Otto Fritz Meyerhof

The German biochemist Otto Fritz Meyerhof (1884-1951) shared the Nobel Prize in Physiology or Medicine for his discovery of the fixed relationship between oxygen consumption and the metabolism of lactic acid in muscle and for establishing the cyclic character of energy transformations in the living cell.

Otto Meyerhof son of Felix Meyerhof, a merchant, was born in Hanover on April 12, 1884. His school education in Berlin was long interrupted by kidney disease, but during his period of absence his intellectual and literary interests, owing to the personal influence of his mother, developed greatly. He became a medical student in the University of Freiburg im Breisgau and also studied at the Universities of Berlin, Strasbourg, and Heidelberg. In 1909 he graduated as a doctor of medicine at Heidelberg. Thereafter he worked in the laboratory of the medical clinic at Heidelberg, where he met the young biochemist Otto Warburg, who encouraged him to use biochemical methods in his studies of the release of energy in the living cell.

Muscle Research at Kiel

In 1912 Meyerhof became an assistant in the department of physiology in the University of Kiel and in 1918 assistant professor. In 1913 he delivered a lecture on the energetics of cell phenomena which became a classic, and he published (1916-1917) three papers on energy exchanges in the nitrifying bacteria, which papers had an important influence on his own work.

Meyerhof was interested in the mechanism by which the energy of the foodstuffs is released and utilized by the living cell. He investigated muscle, because in it energy is released as heat and also as mechanical work. Louis Pasteur held that the yeast cell's need for chemical energy could be satisfied either by oxidation of sugar or by its chemical cleavage. Hence arose the theory that the yeast cell used "intramolecular oxygen," derived from the organic molecules and not from the molecular oxygen of the atmosphere. In 1867 Ludimar Hermann found that muscle can contract in the absence of oxygen, and he thought that muscle contained the hypothetical "inogen" whose molecules had the excess oxygen that was used, by a process analogous to fermentation, for the liberation of energy during muscular activity.

In 1906-1907 (Sir) Walter Morley Fletcher and (Sir) Frederick Gowland Hopkins proved at Cambridge that, when muscle contracts under anaerobic conditions, lactic acid accumulates in it and that when oxygen is supplied the lactic acid disappears. Nothing was known of the chemical reactions involved or the way in which they release energy for contraction. No further work was done until Meyerhof entered the field at the end of World War I. But in the physical field A. V. Hill since about 1910 had been investigating the heat produced in muscle on contraction. He showed that the heat was proportional to the work performed; he also demonstrated that about half the heat appeared during the anaerobic contraction phase, while the other half was evolved during the aerobic recovery phase. Hill concluded early in his work that not enough heat was evolved during the recovery period to account for the oxidation of all the lactic acid produced during contraction.

The method for estimating lactic acid in muscle was complex and required about a week to carry out. Using a new rapid method devised by himself, Meyerhof showed in 1920 that, in anaerobic conditions, the lactic acid was derived from glycogen in the muscle and that the amount of lactic acid formed was proportional to the tension produced in the muscle. Further, in the recovery stage only between one-fifth and one-quarter of the lactic acid was oxidized, and the energy of this reaction was used to reconvert to glycogen the remainder of the lactic acid. Hopkins had this important investigation checked at Cambridge, using the older method for estimating lactic acid. Meyerhof's results were fully confirmed.

In 1917 G. Embden discovered hexose diphosphoric acid in muscle, and he thought it was an immediate precursor of lactic acid. Meyerhof confirmed this finding. He also proved that in anaerobic fermentation, for the release of a given amount of energy, more carbohydrate is used up than is the case if the carbohydrate is oxidized (the Pasteur-Meyerhof effect). He introduced the term "glycolysis" for the anaerobic degradation of glycogen to lactic acid, and he demonstrated for the first time the cyclic character of energy transformations in the living cell. He found that the difference between the combustion heats of glycogen and of lactic acid was 170 calories per gram molecule. But he found also that, when the process took place in muscle, 380 calories, and not 170, were liberated. He made many unsuccessful attempts to elucidate the source of this additional energy, namely, 210 calories. For these researches Meyerhof shared with Hill the 1922 Nobel Prize for Physiology or Medicine.

