The Prime Cause and Prevention of Cancer Otto Warburg

Otto Warburg

The Prime Cause and Prevention of Cancer

(Revised Lindau Lecture)


(Director, Max Planck Institute for Cell Physiology, Berlin-Dahlem, Germany) English Edition by DEAN BURK*), National Cancer Institute, Bethesda, Maryland*)






The Fermentation of Morris Hepatomas




*) For example see C. H. BÖHRINGER SON, Ingelheim am Rhein, the factory Work-Journal “Das Medizinische Prisma” , Vol. 13, 1963. Here a lecture of VAN POTTER (Madison, Wisconsin) is reprinted where owing to the slow-growing Morris-tumors anaerobiosis as prime cause of cancer is rejected and the lack of “intracellular feeding back” is claimed to be the real cause of cancer.





Transformation of Embryonic Metabolism into Cancer Metabolism







**) These experiments show, like the curve of Dean Burk and Mark Woods in Fig. 1, that it is more correct to designate tumor cells as “partial anaerobes” rather than “facultative anaerobes”. A body cell is transformed into a tumor cell if only a part of the respiration is replaced by fermentation.



decreasing the oxygen pressure (Weniger O2 = Less O2, Viel O2 = Much O2)


Fig. 3. Method to measure manometrically respiration and fermentation during

the transformation of embryonic into cancer metabolism*)

(Luft = Air)




The early history of life on our planet indicates that life existed on earth before the earth’s atmosphere contained free oxygen gas. The living cells must therefore have been fermenting cells then, and, as fossils show, they were undifferentiated single cells. Only when free oxygen appeared in the atmosphere – some billion years ago – did the higher development of life set in, to produce the plant and animal kingdoms from the fermenting, undifferentiated single cells. What the philosophers of life have called “Evolution créatrice” has been and is therefore the work of oxygen.


But why oxygen differentiates and why lack of oxygen dedifferentiates? Nobody would dispute that the development of plants and animals and man from unicellular anaerobes is the most improbable process of all processes in the world. Thus there is no doubt, that EINSTEIN descended from a unicellular fermenting organism – to illustrate the miracle, molecular O2 achieved. But according to the thermodynamics of Boltzmann, improbable processes require work to take place.


But why respiratory energy and not fermentation energy can differentiate, whereas in general, for example in growth, respiratory energy and fermentation energy are equivalent? Obviously, there would be no cancer if there were not this discrimination of fermentation energy, that is, if fermentation like respiration could differentiate. Then, when respiration is replaced by fermentation, fermentation would take over differentiation, and a high state of differentiation would be maintained even in the fermenting body cells.


Physics cannot explain why the two kinds of energy are not equivalent in differentiation; but chemistry may explain it. Biochemists know that both respiration energy and fermentation energy do their work as phosphate energy, but the ways of phosphorylation are different. If one applies this knowledge to carcinogenesis, it seems that only oxidative phosphorylation but not fermentative phosphorylation can differentiate, a result, that may in future explain the mechanism of differentiation.

Yet Biochemistry can explain already today why fermentation arises, when respiration decreases. Figure 4 shows that the pathways of respiration and fermentation are common as far as pyruvic acid. Then the pathways diverge. The endproducts of fermentation is reached by one single reaction, the reduction of pyruvic acid by dihydro-nicotinamide to lactic acid. On the other hand, the endproducts of the oxidation of pyruvic acid, H2O and CO2, are only reached after many additional reactions. Therefore, when cells are harmed, it is probable that first respiration is harmed.

In this way the frequency of cancer is explained by reasons of probability.

Figure 4

To sum up:

Impairment of respiration is [more] frequent than impairment of fermentation because respiration is more complicated than fermentation.




To conclude the discussion on the prime cause of cancer, the virus-theory of cancer may be mentioned. It is the most cherished topic of the philosophers of cancer. If it were true, it would be possible to prevent and cure cancer by the methods of virology; and all carcinogens could be eaten or smoked freely without any danger, if only contact with the cancer virus would be avoided.

It is true that some virus-caused cancerb) occur in animals, but no one sure human virus-cancer has been observed so far, whereas innumerable substances cause cancer without viruses in animals and man. Thus viruses do not meet the demands of Pasteur, that is must be possible to trace the prime cause in every case of the disease. Therefore science classifies viruses as remote causes of cancer, leading to anaerobiosis, the prime cause that meets the demands of Pasteur.

b) The chicken Rous sarcoma, which is labeled today as a virus tumor, ferments glucose and lives as a partial anaerobe like all tumors. O. WARBURG, Bioch. Zeitschrift 160, 307, 1925; F. WIND, Klinische Wochenschrift, Nr. 30, 1926.

