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Dolly's Arthritis Raises New Fears About Cloning

Biotech: Sheep born in '96 may be prematurely aging. But scientists don't know whether a genetic defect is to blame.

January 05, 2002|MARJORIE MILLER | TIMES STAFF WRITER

LONDON — A case of arthritis in Dolly the sheep has renewed concerns that the world's first cloned mammal may be aging prematurely.

Ian Wilmut, the professor who cloned Dolly in 1996, revealed Friday that the sheep began to limp several weeks ago and was found to have arthritis--an illness common in older sheep.

He said scientists don't know whether Dolly's arthritis, in her left hip, is a fluke or a genetic defect resulting from cloning, and he suggested that further research is needed.

"The only way we can discover this is by collectively producing a very large number of clones and looking to see if the incidence of arthritis and other conditions is encased in clones, as distinct from animals produced by normal methods," Wilmut told reporters at the Roslin Institute near Edinburgh, Scotland.

"We know from our previous research that only a small proportion of embryos that reproduce develop to become live offspring. It appears from Dolly's condition that one of the other outcomes from this [cloning] will prove that some of the animals will be more vulnerable to some diseases," he said.

Scientists who produce cloned animals must monitor their health throughout their life, he added.

Dolly has been a symbol of success for geneticists, and evidence that her condition is the result of a genetic problem would be seen as a serious setback.

Ever since she was cloned from a 6-year-old ewe and shown to the world as a 7-month-old on Feb. 23, 1997, scientists have debated Dolly's true age. Is she 5 years old, based on her date of birth, or is she in effect 11, based on the age of genetic material from which she was created?

In most regards, Dolly is a normal, healthy sheep. She has given birth to six healthy lambs and some that did not survive--about the same rate of live offspring as for a naturally born ewe, Wilmut said. None of her lambs shows any signs of abnormality.

Wilmut's team already suspected that Dolly was aging prematurely. In 1999, the team saw the first possible symptoms under the microscope. A part of Dolly's chromosomes was found to have shortened more than was normal for her years.

The chromosome structure involved is called a telomere--a long fragment of DNA that sits on the end of each chromosome in a cell like the tip of a shoelace. Each time a cell replicates, a fragment of the telomere is broken off and lost. When the whole telomere is gone, the chromosome breaks down, leaving the cell vulnerable to disease and death.

Scientists don't know whether the shortening of telomeres is a cause of aging or simply a marker for it. But the evidence from Dolly indicates that while a newborn animal gets full-length telomeres, a clone receives shortened telomeres more like those of its genetic parent. In Dolly's case, her telomeres are about 20% shorter than those of uncloned sheep of the same age.

On the other hand, work reported in 2000 by other researchers using mice did not show any shortening of telomeres in clones, leading to doubts about how widespread the effect may be.

Wilmut said in a telephone interview that he did not know whether there was any connection between the shortened cell structures and the development of arthritis.

"We don't even know if the arthritis has anything to do with cloning at all. It could be chance," Wilmut said. He added that Dolly has had an unusual life, housed in a pen and living in the scientific limelight.

"At one point she was overweight and spoiled. This may sound silly, but also she has spent a lot of time standing on her back legs to get food from the journalists and photographers. Sheep don't normally stand on their back legs," he said.

Nevertheless, Wilmut called the development of arthritis "disappointing" and said it is proof of the need for more research into cloning techniques.

Dolly was cloned by destroying the nucleus of a sheep egg and replacing it with a nucleus from a cell from the 6-year-old ewe. Wilmut has shifted his research from sheep to mice to better understand the cloning process. Mice take just 21 days to reproduce, whereas the gestation period for a sheep is 150 days.

"With mice, it's easier to work with 100 embryos in a day," he said.

Animal rights groups and other opponents of cloning say Dolly's arthritis is further proof that technology has outstripped knowledge of the consequences of cloning and is leading scientists into dangerous territory. They also oppose genetic engineering, or changing an animal's genes, because they believe that altering one aspect of an animal's system will affect other functions.

Two rival research teams announced this week that they have cloned pigs that were genetically modified so that their transplanted organs won't be rejected by humans. One of those companies, PPL Therapeutics, is the Scottish group that worked with the Roslin Institute to produce Dolly.

Scientists are aiming to cultivate pig hearts, kidneys and other organs for transplant into human beings to make up for a shortage of human organs.

Wilmut said the birth of the piglets is "very significant." The cloned piglets are female, and males are due to be born within months. The pigs then will be mated and, within a year, blood and tissue tests can be conducted "to confirm what we predicted 15 years ago," Wilmut said.

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Times staff writer Thomas H. Maugh II in Los Angeles contributed to this report.

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