Two Roads to Stockholm

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.

The Russian biochemists Vladimir Engelhardt and his wife M.N. Ljubimowa had just shown that myosin is also an enzyme, because it splits the compound that carries energy within the living cell (adenosinetriphosphate, or ATP). During the early Forties Szent-Györgyi went one step further. He added ATP to fibers extracted from muscle and showed that it makes them contract. His young collaborator Bruno Straub then discovered that these fibers contained an additional protein, which he named actin, because it activated contraction in the presence of ATP. In 1953, these important findings laid the foundation for the discovery of the mechanism of muscular contraction by H.E. Huxley, Jean Hanson, A.F. Huxley, and R. Niedergerde, who showed that neither myosin nor actin filaments change in length; instead they become interlocked like the fingers of one hand between the fingers of the other hand and slide relative to each other when muscle shortens. Each actin filament is surrounded by three myosin filaments for part of its length. When contraction is turned on, the actin filaments are drawn deeper into the spaces between the myosin filaments.

Szent-Györgyi recounts how unpopular he had made himself among his autocratic Hungarian colleagues by cultivating the informal relationships between professor and students that he had come to know at Cambridge. Contemporaries confirm this, yet I remember an episode suggesting that subtle differences remained between Cambridge and Szeged. An old friend of mine ran into Szent-Györgyi in a mountain hut high up in the Alps. After dinner, he found Szent-Györgyi dictating a scientific paper to a student with a typewriter carried all the way up the mountain by a porter for that purpose. In Cambridge, taking one’s student to the mountains as a secretary would have been inconceivable; and the urge to prove one’s ceaseless creativity would have been tempered by the sobering thought that after a hard day’s climb fatigue might cloud the clarity of one’s mind. The student was Straub, who has been proposed as the next president of Hungary.

Szent-Györgyi and Straub did most of their work on muscle in Szeged during the Second World War. The slaughter of Hungarian troops in Russia and the persecution of Jews at home induced Szent-Györgyi to join a party that opposed Admiral Horthy’s authoritarian regime and to sign a courageous public manifesto calling for Hungary’s withdrawal from the war and democracy at home. This manifesto became known in England and earned him great credit. Early in 1943 he went to see the ostensibly profascist prime minister Kállay and proposed to travel to Istanbul, on its face to give scientifc lectures, but in fact to ask Britain and the United States for a separate peace. Kállay gave his blessing, and Szent-Györgyi managed to put his bold plan to the head of the British Secret Service in Istanbul. He received some mild encouragement and returned to Szeged with instructions to set up a clandestine radio station for contact with Britain. With characteristic modesty he was to write later: “I had the whole fate of the war in my hands. I was to be the connecting link between the Prime Minister and the English Government, waiting for a chance to bring Hungary over to the right side.”

Unfortunately all Szent-Györgyi’s contacts and plans were betrayed. In a stormy interview with Admiral Horthy, Hitler himself demanded Szent-Györgyi’s head, and Szent-Györgyi spent the rest of the war in a dangerous game of hide-and-seek with the Gestapo. In view of the strategic situation that prevailed in 1943, I am puzzled that he addressed his overtures to Britain rather than to the Soviet Union. He did take that initiative later, in 1945, when the Russians were already occupying part of Hungary. He planned to seize a Hungarian plane, fly it across the battle lines, and negotiate a surrender with Russia, but this plan was also betrayed. On Molotov’s orders, he and his family were finally rescued by the Russians, probably at Engelhardt’s initiative, and accommodated in luxury as General Malinovsky’s guests.

Szent-Györgyi emerged from the war as a leading political figure, an idealist bent on encouraging the cooperation of East and West through the influence of a Hungary where science and the arts would flourish; but he was soon disillusioned by the Russians’ heavy hand. He sought an interview with Stalin, but found himself rudely shouted at by one of Stalin’s underlings instead. When an industrialist friend who had financed his research was arrested and viciously tortured, Szent-Györgyi together with his wife and daughter fled to the United States, and in September 1947 they settled at Woods Hole. For the nonscientist, Moss’s well-documented account of Szent-Györgyi’s activities during and after the war forms the most interesting part of his book.

Two years after his arrival in America, Szent-Györgyi made his last important scientific observation. For experiments on muscular contraction, scientists used to free muscle from most substances other than myosin and actin by washing it with water, but such muscle quickly lost its ability to contract. Szent-Györgyi extracted muscle fibers with a mixture of glycerol and water instead and then stored them at—20° Celsius. Such fibers maintain their ability to contract and have since become widely used in muscle research.

