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Warburg, Otto Heinrich

WARBURG, OTTO HEINRICH

(b. Freiburg im Breisgau, Baden, Germany, 8 October 1883; d. Berlin-Dahlem, Germany, 1 August 1970), biochemistry.

Warburg was the son of Emil Gabriel Warburg and Elizabeth Gaertner. He came with his parents in 1896 to Berlin, where his father had been called to the chair of physics at the University of Berlin. The elder Warburg later became president of the Physikalische Reichsanstalt. The family originated in the beautiful little town of Warburg, about thirty miles west of Göttingen. They first appear in the mid-sixteenth century.

Otto Warburg’s mother stemmed from a family of public officials and soldiers; her brother, a general in the army, was killed in World War I. Warburg himself served as an officer in the Prussian Horse Guards on the Russian front and was wounded in action. In the early years of this fighting he carried not only a pistol but a medieval lance. Before the war ended, Albert Einstein wrote a remarkable letter to Warburg persuading him to return to the Kaiser Wilhelm Institute for Biology in Dahlem; he had been made a member in 1913 at the instigation of Emil Fischer, his first mentor ten years earlier.

In Berlin, Warburg grew up in two large official residences, both designed by the wife of Helmholtz. Most of the leading scientists of Germany were frequent guests of his parents during this final period of imperial splendor under Wilhelm II.

Later, at the university, Warburg learned chemistry from Fischer, with whom he worked for three years to obtain his doctorate; medicine in the clinic of Ludolf von Krehl at Heidelberg, to whom he was assistant for three years; thermodynamics from Walther Nernst in Berlin, with whom he worked on oxidation-reduction potentials in living systems; and physics and photochemistry from his father, with whom he worked on the quantum requirement of photosynthesis in 1920 in the Physikalische Reichsanstalt.

Warburg’s first scientific work (1903-1906), with Fischer, involved splitting of racemic leucine ethyl ester by pancreatin and resolution of the optically active components. Fischer was a severe master, who instructed Warburg, after he had recrystallized the parent compound first three times, and then five more, “Now go ahead twenty-five times more.”

This seemingly harsh training stood Warburg in good stead all his life, during which he invariably distinguished between experimentation made “Für die Wahrheit” (for the truth) and that made “Für das Volk” (to convince others). Having once satisfied himself as to the truth of a discovery, he always proceeded to repeat his experiments twenty to a hundred times before publishing, which explains why he, like Fischer, produced such a mass of virtually error-free and reproducible results

Warburg learned early that “convincing others” involved much more than steamroller repetition of experimentation. Because of the great number and magnitude of his discoveries, which rank him as the most accomplished biochemist of all time, no biochemist—or scientist—has met with so much controversy, resistance, and delayed acceptance of his work, often lasting (in his own words) ten, twenty, or even fifty years. The reason for this is given by one of his favorite quotations from Hans Fischer (1881-1945), “All science is all too human”; and from Max Planck in his ninetieth year, “A new scientific truth is often accepted, not as a result of opponents becoming convinced and declaring themselves won over, but rather by the opponents dying off, and the oncoming generation of scientists becoming familiar with the new truth right from the start.” He was also fond of Darwin’s statement in the “Conclusion” of the Origin of Species, “…I by no means expect to convince experienced naturalists whose minds are stocked with a multitude of facts all viewed, during a long course of years, from a point of view directly opposite to mine …but I look with confidence to the future,—to young and rising naturalists, who will be able to view both sides of the question with impartiality.” The significance of these quotations increases, of course, with the magnitude of the discovery, since then there is greater upset of previous conceptions.

Warburg endeavored to advance science mainly through his own experimental work, carried out both personally and by technical assistants whom he trained. He believed that many important discoveries were to be made in the laboratory by very simple but heretofore untried variations in experimental conditions. Thus, he discovered the fermentation of tumor cells when he increased by twentyfold the concentration of bicarbonate in the medium. He discovered iron oxygenase (Atmungsferment) by raising the pressure of carbon monoxide from 5 to 95 percent or more. He discovered acyl phosphate when in the oxidation-reduction reaction of fermentation the phosphate concentration was increased twenty times; and the energy cycle and one-quantum reaction of photosynthesis was discovered when the light-dark time intervals measured in manometry were shortened from five minutes to one minute.