Many may remember how anaerobiosis as prime cause of cancer was recently disputed emphatically, when one single cancer – the slow Morris hepatomas – was believed (wrongly) to lack in fermentation. In contrast the virus theory is adhered to although all cancers of man are lacking in virus-origin. This means the surrender of the principles of Pasteur and the relapse into bygone times of medicine.


Of what use is it to know the prime cause of cancer? Here is an example. In Scandinavian countries there occurs a cancer of throat and esophagus whose precursor is the so-called Plummer-Vinson syndrome. This syndrome can be healed when one adds to the diet the active groups of respiratory enzymes, for example: iron salts, riboflavin, nicotinamide, and pantothenic acid. When one can heal the precursor of a cancer, one can prevent this cancer. According to ERNEST WYNDER 3) of the Sloan-Kettering Institute for Cancer Research in New York, the time has come when one can exterminate this kind of cancer with the help of the active groups of the respiratory enzymes.


c) V. CHORINE: C. R. sci. Paris, 220, 150 (1945). – H. FUST and A. STUDER, Schweizerische Z. für allgemeine Pathologie, Band 14; Fasc 5 (1951).

I would like to go further and propose always making dietary additions of large amounts of the active groups of the respiratory enzymes after successful operations when there is danger from metastatic growths. One could indeed never succeed in redifferentiating the dedifferentiated cancer cells, since during the short duration of human life the probability of such a back-differentiation is zero. But one might increase the respiration of growing metastases, and thereby inhibit their fermentation, and – on the basis of the curve of DEAN BURK and MARK WOODS obtained with the Morris hepatomas – thereby inhibit the growth of metastases to such an extent that they might become as harmless as the so-called “sleeping” cancer cells in the prostates of elderly men.

A Second Example of Application

The physicist MANFRED VON ARDENNE has recently attacked the problem of the therapy of cancer. ARDENNE discovered that cancer cells owing to their fermentation, are more acid – inside and on their surface – than normal cells and hence are more sensitive to high temperatures. On this basis, he and his medical colleagues have treated cancer patients, after surgical removal of the primary tumors, by raising the body temperature of the patients to about 109º Fahrenheit for an hour, in the hope that the metastases will then be killed or their growth so slowed up as to become harmless. It is not yet decided whether this idea can be described as a practical success. But the provisional work of ARDENNE is already of great significance in a field where hopes of conventional chemotherapy have been dimmed but might be brightened by combination with extreme or moderate hyperthermy.

A third application. According to an estimate by K. H. Bauer of the Cancer Institute in Heidelberg, at least one million of the now living twenty five million male inhabitants of West Germany will die of cancer of the respiratory tract; still more will die from other cancer. When one considers that cancer is a permanent menace, one realizes that cancer has become one of the most dangerous menaces in the history of medicine.

Many experts agree that one could prevent about 80% of all cancers in man, if one could keep away the known carcinogens from the normal body cells. This prevention of cancer might involve no expenses, and especially would require little further research to bring about cancer prevention in up to 80 percent *).

*) Since this estimate was published, some thought 80% even too low. Yet prevention remained taboo and early diagnosis was the only consolation that was offered.

Why then does it happen that in spite of all this so little is done towards the prevention of cancer? The answer has always been that one does not know what cancer or the prime cause of cancer [might] be, and that one cannot prevent something that is not known.


The Prime Cause and Prevention of Cancer

with two prefaces on prevention


Revised lecture at the meeting of the Nobel Laureates on June 30, 1966 at Lindau, Lake Constance, Germany by Otto Warburg, Director, Max Planck-Institute for Cell Physiology, Berlin-Dahlem


The Second Revised Edition

Published by Konrad Triltsch, Würzburg, Germany, 1969

Otto Warburg 1883-1970

Preface to the Second Revised German Edition of the Lindau Lecture

(The way to prevention of cancer)









He who asked this questions ignored that in 1923 the chemical mechanism of enzyme action was still a secret of living nature alone.1 The first active group of an enzyme, “Iron, the Oxygen-Transferring Part of the Respiratory Enzyme” was discovered in 19242. There followed in two decades the discoveries of the O2-transferring metalloproteins, the flavoproteins and the pyridinproteins, a period that was concluded by the “Heavy Metals as Prosthetic Groups of Enzymes”3 and by the “Hydrogen Transferring Enzymes”4 in 1947 to 1949.

