work
Albert Szent-Györgyi was a flamboyant Hungarian biochemist, famous for having isolated vitamin C and for other important discoveries. He was born in Budapest in 1893, lived in Europe through two world wars, and then spent the remainder of his long life at Woods Hole on Cape Cod, where he died in October 1986. His name is the Hungarian for Saint George, whom he tried to emulate when he attempted single-handedly to save his country from the Nazi and Soviet dragons. The title “Free Radical” is a play on his political and chemical beliefs and the catchy subtitle refers to an alleged battle that occupies no more than thirteen of the book’s 316 pages.
Albert Szent-Györgyi was the son of a landowner who spent his time “thinking about the sheep, the hogs and manure” and of a sensitive, musical mother who was descended from a family of distinguished academics. Albert was a mediocre pupil at first, but at sixteen he began to read widely and decided to follow his uncle, the physiologist Mihaly Lenhossek, into medical research. His uncle’s mistrust of his ability proved one of the spurs to his career. Szent-Györgyi told his biographer that from his earliest days he recognized in himself an intuitive, almost mystical ability to hear the voice of nature, something akin to a poet’s inspiration. This ability was to guide him to success at first; we shall see that it became a recipe for self-deception in later life.
In 1914 Szent-Györgyi was drafted into the Austro-Hungarian army and sent to fight the army of the czar. After three gruesome years he “became increasingly disgusted with the turpitude of military service.” “I could see that we had lost the war…. The best service I could do for my country was to stay alive.”1 He shot himself in the arm so that he could be discharged and complete his medical studies. Szent-Györgyi’s horrifying experiences in the First World War made him fight for peace for the rest of his life. Soon after the end of the war, Szent-Györgyi left Hungary with his young wife and infant daughter to do research abroad. He had no grant, only six hundred pounds sterling from the sale of his father’s estate. This proved insufficient to supplement his meager earnings at a succession of Czech, German, and Dutch universities. He and his family lived under hardships so great that he developed hunger edema, the swelling that comes from malnutrition. Yet he was determined to pursue his own ideas rather than work at his professors’ bidding: “The real scientist is ready to bear privation, if need be starvation, rather than let anyone dictate to him which direction his research must take” (A. Szent-Györgyi in “Science Needs Freedom.” 1943).
During the Twenties and Thirties the chemical mechanism of the oxidation of nutrients, the process from which animals get their energy, posed one of the great unsolved problems of biology. Most of our nutrients, like starch, proteins, or fats, are large molecules. They are first broken down to smaller ones in the digestive tract, and these small molecules then enter the bloodstream. They are made up of carbon, nitrogen, oxygen, hydrogen, and sometimes sulfur. To provide energy, these compounds are broken down further until the carbon is oxidized to carbon dioxide and the hydrogen to water. This breakdown proceeds in our tissues in a series of chemical reactions, each catalyzed (speeded up) by a different enzyme. In 1920 the steps involved in this process were largely unknown. The first of Szent-Györgyi’s beautiful papers made a promising start on unraveling them. They were published in 1925 and caught the attention of the founder of English biochemistry, Frederick Gowland Hopkins, who invited him to his laboratory in Cambridge and helped him to obtain a Rockefeller Fellowship. Szent-Györgyi was overjoyed to have an adequate salary at last and to find himself among brilliant young people in one of the world’s best biochemistry schools.
Szent-Györgyi told his biographer that in 1926 he moved into an “ancient cottage” at 35 Oldstone Road. I moved into the same house ten years later. The road is actually called Owlstone and, like all the other houses in that road, no. 35 is small, plain, suburban, and semi-detached, built in 1913. Szent-Györgyi romanticized it as part of what his biographer describes as “his appealing, self-dramatizing myths…which he had created and perpetuated for sixty years.” Szent-Györgyi also told his biographer that he never talked about science to Hopkins, who shunned people and with whom it was hard to communicate. This memory conflicts with Szent-Györgyi’s own expression of his “deepest gratitude” for Hopkins’s “extreme kindness and helpfulness” at the end of his paper on the isolation of what later proved to be vitamin C. In fact, Hopkins was the most approachable of great men; he regularly wandered around his laboratory for friendly chats with the young scientists about their work. Did old Szent-Györgyi want to forget the help that Hopkins had given young Albert?
Before Szent-Györgyi came to Cambridge he had found that the adrenal cortex contains a chemical factor that bleaches a brown solution of iodine, reducing the iodine to iodide. He wondered what the function of that factor might be, but failed to isolate it. In Cambridge he crystallized it in chemically pure form and showed that it was an acid, related to sugars, that also occurs in oranges and in cabbage. The chemical names of sugars all end in -ose. Not knowing what kind of sugar it was, he first called it “ignose”; when the editor of the Biochemical Journal objected to that flippant name, he changed it to “godnose,” whereupon the incensed editor gave it the prosaic name “hexuronic acid,” because it contained six atoms of carbon.