New Aspects of Muscle Research at Berlin

Shortly after receiving the Nobel Prize, Meyerhof was offered a chair of biochemistry in an important American university. To retain him in Germany, a new department was created for him in the Kaiser Wilhelm Institute for Biology at Berlin-Dahlem; to provide the accommodation, each of the heads of the five existing departments spontaneously offered to give up one of his own rooms to Meyerhof, who was head of this new department from 1924 to 1929.

In 1925 Meyerhof published the first of many joint papers with his assistant Kurt Lohmann. At that time it was thought that the ability of muscle to convert glycogen to lactic acid depended on the integrity of the muscle structure and that, if an extract showed glycolytic activity, bacterial action had probably been responsible. But in 1926 Meyerhof showed that a muscle extract, prepared with an ice-cold solution, contained the glycolytic enzyme systems and that it was active shortly after its preparation. The conclusion was that the glycolysis was not due to bacterial activity. These fundamental observations, published in 1926-1927, are regarded as the experimental foundation of the Emden-Meyerhof theory of glycolysis.

Observations had already been made by others which were inexplicable by the hitherto unchallenged lactic acid theory of muscular contraction. In 1927 P. Eggleton and G. P. Eggleton in London, and Fiske and Subbarow independently in the United States, discovered "phosphagen" in muscle. It was found to be creatine phosphate. The Eggletons showed that in muscle it decreased during the anaerobic contraction phase and that it was resynthesized during the recovery phase. They thought that it might play a part in the mechanism of contraction. In 1928 Meyerhof and Lohmann showed that 12,000 calories per gram molecule of phosphate were liberated during the hydrolysis of creatine phosphate. In 1929 Lohmann discovered in muscle the phosphate compound adenosine triphosphate (ATP). In 1932 he worked out its structure, but at that time its significance escaped all workers. About this time too belong Meyerhof's important observations on coupled oxidations and phosphorylation in muscle extracts.

Overthrow of the Lactic Acid Theory

In 1929 Meyerhof became head of the department of physiology in a new Institute for Medical Research in the University of Heidelberg. In 1929-1930 Einaar Lundsgaard of Copenhagen, in experiments begun in Copenhagen and completed in Meyerhof's new institute, obtained results damaging to the lactic acid theory. Lundsgaard showed that, in a muscle poisoned with iodoacetate, lactic acid formation ceased although contraction still took place. In such muscles the tension produced was proportional to the breakdown of creatine phosphate. He suggested that, even in unpoisoned muscle, the role of creatine phosphate was to supply the energy for contraction, while the role of carbohydrate breakdown was to supply energy for the resynthesis of creatine phosphate. Meyerhof also produced results which discounted the lactic acid theory.

Investigations now turned toward the primary role of creatine phosphate, but there were difficulties. Meyerhof had shown that the hydrolysis of creatine phosphate is an exothermic reaction, but the actual amount of heat produced at the start of contraction did not indicate that creatine phosphate initiated the process. But in 1932 Meyerhof and Lohmann made the important discovery that liberation of the two terminal phosphate groups in ATP produced about 12,000 calories of heat per gram molecule of phosphate. There followed the significant conception of energy-rich bonds.

It was not until 1934 that the fundamental role of ATP began to be realized—5 years after the discovery of ATP itself. In that year Lohmann found that muscle extracts can liberate phosphate from creatine phosphate, but only in the presence of adenylic compounds, for example, adenosine diphosphate (ADP). The creatine phosphate reacts with ADP to give creatine and ATP; then the ATP is hydrolyzed to recreate ADP with the liberation of phosphoric acid. He also showed that the hydrolysis of ATP must precede the breakdown of creatine phosphate. Meyerhof and his coworkers then showed the sequence of chemical events in muscular contraction. They concluded that the essential event is the dephosphorylation of ATP and that both creatine phosphate breakdown and lactic acid production are necessary for the rapid resynthesis of ATP. During the next few years Meyerhof studied intermediate carbohydrate metabolism and the concept of oxidative phosphorylation.