Among the forty rooms in Warburg’s institute, there was no office, no conference room, and no writing room apart from the general library. He never gave lecture courses to students, never served on committees, and never did administrative work. He selected his staff on the basis of technical ability and talent. He preferred to be regarded as an artisan and, as he frequently asserted, a technician. Nevertheless, he was an artist in everything he did, a commanding speaker in English as well as in German, and a uniquely clear writer in both English and German. Warburg’s philosophical outlook is summarized by a statement he made in 1964, “…a scientist must have the courage to attack the great unsolved problems of his time, and solutions usually have to be forced by carrying out innumerable experiments without much critical hesitation.”

Warburg was first and foremost a pioneer in biochemical methodology and in the creation of new tools of investigation-for example, spectrophotometric methods of identification and analysis of cell constituents and enzymes, manometric methods for the study of cell metabolism, numerous microanalytical methods, and methods for the isolation of cell constituents and crystallization of enzymes.

Following is a chronological listing of his major discoveries and fields of interest during more than sixty-five years of research; each item generally involved five to ten publications. Splitting of racemic leucine ethyl ester by pancreatin (first publication 1904); splitting of racemic leucine into its optically active components by means of formyl derivatives (1905), with Emil Fischer; respiration of sea urchin eggs, red blood cells, and grana (1910-1914); development of biochemical manometry (1918-1920-1968); iron catalyses on surfaces, narcotic action-displacement of substrates from surfaces, cyanide action-chemical reactions with iron (1921-1924); quantum requirements of photosynthesis (1920-1924); tissue slice technique (1923); metabolism of tumors (1923-1925); iron, the oxygen-transferring constituent of the respiration enzyme, “iron oxygenase” of Atmungsferment (1924); inhibition of cell respiration by carbon monoxide (1925-1926); action spectrum of iron oxygenase (1927-1932); discovery of the yellow enzymes (1932-1933); first crystallization of a flavin, “luminoflavin” (1932); discovery of nicotinamide as the active group of hydrogen-transferring enzymes (1935); nature of coenzyme action and varying degrees of binding with enzymes (1935); development of the optical methods based upon the ultraviolet absorption band of dihydromicotinamide (1935-1937); mechanism of alcohol formation in nature, dihydronicotinamide + acetaldehyde = nicotinamide + ethyl alcohol (1936); stepwise degradation of phosphorylated hexoses to trioses (1936-1937); discovery of the copper of phenol oxidases and its action through valence change (1937); isolation and crystallization of flavin adenine dinucleotide (1938); crystallization of the oxidizing fermentation enzyme and mechanism of the oxidation reaction of fermentation, glyceric aldehyde diphosphate + nicotinamide = phosphoglyceric-acyl phosphate + dihydro-nicotinamide (1938); crystallization of enolase and chemistry of fluoride inhibition of fermentation (1941); crystallization of muscle zymohexase (1942); in vitro Pasteur reaction with hexosediphosphate and yeast zymohexase (1942); crystallization of the reducing fermentation enzyme from tumors and comparison with the homologous crystallized fermentation enzyme from muscle (1943); fermentation enzymes in the blood of tumor-bearing animals (1943); quinone and green grana (1944); heavy metals as active groups of enzymes and hydrogentransferring enzymes (1946-1947); manometric actinometer (1948); maximum efficiency of photosynthesis (1949); one-quantum reaction and energy cycle in photosynthesis (1950), with Dean Burk, crystallization of the hemin of iron oxygenase (1951); zymohexase and ascites tumor cells (1952); chemical constitution of the hemin of iron oxygenase (1953); oxidation reaction and enzymes in fermentation (1954-1957); measurement of light absorption in Chlorella with the Ulbricht integrating sphere (1954); catalytic action of blue-green light in photosynthesis (1954-1956); oxygen capacity of Chlorella (1956); carbon dioxide in Chlorella (1956); photochemical water decomposition by living Chlorella (1955); origin of cancer cells (1956); functional carbon dioxide in Chlorella (1956); role of glutamic acid in photosynthesis (1957-1964); D-lactic acid and glycolic acid in Chlorella (1957-1964); Hill reactions in photosynthesis (1958-1968); photosynthesis in green leaves (1958-1963); manometric X-ray actinometer and actions of X rays on various cells (1958-1966); phosphorylation in light (1962); effects of low oxygen pressure on cell respiration, growth, and transformation (1960-1965); healing of mouse ascites cancer with glyceric aldehyde (1963); production of cancer metabolism in normal cells grown in tissue culture (1957-1968); red respiratory enzyme in Chlorella (1962-1965); photolyte of photosynthesis, a carbon dioxidechlorophyll complex (1959-1969); facultative anaerobiosis of cancer cells (1962-1965); prime cause and prevention of cancer (1966-1969); chlorophyll catalysis and Einstein’s photochemical law in photosynthesis (1966-1969); action of riboflavin and luminoflavin on growing cancer cells (1967-1968); role of Vitamin B1 (thiamine) on changes of normal to cancer cells and vice versa (1970); changes in chlorophyll spectrum in living chalorella upon splitting and resynthesis of the carbon dioxide photolyte by light(1970).

