The discovery of arthritis in the left hind leg of Dolly the cloned sheep has dented public confidence in the viability of therapeutic animal cloning, the technology that aims to make up the shortfall in human organ donations by harvesting organs from genetically modified animals.

It has been suspected since 1999 that Dolly, the world's first successfully cloned mammal, might age prematurely. In that year investigators found that her telomeres DNA fragments that reside on the ends of chromosomes are about 20% shorter than the average for a sheep of her age. Telomeres shorten with each cell division and are considered a marker of the ageing process.

While arthritis is not uncommon in sheep, the typical age at onset is about 10; Dolly is 5 1/2 years old.

Dolly was cloned by a different method from that commonly used today. They starved the cell to make it quiescent. We don't know what effects that might have. Most animals cloned today come from cells that are still dividing.

A certain type of genetic defect that has been seen in cloned animals may be due to the cells used in the studies, and not the cloning procedure itself.

To clone an animal, scientists remove the nucleus from an egg and replace it with the nucleus of a cell from the "donor" that is to be cloned.

In many experiments in cloning mice, researchers have gotten the donor nuclei from embryonic stem cells. In other attempts at animal cloning, such as the creation of Dolly the sheep, adult or fetal cells have been used.

Animal cloning is a complicated process, and it only occasionally results in a birth. There have also been concerns about genetic anomalies occurring in surviving clones. Just last week, Dolly was reported to have arthritis, raising concerns that the cloning process exacted a genetic defect.

Among the problems that can occur are anomalies in imprinted genes, which play a key role in growth and development. Imprinted genes differ from other genes in that their expression in the body depends on whether they came from the father or mother.

Some research has shown that mice cloned from embryonic stem cells can have abnormalities in their expression of imprinted genes.

In the new study scientists cloned mice using nuclei from adult somatic cells -- cells other than egg or sperm. The investigators found that the embryos, fetuses and full-term animals they created were no more likely than normal mice to have faulty imprinted genes.

The findings suggest that the cloning procedure itself is not to blame for past imprinted-gene abnormalities in mice.

Instead, the problem may have arisen from mutations that accumulated in the donor embryonic stem cells during the process of culturing them.

Cloning procedures have garnered much interest because scientists hope to use them in treating disease. Unlike reproductive cloning, such therapeutic cloning would involve creating new cells and tissue to replace those damaged by disease. Scientists do not foresee using embryonic stem cells as donors in therapeutic cloning.

Still, it is also possible that other potential donor cells, when cultured for long periods, could develop genetic abnormalities.

This might be avoided, the researcher said, by being particularly careful about the cells' culturing conditions. In this study, the researchers used "freshly prepared" donor cells.

Science January 11, 2002;295:297

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