Otto Warburg

The Prime Cause and Prevention of Cancer

(Revised Lindau Lecture)

By OTTO WARBURG

(Director, Max Planck Institute for Cell Physiology, Berlin-Dahlem, Germany) 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 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. 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 it 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 [US] 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 very different 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 pint 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 and 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 studies demonstrate that it is more accurate to refer to tumor cells as “partial anaerobes” rather than “facultative anaerobes,” as shown by the curve of Dean Burk and Mark Woods in Fig. 1. If only a portion of the respiration is replaced by fermentation, a body cell will become a tumor cell.

Fig. 2 shows a technique for changing cancer metabolism from embryonic metabolism by lowering oxygen pressure. (Less O2 is Weniger O2, and More O2 is Viel O2)

Another experimental proof of this theory is the creation of tumors by solid materials put into animals. When solid discs are implanted under the skin of rats, the discs immediately develop live tissue capsules that are supplied by blood vessels from the hypodermis. These capsules frequently form sarcomas. It doesn’t matter if the solid discs are made of chemical polymers, gold, ivory, etc. The type of blood supply given to the tissue around the solid discs, not the chemical makeup of the discs themselves, is what causes cancer. This blood supply varies by site and is insufficient within a single animal, and the low oxygen pressure in the encapsulating disc causes cancer.

Fig. 3 shows a technique for measuring manometric respiration and fermentation as cancer metabolism changes from embryonic metabolism.

*)

Air = Luft (*) There is no shaking of the vessels because shaking stunts development. The oxygen pressure is therefore substantially lower in the liquid phase at the bottom of the vessels than it is in the gas phase. For instance, the oxygen pressure at the bottom of the pipes was 130 mm H2O when the oxygen pressure in the gas phase was 2000 mm H2O. Zeitschr. für Naturforschung 20b, 1070, 1965; O. Warburg, A. Geissler, and S. Lorenz.

Thermodynamics

The next challenge is to explain why reduced respiration causes cancer if decreased oxygen pressure during cell growth, or more broadly, if any suppression of respiration during growth, may do so. We may restate our question since we already know that fermentation happens when respiration is reduced. Why does cancer develop when oxygen-respiration is replaced by fermentation?

According to the early history of life on our planet, there was life on the planet before its atmosphere contained free oxygen gas. Therefore, the living cells must have been fermenting cells at that time, and they were undifferentiated single cells, as evidenced by fossils. The higher development of life did not begin until free oxygen entered the atmosphere, some billion years ago, giving rise to the kingdoms of plants and animals from the fermenting, undifferentiated single cells. What life philosophers refer to as “Evolution créatrice” was and still is oxygen’s doing.

Dedifferentiation is another word for the opposite process that is happening right in front of our eyes right now: the dedifferentiation of life. Undoubtedly, cancer can develop even when free oxygen is present in the air. However, this oxygen may not reach the developing body cells in adequate amounts or the developing body cells’ respiratory apo-enzymes may not be enough saturated with active groups. In any case, along the course of cancer development, oxygen consumption invariably decreases, fermentation emerges, and highly differentiated cells are converted into fermenting anaerobes that merely have the now-useless ability to multiply. As a result, when breathing stops, life continues; nevertheless, the purpose of life also ends. What is left are growing machines that destruct the bodies in which they develop.

But why does oxygen differentiate and why does it dedifferentiate when present? The evolution of unicellular anaerobes into plants, animals, and eventually humans is without a doubt the most unlikely process in the history of the Earth. There is no question that EINSTEIN came from a unicellular fermenting organism as a result, which serves as an example of the miracle that molecular O2 accomplished. But according to Boltzmann’s theory of thermodynamics, unlikely events necessitate work in order to happen.

While it takes effort to create temperature disparities in a uniformly heated gas, such variances naturally equalize themselves without the need for additional effort. Life’s labor is provided by oxygen-respiration, and dedifferentiation starts right away when respiration is hampered in any way. Differentiation, or cancer, is the genuine equilibrium condition in thermodynamic terms, whereas dedifferentiation, or a forced stable state, is what is meant by differentiation. Or, as seen in the following image: The differentiated body cell is like a ball on an inclined plane that would fall if oxygen-respiration wasn’t constantly stopping it. The ball rolls down the plane to the level of dedifferentiation if oxygen respiration is prevented.

