Re: Dolly and telomerase

Robert J. Bradbury (
Tue, 5 Oct 1999 09:09:13 -0700 (PDT)

On 5 Oct 1999, Anders Sandberg wrote:

> Interesting. Telomerase might likely be important for development;
> maybe the failed embryos didn't have the right programmed cell death
> for correct morphogenesis (but isn't that mainly apoptosis rather than
> senescence?).

The question becomes what is regulating telomere "length"? Is it a property of telomerase itself, the chromosomes involved, etc.? Then you get into the question of how they tried to regulate telomerase.

I can imagine that if you turned on telomerase permanently and messed up any of the controls involved in telomere length it would be uniformly fatal.

... "They keep going and going and going" ...
> What about telomerase-enriched mice? I haven't heard anything
> about them, maybe they don't exist yet, or can't exist?

It is important to keep in mind that rodents are *not* good animals in which to do anything with telomeres. Mice for example have much longer telomeres than humans and have a fairly different structure in the sub-telomere regions.

You have to think about telomeres as an anti-cancer mechanism. The telomere length or activity of telomerase has to be tuned on an organism specific basis to match the cancer rates caused by DNA damage.

long telomeres = high cancer rates;
short telomeres = low cancer rates;
too short telomeres = limited cell divsion, particularly in replicative

                      tissues (or even failure to develop properly)
really long telomeres = probably improper DNA replication/cell division (?)

It is probable that the relatively slow shortening of telomeres in epithelial tissue contributes to skin aging, reduced pulmonary capacity, certainly blood vessel aging and even poor nutrient absorption in the elderly. However those short telomeres are what let humans have a relatively low cancer rate due to division blocks on cells that get mutated and start dividing excessively.

The fundamental question to ask about telomeres is what are they like in whales and elephants (that have very low cancer rates for their cell #). It looks like telomere length interacts with genes with genes near the ends of 4+ chromosomes. In whales/elephants does nature increase the number of these "division" control elements? Or do they have better regulation of telomerase? Or a reduction in DNA damage overall? All of these things could allow a larger number of cells with a lower effective cancer rate.

It is worth pointing out that turning on telomerase is not a universal requirement for cancer development, you can get the same results by fusing chromosomes in unusual ways. Turning on telomerase is one of the most common paths to cancer progression however.