Discovery Institute Fellow Jonathan Wells has for some time insisted that genes actually don’t do much, and that mutations in genes cannot play a significant role in evolution. One aspect of this is his claim that mutations in genes play little role in cancer. If he can throw doubt on the ability of genetic mutation to produce cancer, then by implication genetic mutation is not a force in evolutionary biology, and cannot be sculpted by natural selection. I have written about genes, cancer and Jonathan Wells before showing that he is greatly mistaken. However, recently published work has provided yet more evidence for a central role of genetic mutation in cancer, and further demolishes (if that is possible) Wells’s thesis[1,2,3,4].
Cancer is, at its heart, a disease of uncontrolled cell growth. There are many pathways that control cell growth and senescence, so it is not surprising that in cancer mutations are found in several different genes associated with cell growth and senescence. The most common mutations found in humans are mutations in the gene for a protein called p53. p53 activates cell suicide or permanent growth arrest in stressed cells or cells with DNA damage. The mutations in cancer cells inactivate p53, preventing it from stopping out of control cells.
If Wells is right, and mutations are not responsible for (or central to) tumourogenesis, then inactivation or deletion of p53 should do very little. In fact, p53 is shown to be a key player in experimental models. In tissue culture, deletion of p53 alone can send cells into uncontrolled growth. In mice that have had p53 knocked out, virtually all of them develop tumours, while the control mice had no tumours. This strongly suggests that mutations of p53 play a major role in generating tumours. All this was known when Wells wrote his TOPS article, but he mentions none of this evidence.
Three recent papers take the p53 a step further [1,2,3]. In these papers, p53 is replaced or reactivated in tumours in mice. If Wells is right, then reactivating p53 should be of little effect. The three recent papers used different techniques to reactivate p53. Despite this, and the different tumour types in the three papers, reactivation of p53 expression led universally to a prompt and impressive regression of the tumours in vivo. These results reinforce the role of mutations in p53 in cancer.
Wells’s favoured explanation for tumourogenseis is that chromosomal abnormalities, generated by centrosomes, are the key to cancer. I have dealt with his model of centrosomes before, but I will remind people that while chromosomal abnormalities are seen in many cancers, they are not seen in all cancers. Another recent paper has shown that in animals genetically engineered to have increased levels of chromosomal abnormalities , chemically or genetically induced tumour formation was inhibited. Thus, in certain kinds of cancer, chromosomal instability prevents tumourogenesis, the exact opposite of what Wells predicted.
Once again, real research trumps the tales of evolution deniers spun from airy nothingness. Is it any wonder that they do not expose their ideas to peer-review?
- 1. Ventura A, et al., Restoration of p53 function leads to tumour regression in vivo. Nature. 2007 Jan 24; [Epub ahead of print]
- 2. Xue W, et al., Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007 Jan 24; [Epub ahead of print]
- 3. Martins CP, Brown-Swigart L, Evan GI. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell. 2006 Dec 29;127(7):1323-34. Epub 2006 Dec 21.
- 4. Weaver BA, Silk AD, Montagna C, Verdier-Pinard P, Cleveland DW. Aneuploidy acts both oncogenically and as a tumor suppressor. Cancer Cell. 2007 Jan;11(1):25-36. Epub 2006 Dec 28.
- 5. Donehower LA, et al., Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992 Mar 19;356(6366):215-21.