Otto Meyerhof

Madness, Kant and a friend called Warburg

Otto Fritz Meyerhof was born in Hannover on 12 April 1884. His father, Felix Meyerhof, was a merchant whose family came from the Jewish community of nearby Hildesheim; through it the Meyerhofs were related to the families of two later biochemists, Hans Krebs and Carl Neuberg. His mother was Bettina May. The family moved to Berlin soon after his birth, and he went to the Wilhelms-Gymnasium there. At sixteen a kidney illness kept him in bed for a long time. The Nobel Foundation’s biography says he spent it in his mother’s constant company, reading and writing poetry, in “a period of much artistic and mental development”. He then studied medicine at Freiburg, Berlin, Strasbourg and Heidelberg.

At first he wanted to be a philosopher more than a scientist. Since his school days he had known Leonard Nelson, whose circle in Göttingen taught a philosophy based on Kant and on the post-Kantian Jakob Friedrich Fries. His 1909 Heidelberg medical thesis was on a problem in psychiatry. He expanded it into a book, Beiträge zur psychologischen Theorie der Geistesstörungen (Contributions to the Psychological Theory of Mental Disturbances), published in the Fries school’s own series, the Abhandlungen der Fries’schen Schule. He later edited that series for many years. In it he also published an essay on Goethe’s methods as a natural scientist.

The turn came in Ludolf von Krehl’s medical clinic at Heidelberg, which he joined in 1909. Krehl wanted physiology and chemistry brought into medicine. In his clinic Meyerhof met Otto Warburg, a chemist trained by Emil Fischer, who was given the job of teaching the new doctor his techniques for measuring respiration, oxygen consumption and growth in sea-urchin eggs. The two worked together several times at the zoological station in Naples, and Meyerhof also spent a short time studying physical chemistry with Georg Bredig. From Warburg he learned to treat a living process as a set of quantities: how much oxygen goes in, what is produced, how much heat comes out. The friendship lasted, and fifteen years later it saved his career.

A frog muscle in nitrogen

In 1912 Meyerhof moved to Kiel, where he qualified as a lecturer in physiology under Albrecht Bethe in 1913. His lecture that year, “Zur Energetik der Zellvorgänge” (On the Energetics of Cell Processes), set out his life’s programme. It was already known that the heat an animal gives off matches the energy in its food. Meyerhof wanted to know what happens in between: the chain of energy transformations that keeps a cell alive before the energy is lost as heat. Jacques Loeb later had him expand the lecture into a book for an American monograph series, published in 1924. In 1914 he married Hedwig Schallenberg, a painter he had met in Heidelberg. Their children Gottfried, Bettina and Walter were born in 1916, 1918 and 1922. He became Rudolf Höber’s assistant at the Kiel physiology institute in 1915 and an associate professor in 1918.

He chose muscle because in muscle the chemistry, the heat and the mechanical work can all be measured in the same piece of tissue. Walter Fletcher and Frederick Gowland Hopkins had shown that lactic acid builds up in muscle deprived of oxygen and disappears when oxygen returns. A. V. Hill, measuring the heat given off by isolated frog muscle, then found that a contracting muscle gives off heat in two roughly equal parts. The “initial heat” comes during the contraction and is the same with or without oxygen. The “delayed heat” comes afterwards, and only when oxygen is present. In his Nobel lecture Meyerhof said Hill’s discovery was what “made it possible for me to steer a safe course through the shallows”.

The experiment was a piece of accounting. Meyerhof took frog muscles out of the animal, stimulated them in nitrogen until they were exhausted, and analysed them. Lactic acid had built up roughly in proportion to the work done, and a matching amount of glycogen had disappeared. Then he put the muscles back into oxygen. The lactic acid disappeared in exact proportion to the extra oxygen they took up, but that oxygen was enough to burn only a fraction of it. In fully fatigued muscle, of every four molecules of lactic acid that disappeared, one (or its carbohydrate equivalent) was burnt and three were rebuilt into glycogen. In fresh muscle the ratio could reach five or six to one. A one-gram frog muscle in nitrogen could develop 160 kilograms of tension over a thousand contractions. What finally stopped it was not a lack of fuel but the acid itself. In a bath rich in bicarbonate, which drew the acid out of the muscle, it produced more lactic acid and did more work before it gave out.

The heat measurements completed the accounts. Going by tables of combustion heats, turning glycogen into lactic acid should release only about 170 calories per gram of lactic acid. Meyerhof measured 380–390 in working muscle and traced the difference to the acid reacting with the muscle’s buffering proteins. If burning one molecule in four pays for the rest, then about 943 calories are released per gram of carbohydrate consumed. With some 385 of those in the active phase, about 560 should appear during recovery. This roughly matched Hill’s finding that the two heats are about equal. “The muscular mechanism operates so much the more economically,” Meyerhof said, “the more lactic acid molecules can be transformed back into glycogen through the oxidation of one of them.”