After describing the process of isolating it and analyzing its properties, Szent-Györgyi wrote: “The reducing substances of plant juice [i.e., the hexuronic acid] have repeatedly attracted attention, specially from students of vitamin C,”2 but he did not test whether hexuronic acid actually was vitamin C, even though he could easily have done so at the Medical Research Council’s nutrition laboratory, which had opened in July 1927 and was only two miles from the Biochemistry Department. Had he carried out such a test, his claim to the discovery of vitamin C would never have been disputed. In retrospect, Szent-Györgyi attributed this failure to his disdain for applied research, but that does not tally with his triumphal lecture tours once the identity of hexuronic acid and vitamin C had been established.3
This happened in 1932 after Szent-Györgyi had been appointed professor of biochemistry at the Hungarian University of Szeged. In 1931 Joseph Svirbely, a young American Ph.D. of Hungarian descent, arrived there. Having done his thesis on the isolation of vitamin C from lemons with Charles King at the University of Pittsburgh, he asked Szent-Györgyi to let him find out whether hexuronic acid was capable of curing guinea pigs of scurvy. It did, and the dose of hexuronic acid needed was the same as that of vitamin C extracted from lemons. With Szent-Györgyi’s agreement Svirbely wrote this news to King in March 1932 (the exact date is not clear). On April 1 a letter by C.G. King and W.A. Waugh appeared in the American magazine Science to announce that vitamin C from lemons had chemical properties similar to those that Szent-Györgyi had described for hexuronic acid; hence the two compounds must be identical.4 Svirbely’s and Szent-Györgyi’s announcement of the same discovery appeared sixteen days later in the British magazine Nature.5
Szent-Györgyi was terribly upset at having been scooped, needlessly upset because the scientific world saw that he had done the pioneering chemistry of purifying and characterizing the new compound, while King and Waugh had merely repeated a few of his tests to demonstrate the identity of their crystals with his. Besides, Szent-Györgyi had communicated Svirbely’s and his results to the Hungarian Academy of Sciences twelve days before King and Waugh’s letter appeared. However, Szent-Györgyi’s anger was heightened when The New York Times and other American papers hailed King’s discovery without mentioning his name.6
In 1937, when Szent-Györgyi received the Nobel Prize, the American press accused him of having stolen the discovery from King and abused the Swedes for not having awarded the prize to King and Szent-Györgyi jointly. I wondered why King was excluded, and asked the Nobel Committee for Physiology and Medicine if I could look at their files, which are open to inspection fifty or more years after the event. The Nobel committees do not themselves nominate candidates for the prize, but each year they solicit nominations from universities, academies, and individuals worldwide and appoint referees to report on their merits. I found that Szent-Györgyi had been nominated by scientists from Hungary, Czechoslovakia, Germany, Switzerland, Belgium, and Estonia (not by Hopkins, to my surprise), but that no one had nominated King.
In 1934, the committee had asked the Swedish chemist Einar Hammarsten to act as a referee; he wrote a seven-thousand-word report concluding that the discovery of vitamin C and its identity with hexuronic acid deserved a Nobel Prize, that Szent-Györgyi’s role had been outstanding, but that the sum of the contributions made by several others had been equal to or greater than his. Given that no more than three people can share the prize, he could not recommend an award. Hammarsten cites King and Waugh’s papers, but not as prominently as others do.
Meanwhile, Szent-Györgyi continued to work on the problem closest to his heart, the oxidation of nutrients. He discovered that fumaric acid and three other acids whose role in living tissues had been enigmatic represented successive steps in a chain of chemical reactions taking place during oxidation. After the publication of that work Hammarsten and the biochemist Hugo Theorell wrote reports to the Nobel committee recommending that Szent-Györgyi be given the Prize for Physiology or Medicine primarily for that great advance, and he received it in 1937 “for his discoveries in connection with biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid.” His Nobel lecture, not reproduced in Moss’s book, is a model of lucidity, liveliness, and scientific rigor.7
Szent-Györgyi’s Nobel Prize made him a national hero in Hungary, but at that very moment his research on oxidation was overtaken by Hans Krebs, a young German refugee at the University of Sheffield. Krebs showed that Szent-Györgyi’s four acids took part in a cycle of chemical reactions, since known as the Krebs cycle, in which carbon dioxide, water, hydrogen, heat, and chemical energy are abstracted from breakdown products of nutrients in successive small steps. At first, Szent-Györgyi felt disheartened by Krebs’s success, but then he turned to another great problem, the contraction of muscle. The chief component of muscle was known to be a fibrous protein called myosin, but its role in contraction was unclear.