Had Warburg ceased scientific work after the first four decades of his career, his name would now probably be forgotten, When he left his regiment near the end of World War I, his fellow officers said that he would now “return to feeding sea urchins.” Few great scientists have ever matured so late.

Which of Warburg’s discoveries involved the greatest originality of conception, execution, and proof? According to Warburg himself it was his discovery in 1924 of Atmungsferment (iron oxygenase), for which after several more years of study and controversy, he was awarded the 1931 Nobel Prize in physiology or medicien.

Warburg became convinced in 1926 that iron oxygenase was a hemin compound, as a result of inhibition studies with carbon monoxide, which Claude Bernard had long before shown to be an inhibitor of hemoglobin. In 1926, while experimenting with yeast cells suspended in phosphate solutions containing glucose, Warburg found that carbon monoxide also inhibits cell respiration. By measuring the inhibitions obtained at different oxygen pressures, he found that the action is dependent upon the ratio of CO/O2 pressures, which indicates that ferrous iron in the enzyme is the point of attack, in contrast to cyanide inhibition of ferric iron long known to occur. But, as Warburg said in his Nobel lecture, “It would never have been possible to reach any certainty of enzyme constitution here, were it not that the carbon monoxide compounds of iron possess in instances the remarkable property of being dissociated by light, as discovered by Mond and Langer in 1891, and, as shown by J. S. Haldane a few years later to alter the equilibrium between hemoglobin, CO, and O2 in favor of O2” Thus, by alternating periods of light and darkness for cells respiring in mixtures of CO and O,2 Warburg was able to cause respiration to appear and disappear; in light, carbon monoxide is split from the iron, leaving it free for oxygen activation. In a quantitative examination, Warburg found that Einstein’s law of photochemical equivalency was followed, that is, the number of photochemically split Fe—CO groups is equal to the number of light quanta absorbed, independently of wavelength of light. By irradiating with monochromatic light of various wavelengths but of the same intensity, he was able to determine the absorpotion spectrum of the iron oxygenase-carbon monoxide complex, as judged by the magnitude of respiration increase. This absorption spectrum showed a remarkable similarity to that of CO—hemoglobin, but with some displacement towards the longer wave-lengths, yet clearly identifying the iron oxygenase as a hemin compound, in which the iron is bound to nitrogen by two electron pairs and the porphyrins are cyclic compounds formed. as shown by Hans Fischer, by the linkage of four pyrrole rings through methylene bridges. Finally, the absolute absorption spectrum of the enzyme was determined from time-rate measurements of the light action on respiration, in relation to absolute light absorptions at different wavelengths. It became clear that iron oxygenase has an exceptionally strong light absorption, corresponding to an exceedingly minute concentration in the cell, where it is indeed found in the particulate grana (mitochondria) as adumbrated by some of Warburg’s studies prior to World War I. In later decades Warburg succeeded in isolating and analyzing further structural details of the iron oxygenase, the prime cellular respiratory enzyme, and showed that it contains somewhat less nitrogen and iron but more carbon than does blood hemin, and also an unusual hydrocarbon chain whose structure was elucidated by Lynen in 1963. Warburg’s subsequent work indicated that the heme pigments of both blood and plants (as in chlorophyll) arise in evolution from the iron oxygenase heme.