Szent-Györgyi had a strangely divided personality. The Saint was an original thinker, an inspiring evangelist of science, a rigorous investigator, and a fearless, radical advocate of democracy and peace. He fought fascisim, anti-Semitism, McCarthyism, nuclear tests, and the war in Vietnam. He was an internationalist who once said: “An Indian or Chinese scientist is closer to me than my own milkman.” George on the other hand could not distinguish fact from fantasy, sometimes came near to megalomania (“I am always several steps ahead of everyone else”), made essentially false claims to solicit money for his research, and surrounded himself with people who did not contradict him.

Before the Second World War the Saint prevailed; afterward George seems to have become increasingly dominant. In 1950, he wrote to the Rockefeller Foundation: “I am approaching the solution of rheumatic fever, hypertension and myasthenia [gravis],” and asked peremptorily for support; later he often claimed to have discovered the cause of cancer and to be on the verge of discovering how to cure it.

I attended one of Szent-Györgyi’s lectures in Cambridge after the war, excited to hear the great man, but disappointed when he solemnly proclaimed that proteins conduct electricity, because I knew that they are insulators. Later he asserted that “proteins are built to a great extent of free radicals,”⁸ molecules made reactive by the loss or gain of single electrons or hydrogen atoms. This seemed equally wrong to chemists. Another of his claims was that tissues contain “charge transfer complexes,” small molecules packed together so tightly that electrons can easily jump across from one to the other. Only one such complex has been found in living cells, in a compound that Szent-Györgyi specifically excluded from his theory. He also advanced naive, nonsensical theories about cancer. For example, he distinguished between two states of living matter, which he called α and ß. The α-state prevailed before the appearance of oxygen in the earth’s atmosphere, when cell division is supposed to have proceeded uncontrolled. After the appearance of oxygen the ß -state evolved, in which cell division is supposed to be controlled by the chain of enzymes that transfer electrons from nutrients to oxygen. According to Szent-Györgyi cancer is a reversion from the ß– to the α-state. This is all science fiction.

An outsider might think that scientists take no notice of far-fetched theories that run counter to firmly established knowledge, however eminent their source, but this is not what happened. Szent-Györgyi’s theory of electrical conduction in proteins was claimed to have been confirmed experimentally by English chemists, and his ideas about free radicals were apparently confirmed by a Russian group who reported their presence not in proteins but in DNA. An experiment is an experiment and calls for an explanation, but it can be hard to discover the explanation for someone else’s spurious results, and without it they cannot be convincingly disproved. A scientist at Bell Laboratories in New Jersey repeated the Russians’ experiment but, however he prepared his DNA, he found no sign of free radicals. One day he played a fast game of squash; afterward he wrung out his shirt and added a drop of the liquid to the DNA. Immediately there was a strong signal of free radicals, which made him realize that the Russians’ result had come from their sweaty fingers. The electrical conductivity of proteins detected by the English chemists was eventually tracked down to contamination with traces of salt.

Living tissues do produce free radicals, not usually as part of protein molecules as Szent-Györgyi believed but as toxic side-products of chemical reactions or under the influence of ionizing radiations. Most of these toxic radicals are either molecules of oxygen that have gained an electron or molecules of water that have lost an atom of hydrogen. White blood cells actually produce them as weapons against invaders, but when they react with DNA they can give rise to cancer. Animals have evolved mechanisms to scavenge for and inactivate toxic radicals, and one of the most important scavengers is vitamin C. The chemical reaction of vitamin C with free radicals is the same as that involved in the bleaching of iodine, which first brought its existence to Szent-Györgyi’s attention; but by the time this became known, Szent-Györgyi was set on proving his own theories and never seems to have noticed the true connection between free radicals, cancer, and vitamin C that has given his original discovery of the vitamin added importance.

Peter Medawar wrote that “a senior scientist…should always hear behind him a voice such as that which reminded a Roman emperor of his mortality, a voice that should now remind a scientist how probably he may be, and how often he probably is, mistaken.” What deafened Szent-Györgyi to that voice? Being scientific top dog in Hungary? A life of high adventure, hobnobbing with the powerful during the war? Presiding over his own isolated research institute at Woods Hole where no one contradicted him? Moss accepts all Szent-Györgyi’s works as gospel and therefore never asks the question. The great advances in molecular biology and in our understanding of chemical reactions that have revolutionized biochemistry during the last forty years passed Szent-Györgyi by. Moss gives no hint of this and is so dazzled by his charisma and his Nobel Prize that he compares him to Einstein, but Einstein’s insights into the workings of nature are comparable only to those of Newton. Moss’s biography of this complex and colorful man is interesting to read as long as you don’t believe everything in it.