However, why can’t respiratory energy and fermentation energy discriminate when, in general, for instance in growth, both types of energy are equal? Without this energy discrimination in fermentation, that is, without fermentation being able to separate from respiration, there would undoubtedly be no cancer. After that, fermentation would take over differentiation when respiration was replaced by it, and a high stage of differentiation would be maintained even in the fermenting body cells.

Physics cannot explain why the two types of energy differ in their ability to differentiate, but chemistry may be able to. Biochemists are aware that phosphate energy is used for both respiration and fermentation, but that phosphorylation occurs in several ways. When this knowledge is applied to the development of cancer, it appears that only oxidative phosphorylation, and not fermentative phosphorylation, may differentiate; this finding suggests a potential explanation for the mechanism of differentiation in the future.

However, biochemistry can already already explain why fermentation occurs when respiration declines. Figure 4 demonstrates that, in terms of pyruvic acid, the routes of respiration and fermentation are similar. The routes then split apart. One single reaction—the conversion of pyruvic acid by dihydro-nicotinamide to lactic acid—leads to the end products of fermentation. On the other hand, it takes numerous more processes before the end products of the oxidation of pyruvic acid, H2O and CO2, are obtained. Therefore, it is likely that the first process to suffer damage when cells are damaged is respiration.

In this manner, probabilistic explanations are used to explain the prevalence of cancer.

Figure 4 Overall

Because respiration is more involved than fermentation, impairment of respiration is [more] common than impairment of fermentation.

Fermentation is a simple replacement for the compromised respiration because they both use nicotinamide as a catalyst.

The result of replacing respiration with fermentation is mostly glycolysis, which leads to cell death from a shortage of energy. Anaerobiosis results only when the energy of fermentation equals the energy lost during respiration. Anaerobiosis denotes life by fermentation, whereas glycolysis signifies death by fermentation.

Cancer develops because only respiration—not fermentation—can keep body cells at a high level of differentiation and produce new ones.

The virus-theory of cancer may be mentioned to wrap up the discussion on the main cause of cancer. It is the subject that cancer philosophers adore the most. If this were the case, cancer could be prevented and treated using virological techniques, and all carcinogens could be consumed or smoked without risk as long as contact with the cancer virus was avoided.

It is true that some viruses can cause cancer in animals, but no one has definitively seen a virus create cancer in humans up to this point. On the other hand, numerous substances can cause cancer in humans and animals without viruses. Thus, viruses do not adhere to Pasteur’s requirements that the root cause of any disease may be identified. Since anaerobiosis is the primary cause of cancer and satisfies Pasteur’s criteria, science defines viruses as distant causes of cancer.

1. b) Like other cancers, the chicken Rous sarcoma, now classified as a virus tumor, ferments glucose and exists as a partial anaerobe. O. WARBURG, Biochemical Times, Volume 160, Number 307, 1925; F. WIND, Klinische Wochenschrift, Volume 30, Number 30, 1926

Many people may recall how anaerobiosis was recently strongly questioned as the primary cause of cancer when one specific disease—the sluggish Morris hepatomas—was mistakenly thought to lack in fermentation. In contrast, despite the lack of a viral etiology for all human cancers, the virus idea is still widely accepted. This entails a renunciation of Pasteur’s concepts and a return to antiquated medical practices.

Applications

Knowing the primary etiology of cancer is useless. Here’s an illustration. The so-called Plummer-Vinson syndrome is a precursor to the throat and esophageal cancer that is prevalent in Scandinavia. The active groups of respiratory enzymes, such as iron salts, riboflavin, nicotinamide, and pantothenic acid, can be added to the diet to treat this syndrome. When a cancer’s precursor is treated, the cancer itself can be avoided. The time has come to eradicate this type of cancer with the aid of the active groups of the respiratory enzymes, according to ERNEST WYNDER 3 of the Sloan-Kettering Institute for Cancer Research in New York.

It is noteworthy in this context that nicotinamide, one of these active groups of the respiratory enzymes, can treat tuberculosis just as effectively as streptomycin while avoiding the latter’s negative effects. c). This discovery, which was made in 1945, is the most significant development in the field of chemotherapy overall since the discovery of sulfonamides and antibiotics. It inspires efforts to prevent cancer by supplementing the diet with significant amounts of the active groups of respiratory enzymes, especially in light of the experiences in Scandinavia. Such trials cannot damage anyone because an overdose is highly unlikely.