The 1922 Nobel Prize in Physiology or Medicine was presented in 1923 and divided between Hill and Meyerhof, who was honoured “for his discovery of the fixed relationship between the consumption of oxygen and the metabolism of lactic acid in the muscle”. In his lecture on 12 December 1923 he thanked Hill as a friend “with whom, in spite of the present political unrest, I have worked in cooperation”. Five years earlier their countries had been at war. The prize did nothing for him in Kiel. According to the Nobel Foundation’s history of his institute, he worked almost alone there. Antisemitism, and resentment of his pacifism during the First World War, cost him the faculty’s support, and he was refused promotion despite good references. In 1923 he was offered a professorship of biochemistry in the United States. He was depressed and close to emigrating when Warburg lobbied Adolf von Harnack, president of the Kaiser Wilhelm Society, on his behalf. In late 1924 Warburg offered him space in his own institute in Berlin-Dahlem.

Dahlem, Heidelberg and a theory let go

Dahlem put him among Warburg, Carl Neuberg, Fritz Haber, Michael Polanyi, Herbert Freundlich and Otto Hahn. In 1925 he made an extract of minced muscle, using potassium chloride, that turned glycogen into lactic acid with no living cells present. This did for muscle what Eduard Buchner, and later Arthur Harden and William Young, had done for yeast fermentation. It meant glycolysis could be taken apart and studied one reaction at a time. Back in 1918 he had already shown that the coenzyme Harden had found in yeast also occurs in animal cells, an early sign of his belief that the same chemistry runs through all life. In 1927 he described hexokinase, the enzyme now known to start the pathway by moving a phosphate group from ATP onto glucose.

In late 1928 Karl Lohmann, the chemist who worked with him from 1924 to 1937, isolated a new phosphate compound from muscle. According to the Nobel archive, Lohmann then identified a muscle cofactor found by another colleague, Karl Meyer, as Gustav Embden’s adenylic acid combined with that compound. This was adenosine triphosphate, ATP. Meyerhof pushed him to publish, and the paper appeared in Naturwissenschaften in August 1929. Cyrus Fiske and Yellapragada SubbaRow at Harvard had isolated the same compound and published in October. The Nobel archive describes “a low-key argument” between Fiske and Lohmann after Lohmann’s talk at the physiology congress in Boston that August, witnessed by Severo Ochoa, and gives Lohmann priority. Meyerhof’s own memorialists, Nachmansohn, Ochoa and Lipmann, describe the two isolations as simultaneous. At the time nobody knew what ATP was for.

In 1929 Meyerhof moved to Heidelberg to head the physiology department of the new Kaiser Wilhelm Institute for Medical Research, which he had been able to help design. Krehl, his old chief, ran the institute. Warburg had been Krehl’s first choice and had turned it down, and he urged Krehl to take Meyerhof instead. The core of the team came with him from Dahlem: Lohmann, Fritz Lipmann, David Nachmansohn, Hermann Blaschko, Severo Ochoa and the technician Walter Schulz.

For nearly a decade it had been taken for granted that making lactic acid was what powered a contraction. After a heated dispute with Embden, who proposed a different energy source, this view became known in some circles as the “Meyerhof dogma”. In 1930 a letter arrived from the Danish physiologist Einar Lundsgaard. Muscles poisoned with iodoacetic acid could not make lactic acid, he reported, but they still contracted, using up creatine phosphate instead. Meyerhof invited him to come straight away. Lipmann met him at the station and took him directly to the laboratory, and Lundsgaard stayed more than six months, working with Meyerhof, Lohmann, Lipmann and Blaschko. In 1931 Meyerhof formally abandoned the idea that making lactic acid is part of the mechanism of contraction. Within a few years his group had concluded that the splitting of ATP comes first, and that creatine phosphate and lactic acid formation serve only to rebuild it. The cycle that had won him the Nobel Prize remained real, but as the chemistry of recovery rather than the engine of contraction.

Embden’s map, Meyerhof’s laboratory

In 1932 Gustav Embden, Meyerhof’s main rival, proposed a sequence of reactions for almost the whole route from sugar to lactic acid. He died in 1933, before he could test it. Meyerhof recognised its value. Over the next five years his group, along with those of Jakub Parnas, Dorothy Needham, Warburg, Carl and Gerty Cori and Hans von Euler, worked out the steps, and the Nobel archive credits Heidelberg with the largest share. Meyerhof and Lohmann identified phosphoenolpyruvate and dihydroxyacetone phosphate in 1934. Meyerhof and Kiessling identified 2-phosphoglycerate and the enzyme enolase in 1935. Meyerhof, Lohmann and Schuster identified glyceraldehyde 3-phosphate and the splitting enzyme aldolase in 1936. Lohmann showed that ATP releases a great deal of heat when it is split, and found the reaction, still named after him, by which creatine phosphate recharges ATP.