Rita Levi-Montalcini received the Nobel Prize for Physiology or Medicine in 1986, together with Stanley Cohen, for their discovery of growth factors made thirty years earlier while they were working together at St. Louis. Her book recalls her life from her childhood in Turin to her return to Italy from America in 1963. The first part gives an interesting account of life in a Jewish middle-class, family in fascist Italy before and during the Second World War, especially during the Nazi terror, when the Levis were hidden in Florence under false names by good-natured, courageous gentiles who pretended not to know that they were Jews. A far greater proportion of Jews survived in Italy than in most other countries of continental Europe because compassionate gentiles helped and hid them, often at the risk of their lives.

Levi-Montalcini derives the title of her book from a poem by Yeats:

The intellect of man is forced to choose
Perfection of the life, or of the work,
And if it take the second must refuse
A heavenly mansion, raging in the dark.

She chose the work. The French biologist André Lwoff once wrote that “the scientist’s art is first of all to find himself a good master,” to which I should add “and next, to find himself a good problem.” Levi-Montalcini found her problem in a laboratory rigged up in her bedroom during World War II, when Mussolini’s anti-Semitic legislation, a cowardly copy of German racial laws, forced Turin University to expel all Jews, including her professor Giuseppe Levi, who was one of Europe’s leading anatomists. He had aroused her interest in the development of the nervous system while she was an intern; he worked with her in her improvised laboratory, and encouraged her for the rest of his long life. (They were not related.) Together they wondered what determines the beautifully ordered development of the nervous system in early chick embryos whose spinal chords develop before they grow limbs; nerves then grow from the cord into the limbs. When Rita and Giuseppe Levi excised the budding limbs from the embryos before these nerves had started to grow, the nerves never developed further; this suggested that the growing limbs release a chemical factor that attracts the nerves. After the war their publication came to the attention of Viktor Hamburger a German émigré and pupil of the great embryologist Hans Spemann. Hamburger invited Levi-Montalcini to spend a semester with him at Washington University in St. Louis. That semester was to last sixteen years.

The decisive observations came in an experiment that illustrates the importance of the prepared mind. Elmer Bueker, a former pupil of Hamburger, sent him an article that described how a cancerous mouse tumor, grafted onto a chick embryo, had become invaded by nerve fibers from the embryo. Bueker concluded that the tumor had provided more ample terrain for the growth of the nerve fibers than the nearby embryonic limb, but Levi-Montalcini thought otherwise. In a euphoric mood, she dropped all current work in order to repeat Bueker’s work. On being grafted to her embryos, the tumors Bueker had used became invaded by nerves as Bueker had described, but another tumor sent to her (by mistake?) produced a far more dramatic effect. It caused the organs of the embryo that are normally free from nerve fibers, including its gut and blood vessels, to be invaded by large bundles of nerve fibers. She concluded that the tumor had released a chemical compound, a factor that dissolved in the body fluids, accelerated normal growth of nerve fibers to their predetermined destinations, and also caused excessive growth of abnormal nerves.

If a biochemist suspects tumors of producing such a factor, his next step is to make an extract of the tumor and see if it has the same effect as the tumor itself. Rita Levi made such extracts and tested them, not on whole chick embryos but on nerve ganglia excised from their spinal cords. Such ganglia can be pictured as microscopic telephone switchboards. When Rita Levi applied her tumor extracts to the ganglia, haloes of nerve fibers grew around them, but only if the tumors had first been transplanted into chick embryos and then cut out again, as if the embryo induced the synthesis of the compound she was looking for.

Levi-Montalcini and Cohen spent the next year trying to extract enough of the growth factor from such transplanted mouse tumors but reaped so meager a harvest that it was hard to tell if their factor was made up of nucleic acid and protein or of protein alone. Wondering if the nucleic acid was a contaminant, Cohen asked the later Nobel laureate Arthur Kornberg, then at Washington University, for advice. Kornberg suggested treating the extract with snake venom, which contains an enzyme that breaks down nucleic acids. When Cohen tried this the activity of the extract rose spectacularly. It turned out that snake venom contained a several thousand times greater concentration of the growth factor than the mouse tumors. This discovery allowed Cohen to isolate and characterize the factor and provided Levi-Montalcini with pure factor to inject into her embryos. Had they been able to buy the pure enzyme, which is now on sale commercially, they would never have discovered this.

At first the nerve growth factor was regarded as an isolated phenomenon of no general significance, but scientists have now found several other growth factors that are crucial to animal development. If produced in excess, or if the chemical machinery that they normally set in motion is out of gear, they can also give rise to cancer. Levi-Montalcini’s and Cohen’s discovery has laid the foundations for that work and this is why they have recently been awarded the Nobel Prize. Paul Ehrlich has said that success in research needs four G’s: Glück, Geduld, Geschick, and Geld (luck, patience, skill, and money). Levi-Montalcini’s book shows that she had the first three in good measure and needed little of the fourth.