Published online 14 November 2007 | Nature | doi:10.1038/news.2007.245

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Cloned monkey stem cells produced

Stem cells extracted from cloned primate embryos.

The skin cell inserted into a primate egg (shown) came from a monkey called Semos - also the name of the god in the popular sci-fi work Planet of the Apes.Shoukhrat M. Mitalipov

Researchers have for the first time created cloned primate embryos and used them to make embryonic stem-cell lines. The achievement has led to speculation about when similar success in humans might open up the door for therapeutic cloning.

Embryonic stem cells can differentiate into almost any cell in the body and so have tremendous potential for therapy. If they are taken from an embryo cloned from a patient, as they were here from monkeys, they would be genetically matched and thus avoid immune rejection.

The research community had once thought that cloned embryonic stem cells had been created from humans: in February 2004, Woo Suk Hwang, then at Seoul National University in South Korea, claimed to have created stem-cell lines from cloned human embryos. But Hwang’s results were later found to have been faked. The only other animal in which cloned embryonic stem cells have been created is mice.

The accomplishment in primates is "like breaking the sound barrier", says Robert Lanza, with Advanced Cell Technology in Los Angeles, California.

Although the rapid succession of clones after Dolly the Sheep was announced in 1997 gave confidence to the field of cloning, continued failure to clone human or monkey embryos led to some pessimism. Primate-cloning researcher Gerald Schatten stated in 2003, after his study of 716 monkey eggs that failed to produce a clone1, that it might be impossible to do so. "With current approaches, NT [nuclear transfer, a cloning technique] to produce embryonic stem cells in non-human primates may prove difficult — and reproductive cloning unachievable."

In 2004, Schatten said that he had made some ground with primate embryos, but he did not produce a stem-cell line or any successful pregnancies (see Biologists come close to cloning primates).

From failure to success

A team led by Shoukhrat Mitalipov at Oregon Health and Science University in Portland, had been trying for nearly a decade to achieve reproductive cloning in primates, and had used some 15,000 eggs in the process. After Hwang's results turned out to be fraudulent, the group decided to move from reproductive cloning to try to establish a cloned embryonic stem-cell line instead — theoretically, a more achievable goal.

Last autumn, the researchers had a false start when a cloned embryo, created by inserting a monkey skin cell into a monkey egg that had had its DNA removed, produced what seemed to be viable embryonic stem cells. After a week, they watched in dismay as the cells started to differentiate uncontrollably, losing their nature as embryonic stem cells.

Semos: the donor of the cells used to create cloned embryos.Oregon Health & Science University

But by January 2007, they had another line that retained its embryonic stem-cell properties, and a couple of months later, they had created yet another. These results are outlined in Nature2. David Cram, a researcher from Monash University in Victoria, Australia, and his colleagues have independently confirmed the results3.

Mitalipov credits their use of a machine called Oosight, which allows them to see the structures in the egg that carry DNA, thereby easing its extraction – the first step in nuclear transfer.

Conventionally, researchers have used a dye called Hoechst and ultraviolet light to locate and remove an egg's DNA. But Mitalipov's group found that both the light and the dye damaged the egg.

Hundreds of eggs

Schatten calls the work "a highly significant achievement". But he warns that "the rate of success still is very low". Mitalipov’s team produced just 2 embryonic stem-cell lines from 304 eggs. The researchers still have little idea of what separates the successes from the failures.

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Repeating the results in humans might be theoretically possible, but it would probably require a similar number of eggs. Lanza says that this is unlikely to be feasible with the current regulations in places such as California and Massachusetts, which do not allow any compensation to the prospective donors.

Lanza says that he had run "a hundred ads in newspapers and magazines over the past year and only got one donor" for his own research. He hopes that the success in primates might convince regulators that they should change their rules. "Yes, we have it working in primates. Now let us go into humans," says Lanza.

Clones a long way off

Mitalipov says that it is still too early to hope for success in reproductive cloning in monkeys, let alone humans; the community is generally against reproductive cloning in people.

So far, the recipe Mitalipov used for his embryonic stem-cell lines has not worked for reproductive cloning. This April, the team tried to transfer 77 embryos into about a dozen surrogates. The embryos ranged in their stage of development: some were 2 days old, some were 5-day-old blastocysts. "But no pregnancy made it even to day 25," says Mitalipov.

Mitalipov says that primates seem to be harder to clone reproductively than other species because the cycle of the cloned embryo has to be perfectly synchronized with the cycle of the mother that will act as surrogate. "We have 30 to 40 animals. That's a relatively large colony, but we have to screen for weeks and the chance that they'll be in the right stages is low." 

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