1. c) C. R. sci. Paris, 220, 150; V. CHORINE (1945). – H. FUST and A. STUDER, Swiss Journal of General Pathology, Band 14, Fac 5 (1951).

Further, I would like to suggest that when there is a risk of metastatic growths, the active groups of the respiratory enzymes should always be added to the diet in high amounts. Since there is no chance of such a back-differentiation occurring throughout the brief lifespan of a human, it is true that one could never succeed in redifferentiating the dedifferentiated cancer cells. According to the curve DEAN BURK and MARK WOODS obtained with the Morris hepatomas, however, increasing the respiration of growing metastases could inhibit their fermentation and, in turn, slow their growth to the point where they become as harmless as the so-called “sleeping” cancer cells in aging men’s prostates.

Another Useful Illustration

Recently, the issue of cancer therapy has been tackled by physicist MANFRED VON ARDENNE. ARDENNE observed that cancer cells are more vulnerable to high temperatures because, as a result of their fermentation, they are more acidic both internally and externally than normal cells. Based on this, he and his medical colleagues have treated cancer patients by raising their body temperatures to approximately 109° Fahrenheit for an hour after surgically removing the primary tumors in the hopes that the metastases will then be killed or their growth will be so slowed down as to become harmless. Whether or not this concept may be deemed a practical success is still up for debate. However, the preliminary work of ARDENNE is already of tremendous significance in an area where traditional chemotherapy hopes have been dashed but may be revived by combining with intense or mild hyperthermia.

An additional application. K. H. Bauer of the Heidelberg Cancer Institute predicted that at least one million of the 25 million male residents of West Germany who are currently alive will die from cancer of the respiratory tract, and even more will die from other cancers. Cancer has evolved into one of the most deadly threats in medical history when one considers that it is a constant threat.

Many specialists concur that if known carcinogens could be kept out of normal bodily cells, one might prevent around 80% of all cancers in humans. Cancer prevention may not incur any costs, and would especially require little additional research to prevent cancer in up to 80% of cases*). Since this number was made public, some people have believed it to be as low as 80%. However, prevention remained frowned upon, and the only solace given was early diagnosis.

Why then is there such a lack of action taken to prevent cancer despite all of this? The response has always been that one cannot avoid something that is unknown since one does not know what cancer or the primary cause of cancer [may be].

However, no one can claim today that they are ignorant of the nature of cancer or its likely primary cause. Contrarily, no disease has a more well-known primary cause, hence ignorance is no longer a defense for not taking greater preventive action. There is no question that cancer prevention will eventually exist since man wants to live. However, the length of time that prevention will be postponed will depend on how long the agnostic prophets are able to stop the use of scientific knowledge in the fight against cancer. Millions of men must needlessly die from cancer in the meanwhile.

Two prefaces on prevention are included in The Prime Cause and Prevention of Cancer.

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

National Cancer Institute, Bethesda, Maryland, USA, Dean Burk, English Edition

The Second Edition Revised

In 1969, Konrad Triltsch of Würzburg, Germany, published the book.

Thomas Warburg 1883-1970

The Lindau Lecture, Second Revised German Edition, Preface (The way to prevention of cancer)

Since the Lindau talk in June 1966, numerous doctors have investigated the practical ramifications of the anaerobiosis of cancer cells—and not without success. We will learn what is possible sooner if more people take part in these exams. These tests are unique in that they may be conducted in huge numbers on human patients without harm, whereas trials on animals have frequently led to false conclusions. The interaction between the biochemistry of man and that of cancer will lead to the treatment of human cancer.

We just added cytohemin and d-amino-Levulinic acid, the precursor of oxygen-transferring hemins, to a list of selected active groups of respiratory enzymes that will shortly be published. In the interim, it is possible to utilize commercial vitamin preparations that, in addition to other ingredients, include numerous active groups of the respiratory enzymes. The majority of these can be included in food. Vitamin B 12 and cytohemin can both be administered subcutaneously. (An enzyme’s “prosthetic group” is a synonym for the term “active group”).