In 1938, owing to the racial policy of the Nazis, Meyerhof and his family emigrated to Paris. He was appointed director of research at the Institut de Biologie Physico-Chimique. In June 1940, on the invasion of France, he escaped to Toulouse and thence to the United States.

Later Life

Meyerhof was appointed research professor of physiological chemistry at the School of Medicine of the University of Pennsylvania. During 10 years in the United States he published 50 papers. In 1946 he partially separated the calcium-activated enzyme adenosine-triphosphatase (ATPase), found in muscle, from myosin. In 1948 he demonstrated in muscle a new ATPase which was magnesium-activated, and he associated it with the microsomal fraction of the cell. During this period he also worked on the Harden-Young reaction and measured the equilibrium constants of the hydrolysis and synthesis of phosphate esters. He died in Philadelphia on Oct. 6, 1951.

In addition to 400 papers in scientific journals, Meyerhof published Chemical Dynamics of Life Phenomena (1924) and Die Chemischen Vorgänge im Muskel (1930), a comprehensive discussion of the subject. He received many honors in addition to his Nobel Prize. In 1937 he was elected a Foreign Member of the Royal Society, and he was a member of other learned societies in the United States, Germany, France, and Italy. He was an honorary graduate of the University of Edinburgh.

Further Reading

There is a biography of Meyerhof in Nobel Lectures, Physiology or Medicine, 1922-1941 (1965), which also includes his Nobel Lecture. For the biochemical background see G. H. Bell, J. N. Davidson, and H. Scarborough, Textbook of Physiology and Biochemistry (6th ed. 1965). For a full account of Meyerhof's work on muscle see the sections by Dorothy M. Needham in G. H. Bourne, ed., The Structure and Function of Muscle, vol. 2 (1960), and her Machina Carnis (1971). □

MEYERHOF, OTTO

(b. Hannover, Germany, 12 April 1884; d. Philadelphia, Pennsylvania, 6 October 1951)

biochemistry.

The son of Felix Meyerhof, merchant, and Bettina May, Meyerhof received the M.D. from the University of Heidelberg in 1909. While at the medical clinic of Ludolf von Krehl, he came under the influence of Otto Warburg, who turned Meyerhof’s interest from psychology and philosophy to cellular physiology. He worked at the Institute of Physiology at the University of Kiel from 1913 to 1924 and then at the Kaiser Wilhelm Institute for Biology in Berlin-Dahlem until 1929, when he became head of the department of physiology at the Kaiser Wilhelm Institute for Medical Research in Heidelberg. Like other scientists of Jewish extraction, Meyerhof lefl Germany (in 1938) after the Nazi rise to power; he joined the Institute of Physicochemical Biology in Paris but was forced to flee in 1940, when the Germans invaded France. He came to the United States lale in 1940 and was research professor of physiological chemistry at the School of Medicine of the University of Pennsylvania until his death.

Meyerhof’s work on the chemical processes in muscle laid the basis for the elucidation of the chemical pathway in the intracellular breakdown of glucose to proyide energy for biological processes. In 1919 he demonstrated that during muscle contraction in the absence of oxygen, muscle glycogen is converted to lactic acid. In the presence of oxygen, about one-fifth of the lactic acid is oxidized to carbon dioxide and water; and the energy yielded by this oxidation is used to regenerate glycogen from the remaining lactic acid. This discovery provided a chemical basis for the interpretation of the heat changes during muscle contraction and subsequent recovery, studied by A. V. Hill in 1913–1914. Hill and Meyerhof shared the 1922 Nobel Prize in physiology or medicine, awarded in 1923.

Meyerhof’s choice of muscle as the experimental material was prompted by his philosophical commitment to the idea that the dynamics of biological processes can be described in the language of chemistry and physics. From his early article “Zur Energetik der Zellvorgänge” (1913) to his last writings, this affirmation of the antivitalist position is evident; outside his scientific work he retained an attachment to the transcendental idealism of Kant and J. F. Fries.

