Telomerase deficient mice
Aubrey de Grey
ag24 at mole.bio.cam.ac.uk
Fri Apr 9 08:09:38 EST 1999
Tom Mahoney wrote:
> >> Many cells in rodents such as "normal diploid rodent fibroblasts"
> >> possess active telomerase throughout their proliferative life span
> >> and are basically already immortalized, see Oncogene 16(13):1723-30.
> >So why do they have a finite (indeed, short) proliferative lifespan?
> Those mouse cells that have active telomerase do not have a short
> proliferative lifespan.
Hang on. Normal diploid rodent fibroblasts reach a slow growth phase,
normally termed "senescence", after about 10 divisions. Are you defining
(as I was) their proliferative lifespan as ending then or not? Evidently
not. But after that, after they escape from slow growth, they are no
longer normal diploid rodent fibroblasts!
> The novel finding of this research, that the mice cells that do not
> normally express telomerase can also be immortalized with the
> introduction of telomerase, is not an unexpected result meriting great
> scrutiny and has been previously demonstrated when these cells have
> degenerated into tumorous growths, (Nat Genet 1996 Feb;12(2):200-4).
No! Sure, telomerase is (eventually) activated in tumours; equally
sure, it -- or some other telomere maintenance system -- needs to be
activated (eventually), else even mice's initially long telomeres will
curtail the growth of the cells (in vitro) in the end. But as we all
know, the pivotal feature of Geron's immortal human cells is that they
are NOT tumorous.
> In fact they are basically immortalized, (Int J Mol Med 2(4):437-444).
Again, this paper is about tumours, not about normal cells.
> Mouse cells without telomerase normally present can go through approx.
> 30 population doublings, depending on the strain, before experiencing
> crisis and dying, (Biochemistry (Mosc) 1997 Nov;62(11):1296-305
And this paper too is about spontaneously transformed cells.
> There is still controversy over what causes this slow growth stage. It
> has been argued that this is the result of the the shortening of the
> shortest telomeres described in; (Proc Natl Acad Sci U S A 1997 Jul
> 8;94(14):7423-8). Others have suggested that there is a "growth
> factor-sensitive, mammalian senescence mechanism unrelated to telomere
> maintenance.", (Oncogene 1998 Dec 31;17(26):3417-26).
Precisely -- it is still open whether telomere shortening causes mouse
cell senescence. Moreover, many people think it probably doesn't, simply
because mouse telomeres are still so long when senescence occurs; as you
say, however, we don't know how long the shortest telomeres are. That is
exactly why a study which successfully immortalised mouse cells, without
also inducing any cancer-like changes, would be so important -- it would
resolve this vital point.
> telomerase immortalizes the cells. ... What research have
> you seen that would suggest otherwise?
You've just cited one! Its title is: "A telomere-independent senescence
mechanism is the sole barrier to Syrian hamster cell immortalization".
(Oncogene 1998 Dec 31;17(26):3417-26)
> By contract, I am barred from pre-maturely releasing the names and
> affiliation of the researchers conducting this particular study.
OK, though I must say it's a very unusual researcher who wants that sort
> But I have made no representation in my posts that can't be confirmed
> from numerous other sources, some of which are cited above.
Not so, as explained above. NONE of your citations confirms your original
assertion that "the replicative cells of mice respond in the same manner
as human cells when the catalytic component for telomerase is introduced"
(i.e. they are immortalised without becoming cancerous).
> I'm not confusing the issue, this is the issue!
Evidently I should spell this out. The WIDE issue, determining how and
why mice and people age and die, cannot be productively addressed in the
context of erroneous beliefs regarding NARROW issues, such as whether
mouse cells can be immortalised by telomerase without becoming cancerous.
Thus it is counter-productive to flit between narrow issues, failing to
resolve them. When a narrow issue comes up that is a matter of debate,
it should be pursued in a focused manner, free of distraction from other
narrow issues which do not bear on it; otherwise discussion of the wider
issue cannot benefit.
Thus, I repeat: Do you, in fact, know of any study -- published or not --
in which telomerase successfully immortalised mouse cells without also
inducing any cancer-like changes? If you don't, please just say so and
let's be done with it. If you do, please tell us as much as you are
contractually allowed to about the study.
Aubrey de Grey
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