Warburg worked more or less continuously for the last fifty years of his life on various aspects of photosynthesis. His first major contribution was to demonstrate that photosynthesis can be made to take place, under appropriate conditions, with almost perfect thermodynamic efficiency. In the equation CO2+H2O = sugar equivalent + O2, some 110,000 calories of energy are thermodynamically required per mole of CO2 reduced and O2 produced ; and he found that this could be supplied by no more than four mole quanta of red light of 43,000 calories per mole, corresponding to an efficiency of 112,000 (4 X 43,000), or 65 percent. In later years, under even better conditions, three mole quanta were found to suffice, corresponding to an efficiency approaching 100 percent conversion of light energy into chemical energy. Again, this quantum requirement was found to be independent of wavelength of light in the visible spectrum, just as was the action of light on the iron oxygenase-carbon monoxide splitting already described.

In 1950 it was found that the mechanism of light energy conversion proceeded in steps of one quantum each, as required or predicted by the Einstein law of photochemical equivalence. Indeed, when Warburg told Einstein in 1923 about his “four quantum” requirement measurements, Einstein said, “When you get down to one quantum, come back and tell me about it.” Between 1923 and 24 October 1950, Warburg worked on the “quantum riddle” ; how can four quanta (or three) seemingly act together simultaneously to reduce one molecule each of CO2 and water to one molecule of O2 (and sugar equivalent)? On the latter date it was found that XO2 + 1 quantum = X + 1 O2. XO2 was the substance from which the O2 developed, and at the same time approximately 1 molecule of CO2 disappeared. This occurred over a period of about a minute of illumination and was accompanied and followed by a dark reaction in which the substance XO2 was restored at the expense of two-thirds of the O2 produced in the light reaction. This dark reaction showed up experimentally as a greatly increased rate of respiration (O2 consumption and CO2 production), yielding after three such cycles a net and stable requirement of three quanta for the overall photosynthetic reaction as first written above, and persisting for long periods of time.

It is interesting that the above solution of the quantum riddle was arrived at purely experimentally; no one—not even Einstein—had hypothesized the finally observed quantum mechanism.

Although the experimental solution of the quantum riddle has never been effectively challenged, with respect to the observed one-quantum requirement, nevertheless, the three- or four-quanta requirement for overall photosynthesis, especially during the 1940’s and 1950’s, was objected to by a host of (but not all) workers who would not or could not adequately reproduce Warburg’s experimental conditions. In the late 1950’s Warburg proposed to the National Academy of Sciences that a team of selected workers be sent to Dahlem to “see for themselves,” but this proposal was not accepted.

Warburg’s third great area of endeavor, also on the cancer research, also covered the last fifty years of his life. There were far more scientists and laymen interested in this problem than in cellular respiration and photosynthesis and opposition to many of his findings was much more intense. Beginning in 1922, Warburg discovered the remarkably high production of lactic acid from glucose by cancer cells, both in vitro and in vivo, as well as aerobically and anaerobically, and, of course, varying in degree over a wide spectrum from cancer to cancer. In contrast, no growing normal tissue in the animal body produced lactic acid from glucose under aerobic conditions. A few non-growing tissues might, but, as in the case of muscle, usually from glycogen and at rates ordinarily far below that of well-developed malignant tumors.

Accompanying the greatly increased glucose fermentation (glycolysis) by cancer cells was an injured respiration, manifested in a variety of ways—decreased rate, uncoupled rate, low succinate oxidative response, loss of Pasteur effect, etc.

These two major findings led Warburg in the 1950’s to the following view of cancer causation:

Cancer cells originate from normal body cells in two phases. The first phase is the irreversible injuring of respiration …followed …by a long struggle for existence by the injured cells to maintain their structure, in which part of the cells perish from lack of energy, while another part succeed in replacing the irretrievably lost respiration energy by fermentation energy. Because of the morphological inferiority of fermentation energy, the highly differentiated body cells are converted into undifferentiated cells that grow wildly—the cancer cells …Oxygen gas, the donor of energy in plants and animals, is dethroned in the cancer cells and replaced by an energy yielding reaction of the lowest living forms, namely, a fermentation of glucose.1

According to Warburg this is the prime cause of cancer, prime cause being defined as “one that is found in every case of the disease.” Thus,

…the prime cause of the plague is the plague bacillus, but secondary causes of the plague are filth, rats, and the fleas that transfer the plague bacillus from rats to man … Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause … There is no disease whose prime cause is better known.2

In his famous 1966 Lindau lecture Warburg recommended, for both prevention and treatment of cancer, dietary additions of large amounts of the active groups of the various respiratory enzymes, these active groups constituting first and foremost iron and certain of the B vitamins. This provoked overnight the most widespread controversy, not only throughout Germany but also the Western world.

