English Edition by DEAN BURK, National Cancer Institute, Bethesda, Maryland
(Note by DEAN BURK: Adapted from a lecture originally delivered by O. Warburg at the 1966 annual meeting of Nobelists at Lindau, Germany. O. Warburg won the Nobel Prize in Medicine in 1931 for his discovery of the oxygen transferring enzyme of cell respiration, and was voted a second Nobel Prize in 1944 for his discovery of the active groups of the hydrogen transferring enzymes. Many universities, like Harvard, Oxford, Heidelberg have offered him honorary degrees. He is a Foreign member of the Royal Society of London, a Knight of the Order of Merit founded by Frederick the Great, and was awarded the Great Cross with Star and Shoulder Ribbon of the Bundesrepublik. His main interests are Chemistry and Physics of Life. In both fields no scientist has been more successful.)
There are prime and secondary causes of diseases. For example, the prime cause of the plaque is the plaque bacillus, but secondary causes of the plaque are filth, rats, and the fleas that transfer the plaque bacillus from rats to man. By a prime cause of a disease I mean one that is found in every case of the disease.
Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar. All normal body cells meet their energy needs by respiration of oxygen, whereas cancer cells meet their energy needs in great part by fermentation. All normal body cells are thus obligate aerobes, whereas all cancer cells are partial anaerobes. From the standpoint of the physics and chemistry of life this difference between normal and cancer cells is so great that one can scarcely picture a greater difference. 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.
The key to the cancer problem is accordingly the energetics of life, which has been the field of work of the Dahlem institute since its initiation by the Rockefeller Foundation about 1930. In Dahlem the oxygen transferring and hydrogen transferring enzymes were discovered and chemically isolated. In Dahlem the fermentation of cancer cells was discovered decades ago; but only in recent years has is been demonstrated that cancer cells can actually grow in the body almost with only the energy of fermentation. Only today can one submit, with respect to cancer, all the experiments demanded by PASTEUR and KOCH as proof of the prime causes of a disease. If it is true that the replacement of oxygen-respiration by fermentation is the prime cause of cancer, then all cancer cells without exception must ferment, and no normal growing cell ought to exist that ferments in the body.
An especially simple and convincing experiment performed by the Americans MALMGREN and FLANEGAN confirms the view. If one injects tetanus spores, which can germinate only at very low oxygen pressures, into the blood of healthy mice, the mice do not sicken with tetanus, because the spores find no place in the normal body where the oxygen pressure is sufficiently low. Likewise, pregnant mice do not sicken when injected with the tetanus spores, because also in the growing embryo no region exists where the oxygen pressure is sufficiently low to permit spore germination. However, if one injects tetanus spores into the blood of tumor-bearing mice, the mice sicken with tetanus, because the oxygen pressure in the tumors can be so low that the spores can germinate. These experiments demonstrate in a unique way the anaerobiosis of cancer cells and the non-anaerobiosis of normal cells, in particular the non-anaerobiosis of growing embryos.
The Fermentation of Morris Hepatomas
A second type of experimentation demonstrates a quantitative connection between fermentation of tumors and growth rate of tumors.
If one injects rats with cancer-inducing substances of different activities, one can create, as HAROLD MORRIS of the National Cancer Institute in Bethesda has found, liver cancers (hepatomas) of verydifferent degrees of malignancy. Thus, one strain of tumor may double its mass in three days, another strain may require 30 days. Recently DEAN BURK and MARK WOODS 3), also of the National Cancer Institute, measured the in vitro rates of anaerobic fermentation in different lines of these hepatomas, and obtained a curve (Fig. 1) that shows a quantitative relationship between fermentation and growth rate, and therefore between fermentation and malignancy, in these various tumor strains. The fermentation increases with the malignancy, and indeed the fermentation increases even faster than the malignancy.
Special interest attaches to the fermentation of the most slowly growing hepatomas, because several investigators in the United States believed that they had found *) that such tumors had no fermentation; that is that anaerobiosis cannot be the prime cause of cancer.
*) 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.
Fig. 1. Velocity of growth and fermentation of the Morris-Hepatomas, according to DEAN BURK and MARK WOODS
DEAN BURK and MARK WOODS saw immediately from their curves that in the region of the zero point the rate of fermentation was so small that it could no longer be measured by the usual gross methodology employed by the aforementioned workers, whereas in the same region the smallest growth rate was always easily measurable. BURK and WOODS saw, in other words, that in the region of the zero point of their curves the growth test was more sensitive than the usual fermentation test. With refined and adequate methods for measuring fermentation of sugar (glucose) they found, what any physical chemist after a glance at the curve would realize, that even the most slow-growing Morris hepatomas fermented sugar.
