Cloning and Telomeres

Question

I read that the length of telomeres in Dolly was shorter, because the DNA was taken from an old sheep. Shorter telomeres may lead to early aging. What is happening now with cloning? Do we use a telomerase to restore the length in a donor cell?

Answer 1

No, it doesn't seem to be common practice. A telomerase treatment would probably do more harm than good, and may be completely unnecessary in the first place.

Betts and coworkers published a study in which they examined telomere length in cloned cattle. They found that while telomere length in cloned embryos does start out somewhat shorter than in naturally produced embryos, by the time that the normal processes of embryonic development were in full swing telomere length in cloned and natural embryos was equivalent.

Betts' results make sense in light of the fact that telomerase activity (and the activity of many, many related proteins) is normally upregulated in embryonic cells.

As for Dolly, while it is true that her telomeres were shorter than those of an average age-matched sheep at the time of her death, it's far from clear that those short telomeres had anything to do with her decline. Also keep in mind that she didn't just keel over suddenly in the night, she was euthanized. A subsequent autopsy showed that she had a form of lung cancer caused by a retrovirus common in sheep.

Edit: why were Dolly's telomeres shortened?

This is a good question, as the findings of shortened telomeres in Dolly's case do contradict the findings in the Betts paper. Clearly we need more citations:

-"Analysis of telomere lengths in cloned sheep." Shiels et al, 1999

This is the original citation for the claim that Dolly's telomeres were shortened. There isn't too much extra information to be had as it's a very short paper (1 page letter). They did look at other cloned sheep created from types of cells other than skin cells (as Dolly was) and saw the same kind of telomere shortening relative to controls. They also make a point of mentioning that Dolly's telomere length may be within the normal variation for sheep.

-"Remarkable differences in telomere lengths among cloned cattle derived from different cell types." Miyashita et al, 2002

The investigators found that telomere length in cloned cattle was strongly dependent on the type of cell from which the clone was derived. For example, clones made from mammary cells tended to have shortened telomeres, whereas those derived from muscle cells had normal length telomeres.

-"The analysis of telomere length and telomerase activity in cloned pigs and cows.", Jeon, 2005

This group found that cloned cattle had normal length telomeres, whereas cloned pigs had elongated telomeres. By way of explaining these results, they found that telomerase activity was upregulated in cloned pigs relative to control pigs, whereas telomerase activity in cloned cattle matched that of control cattle.

How should we take all of this information? At the very least we can say that telomere length in clones is highly dependent on species and on source tissue, and that telomere length can increase, decrease, or stay the same in cloned animals relative to control animals. Clearly telomere length in cloned animals is a fiddly property. It is very likely that it also depends on the exact details of the cloning protocol as it was carried out (i.e. how much did the experimenter's hands shake when they inserted the needle to suck out the nucleus?, etc.).

So I would say not to read too much into Dolly's shortened telomeres. They may have been a result of her being a clone, or they may have been a result of natural variation. In either case the shortened telomeres were not linked to her ill-health, and it's likely that small tweaks to the cloning protocol would eliminate any telomere length discrepancies in future clones.