TRIPPING OVER THE TRUTH

The German biochemist, Dr Otto Warburg (1883-1970), won the Nobel Prize in Physiology or Medicine in 1931 for work he had done the nature and mode of action of the respiratory enzyme. His father was professor of physics in Berlin and while serving in the army during the First World War he received an unexpected letter from Albert Einstein begging him to find a way of extricating himself from the front in the interests of scientific research. He had already been appointed a Professor at the Kaiser Wilhelm Society for the Advancement of Science, and this gave him high status and no responsibilities so that he could devote himself entirely to research. His aim was to find a cure for cancer. This readable and informative book tells the history of approaches to cancer, but with special emphasis on Warburg's metabolic theory of cancer in relation to the prevailing orthodoxy of somatic mutation theory (SMT).

This theory was succinctly stated by Warburg himself: 'Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. Summarised in few words, the prime cause of cancer is the replacement of the respiration of the oxygen in normal body cells by a fermentation of sugar.' The underlying message is that researchers have become enmeshed in a complex web of genetic analysis, culminating in The Cancer Genome Atlas (TCGA), and that this has distracted them from considering the possibility that 'cancer is not a disease of damage to DNA but rather one of defective metabolism.' As it happens, this overwhelming complexity in terms of potential mutations may turn out to be catalysing factor in shifting the mainstream view. The book explains in detail how cancer came to be known as a genetic disease.

Warburg's theory, by contrast, is simple, orderly and elegant. He discovered that 'unlike normal cells, cancer cells ferment glucose in the presence of oxygen', producing energy in a different way through fermentation; also abnormal amounts of lactic acid. He discovered this defective metabolism in all types of tumour cells, where 'the shift from aerobic to anaerobic energy generation was the significant difference between cancer cells and normal cells.' Moreover, when normal healthy cells are deprived of oxygen, they turn cancerous without any other factors being required. The decline of the popularity of Warburg's theory also signalled a shift in primacy from biochemistry to molecular biology, as observed by James Watson: the therapeutic emphasis was on agents that inhibited cell division. By the time he died, colleagues felt that Warburg's theory was completely outdated – it was 'too simplistic for serious consideration.'

His work was taken up by Pete Pedersen at Johns Hopkins, who thought that the 'metabolism of cancer might be the missing piece to the puzzle that genetics not been able to solve.' The book describes his decades of research before the advent of epigenetics provided a new context of understanding. As early as 1977, he had discovered that a single molecular alteration in the cell – in mitochondrial hexokinase – was responsible for the shift in ATP energy generation using oxygen to a much less efficient process involving glucose and generating lactic acid as a waste product. (p. 62). It is this mechanism that is addressed in ketogenic diets where the idea is to starve the cancer cells of the necessary glucose by shifting energy generation into fats. Later, Thomas Seyfried realised that the crucial link is epigenetic signalling from the mitochondria to nuclear DNA: 'the signal then altered the expression of a plethora of key cancer-causing oncogenes – a classic epigenetic system' involving the transformation of hexokinase to hexokinase II.

As mentioned earlier, the sheer complexity emerging from the TCGA called into question the predictions of SMT in terms of causal mutations, for instance in breast-cancer (p. 113) – the samples were heterogeneous, and neither a single mutation nor a combination of mutations to initiate the disease could be found. Moreover, 'mutations are rare and infrequent events.' Even Robert Weinberg has now added 'the reprogramming of energy metabolism' to a list of cancer hallmarks. All this led James Watson to reconsider the significance of Warburg's legacy, recommending that 'we may have to turn our main research focus away from decoding the genetic instructions behind cancer and towards understanding the chemical reactions (metabolism) within cancer cells.' (p. 126)

Werner Heisenberg famously observed that 'what we observe is not nature in itself but nature exposed to our method of questioning', a remark we would do well to remember and reinforced by the physicist Paul Davies, who was brought in by the NCI for an outside view on causation and cancer. He was highly critical of SMT, remarking that 'never has science offered a clearer example of a preoccupation with trees at the expense of the forest.' (p. 189) Contrary to the genetic complexity view, the metabolic theory proposes that cancer is a disease of order, whereby 'to transition to energy creation by fermentation means that the cell must drastically alter its enzymatic profile in an orderly manner. (p. 181) As a non-specialist, this makes a great deal of sense to me and suggests that the way forward is along the lines proposed by Watson in terms of focusing on metabolism as well as genetics, especially in the light of the activating role of epigenetic signalling. The 1976 accusation by Sidney Whitehouse that Warburg's theory was too simplistic may in fact transform this pejorative word into the elegance of simplicity – time will tell.