Their method was to take the process apart. Radioactive tracers were not yet available, so the group isolated each short-lived intermediate and each enzyme, ran single steps in extracts, and fitted the steps back into sequence. Meyerhof expected the pattern to be the same across living things. In 1935, with Kiessling, he showed that glycolysis in muscle and alcoholic fermentation in yeast follow essentially the same pathway. Comparative work also turned up phosphoarginine, which does the job of creatine phosphate in invertebrate muscle. He coined the phrase “energetic coupling” for the link between the oxidation step in glycolysis and the making of ATP; Warburg later showed how that coupling works. The textbook name, the Embden–Meyerhof (or Embden–Meyerhof–Parnas) pathway, records a joint result rather than a single discoverer.

The institute was international and, by German standards of the time, informal. Severo Ochoa worked there in 1930–31 and again in 1936–37, and André Lwoff and George Wald also passed through. Lipmann (1953), Ochoa (1959), Lwoff (1965) and Wald (1967) later won Nobel Prizes. Hill, Lundsgaard, Warburg and Hans Krebs came as visitors.

After 1933 his colleagues and students left Germany one by one, among them Blaschko, Lipmann, Neuberg, Nachmansohn, Ochoa and Krebs. Krehl and the Kaiser Wilhelm Society urged Meyerhof to stay. His fame gave him some protection, his work was going well, and the Nobel archive says he believed the Nazis would not last, so he stayed “dangerously late”. In 1937 he began to plan in secret. Nachmansohn, writing in code, arranged a position for him in France. In 1938 Otto and Hedwig got permission to cross into Switzerland and went on from there to Paris. The Nobel archive says the permission was for medical treatment of their youngest son, but the US Holocaust Memorial Museum’s family record has Walter studying in England from 1936. To keep the departure secret Meyerhof told none of his colleagues, and he left behind his data, his possessions and his library.

Paris, Banyuls and the path to Portbou

In Paris, through the efforts of Jean Perrin, René Wurmser and Henri Laugier, Meyerhof became director of research at the Institut de Biologie Physico-Chimique, paid partly by the Josiah Macy Jr. Foundation. He rebuilt a laboratory and kept publishing, on the oxidation–reduction step of glycolysis, on the triose phosphates, and on the claim that carbohydrate cannot be broken down in any cell without phosphorylation. His memorialists paraphrase a later review of his: glycolysis without phosphorylation existed only “in the imagination of a few people”. Walter, now a physics student, joined his parents in 1939. When war broke out he was briefly interned as an enemy alien.

In June 1940, as the German army advanced, Otto and Hedwig fled Paris. The accounts differ on the route. The Nobel Foundation’s biography says they drove to Toulouse, where the medical faculty befriended them. Susan Subak’s history of the Unitarian Service Committee, Rescue and Flight, says they took a taxi to Bordeaux hoping for a ship to England, and were refused a British visa. By late July they were in Marseille, at the Hotel Splendide. Walter had been drafted into the French army as a foreign “prestataire” in May and was then held in camps at Chambaran and Le Cheylard. His parents bought him a forged demobilisation order, and he slipped away and joined them.

By chance Varian Fry, the American sent by the Emergency Rescue Committee to get endangered writers, artists and scholars out of France, was staying at the same hotel. Meyerhof was not on his list, but Fry helped anyway, working with the Unitarian minister Waitstill Sharp. Subak’s account goes as follows. Fry gave the Meyerhofs the name of a French customs officer near Banyuls who would take a bribe to get them across the border, but the man backed out when he realised how famous Meyerhof was. By then Meyerhof was depressed and passive. Sharp came to Banyuls, walked with him along the beach, and argued, as a minister speaking to a scientist, that the ethical course was an illegal crossing. Fry’s guide Dick Ball, an American from Montana, then led Otto and Hedwig over the hill paths from Cerbère to Portbou, the first of his many trips. At the Spanish post the officials would not stamp them in until John Hurley of the American consulate in Marseille, who happened to be at the border, intervened. (In another passage Subak has the couple escorted over the mountains by the mayor of Banyuls, Azéma.) The State Department had issued special emergency visas for a small group that included the Meyerhofs. They travelled on through Spain to Lisbon and reached the United States in the autumn of 1940: September according to the Holocaust Memorial Museum’s record, October according to the Nobel biography.

Walter, who had no American visa, had to stay behind in a boarding house in Banyuls, where he ran errands for Lisa and Hans Fittko, the couple who guided refugees over the mountains. From Pennsylvania, at Christmas, his father wrote to the Sharps: “He stays, in liberty, in Banyuls, and has some elderly people protecting him, this is good, but he must get his visa.” Penn colleagues wrote affidavits, the Rockefeller Foundation paid his passage, and diplomats pressed Vichy and Madrid for visas. In the end it took the Unitarian Charles Joy, who in the spring of 1941 took Walter along as his “secretary” and handed a Spanish border agent at Portbou forty dollars. Walter sailed from Lisbon in April 1941.