Moreover, during the first decades after 1923 glycolysis and anaerobiosis were constantly confused, so that nobody knew what was specific for tumors. The three famous and decisive discoveries of DEAN BURK and colleagues5 of the National Cancer Institute at Bethesda were of the years 1941, 1956 and 1964: first, that the metabolism of the regenerating liver, which grows more rapidly than most tumors, is not cancer metabolism, but perfect aerobic embryonic metabolism; second, that cancer cells, descended in vitro from one single normal cell, were in vivo the more malignant, the higher the fermentation rate; third, that in vivo growing hepatomas, produced in vivo by different carcinogens, were in vivo the more malignant, the higher the fermentation rate. Furthermore, the very unexpected and fundamental fact, that tissue culture is carcinogenic and that a too low oxygen pressure is the intrinsic cause were discovered6-8 in the years 1927 to 1966. Anaerobiosis of cancer cells was an established fact only since 1960 when methods were developed7 to measure the oxygen pressure inside of tumors in the living body.



Wiesenhof über Idar-Oberstein, August 1967



Preface to the First Edition

(Prevention of endogenous cancer)



Today we know two methods to influence cell respiration.1 The first is to decrease the oxygen pressure in growing cells. If it is so much decreased that the oxygen transferring enzymes are no longer saturated with oxygen, respiration can decrease irreversibly and normal cells can be transformed into facultative anaerobes.

The second method to influence cell respiration in vivo is to add the active groups of the respiratory enzymes to the food of man. Lack of these groups impairs cell respiration and abundance of these groups repairs impaired cell respiration – a statement that is proved by the fact that these groups are necessary vitamins for man.2



Wiesenhof, August 1966


Literature to Preface of Second Edition:

1. WILLSTAETTER, WIELAND and EULER, Lectures on enzymes at the centenary of the Gesellschaft Deutscher Naturforscher. Berichte der Deutschen Chemischen Gesellschaft, 55, 3583, 1922. The 3 lectures of the 3 chemists show that in the year 1922 the action of all enzymes was still a mystery. No active group of any enzyme was known.

2. OTTO WARBURG, Biochem. Zeitschrift, 152, 479, 1924.

3. OTTO WARBURG, Heavy Metals as prosthetic groups of enzymes, Clarendon Press, Oxford, 1949.

4. OTTO WARBURG, Wasserstoffübertragende Fermente, Verlag Werner Sänger, Berlin, 1948.

5. DEAN BURK, 1941. On the specificity of glycolysis in malignant liver tumors as compared with homologous adult or growing liver tissues. In Symposium of Respiratory Enzymes, Univ. of Wisconsin Press. pp. 235-245,1942. DEAN BURK, Science 123,314,1956. Woods, M. W., Sandford, K. K., Burk, D., and Earle, W. R. J. National Cancer Institute 23, 1079-1088, 1959. DEAN BURK, Burk, D., Woods, M. and Hunter, J. On the Significance of Glucolysis for Cancer Growth, with Special Reference to Morris Rat Hepatomas. Journ. National Cancer Institute 38, 839-863, 1967.

6. O. WARBURG und F. KUBOWITZ, Bioch. Z. 189, 242, 1927; H. GOLDBLATT und G. CAMERON, J. Exper. Med. 97, 525, 1953.

7. O. WARBURG, 17. Mosbacher Kolloquium, April 1966. Verlag Springer, Heidelberg, 1966.

8. O. WARBURG, K. GAWEHN, A. W. GEISSLER, D. KAYSER and S. LORENZ, Klinische Wochenschrift 43, 289, 1965.

9. O. WARBURG, Oxygen, The Creator of Differentiation, Biochemical Energetics, Academic Press, New York, 1966.

10. O. WARBURG, New Methods of Cell Physiology, Georg Thieme, Stuttgart, and Interscience Publishers, New York, 1962.


Literature to Preface of First Edition:


1. OTTO WARBURG, A. W. GEISSLER, and S. LORENZ: Über die letzte Ursache und die entfernten Ursachen des Krebses. 17. Mosbacher Kolloquium, April 1966. Verlag Springer, Heidelberg 1966.

2. Any book on vitamins, such as Th. Bersin. Biochemie der Vitamine. Akad. Verlags.-Ges. Frankfurt 1966.

3. ERNEST L. WYNDER, SVEN HULTBERG, FOLKE JACOBSSON, and IRWIN J. BROSS, Environmental Factors in Cancer. Cancer, Vol. 10, 470, 2057.

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