A. Szent-Györgyi, "Lost in the Twentieth Century," Annual Review of Biochemistry, Vol. 32 (1963), p. 1.↩
A. Szent-Györgyi, "Observations on the function of the peroxidase systems and the chemistry of the adrenal cortex," Biochemical Journal, Vol. 22 (1928), p. 1387.↩
According to Kenneth J. Carpenter's scholarly account of the History of Scurvy and Vitamin C, knowledge about the antiscorbutic effect of cabbage, oranges, and lemons goes back a long way (Cambridge University Press, 1986). Captain James Cook reported to the Royal Society in 1776 on "The method taken for preserving the health of the crew of His Majesty's ship the Resolution during her late voyage round the world" (Philosophical Transactions of the Royal Society, Vol. 66, 1776, p. 402). That method included taking sauerkraut, oranges, and lemons. The name vitamin C for the still unidentified antiscorbutic factor was coined by the British biochemist and nutritionist Jack C. Drummond in 1920 (Biochemical Journal, Vol. 14, 1920, p. 660).↩
C.G. King and W.A. Waugh, "The Chemical Nature of Vitamin C," Science (April 1, 1932), p. 357.↩
J. Svirbely and A. Szent-Györgyi, "Hexuronic Acid as the Antiscorbutic Factor," Nature (April 16, 1932), p. 574.↩
Szent-Györgyi suspected King of having drafted his letter to Science after he had received Svirbely's news, and Moss seeks to corroborate that suspicion by reproducing King's reply to Svirbely, dated March 15, 1922. The letter states: "The product (vitamin C from lemon juice) appears to be identical with S.-G.'s product, but further chemical work will have to be done to be sure." Moss takes this to mean that King was not yet ready to publish, but pays no attention to a sentence further on: "In a note that should appear in Science in a few weeks, I cite your paper [Svirbely's earlier work on lemon juice published in the Journal of Biological Chemistry] as leading up close to where we are now." This is the note that appeared on April 1. When a scientist refers to "a note that should appear," he means that it is about to be printed, as King's paper must have been on March 15 in order to come out on April 1, because the lapse of time between submission and publication of a scientific paper was, and still is, a matter of a few weeks at least. The geneticist Thomas Jukes recently recalled that King submitted an abstract with his news to a scientific meeting several weeks before the arrival of Svirbely's letter, probably before the end of February (Nature, March 31, 1988, p. 390).↩
A. Szent-Györgyi in Les Prix Nobel (Stockholm: 1933).↩
A. Szent-Györgyi, “Lost in the Twentieth Century,” Annual Review of Biochemistry, Vol. 32 (1963), p. 1.↩
A. Szent-Györgyi, “Observations on the function of the peroxidase systems and the chemistry of the adrenal cortex,” Biochemical Journal, Vol. 22 (1928), p. 1387.↩
According to Kenneth J. Carpenter’s scholarly account of the History of Scurvy and Vitamin C, knowledge about the antiscorbutic effect of cabbage, oranges, and lemons goes back a long way (Cambridge University Press, 1986). Captain James Cook reported to the Royal Society in 1776 on “The method taken for preserving the health of the crew of His Majesty’s ship the Resolution during her late voyage round the world” (Philosophical Transactions of the Royal Society, Vol. 66, 1776, p. 402). That method included taking sauerkraut, oranges, and lemons. The name vitamin C for the still unidentified antiscorbutic factor was coined by the British biochemist and nutritionist Jack C. Drummond in 1920 (Biochemical Journal, Vol. 14, 1920, p. 660).↩
C.G. King and W.A. Waugh, “The Chemical Nature of Vitamin C,” Science (April 1, 1932), p. 357.↩
J. Svirbely and A. Szent-Györgyi, “Hexuronic Acid as the Antiscorbutic Factor,” Nature (April 16, 1932), p. 574.↩
Szent-Györgyi suspected King of having drafted his letter to Science after he had received Svirbely’s news, and Moss seeks to corroborate that suspicion by reproducing King’s reply to Svirbely, dated March 15, 1922. The letter states: “The product (vitamin C from lemon juice) appears to be identical with S.-G.’s product, but further chemical work will have to be done to be sure.” Moss takes this to mean that King was not yet ready to publish, but pays no attention to a sentence further on: “In a note that should appear in Science in a few weeks, I cite your paper [Svirbely’s earlier work on lemon juice published in the Journal of Biological Chemistry] as leading up close to where we are now.” This is the note that appeared on April 1. When a scientist refers to “a note that should appear,” he means that it is about to be printed, as King’s paper must have been on March 15 in order to come out on April 1, because the lapse of time between submission and publication of a scientific paper was, and still is, a matter of a few weeks at least. The geneticist Thomas Jukes recently recalled that King submitted an abstract with his news to a scientific meeting several weeks before the arrival of Svirbely’s letter, probably before the end of February (Nature, March 31, 1988, p. 390).↩
A. Szent-Györgyi in Les Prix Nobel (Stockholm: 1933).↩