The results of DEAN BURK and MARK WOODS were confirmed and extended by other workers with independent methods. PIETRO GULLINO, also in Bethesda, developed a perfusion method whereby a Morris hepatoma growing in the living animal could be perfused for long periods of time, even weeks, by means of a single artery and single vein, and the blood entering and leaving any given tumor could be analyzed. GULLINO found with this method that the slow-growing Morris hepatomas always produced fermentation lactic acid during their growth. This was in contrast to liver, where, as known since the days of CLAUDE BERNARD, lactic acid is not produced but consumed by liver; the difference between liver and Morris tumors in vivo is thus infinite (+ vs. -). GULLINO further found that tumors grow in vivo with diminished oxygen consumption. In summary, GULLINO's findings indicate that the slow-growing Morris hepatomas are partial anaerobes. SILVIO FIALA, a biochemist at the University of Southern California, found that not only did the slow-growing hepatomas produce lactic acid, but also that the number of their oxygen-respiring grana was reduced.
The slow-growing Morris hepatomas are therefore far removed from having refuted the anaerobiosis of tumors. On the contrary, they are the best proof of this distinctive characteristic. For forty years cancer investigators have searched for a cancer that did not ferment. When finally a non-fermenting tumor appeared to have been found in the slow-growing Morris tumors, it was shown to be a methodological error.
Transformation of Embryonic Metabolism into Cancer Metabolism
A third type of experiment, from the institute in Dahlem with coworkers GAWEHN, GEISSLER and LORENZ, is likewise highly pertinent. Having established that anaerobiosis is that property of cancer cells that distinguishes them from all normal body cells, we attacked the question, namely, how normal body cells may become transformed into anaerobes 6)7)8).
If one puts embryonic mouse cells into a suitable culture medium saturated with physiological oxygen pressures, they will grow outside the mouse body, in vitro, and indeed as pure aerobes, with a pure oxygen respiration, without a trace of fermentation. However, if during the growth one provides an oxygen pressure so reduced that the oxygen respiration is partially inhibited, the purely aerobic metabolism of the mouse embryonic cells is quantitatively altered within 48 hours, in the course of two cell divisions, into the metabolism characteristic of fermenting cancer cells. Fig. 2 illustrates the very simple experimental procedure involved.
If one then brings such cells, in which during their growth under reduced oxygen pressure a cancer cell metabolism has been produced, back under the original high oxygen pressure, and allows the cell to grow further, the cancer metabolism remains. The transformation of embryonic cell metabolism into cancer cell metabolism can thus be irreversible, and important result, since the origin of cancer cells from normal body cells is an irreversible process. It is equally important that these body cells whose metabolism has thus been transformed into cancer metabolism now continue to grow in vitro as facultative anaerobes. The duration of our experiments is still too limited to have yielded results of tests of inoculation of such cells back into mice, but according to all previous indications such cells will later grow as anaerobes upon transplantation into animals.
In any case, these experiments belong to the most important experiments in the field of cancer investigation since the discovery of the fermentation of tumors. For cancer metabolism, heretofore, measured so many thousand of times, has now been induced artificially in body cells by the simplest conceivable experimental procedure, and with this artificially induced cancer metabolism the body cells divide and grow as anaerobes in vitro*).
*) The experiments were at once repeated, when they were published, of course without acknowledgment. See for example Th. Goodfriend, D. M. Sokol and N. O. Kaplan, J. molecular Biol. 15, 18, 1966.
In recent months we have further developed our experimental arrangements so that we can measure manometrically the oxygen respiration and fermentation of the growing mouse embryonic cells during the metabolic transformation. Fig. 3 shows the experimental arrangement. We find by such experiments that 35 percent inhibition of oxygen respiration already suffices to bring about such a transformation during cell growth**). Oxygen pressures that inhibit respiration 35 percent can occur at the end of blood capillaries in living animals, so that the possibility arises that cancer may result when too low oxygen pressures occur during cell growth in animal bodies.