No account of Warburg’s life and work should fail to mention his close association with Jacob Heiss of Kirn, in Southern Germany. Heiss was a person of remarkable character, ability, and shrewdness, who from 1918 until Warburg’s death entered into virtually all of his activities. He served as administrator, monitor of all scientific papers, financial adviser, and consultant on all affairs, however small, on a daily-even hourly-basis. They were a unique combination, yet the personal character of each was entirely different. Warburg never married; Heiss was his sole heir.

Throughout his life, Warburg was extremely fond of walking, sailing, dogs, and horses, and kept himself in remarkable physical trim. He rode every morning before going to work, for the better part of an hour, during which time he did much of his sustained thinking. He frequently stated that he was a “slow thinker.” To many a question put to him he would reply, “Man muss es überlegen” (I must think it over), and the answer would be delivered the next day, after a ride. In his eighty-second year, the day after he received his honorary degree from Oxford, he was standing at the Park Lane end of Rotten Row in London, when he saw a riderless horse charging down the Row. He immediately stepped over the low guardrail in front of the oncoming horse and, with both arms upraised, caught it-to cheers of bystanders. One of them, noting Warburg’s bowler hat, remarked, “Those boys from the City have something on us West Enders.”

Warburg for decades vacationed in England, for whose inhabitants he had an unbounded admiration, and he was an inveterate reader of the London Times and Manchester Guardian, as well as of innumerable, English authors of all sorts, including Churchill, the Mitfords, and various “aristocrats,” of whom he considered himself, with amused emphasis, an example par excellence. The American he most admired was Charles Huggins, winner of the 1966 Nobel Prize for physiology or medicine. The person whom he most enjoyed telling playful stories about was himself.

NOTES

1. “On the Origin of Cancer Cells,” in Science123 (1956), 312; The Prime Cause and Prevention of Cancer, D. Burk, ed., 2nd ed., rev. (Würzburg, 1969),6.

2.Ibid., 6; 16.

BIBLIOGRAPHY

Most, although not quite all, of Warburg’s original experimental papers to 1961 are, fortunately and conveniently, found in the following books published under his sole authorship: Ueber den Stoffwechsel der Tumoren (Berlin, 1926), English trans. by Frank Dickens, The Metabolism of Tumours (London-New York, 1930); Ueber die katalytischen Wirkungen der lebendign Substanz (Berlin, 1928); Schwermetalle als Wirkungsgruppen von Fermenten (Berlin, 1946); Wasserstoffueber-tragende Fermente (Berlin, 1948); Weiterentwicklung der zellphysiologichen Methoder (Stuttgart-New York, 1962); and The Prime Cause and Prevention of Cancer, Dean Burk, trans. (Würzburg, 1969). These collected works contain 200 articles in over 2,000 pages-less than has been written about them by way of reviews, recapitulations, objections, and capitulations.

Dean Burk

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Warburg, Otto Heinrich

Otto Heinrich Warburg (ŏt´ō hīn´rĬkh vär´bŏŏrkh), 1883–1970, German physiologist. He was director (1931–53) of the Kaiser Wilhelm Institute (now Max Planck Institute) for cell physiology at Berlin. He investigated the metabolism of tumors and the respiration of cells, particularly cancer cells. For his discovery of the nature and the mode of action of (Warburg's) yellow enzyme, he won the 1931 Nobel Prize in Physiology or Medicine. He edited The Metabolism of Tumours (tr. 1931) and wrote New Methods of Cell Physiology (1962).

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Warburg, Otto Heinrich

Warburg, Otto Heinrich (1883–1970) German biochemist; discovered the role of flavins and nicotinamide coenzymes in oxidative metabolism; Nobel Prize 1931.

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