Albert Szent-Györgyi

A bullet through the left arm

Szent-Györgyi was born in Budapest on 16 September 1893. He grew up in a flat in Pest with his mother Jozefina, her mother and his brothers, while his father ran the family estate in the country. His mother’s family, the Lenhosséks, had produced three generations of anatomists. By his own account he was a dull child who hated books. When he announced at sixteen that he would be a researcher, his uncle Mihály Lenhossék said science had no room for dim-wits.

He entered Budapest Medical School in 1911 and was soon bored by medicine, so he drifted into his uncle’s anatomy laboratory. His uncle let him stay on one condition: he would study the rectum and anus, apparently because the uncle suffered from haemorrhoids. His first paper, in 1913, was on the epithelium of the anus. “Because of my uncle,” he joked later, “I started science at the wrong end.”

In 1914 he went to the front as an army medic and won a medal for bravery. By 1916, after two years of trench war, he was disgusted with it and expected to die in it. He shot himself through the left upper arm and claimed it was enemy fire. His own later tellings differ on the weapon, a rifle on the Russian front in one and a revolver in another, but they agree on the motive. In the version the Science History Institute quotes, it was “a mad desire to return to science.” He finished his MD while the wound healed in 1917, and that year married Cornelia “Nelly” Demény, daughter of Hungary’s postmaster general.

Posted to an army clinic in northern Italy, he reported a Viennese doctor two ranks above him for dangerous experiments on Italian prisoners of war. In his telling, the punishment was a transfer to the malarial swamps, and the war ended before it took effect. A daughter, also Cornelia, was born in October 1918. After the war he worked in pharmacology in Pozsony until the city became Czechoslovak Bratislava in 1919 and Hungarians were told to leave. Laboratories in Prague, Berlin, Hamburg and Leiden followed, on very little money.

A one-second delay before the blue

In Groningen he took up biological oxidation, the controlled burning of food in cells. He was convinced that plants and animals do it by the same basic means. He studied why a cut potato goes brown, hoping it would explain the bronze skin of patients whose adrenal glands were failing. He later called this a false supposition, but it led him somewhere real.

The useful observation was a delay of about a second. Peroxidase and hydrogen peroxide turn benzidine deep blue at once. When he used raw juice from plants that do not brown in place of purified enzyme, the blue came about a second late. Something in the juice was reducing the oxidised dye back until it ran out. “There was great excitement in my little basement room in Groningen,” he told the Nobel audience, when he found that the adrenal cortex held the same reducing substance in quantity.

In 1926 Frederick Gowland Hopkins brought him to Cambridge on a Rockefeller fellowship. There he isolated the substance from adrenals and plants and showed that it was C₆H₈O₆, related to the sugars, and Cambridge gave him a PhD for the work. He wanted to name it “ignose”, from the Latin for “I don’t know”. Arthur Harden, the journal editor, refused it, and refused “godnose” too. It was published as hexuronic acid.

Getting enough of it was the problem. Norman Haworth at Birmingham wanted material to solve the structure, but adrenal glands were the only rich source and they were scarce in England. August Krogh flew glands from Copenhagen, and the substance perished on the way. In 1929–30 Edward Kendall and the Mayo Foundation gave him the run of American slaughterhouse adrenals, and a year’s work produced 25 grams of crystals. He gave half to Haworth, which was not enough for a structure. He already suspected the acid was vitamin C but admitted that his unsettled life did not suit feeding trials.

The chemistry of biological combustion

In January 1931 he took the chair of medical chemistry at Szeged. The education minister, Kuno Klebelsberg, had recruited him with Rockefeller money behind the plan. His students loved him, and older faculty were startled by a professor who ate and played sport with them, rode an English BSA motorcycle, drove an imported Buick and later flew sport planes solo. The Rockefeller relationship set a pattern that lasted all his life: enthusiasm at first, then frustration on both sides as he asked for more money and resisted detailed plans and budgets.

