May 27, 1999

Sheep Clone's Cells Aging Faster Than She Is

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By GINA KOLATA

he scientists in Scotland who created Dolly, the sheep that was the first animal that was a clone of an adult, report on Thursday that the genetic material in her cells may show a sign of aging, appearing, in effect, older than Dolly herself.

If the findings are confirmed, they would be the first sign of possible genetic abnormalities in cloned animals. So far, cloned animals seem healthy and they are fertile, but a genetic disturbance could cast a cloud over the future of cloning animals, and certainly humans.

Leading investigators said in interviews, however, that they were not yet convinced by the preliminary data, which are being published on Thursday in the journal Nature.

The data are from Dr. Paul Shiels of PPL Therapeutics in Roslin, Scotland, and his colleagues, including Dr. Ian Wilmut of the Roslin Institute, who created Dolly.

In their letter to Nature, the scientists report that Dolly's cells had slightly stunted telomeres, the tickertape-like appendages to chromosomes. Telomeres have been described as a virtual aging clock for cells grown in the laboratory, shortening with each cell division and marking off the number of divisions remaining before a cell dies. Moreover, the telomeres in older animals tend to be shorter than they are in younger animals.

Many scientists have longed to know whether Dolly's telomeres are of normal length. To make Dolly, Wilmut and his colleagues slipped an udder cell from a six-year-old sheep into a sheep's egg whose own genetic material had been removed. Using the udder cell's genes as a blueprint, the egg divided and grew, eventually becoming Dolly, who is a clone, an identical twin of the sheep whose udder cell was used to create her.

The udder cell that was used to create Dolly had shortened telomeres, the Roslin scientists report in their paper, which is what they expected because the animal was 6 years old, ancient for a sheep. And, most important for telomere length, the udder cell had been grown in the laboratory before it was used for cloning, a process that is known to markedly erode telomeres.

The question was, would Dolly's telomeres be short, commensurate with her origins in an aged, laboratory-cultured cell?

Some experts on the subject said they were betting that Dolly's telomeres would be normal. A cellular enzyme normally lengthens telomeres in embryo and fetal life, and should have lengthened Dolly's telomeres as well, they said.

But Dr. Alan Colman, the research director of PPL Therapeutics, said scientists had repeatedly asked his group to check on Dolly's telomeres. "Right from the start, when Dolly's birth was announced, people said, 'Have you looked at the telomeres yet?"' Colman reported.

Shiels and his colleagues compared Dolly's telomeres to those taken from cells of 18 other sheep and to those from a sheep cloned from an embryo cell and one cloned from the cell of a fetus.

Dolly's telomeres were about 20 percent shorter than those of the sheep that were not clones, the scientists said.

The sheep cloned from an embryo cell also had slightly shorter telomeres, but the stunting was less than with Dolly, the researchers said. The sheep cloned from a fetal cell did not have shortened telomeres, they reported.

But other scientists said they remained to be convinced that the paper published on Thursday demonstrates that Dolly's telomeres or those of the sheep cloned from embryo cells are shorter than normal.

"It is very difficult to distinguish between 22-kilobase-long telomeres and 19-kilobase-long telomeres, and that's really what we're talking about here," said Dr. Robert Weinberg, a cancer researcher at the Whitehead Institute of the Massachusetts Institute of Technology. "The resolution of the gels is not very good in that range."

"It's premature to draw rock-solid conclusions from this scant amount of data," Weinberg said.

Dr. Judith Campisi, who studies cellular aging at the Lawrence Berkeley Laboratory, said, "I'm not convinced the results are meaningful."

Dr. Huber Warner, deputy director of the biology of aging program at the National Institute on Aging in Bethesda, Md., called the results "a little messy." A 20 percent difference in telomere length could just be within the ordinary variation for sheep, he said.

Colman said the critics had a point. "At the end of the day, that's a criticism that has probably got some justification to it," he said.

Dr. Harry Griffin, assistant director of the Roslin Institute, noted that the report was a letter, not a full scientific paper. "You have to appreciate that the measurement of telomere length is not an exact science," Griffin said.