In 1925 Meyerhof succeeded in extracting from muscle the group of enzymes responsible for the conversion of glycogen to lactic acid. This preparation of a cell-free glycolytic system was a counterpart of the earlier successful extraction from yeast of the enzyme system (zymase) that converts glucose to alcohol and carbon dioxide during fermentation (Buchner, 1897). In 1917–1918 Meyerhof had shown the presence in animal tissues of the “cozymase” of yeast fermentation, discovered by Harden and W. J. Young in 1906. After 1925 the study of the chemical pathway in the breakdown of glucose by muscle and by yeast was found to be very similar, and this pathway was shown to be operative in many other biological systems. The development pioneered by Meyerhof thus provided striking evidence of the unity of biochemical processes amid the manifold diversity of the forms of life.

The discovery of phosphocreatine (in 1926) and of adenosine triphosphate tin 1929) as constituents of mammalian muscle was followed by Einar Lundsgaard’s demonstration in 1930 that muscle contraction depends more directly on the enzymic cleavage of these two substances than on the production of lactic acid. These advances provided essential links in Meyerhof’s later analysis of the energy relations between chemical change and the physical events in muscle contraction, and his studies led to the recognition of the central role in muscle contraction (and in other energy-requiring processes of biological systems) of adenosine triphosphate, the resynthesis of which in muscle is driven by the breakdown of phosphocreatine and the production of lactic acid. His measurements of the heat released in the hydrolysis of adenosine triphosphate and related compounds, although subsequently refined, permitted the first quantitative estimates to be made of the efficiency of muscle operating as a chemical machine.

Meyerhof’s influence on the development of biochemistry was profound and continued past the middle of the twentieth century through the work of his former students; noteworthy among them were Fritz Lipmann and Severo Ochoa, both Nobel laureates.

BIBLIOGRAPHY

I. Original Works. Meyerhof’s books include Chemical Dynamics of Life Phenomena (Philadelphia, 1925); Die chemischen Vorgänge im Muskel und ihr Zusammenhang mit Arbeitsleistung und wärmebildung (Berlin, 1930); and Chimie de la contraction musculaire (Paris, 1933). He published some 400 scientific articles; a list of his publications is given in Biographical Memoirs. Nstional Academy of Sciences, 34 (1960), 164–182.

II. Secondary Literature. See D. NaChmansohn, S. OChoa, and F. A. Lipmann, in Science, 115 (1952), 365–369; and C. L. Gemill, Medical College of Virginia Quarterly, 2 (1966), 141–142.

Joseph S. Fruton

MEYERHOF, OTTO

MEYERHOF, OTTO (1884–1951), German biochemist and Nobel Prize winner. Meyerhof, who was born in Hanover, was first concerned with psychology (he wrote a book Contributions to a Psychological Theory of Mental Diseases) and philosophy (he edited a journal Abhandlungen der Friesschen Schule, mainly for neo-Kantian philosophers), and worked in Krehl's clinic and at the Marine Zoological Laboratory in Naples. In 1913 he joined the University of Kiel, where he became professor of physiological chemistry (1918–24). In 1923 Meyerhof was awarded the Nobel Prize in physiology and medicine (shared with A.V. Hill) "for his discovery of the fixed relationship between the consumption of oxygen and the metabolism of lactic acid in the muscle." An associated phenomenon is known as the Pasteur-Meyerhof effect. In 1924 Meyerhof became head of a division in the Kaiser Wilhelm Institute of Biology in Berlin-Dahlem, and in 1929 head of the department of physiology in the Institute for Medical Research in Heidelberg. He elucidated the roll played by atp (adenosine triphosphate) in energy transfer in biological systems and introduced the term "energy coupling." He was forced to leave Germany in 1938, and became director of research at the Institut de Biologie Physicochimique in Paris. When the Germans conquered France, he escaped, first to southern France, and then to America. He then became research professor of physiological chemistry at the University of Pennsylvania's medical school.

bibliography:

Nachmansohn, in: Science, 115 (1952), 365–8; idem, in: Biochimica et Biophysica Acta, 4 (1950), 1–3; T.N. Levitan, Laureates: Jewish Winners of the Nobel Prize (1960), 124–7.

[Samuel Aaron Miller]

Meyerhof, Otto Fritz (1884–1951) German physiologist; demonstrated that lactic acid is formed from glycogen in muscle, and is used for glucose synthesis in the liver; Nobel Prize 1922.