**) 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.
Fig. 2. Method to transform embryonic metabolism into cancer metabolism by decreasing the oxygen pressure. The induction of cancers by solid materials injected into animals is a further experimental indication of this possibility. If one implants discs of solid substances under the skin of rats, the discs will soon be surrounded by capsules of living tissue that will be nourished with blood vessels from the hypodermis. Sarcomas very frequently develop in these capsules. It is immaterial whether the solid discs are chemically plastics, gold, or ivory, etc. What produces the cancer is not the chemical nature of the solid discs, but the special kind of blood nourishment supplied to the tissue encapsulating the discs. This blood provision varies with the site and in adequacy within a given animal, and induces cancer from the low oxygen pressure in the encapsulating disc.
Fig. 3. Method to measure manometrically respiration and fermentation during the transformation of embryonic into cancer metabolism*)
*) The vessels are not shaken, because shaking inhibits growth. Therefore, the oxygen pressure in the liquid phase at the bottom of the vessels is much lower than in the gas phase. For example, when the oxygen pressure in the gas phase was 2000 mm H2O it was 130 mm H2O at the bottom of the vessels. (O. Warburg, A. Geissler and S. Lorenz, Zeitschr. Für Naturforschung 20b, 1070, 1965.)
Thermodynamics
If a lowered oxygen pressure during cell growth may cause cancer, or, more generally, if any inhibition of respiration during growth may cause cancer, then a next problem is to show why reduced respiration induces cancer. Since we already know that with a lowering of respiration fermentation results, we can re-express our question: Why does cancer result if oxygen-respiration is replaced by fermentation?
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.
The reverse process, the dedifferentiation of life, takes place today in greatest amount before our eyes in cancer development, which is another expression for dedifferentiation. To be sure, cancer development takes place even in the presence of free oxygen gas in the atmosphere, but this oxygen may not penetrate in sufficient quantity into the growing body cells, or the respiratory apo-enzymes of the growing body cells may not be saturated with the active groups. In any case, during the cancer development the oxygen - respiration always falls, fermentation appears, and the highly differentiated cells are transformed to fermenting anaerobes, which have lost all their body functions and retain only the now useless property of growth. Thus, when respiration disappears, life does not disappear, but the meaning of life disappears, and what remains are growing machines that destroy the body in which they grow.
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. It requires work to produce temperature differences in a uniformly temperatured gas; whereas the equalization of such temperature differences is a spontaneous process that does not require work. It is the oxygen - respiration that provides in life this work, and dedifferentiation begins at once when respiration is inhibited in any way. In the language of thermodynamics, differentiation represents a forced steady state, whereas dedifferentiation - that is, cancer - is the true equilibrium state. Or, illustrated by a picture: the differentiated body cell is like a ball on an inclined plane, which, would roll down except for the work of oxygen-respiration always preventing this. If oxygen respiration is inhibited, the ball rolls down the plane to the level of dedifferentiation.
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.
Chemistry
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 end product of fermentation is reached by one single reaction, the reduction of pyruvic acid by dihydro-nicotinamide to lactic acid. On the other hand, the end products 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.
To sum up:
- Impairment of respiration is more frequent than impairment of fermentation because respiration is more complicated than fermentation.
- The impaired respiration can be easily replaced by fermentation, because both processes have a common catalyst, the nicotinamide.
- The consequence of the replacement of respiration by fermentation is mostly glycolysis, with death of the cells by lack of energy. Only if the energy of fermentation is equivalent to the lost energy of respiration, is the consequence anaerobiosis. Glycolysis means death by fermentation, anaerobiosis means life by fermentation.
- Cancer arises, because respiration, but not fermentation, can maintain and create the high differentiation of body cells.
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 cancer b) 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.
Applications
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.
It is of interest in this connection that with the help of one of these active groups of the respiratory enzymes, namely nicotinamide, tuberculosis can be healed quite as well as with streptomycin, but without the side effects of the latter c). Since the sulfonamides and antibiotics, this discovery made in 1945 is the most important event in the field of chemotherapy generally, and encourages, in association with the experiences in Scandinavia, efforts to prevent cancer by dietary addition of large amounts of the active groups of the respiratory enzymes.
Since there can scarcely be overdosage, such experiments can do no harm.
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 to low. Yet prevention remained tabooand 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 be, and that one cannot prevent something that is not known.
But nobody today can say that one does not know what cancer and its prime cause be. On the contrary,there is no disease whose prime cause is better known, so that today ignorance is no longer an excuse that one cannot do more about prevention. That prevention of cancer will come there is no doubt, for man wishes to survive. But how long prevention will be avoided depends on how long the prophets of agnosticism will succeed in inhibiting the application of scientific knowledge in the cancer field. In the meantime, millions of men and women must die of cancer unnecessarily.
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