That autumn J. L. Svirbely arrived from Charles Glen King’s vitamin laboratory in Pittsburgh. In Szent-Györgyi’s words, he brought vitamin experience and the conviction that hexuronic acid was not vitamin C. Svirbely fed the last of the Mayo crystals to guinea pigs on a scurvy-producing diet. By autumn 1931 the results showed the acid was powerfully anti-scorbutic, and that the anti-scurvy activity of plant juices matched their hexuronic acid content. They repeated the tests before publishing. In March 1932 Svirbely wrote to King about the results. On 1 April Science published King’s announcement that vitamin C was hexuronic acid, citing Szent-Györgyi’s chemistry but not the Szeged feeding tests. The Szeged note followed in Nature.

King had worked on the problem for years and had his own active crystals from lemon juice. His supporters called Szent-Györgyi a plagiarist, European chemists backed Szent-Györgyi, and the dispute over who came first ran for a decade. The National Library of Medicine’s account says King published “possibly on the basis of news from Svirbely”; the surviving record does not settle the question.

By then the supply was gone again. One evening in 1932, in his own account, he did not want to eat the peppers his wife Nelly served and took them to the laboratory instead. Szeged was the centre of Hungary’s paprika industry, and that night’s test showed paprika was “an unbelievably rich source” of the acid. With money from the Josiah Macy Jr. Foundation and the last weeks of the season, the laboratory crystallised more than half a kilogram, and more than three kilograms the next year. He did not patent it. He sent it to anyone working on it, including Haworth and Paul Karrer, whose structural work it made possible. With Haworth he renamed it ascorbic acid, the anti-scurvy acid. A crystalline derivative he made with Varga could be turned back into ascorbic acid with its activity intact, which proved that the vitamin was the acid itself and not an impurity.

Not all of it held up. A colleague with a bleeding disorder improved on paprika but not on pure vitamin C. With István Rusznyák, Szent-Györgyi isolated a flavonoid mixture from lemons, called it citrin, and proposed a “vitamin P”. His own Nobel lecture admitted that its vitamin properties had not been shown in an “irreproachable and reproducible fashion”, and no deficiency disease was ever found. He also spent years “preaching vitamin C” for colds and other illnesses, an idea British biochemists thought crankish.

The prize was mostly for something else. Minced pigeon breast muscle keeps respiring after it is ground up. Szent-Györgyi showed that small additions of four related acids, succinic, fumaric, malic and oxaloacetic, raised its oxygen use far beyond what burning the acids themselves required. They were acting as catalysts, not fuel. In his model, hydrogen stripped from food passed from oxaloacetate to malate, then from fumarate to succinate, on its way to cytochrome and oxygen. Each step released a little energy, “converting the large banknote into small change.” He credited Annau, Banga, Gözsy, Laki and Straub for the measurements.

F. J. Stare and C. A. Baumann proved the catalysis decisively in December 1936. Early in 1937 Hans Krebs in Sheffield found that citrate worked the same way, and after Martius and Knoop’s work he closed the loop as the citric acid cycle. Krebs’s 1953 Nobel lecture calls Szent-Györgyi’s pigeon-muscle work “an important development” but notes that he could not explain the catalysis. His focus on malate and oxaloacetate as a hydrogen shuttle was a wrong turn.

On 28 October 1937 the Karolinska Institute awarded him the Nobel Prize in Physiology or Medicine “for his discoveries in connection with the biological combustion processes, with especial reference to vitamin C and the catalysis of fumaric acid.” Haworth and Karrer shared that year’s chemistry prize. He was the first Hungarian laureate to win while living in Hungary, and Szeged made him an honorary citizen.

Threads that shortened under the microscope

After the prize he wanted a more complex biological process to study. Muscle, with what he later called its “violent physical, chemical, and dimensional changes”, was the obvious candidate. Others had laid the groundwork. Willy Kühne extracted a viscous “myosin” from muscle in 1864. Hans Hermann Weber made threads by squirting myosin solution into water. In 1939 Vladimir Engelhardt and Militsa Lyubimova in Moscow reported that myosin splits ATP, the cell’s energy currency.

Ilona Banga made the first break. The standard method left minced rabbit muscle in strong potassium chloride for 20 minutes. As she later recalled, she finished late one day and left a batch overnight in the cold room, and by morning it had turned to jelly. This 24-hour extract, which they called “myosin B”, was far more viscous than the 20-minute “myosin A”. Adding ATP made its viscosity drop sharply, and it set again once the ATP was used up. Myosin A barely responded. Szent-Györgyi took the drop in viscosity on adding ATP as his measure of myosin’s activity.

