Scientists Have Perfected Mouse Re-Cloning to the 25th Generation

Perfect clones down to the 24th and 25th generations, doing what mice do, above. Image from the RIKEN Center for Developmental Biology in Kobe, Japan, via The AlphaGalileo Foundation

Remember Dolly the Sheep? Having started her life in a test tube in 1996, she was the first animal cloned by scientists using a somatic cell (as distinct, say from a germline cell, or “gamete,” like sperm and eggs). Dolly was beautiful. She was Scottish. Her mere existence was profound.

It was also unusually short, at just six years. But scientists in Japan announced yesterday they have succeeded in cloning mice using the same technique that created Dolly with more or less perfect results: The mice are healthy, they live just as long as regular mice, and they’ve been flawlessly cloned and recloned from the same source to the 25th generation.

Researchers claim it’s the first example of seamless, repeat cloning using the Dolly method—known as “somatic cell nuclear transfer” (SCNT)—in which the nucleus from an adult source animal is transferred to an egg with its nucleus removed. Until recently, the process was fraught with failures and mutations. But the team led by Teruhiko Wakayama, whose results were published today in the journal Cell Stem Cell, was able to create 581 clones from the same original mouse.

Scientists, including Dolly’s creator, have long felt the process was still too unstable—and too wasteful of precious eggs, given the failure rate—to be used on humans any time soon. But perhaps it’s not so far off, after all. Cue the Clone Wars fantasies.

Cloning of this kind has been fraught with trouble since the beginning, though to be fair Dolly was an unequivocal success story, whose early demise was relatively inconclusive.

To be sure, Dolly developed arthritis at the young age of four and died of a kind of lung cancer when she was not yet six. Most sheep like her live to about 11 or 12. But the cancer that killed her was caused by a common, contagious virus that is deadly to any sheep, her creators concluded. In other words, they claimed, Dolly’s death wasn’t specifically linked to her having been cloned.

But Dolly had certain abnormalities that were indicative of the sorts of problems researchers would face using the SCNT method. With Dolly, the telomeres in her cells—which act a bit like “molecular clocks” for the length of time cells can effectively renew—were abnormally short. They were identical in length to the telomeres of the source sheep from which Dolly was cloned, which was six years-old.

In other words, there’s a good chance she was never long for this world, with or without the cancer. The early-onset arthritis hinted as much, though according to the scientists who created her, the arthritis was never explained.

Cloning experiments since then have produced varying results. In experiments with cattle, for example, some scientists found their clones’ telomeres had been restored to their original lengths. What seemed consistent, however, was that cloning successive generations from the same source—creating a clone of a clone, and so on—always led to some kind genetic degradation, worsening from one copy to the next. It’s thought that the genetic abnormalities we all possess simply worsened with each repeat.

Cloning clones was like dubbing copies of copies of cassettes. Eventually, the copies were useless. In the case of animals, they always failed after just a few replications.

Beginning in 2005, however, Wakayama and his team began adding trichostatin, a histone deacetylase inhibitor, to the medium used to facilitate the cell-cloning process. Doing so seems to have inhibited what the study’s authors describe as “accumulations of epigenetic or genetic abnormalities in the mice, even after repeated cloning.” We don’t know yet if the process holds up indefinitely, but the 25 generations the Japanese researchers have created so far is a pretty good start.

Which could be good news for cattle breeders or for conservationists who hope to revive stocks of endangered species, the researchers note—to say nothing of one day creating a clone army to take over the universe.

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