Aubrey de Grey wrote:
> I see that James has not got round to replying; apologies to him if he
> is doing so as I write :-) Note first that James said that constitutive
> telomerase expression would "cause cancer", not "make cells cancerous":
> this distinction is important.
>> It is necessary to consider cells in vivo and in vitro separately. In
> vivo, we know (from very many studies, of which I believe the first was
> Counter et al, EMBO J 11(5):1921-1929) that telomerase is expressed in
> most human tumours at levels a good deal higher than in any non-cancerous
> somatic tissue yet found. This has been taken to indicate that activation
> of telomerase, though not absolutely necessary for tumour progression, is
> a big step towards it, ie a telomerase-positive cell needs fewer other
> mutations to become a full-blown tumour than a telomerase-negative one.
> Since mutations are stochastic, this implies that a human all of whose
> cells are telomerase-positive from birth will get cancer sooner than a
> normal human.
I agree that this is probably the case, and it also seems likely to me
(admittedly without any reading or research) that the cells in the body that
have been shown capable (or are suspected) of expressing telomerase are the
ones that are the sites of many of the more common cancers.
I think however that there is a subtle difference between increasing the
likelihood of cancer and "causing cancer". Without getting into a semantic
agument I felt that James' use of 'cause' implied some measure of certainty
that it was going to occur, as opposed to a simple causal link that may have
had a low rate of occurrence. If cancer can occur without telomerase initially
being present, and telomerase can be present without cancer occurring, does
telomerase 'cause' cancer?
For example,I assume that the only part of the body where telomerase is
expressed continually is the testes, but we don't all get testicular cancer.
The presence of telomerase may increase the incidence of cancer when compared
to other organs, but that doesn't make it certain to occur.
It may be that in telomerase expression may not occur in cells other than
those that require high turnover rates as a way of reducing the possibility
of cancers getting a foothold. The natural limiting of telomere length may be
like putting an aggressive dog on a chain - at least if it goes beserk it
won't get far or do much damage before it chokes.
> So to the in vitro case. The experiments by Geron are just as you say:
> in fact, the whole reason why they are interesting is that the cells are
> not cancerous, since cancerous cells already have indefinite replicative
> capacity. But this does not conflict with the in vivo argument above.
> Why not? Because non-cancerous normal human cells NEVER spontaneously
> become cancerous in vitro. When I say "never" I of course can only mean
> "not in the finite number of cultures examined so far", but that finite
> number is quite large. This is not actually much of a surprise, because
> (a) people are bigger than cultures, and (b) the environment of a cell in
> culture may be a good deal less mutagenic than that of a cell in the body.
> So this means that Geron's cells may be a lot more prone to cancer than
> telomerase-negative cells, but not prone enough to have become cancerous
> in the time (and in the number of cultures) yet examined.
So I guess the next step is to expose Geron's immortalised cells to a mutagen
and see how the incidence of cancerous transformation compares to normal cells
exposed to the same mutagen. That may at least confirm your hypothesis that
telomerase activity would increase the incidence of cancer.
I guess the implication for any sort of future telomerase based therapy for
aging is that a one time activation of telomerase that added a reasonable
number of bases to the telomeres would be safer than an approach that relied
on regular expression of just enough telomerase to add a small amount to the
telomeres prior to each cell division.
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