Then came the threads. Szent-Györgyi made Weber threads from myosin B and suspended one under the microscope in juice from rabbit muscle. The juice was minced muscle stirred for five minutes at 0 °C in a millilitre of water per gram, squeezed through cloth and filtered. “A violent contraction will be seen,” he wrote. Within 30 seconds the thread was under half its length. Within two or three minutes it had lost two-thirds of its length and grew thinner and darker, turning opaque white under side lighting. Threads of myosin A hardly moved.

Next he worked out what in the juice was doing it. Juice left overnight did nothing, because the muscle’s own enzymes had broken down its ATP; adding ATP back restored the contraction. ATP in plain water did nothing either, but ATP dissolved in boiled juice worked, and so did ATP in juice that had been burned to ash. So the juice’s salts mattered too. A solution of 0.1 molar potassium chloride with a little magnesium chloride gave the full effect: ATP, potassium and magnesium were the three factors. Adenylic acid, a stripped-down relative of ATP, had no effect, and at higher potassium chloride concentrations the thread dissolved instead of contracting. “To see them contract for the first time,” he wrote later, “and to have reproduced in vitro one of the oldest signs of life, motion, was perhaps the most thrilling moment of my life.”

Brunó Straub showed what myosin B was. He dried washed muscle residue with acetone, which leaves myosin insoluble, and extracted a second protein from the powder with water. Mixed with myosin A, it brought back myosin B’s high viscosity and response to ATP. They named it actin, and the combination actomyosin. Straub went on to show that actin has a globular form and, when salts are added, a long fibrous one: G-actin and F-actin. His acetone-powder method is still the basis for purifying muscle actin. Banga found that magnesium speeds up actomyosin’s splitting of ATP, Mihály Gerendás worked out the thread technique, Wilfried Mommaerts measured ATP’s effects, and T. Erdős linked rigor mortis to running out of ATP. In Cambridge the Needhams’ group found independently that ATP lowers myosin’s viscosity. The war kept the two laboratories apart.

Wartime Hungary was cut off even from Nature and Science, so the laboratory printed its own Studies from the Institute of Medical Chemistry, University Szeged. Volume I, Myosin and Muscular Contraction, went to press on 6 July 1942, and two more volumes followed by December 1943. Sceptics, among them William Astbury and Otto Meyerhof, argued that shrinking protein threads were an artefact of the test tube, not a model of muscle. The answer came in 1949 at Woods Hole. Rabbit psoas muscle soaked in cold 50 percent glycerol loses its ATP but keeps its structure, and when ATP is added back it pulls with a tension comparable to living muscle. Glycerinated fibres are still used in muscle research.

The muscle work brought a second Nobel nomination in 1951 and the Lasker Award in 1954. Banga had become Szeged’s first woman docent in 1940 and later co-discovered the enzyme elastase with her husband, József Baló. Straub became a powerful figure in Hungarian science and, in 1988–89, Hungary’s head of state.

Istanbul, the Gestapo and a Swedish name

Politics, he said, entered his life “when books were burned and my Jewish friends were persecuted.” In the 1930s he helped Jewish colleagues get out, Hans Krebs among them according to the National Library of Medicine. As professor, and as rector in 1940–41, he faced down angry groups of militant students. He helped draft the manifesto of the Hungarian National Independence Front, which demanded that Hungary leave the war and break with Germany. In 1941 he divorced Nelly and married Márta Borbíró, formerly Miskolczy.

In 1943 the former prime minister István Bethlen, who knew the British trusted a Cambridge man, urged him to make contact with them in neutral Turkey. Szent-Györgyi took the plan to the prime minister, Miklós Kállay, half expecting to be arrested. Instead, in his account, Kállay asked him to carry messages. He went to Istanbul on the pretext of a lecture, reached British intelligence and was told to go home and set up a secret radio link between the two governments. German agents found out. He said afterwards that Hitler raged at the regent, Horthy, and demanded he be handed over as a Schweinehund. By the summer of 1944, with Germany occupying Hungary, he was under house arrest at Hitler’s demand. He slipped away and spent the rest of the war in hiding in Szeged and Budapest.

