After all, Dolly, the sheep, did not develop premature arthritis, and that’s good news for cloning



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Dolly the sheep was only six and a half years old when she died, more than half the age at which most sheep live. However, despite his relative youth, he was also thought to be suffering from osteoarthritis, a disease that is usually found in much older sheep. Dolly was the first cloned animal of a fully developed adult, and some speculated that this meant that their biological age (how old their DNA was) was actually older than their chronological age (how long they were alive).

Evidence that Dolly's DNA was older than that of an uncloned sheep of similar age, and its diagnosis of early-onset osteoarthritis at the age of five and a half seemed to confirm it.

But my colleagues and I have published new research that reveals that Dolly and other clones born at that time showed no abnormal pattern of osteoarthritis after all. This is important because it means that it should be possible to reprogram adult cells to use for cloning without overcoming the aging legacy of the original organism. In short, clones can be like new organisms instead of copies of old ones.

Since the birth of Dolly in 1997, more than 20 animal species have been cloned using somatic cell nuclear transfer (SCNT), the process of converting adult cells into new embryos. Several studies have investigated the health of cloned offspring, but mostly observe the loss of embryos during pregnancy and the complications that occur around and shortly after the time of birth. Few studies were able to evaluate the long-term health implications of cloning and, therefore, we did not know whether the clones were disproportionately suffering from common age-related diseases such as diabetes, heart disease and osteoarthritis.

Professor David Gardner radiographs.
University of Nottingham

Then, in 2016, my colleagues and I evaluated a group of 13 cloned sheep aged (eight to nine years old), four of which were cloned from the mammary gland cell line that resulted in Dolly. Therefore, these animals were effectively Dolly clones. We found mild evidence, and in a moderate case, of osteoarthritis in these sheep after X-ray and MRI badysis.

None of these animals showed clinical symptoms of this disease and, otherwise, were perfectly healthy. This led us to question the nature and extent of osteoarthritis in Dolly and whether cloning by SCNT contributed to this disease in Dolly.

New evidence

Unfortunately, the X-ray records of Dolly osteoarthritis (taken about 16 years ago) were not preserved. In any case, they were limited to the registers of the left and right knees. Fortunately, the National Museum of Scotland, which has an exhibition on Dolly, keeps the skeleton of Dolly and that of two other important cloned sheep (Megan and Morag) created at the Roslin Institute of the University of Edinburgh. Dolly and Morag died prematurely after contracting a virus that causes lung tumors in sheep.

We did detailed X-ray badyzes of the skeletons and the first Dolly lamb (Bonnie) that was naturally conceived and lived for nine and a half years. . We found that the nature and extent of osteoarthritis in Dolly was not different from that of the sheep cloned in Nottingham, nor was it different from the sheep of similar age conceived naturally.

The X-ray evidence of osteoarthritis was higher for Megan, who lived at 13 and a half (equivalent in human terms to someone in their 90s). In contrast, there was no evidence of osteoarthritis in his Morag clone, which died at four and a half years.

Professor Sandra Corr reviewing x-rays.
University of Nottingham

From this evidence, we concluded the original concerns that cloning by SCNT had caused early onset osteoarthritis in Dolly was unfounded. There are many other natural factors that could explain why Dolly, and not the Nottingham-Dolly clones, showed clinical signs of arthritis. No less important is the fact that Dolly produced six lambs in her life, including a pair of twins and a group of triplets, while the sheep cloned in Nottingham were not bred.

This study, and the one we published last year on the health of cloned animals, indicates that it can produce perfectly normal and healthy animals using advanced breeding technologies such as SCNT. Although the number of animals we have produced in this way is small, they show that it is possible and that many more could follow.

Since the birth of Dolly, there have been considerable improvements in the overall efficiency of cloning by SCNT. Work in several countries continues to seek additional improvements and it is likely that the problems badociated with pregnancy losses and complications will be further reduced. Improvements of this nature could open the possibility of, for example, using SCNT to create genetically modified animals that are resistant to certain diseases such as swine flu. This would help minimize the need for antibiotics and reduce the risk of transmission to humans.

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