324 On the Origin of Cancer Cells 



recent years it has been recognized that subnarcotic doses of urethane cause lung 

 cancer in mice in 100 percent of treatments. Urethane is particulary suitable as a 

 carcinogen, because, in contrast to alcohol, it is not itself burned up on the res- 

 piring surfaces and, unlike ether or Chloroform, it does not cytolyze the cells. Any 

 narcotic that has these properties may cause cancer upon chronic administration 

 in small doses. 



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 trans- 

 plantable cancer cells, whereas in the control cultures that were maintained without 

 oxygen deficiency, no cancer cells resulted. 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 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 inter- 

 mittent 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 dan- 

 gerous than a single large dose, where there is always the chance that the cells will 

 be killed rather than that they will become carcinogenic. 



Grana 



If an injury of respiration is to produce cancer, this injury must, as already men- 

 tioned, be irreversible. We understand by this not only that the inhibition of respira- 

 tion remains after removal of the respiratory poison but, even more, that the inhibi- 

 tion of respiration also continues through all the following cell divisions, for measure- 

 ments of metabolism in transplanted tumors have shown that cancer cells cannot re- 

 gain normal respiration, even in the course of many decades, once they have lost it. 

 This originally mysterious phenomenon has been explained by a discovery that 

 comes from the early years of cell physiology 4 . When liver cells were cytolyzed by 

 infusion of water and the cytolyzate was centrifuged, it was found that the greater 

 part of the respiration sank to the bottom with the cell grana. It was also shown 

 that the respiration of the centrifuged grana was inhibited by narcotics at concen- 

 trations affecting cell structures, from which it was concluded — already in 1914 — 

 that the respiring grana are not insoluble cell particles but autonomous organisms, 

 a result that has been extended in recent years by the English botanist Darlington 5 

 and particularly by Mark Woods and H. G. du Buy ö of the National Cancer Insti- 

 tute in Bethesda, Md. Woods and du Buy have experimentally expanded our con- 

 cepts concerning the self-perpetuating nature of mitochondrial elements (grana) 

 and have demonstrated the hereditary role of extranuclear aberrant forms of these 

 in the causation of neoplasia. The autonomy of the respiring grana, both biochemi- 

 cally and genetically, can hardly be doubted today. 