Sweden made him a citizen so that its legation could protect him, and he and Márta lived as “Mr. and Mrs. Swenson”. Not expecting to survive, he wrote up the Szeged muscle work in hiding. On 1 August 1944 he sent the manuscript, titled Muscle, to Hugo Theorell in Stockholm. Theorell, with no idea where he was, sent word of its arrival to the Swedish legation, where Szent-Györgyi was in fact sheltering. He had to be smuggled out before men of the Arrow Cross, the Hungarian Nazi party, broke into the legation looking for him and looted it. The paper appeared in Acta Physiologica Scandinavica in 1945.

He welcomed the Red Army as liberators. In his own telling, a unit sent on Molotov’s orders found him and took him to Moscow, where he ate caviar three times a day. Back in Budapest he was a national hero, talked of as a possible president. He took the Budapest chair of biochemistry, sat in the new parliament and helped re-found the Academy of Sciences. Repeated visits to Moscow later counted against him in Washington.

By 1946 he was quietly looking for posts in America. In 1947 his friend and backer, the industrialist István Ráth, was arrested and tortured. Szent-Györgyi used all his influence to get him out, and that summer they applied to emigrate. American visas were held up for months over his Soviet contacts. He and Márta reached the United States in August 1947.

Woods Hole on a meatpacker’s money

He chose the Marine Biological Laboratory at Woods Hole, remembered from a 1929 visit as a place where he could rent bench space and be left alone. Ráth, now Stephen Rath, set up a foundation to bring over his Hungarian team, but nothing came easily. The Office of Naval Research withdrew a promised contract in 1949, the FBI kept watching him for “Communist associations”, and his money was stuck in British banks. A research post at the National Institutes of Health from 1948 kept him afloat, commuting between Bethesda and Woods Hole. In 1950 the Armour meat company agreed to pay for “fundamental studies in the field of muscle research”, the American Heart Association added a grant, and the foundation became the Institute for Muscle Research.

He worked year round at what was mainly a summer laboratory and gave parties at Seven Winds, his house on Penzance Point. Short books on muscle made his name in America. His cousin Andrew Szent-Györgyi and Andrew’s wife Eva found that myosin splits into subunits, the meromyosins, and the group did early electron microscopy of muscle. He became an American citizen in 1955 and joined the National Academy of Sciences in 1956.

From the late 1950s he turned to cancer. From thymus gland he extracted a substance that slowed growth, which he called retine, and one that promoted it, promine. Animal experiments suggested retine could shrink some tumours, but neither was ever identified, and he refused to offer an unknown substance as a treatment. Márta died of cancer in 1963, and his daughter Nelly also died of cancer in the 1960s. A brief third marriage, to June Wichterman, daughter of the Woods Hole biologist Ralph Wichterman, ended in divorce.

Nuclear weapons and Vietnam drew him back into politics. He signed petitions, joined protests and drew large crowds of young summer visitors to his lectures. In The Crazy Ape (1970) he made a pessimistic case that scientific power had outrun political sense.

Below the molecule

The electronic idea went back to 1941, when he first argued that biochemistry needed the physics of electrons as well as molecules. Bioenergetics (1957) and Introduction to a Submolecular Biology (1960) built it out. Molecular biology, he said, pictured closed molecules jostling and colliding in the heat. He thought living matter must also depend on mobile electrons moving through ordered proteins, which might behave something like semiconductors.

At the 1969 Lindau meeting he set out the mechanism. He started from Weiss’s 1942 finding that a strong oxidising agent and a strong reducing agent form a complex with separated charges. In this charge transfer an electron passes from a donor to an acceptor, and under favourable conditions the pair splits into free radicals that an electron spin resonance (ESR) machine can detect. The body has no light and no strong oxidising agents, so his question was whether its mild substances could transfer charge at all. With a strong acceptor added in a suitable solvent, his laboratory got clear ESR signals. Spare electron pairs on atoms such as oxygen and sulphur could be given up (“électrons célibataires”, he joked, unmarried electrons), and every peptide bond in a protein contained both a donor and an acceptor.

Read these books as research programmes, not settled chemistry. The idea that proteins work like semiconductors stayed contested, and many colleagues doubted that proteins could conduct electrons at all. They show how far he would follow a hunch, but they are not continuations of the vitamin and muscle discoveries.