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Most of the errors in reprogramming, scientists say, can be traced to a process known as DNA methylation. During normal development, molecules called methyl groups attach themselves to DNA in precisely timed patterns that regulate which genes are expressed at which times. During cloning, however, those patterns are not always reconstructed in exactly the same way. It's a bit like taking all the words in a novel, jumbling them up and then trying to re-create the original book, putting sentences, pages and chapters back in the right order. The chances of that happening with 100% accuracy are minuscule, which helps explain why cloning is so inefficient. Rudolf Jaenisch, a geneticist at the Massachusetts Institute of Technology, estimates that 4% to 5% of the genes in a cloned animal's genome are expressed incorrectly--probably because of faulty methylation. "If you reprogram, it affects the whole genome," he says. "From what we know, I would argue that cloned animals cannot be normal. They can be closer to normal, but not normal."
The mammalian body is surprisingly forgiving and can often compensate for minor programming errors. That's why some genetic changes in clones may not have any measurable functional effects on the animals.
Dolly seems to have been one of those lucky ones. She showed just two signs of her unusual provenance. One was the arthritis she developed at an early age. The other was shortened telomeres in her cells. Telomeres are bits of DNA that sit at the ends of chromosomes and serve as a biological clock chronicling a cell's age. In general, the shorter the telomeres, the older the cell. Dolly, a clone of a 6-year-old ewe, had cells whose telomeres were closer in length to those of her biological mother than to those of a baby lamb. We will never know, though, whether her shortened telomeres would have shortened her life. In 2003 Wilmut and his team decided to put Dolly to sleep after she developed lung cancer caused by a viral infection common among sheep. An autopsy revealed that she was otherwise normal.
But the fact that clones have defects--however minor--only bolsters the arguments that scientists have made against human cloning. Based on his studies of the faults introduced by reprogramming, Jaenisch, for one, thinks human cloning is now out of the question. "I think we cannot make human reproductive cloning safe," he says. "And it's not a technological issue. It's a biological barrier. The pattern of methylation of a normal embryo cannot be re-created consistently in cloning."
But Jaenisch and Wilmut both see a role for cloning in treating human diseases--and perhaps someday conquering some of man's most intractable conditions. Wilmut and others have already created cow, sheep and pig cells genetically engineered to produce a particularly beneficial human protein, then cloned those cells to generate live animals able to make copious amounts of the target protein in their milk. It may be another 10 years or more before that approach yields anything safe and reliable enough to be used in real patients, and there is no guarantee that it will ever be successful. But as Wilmut points out, nobody thought Dolly was possible until she made history that warm July night 10 years ago.