Today, there is no substitute for the cancer prevention strategy outlined at Lindau. It is the approach that is experimentally most advanced and that most directly combats the primary cause of cancer. Indeed, several studies on humans have demonstrated that removing the active groups of the respiratory enzymes from food impairs cell respiration; adding these groups back to food, however, immediately restores cell respiration. This is due to the action of particular vitamins. A illness whose primary cause is decreased breathing cannot be prevented or treated in any way that is more scientifically supported. Since neither cancer viruses nor anaerobiosis genetic codes have been identified in humans to date, they are not alternatives to anaerobiosis today. However, anaerobiosis has been identified. 8

What can the active groups accomplish once tumors have already formed? The answer is unsure since tumors exist in the body practically anaerobically, which means they do so in an environment where the active groups are unable to function.

On the other hand, since immature metastases function practically aerobically within the body, suppression by active groups should be feasible. As a result, we suggest starting by removing all compact tumors, which are the anaerobic metastatic foci. Then, for many years, even forever, the most amount of the active group should be introduced to the food. This project has potential. If it is successful, cancer will be a treatable condition.

Furthermore, we recently a) found that very low concentrations of some chosen active groups totally suppress fermentation and the growth of cancer cells over the course of a few days in trials using developing cancer cells in vitro. From these studies, it may be inferred that dedifferentiated cells perish if their metabolism is attempted to be normalized. It is an unanticipated outcome that supports the aim of preventing metastases from growing by using active enzyme groups.

It should be stressed that the primary requirement of the suggested treatment is that all developing body cells be completely saturated with oxygen. Exogenous carcinogens must be kept out, at least for the course of treatment, as a second prerequisite. There are no cancer cells that do not have compromised respiration, which serves as evidence that all carcinogens either directly or indirectly limit respiration by reducing capillary circulation. Of course, if breathing is also being hampered by carcinogens, it cannot be restored.

After the Lindau talk, people began to wonder why, despite the cancer cell’s fermentation having been identified as early as 1923, the repair of respiration by the active groups of enzymes was first postulated in 1966. Why was there such a time lag?

The person who posed this question neglected the fact that in 1923, only living things in the natural world knew the chemical basis of enzyme action.

1 Iron, the oxygen-transferring portion of the respiratory enzyme, was identified as the first enzyme active group in 19242. The discovery of O2-transferring metalloproteins, flavoproteins, and pyridinproteins came next, and in the two decades that followed, the research on “Heavy Metals as Prosthetic Groups of Enzymes”3 and “Hydrogen Transferring Enzymes”4 was completed.

Additionally, during the initial decades following 1923, anaerobiosis and glycolysis were frequently mixed, making it impossible to determine which was unique to tumors. The National Cancer Institute at Bethesda’s DEAN BURK and colleagues5 made three significant discoveries in the years 1941, 1956, and 1964. The first was that the metabolism of the regenerating liver, which grows faster than most tumors, is not cancer metabolism but rather a perfect aerobic embryonic metabolism. The second was that cancer cells, which were derived in vitro from a single normal cell, were in vivo more malignant, and the fermentation rate increased with malignancy. The third was that Additionally, between the years of 1927 and 1966, it was discovered6–8 that tissue culture is carcinogenic and that a low oxygen pressure is the basic reason. Only after 1960, when techniques for measuring the oxygen pressure inside tumors in a living organism were discovered, was anaerobiosis of cancer cells proven to be a real phenomenon.

This condensed history demonstrates that not even the greatest genius could have offered what was proposed at Lindau in 1966 in 1923. The possibility of cancer prevention was as unknown in 1923 as the primary cause of cancer.

It would have been too much to ask that anaerobiosis of cancer cells should be recognized right away by all scientists given that life without oxygen in a living universe that has been produced by oxygen9 was so unexpected. However, the majority of resistance vanished after it was made clear at Lindau that, if man is ready to submit to experiments and facts, there is now a real possibility to eradicate this dreadful sickness. It is true that learning how to accomplish it took more than 40 years. However, 40 years is a brief period in scientific history. 10

August 1967, Wiesenhof over Idar-Oberstein

WARBURG, OTTO

By incorporating the active groups of respiratory enzymes into food, LINUS PAULING proposed to manage mental disorders two years after the Lindau speech (Science Vol. 160, Page 265, 1968). But in this case, there was no experimental support. There is currently no documented mental illness whose primary cause is a defect in brain cell respiration.

