Quantitative Resolution to some 'Absolute Discrepancies' in Cancer Theories: a View from Phage lambda Genetic Switch

While the support for their own advocated chromosomal cancer theory appears strong, it seems that their wholesale criticism on mutation cancer theory is premature. In this letter the quantitative evidence against one of their major reasons for dismissing mutation cancer theory, by both in vivo experiment and a first principle computation, is explicitly pointed out.

Duesberg et al (2005) listed 9 “absolute discrepancies” or questions which they believe the mutation cancer theory cannot answer: “(1) How would non-mutagenic carcinogens cause cancer?

(2) What kind of mutation would cause cancer only after delays of several decades and many cell generations?

(3) What kind of mutation would alter the phenotype of mutant cells perpetually, despite the absence of further mutagens? (4) What kind of mutation would be able to alter phenotypes at rates that exceed conventional gene mutations 4-11 orders of magnitude?

(5) What kind of mutation would generate resistance against many more drugs than the one used to select it? (6) What kind of mutations would change the cellular and nuclear morphologies several-fold within the same “clonal” cancer? (7) What kind of mutation would alter the expressions and metabolic activities of 1000s of genes, which is the hallmark of cancer cells? (8) What kind of mutation would consistently coincide with aneuploidy, although conventional gene mutations generate infinite numbers of new phenotypes without altering the karyotype? (9) Why would cancer not be heritable via conventional mutations by conventional Mendelian genetics?” Evidently those important questions should be considered seriously by any cancer re-searcher. There are, however, two general reasons that the temporally inability to address them is not enough to dismiss mutation cancer theory. First, in many situations whether the effects are the causes or the consequences, or mutual causes to each other, are still poorly understood, though their associations with cancers may be obvious. The clarification of such confusing requires further and more experimental and clinical studies. Such efforts have been carrying out, for example, by Weiss Second, the absence of an explanation or of a theory is not a proof that it would not ever exist. If there were already enough amount of consistent experimental and clinical observations, the emergence of a theory would be simply a matter of time. It is a test to our creativity and imagination. Therefore, those “absolute discrepancies” are logically not necessarily against the mutation cancer theory. Having given a “dodged” defense, here I would like to call the attention to one evidence specifically addressing above 4th discrepancy: “(4) What kind of mutation would be able to alter phenotypes at rates that exceed conventional gene mutations 4-11 orders of magnitude?” The question (4) can be answered by mutation cancer theory in a quantitative and first principle manner. The quantitative evidence also suggests answers to questions (1) and (2) of Duesberg et al.

In the phage lambda system, a bio-system arguably started the modern molecular biology I. Zhu et al (2004Zhu et al ( , 2006)). There are 5 different phage lambda phenotypes, including the “wild type”, which have been systematic studied experimentally (Little et al 1999). The switching rate is the probability to switch from lysogenic to lytic states per minute under normal lab condition. The symbol ? indicates that there is no stable lysogenic state, that is, the phage lambda would immediately switch to lytic state.

The switching rate is then “infinite”.

Quantitative answer to “absolute discrepancy” 4:

The point should be emphasized is that the mathematical calculation is based on first principle modelling without “free” parameters. What the “first principle” means is that the interaction between involved proteins and the protein-DNA binding are based on carefully reasoned physical, chemical and biological principles during past 40 years. What the “parameter free” means is that all the kinetic parameters needed for the mathematical modelling have been fixed by other experiments. Thus, the remarkable consistency over at least 8 orders of magnitude between the experimental data and mathematical calculation shows that it is unlikely due to artifacts in experiment and/or in modelling. Because such effect can occur in phage lambda, there is no reason that same thing cannot occur in higher organisms Qu

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