The catastrophic failure of a single gene’s regulation seems to explain the early death of most cloned embryos, suggests a new study in mice.
Hans Schöler of the University of Pennsylvania and his colleagues found that the gene that encodes the protein Oct4 was mis-regulated in about 90 per cent of clones from somatic or adult cells.
Oct4 is a transcription factor protein responsible for switching on other genes. Because the gene for Oct4 known is crucial for embryonic development, its failure alone could account for the majority of clone deaths.
The work should be an additional warning to self-proclaimed human cloners such as the controversial Italian fertility doctor Severino Antinori, says Schöler. “Antinori has said he’ll be able to pick only good embryos for human cloning. Our embryos can look very nice. But they are ticking time bombs.”
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“This is top notch, brilliant work,” says Robert Lanza at the Massachusetts-based company Advanced Cell Technology.
Sensitive barometer
In cloning, a donor cell is fused with or injected into an egg stripped of its own genetic material. Unknown factors in the egg are then able to “reprogram” the cell to begin life again as an embryo.
But only a few per cent of cloned embryos survive to birth and some of the survivors are unhealthy or develop illnesses later in life.
Experts suspect that part of the trouble is that the reprogramming is sometimes incomplete. But they have not been able to pinpoint the problem at a genetic level. Schöler decided to look at the activity of the Oct4 gene as a model for reprogramming, because it is such a sensitive barometer of early embryonic development.
The gene is shut off in virtually all adult cells. It is switched on in the inner cell mass (ICM), the part of the embryo that becomes the fetus and from which embryonic stem cells or ESCs are harvested.
Work by other groups has shown that Oct4 mis-regulation can derail normal embryonic development. The researchers expected to see the gene go awry occasionally. But they found that two-thirds of the embryos did not switch the Oct4 gene on at all or did not limit expression to the ICM. About another quarter of the embryos produced excessive or inadequate amounts of Oct4.
“Like cockroaches”
Schöler concludes that poor reprogramming of Oct4 is enough to sink 90 per cent of mouse clones, close to the actual failure rate of about 98 per cent.
Lanza thinks the work raises the exciting prospect that fine-tuning the cloning procedure to improve Oct4 reprogramming could give a dramatic boost to cloning efficiency. “This will be a very valuable research tool to optimize cloning,” he says.
But Schöler is less optimistic. He sees proper Oct4 expression as only one of the first barriers most cloned embryos must cross.
Davor Solter of the Max-Planck Institute of Immunobiology in Freiburg, Germany agrees. “Misreprogrammed genes are like cockroaches,” he writes in a commentary on Scholer’s article. “Where you see one there are likely to be many more under the surface.”
Journal reference: Genes and Development (vol 16)
