Dr. Otto Warburg, "On The Origin of Cancer Cells,"
SCIENCE, (FEB. 24, 1956) Volume 123, Number 3191, pp. 309-314.
Professor Warburg was director of the Max Planck Institute for Cell Physiology, Berlin-Dahlem, Germany. This article is based on a lecture delivered at Stuttgart on 25 May 1955 before the German Central Committee for Cancer Control.
The era in which the fermentation of the cancer cells or its importance in carcinogenesis could be disputed is over, and no one today can doubt that we understand the origin of cancer cells from damaged respiration and the excessive fermentation of cancer cells.
We now understand the chemical mechanism of respiration and fermentation almost completely. We know that cancer cells can obtain approximately the same amount of energy from fermentation as from respiration, whereas the normal body cells obtain much more energy from respiration than from fermentation. For example, the liver and the kidney of an adult animal obtain about 100 times as much energy from respiration as from fermentation.
Injuring of Respiration
Since the respiration of all cancer cells is damaged, the question is, 'How can the respiration of body cells be injured?' Of this damage to respiration, it can be said at the outset that it must be irreversible, since the respiration of cancer cells can never return to normal. Second, the injury to respiration must not be so great that the cells are killed, for then no cancer cells could result.
One method for the destruction of the respiration of body cells is removal of oxygen. If, for example, embryos are exposed to an oxygen deficiency for some hours and then placed in oxygen again, 50 percent more or more of the respiration in destroyed. The cause of this destruction of respiration is lack of energy. The cells need their respiratory energy to preserve their structure, and if respiration is inhibited, both structure and respiration disappear.
Another method for destroying respiration is respiratory poisons. From the standpoint of energy, this method comes to the same result as the first method. No matter whether oxygen is withdrawn from the cell or whether the oxygen is prevented from reacting in the cell by a poison, the result is the same in both cases - namely, impairment of respiration from lack of energy.
The first notable experimental induction of cancer by oxygen deficiency was described by Goldblatt and Cameron (3), who exposed heart fibroblasts in tissue culture to intermittent oxygen deficiency for long periods and finally obtained transplantable cancer cells. Clinical experiences along these lines are innumerable: the production of cancer by intermittent irritation of the outer skin and of the mucosa of internal organs, by the plugging of the excretory ducts of glands, by cirrhoses of tissues, and so forth. In all these cases, the intermittent irritations lead to intermittent circulatory disturbances. Probably chronic intermittent oxygen deficiency plays a greater role in the formation of cancer in the body than does the chronic administration of respiratory poisons.
Any respiratory injury due to lack of energy, however, whether it is produced by oxygen deficiency or by respiratory poisons, must be cumulative, since it is irreversible. Frequent small doses of respiratory poisons are therefore more dangerous than a single large dose, where there is always the chance that the cells will be killed rather than that they will become carcinogenic. If an injury of respiration is to produce cancer, this injury must be irreversible. We understand by this not only that the inhibition of respiration remains after removal of the respiratory poison but, even more, that the inhibition of respiration also continues through all the following cell divisions, for measurements of metabolism in transplanted tumors have shown that cancer cells cannot regain normal respiration, even in the course of many decades, once they have lost it.
Increase of Fermentation
When the respiration of body cells has been irreversibly damaged, cancer cells by no means immediately result. For cancer formation there is necessary not only an irreversible damaging of the respiration but also an increase in the fermentation of great enough magnitude that it compensates energetically. But how does this increase of fermentation come about?
There is no physical or chemical agent with which the fermentation of cells in the body can be increased directly. For an increase in fermentation, a long time and a great many cell divisions are always necessary. The mysterious latency period of the production of cancer is, therefore nothing more than the time in which the fermentation increases after a damaging of the respiration due to oxygen deprivation. This time is long in man and often amounts to several decades, as can be determined by the cases in which the time of the respiratory damage is known -- for example, in cancer due to radiation.
The driving force of the increase of fermentation is the energy deficiency under which the cells operate after destruction of their respiration, which forces the cells to replace the lost respiration energy in some way. They are able to do this by a selective process that makes use of the fermentation by the normal body cells. The more weakly fermenting body cells perish, but the more strongly fermenting ones remain alive, and this selective process continues until the lowered energy level due to respiratory failure is compensated for by the increase in fermentation. Only then has a cancer cell resulted from the normal body cell.