Preface to the First Edition (Prevention of Endogenous Cancer) The majority of experts concur that if all interaction with the known exogenous carcinogens could be avoided, then about 80% of malignancies might be averted. But how may endogenous or so-called spontaneous tumors, which make up the remaining 20%, be avoided?

It is undeniable that cancer might be averted if the respiration of body cells was maintained because there is no cancer cell that has an intact respiration.

Currently, we are aware of two ways to affect cell respiration.

The first is to lower the oxygen pressure in cells that are expanding. Respiration can diminish irreversibly and normal cells can become facultative anaerobes if it is so much lower that the oxygen transferring enzymes are no longer saturated with oxygen.

The active groups of the respiratory enzymes can be added to meals for humans as a second way to affect cell respiration in vivo. The fact that these groups are essential vitamins for humans proves that a lack of these groups inhibits cell respiration while an excess of these groups restores damaged cell respiration. 2

The first step in preventing cancer is to maintain a blood flow that is fast enough for venous blood to still contain enough oxygen. The second step is to maintain a high hemoglobin concentration in the blood. The third step is to always include the active groups of respiratory enzymes in food, even if a person is healthy, and to increase the doses of these groups if a precancerous state3 has already developed. The majority of malignancies can currently be averted if external carcinogens are carefully removed at the same time.

These ideas are not at all utopian. On the other hand, anyone, anywhere, at any time, could come to realize them. Contrary to many other diseases, cancer cannot be prevented with additional funding or assistance from the government.

August 1966 at Wiesenhof

1. WILLSTAETTER, WIELAND, and EULER, Lectures on Enzymes at the Centennial of the Gesellschaft Deutscher Naturforscher. Literature for the Preface of the Second Edition. Reports of the German Chemical Society, volume 55, issue 3583, 1922. The three lectures by the three scientists reveal that the function of every enzyme was still unknown in 1922. There was no known enzyme active group.
2. OTTO WARBURG, Biochemical Zeitschrift, 152, 479, 1924
3. OTTO WARBURG, Heavy Metals as Prosthetic Groups of Enzymes, Oxford: Clarendon Press, 1949
4. OTTO WARBURG, Wasserstoffübertragende Fermente, Berlin: Verlag Werner Sänger, 1948
5. DEAN BURK, from 1941 With comparison to similar adult or developing liver tissues, the specificity of glycolysis in malignant liver tumors. University of Wisconsin Press, 1942. Symposium on Respiratory Enzymes, pp. 235-245. Science 123,314, 1956; DEAN BURK. National Cancer Institute 23, 1079–1088, 1959. Woods, M. W., Sandford, K. K., Burk, and Earle. On the Significance of Glucolysis for Cancer Growth, with Special Reference to Morris Rat Hepatomas, DEAN BURK, Burk, D., Woods, M., and Hunter, J. National Cancer Institute Journal 38, 839–863 (1967).
6. H. GOLDBLATT and G. CAMERON, J. Exper. Med. 97, 525, 1953; O. WARBURG and F. KUBOWITZ, Bioch. Z. 189, 242, 1927.
7. Mosbacher Kolloquium, April 1966, 7. O. WARBURG Heidelberg: Verlag Springer, 1966.
8. Klinische Wochenschrift 43, 289, 1965. O. Warburg, K. Gawehn, A. W. Geissler, D. Kayser, and S. Lorenz.
9. O. WARBURG, Oxygen: The Originator of Differentiation, Biochemical Energetics, Academic Press, New York, 1966.
10. O. WARBURG, New Methods of Cell Physiology, Interscience Publishers, New York and Georg Thieme, Stuttgart, 1962

Literature to the First Edition’s Preface:

1. OTTO WARBURG, A. W. GEISSLER, and S. LORENZ: On the most recent and remote causes of cancer. 17. April 1966 Mosbacher Kolloquium. Heidelberg: Verlag Springer, 1966.
2. Any book on vitamins, such as Biochemie der Vitamine by Th. Bersin. Frankfurt, Germany: Akad Verlags-Ges, 1966
3. Environmental Factors in Cancer, by ERNEST L. WYNDER, SVEN HULTBERG, FOLKE JACOBSSON, and IRWIN J. BROSS. Cancer, Vol. 10, 470, 2057.