Human Clones: One Step Closer

The science of cloning and stem cells has been somewhat of an unholy mess, what with fraudulent claims (by a South Korean biologist) of generating custom-made stem cells lines and, sigh, of producing a baby through cloning. (The little cloned boy should be 5 now; we wish him well in kindergarten.) The latest advance therefore shouldn’t inspire headlines about cloned babies being right around the corner, but here goes: scientists have transferred DNA from an adult human cell into a human egg, and made the egg to “reprogram” the donor DNA back to its embryonic state, producing a pattern of gene activation like that in normal IVF embryos--and therefore, it seems, the pattern necessary to create an embryo.

What this means, in a nutshell, is that if the study holds up, it will look increasingly likely that there are no known technical obstacles to reproductive cloning, the creation of human clones not for stem cells (in which case the clone never gets further than a days-old ball of cells) but for babies.

When they began their experiments, scientists led by Robert Lanza, chief scientific officer of the biotech company Advanced Cell Technology, had no such goal in mind. They just wanted to see whether putting adult human DNA into (non-human) animal eggs would send the DNA back in time, so to speak, to its embryonic stage. Such “reprogramming” could, in theory, produce a days-old ball of cells from which scientists could extract stem cells that, with some coaxing, could be used to treat patients with diabetes, spinal cord injury, Parkinson’s disease and other ailments. If the DNA came from the patient himself, the stem cells would be perfect and personalized genetic matches, eliminating the risk that they would be rejected by the recipient's immune system.

The reason human DNA would be put into animal eggs rather than human eggs is that the latter are hard to get. Harvard’s Kevin Eggan, for one, has described “stomping around to different disease advocacy groups, tea circles, knitting circles, trying to find anyone and everyone who would donate their oocytes,” to little avail. The new study throws cold water on the hope of using animal ova.

The scientists used standard methods to transfer DNA from adult human cells into ova (human, cow and rabbit) whose own DNA had been sucked out. All three kinds of ova yielded about the same success rate in getting the ovum to divide like a fertilized egg  (39%, 36% and 36%, respectively, formed balls of 12 to 32 cells). But when the scientists tested these embryos to see which genes were active, they found a stark difference. The pattern “was dramatically different” in embryos created from human ova and from cow or rabbit ova, they report online ahead of print in the journal Cloning and Stem Cells. The human-human clones had gene activity patterns that matched those of normal embryos created at IVF clinics—that is, they seemed to follow the recipe for baby making in that the adult donor DNA had been reprogrammed back to an embryonic state. The human-animal hybrids had a different pattern, Lanza told me: “The donor DNA just wasn’t being reprogrammed.”

Several key genes were activated in the human-human clones but not the human-animal ones. Called Oct-4, Sox-2 and nanog, they seem to be the keys to directing the entire genome to revert to the embryonic state necessary to create both stem cells and babies. Called pluripotency genes, they had been “effectively silenced” in the human-animal hybrids, said Lanza, making it impossible for the hybrid to produce stem cells. “These data call into question the potential use of [animal ova] to generate patient-specific stem cells,” the scientists conclude.

Now about those human embryos. There have been several previous claims (such as one in 2001, by a team that included Lanza, and one last year by a company in California called Stemagen). But although some of the balls of cells looked normal (others did not), there was no molecular evidence that the donor DNA had been reprogrammed back to an embryonic state. In the new study, gene chips that test for DNA expression confirmed that the donor DNA had been reprogrammed to a state “very similar to normal IVF embryos,” said Lanza. “This is the first real evidence that the donor DNA is reprogrammed, and the first time anyone has furnished hard evidence that human cloning is indeed possible, at least in terms of proving that the donor human cell was actually reprogrammed.”

Ian Wilmut, who led the team that cloned Dolly the sheep in 1997, the first mammalian clone, is now director of the MRC Centre for Regenerative Medicine at the University of Edinburgh. He told me in an email that the study underlines “an important difference in gene expression from transferred human nuclei depending upon whether they were transferred into a human oocyte or a non-human oocyte.” Although it does not “absolutely rule out the use of animal oocytes, . . . the balance of probability is that transfer into human oocytes is more likely to work” for generating therapeutic stem cells.

And if Lanza and his team are right, the idea that nature erects insurmountable barriers to human cloning will seem like a misplaced hope.
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