Why are the body cells dedifferentiated when their respiration energy is replaced by fermentation energy? At first, one would think that it is immaterial to the cells whether they obtain their energy from respiration or from fermentation, since the energy of both reactions is transformed into the energy of adenosine triphosphate, and ATP = ATP. This equation is certainly correct chemically and energetically, but it is incorrect morphologically, because the ATP synthesized by respiration involves more structure than the ATP synthesized by fermentation.
It is as if one exposed the same amount of silver on a photographic plate with the same amount of light, but in one case with diffused light and in the other with patterned light. In the first case, a diffuse blackening appears on the plate, but in the second case, a picture appears; however, the same thing happens chemically and energetically in both cases. Just as one type of light energy involves more structure than the other type, the adenosine triphosphate energy involves more structure when it is formed by respiration than it does when it is formed by fermentation.
It has been known for a long time that fermentation -- the energy supplying reaction of the lower organisms -- is morphologically inferior to respiration. Not even yeast, which is one of the lowest forms of life, can maintain its structure permanently by fermentation alone; it degenerates to bizarre forms. However, as Pasteur showed in 1876, it is rejuvenated in a wonderful manner, if it comes in contact with oxygen for a short time. The explanation is the strong connection of respiration with structure and the weak connection of fermentation with structure.
This, therefore, is the physiochemical explanation of the dedifferentiation of cancer cells. If the structure of yeast cannot be maintained by fermentation alone, one need not wonder that highly differentiated body cells lose their differentiation upon continuous replacement of their respiration with fermentation.
When one irradiates a tissue that contains cancer cells as well as normal cells, the respiration of the cancer cells, already too low, will decline further. If the respiration falls below a certain minimum that the cells need unconditionally, despite their increased fermentation, they die; whereas the normal cells, where respiration may be harmed by the same amount, will survive because, with a greater initial respiration, they will still possess a higher residual respiration after irradiation. This explains the selective killing action of x-rays on cancer cells. But the descendants of the surviving normal cells may, in the course of time, compensate for the decrease of respiration by the increase of fermentation and, thence, become cancer cells. Thus it happens that radiation which kills cancer cells can also at the same time produce cancer.
Sleeping Cancer Cells
Since the increase in fermentation in the development of cancer cells takes place gradually, there must be a transitional phase between normal body cells and fully formed cancer cells. Thus, for example, when fermentation has become so great that dedifferentiation has commenced, but not so great that the respiration defect has been fully compensated for energetically by fermentation, we may have cells which indeed look like cancer cells but are still energetically insufficient. Such cells, which are clinically not cancer cells, have lately been found, not only in the prostate, but also in the lungs, kidney, and stomach of elderly persons. Such cells have been referred to as "sleeping cancer cells."
Aerobic fermentation is a property of growing cancer cells, but aerobic fermentation without growth is a property of all damaged body cells - for example, embryos that have been transferred from amniotic fluid to Ringer's solution. Since it is always easy to detect aerobic fermentation but generally difficult to detect growth of body cells, aerobic fermentation should not be used as a test for cancer cells, as I made clear in 1928.
Cancer cells originate from normal body cells in two phases. The first phase is the irreversible injuring of respiration. There are a great many secondary causes of cancer -- tar, X-rays, arsenic, urethane -- but there is only one common cause into which all other causes of cancer merge, the irreversible injuring of respiration.
The irreversible injuring of respiration is followed, as the second phase of cancer formation, by a long struggle for existence by the injured cells to maintain their structure, in which a part of the cells perish from lack of energy, while another part succeeds in replacing the lost respiration energy by fermentation energy. Because of the morphological inferiority of fermentation energy, the highly differentiated body cells are converted by this into undifferentiated cells that grow wildly -- the cancer cells.
The other theories of cancer origin (mutation and carcinogen) are not viable alternatives, but empty words. Even more harmful in the struggle against cancer is the continual uncovering of miscellaneous cancer agents and cancer viruses, which, by obscuring the true cause, lack of oxygen, may hinder necessary preventive measures and thereby become responsible for cancer cases.
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