Cell division in cancer
A life-threatening cancer contains billions of cells that are thought to originate from a single progenitor. During the evolution of cancer, multiple mutations (perhaps in the order of a dozen) have to arise, to gradually overcome our cells', bodies' and clinical therapys' multiple cancer defense mechanisms. Each of these mutations typically happens only in one or very few cells, that have to repopulate the entire tumor volume to confer the new genotype on it. In addition, tumor cells are constantly removed by the defense mechanisms themselves. Thus, the number of clone doublings that are required before a tumor can become life-threatening might plausibly be in the order of hundreds.
Such a massive amount of cell division has never been observed without a means to lengthen telomeres. Thus, it is thought that cancers cannot arise without lengthening their telomeres.
Telomeres and Telomerase
Telomeres are repetitive sequences at the ends of each of our chromosomes. They consist of hundreds to thousands of TTTAGGs repeats. Telomeres shorten with each cell division due to the so-called end-replication problem. When telomeres become critically short, they are thought to be recognized as a DNA single-stranded break, which causes the cell to remove itself from cell division by either apoptosis or senescence.
This is thought to limit the number of times most human somatic cells can double. Some cell types, including stem cells and germ cells make telomerase, an enzyme which lengthens telomeres. To prevent excessive lengthening, a partially characterized telomere length homeostatsis system is in place.
The mouse, unlike us, makes telomerase most body cells.
Some cancers do not express telomerase, but do lengthen their telomeres. They do this by a mechanism termed ALT. ALT is unfortunately not very well characterized. It seems to involve certain DNA repair factors and DNA-polymerase mediated, DNA template-dependent synthesis of telomeric repeats.
WILT (Whole-body Interdiction of Lengthening of Telomeres) proposes to delete the gene for telomerase, find a gene that is critical for ALT and delete it, too. Thus, telomeres could not be lengthened and cancers could not reach a life-threatening stage. No mutation could arise that rescues telomere lengthening, because the genes would be completely missing. Random mutations that generate whole genes out of thin air are thought to be way too unlikely to happen, even in the context of cancer.
As mentioned above, some cells in our bodies depend on telomerase. E.g. many rapidly dividing stem cells could not sustain their function without it. For example, this is important in the intestinal mucosa and the blood, the stem cells of which divide very rapidly to balance the rapid loss of cells in these organs. Thus, it is part of the WILT proposal to regularly reseed these tissues with fresh stem cells that have long telomeres, but no telomere lengthening mechanism.
Another brief introduction to WILT is here, the original paper is freely available here and a follow-up paper is also freely avaliable here.