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dolly, the cloned sheep, has celebrated her fifth birthday. Most other cloned animals aren't so lucky. They rarely reach adulthood. Some die in the process of cloning itself. The unpredictability of cloning seems to arise from some uncertain genes. Researchers based in the us are now beginning to understand the reason behind the low success rate of cloning. The activation of human genes depends on which parent they come from. Which of these so-called 'imprinted' genes are switched on and off varies greatly between cloned and normal embryos ( www.nature.com , July 19, 2001).
Rudolf Jaenisch, researcher at the Massachusetts Institute of Technology, Cambridge, and his colleagues cloned mice from the nuclei of embryonic stem cells, which have a better record of success than adult cells. The researchers studied six imprinted genes. They found that the genes were not working normally in any of the mice. There are between 100 and 200 imprinted genes in the genome. Which implies, says Jaenisch, that one can't expect to have normal clones -- even if they appear healthy they may have abnormal gene expression. These abnormal gene-expression patterns were seen to be persisting into the mice's adulthood. This might not matter in a mouse or a domestic animal such as Dolly, but it is another reason why cloning humans might not be a good idea, the researchers opine.
The results also show how tolerant development is to errors in gene regulation. A pattern to the misfiring of the genes has not emerged. Genetic instability in stem cells seems to be a random process; developmental abnormalities are the cumulative effect of many malfunctions. But the use of stem cells leaves it unclear whether the explanation also stands for cloning in general, says Alan Colman, research director at ppl Therapeutics in Roslin, Scotland. Larger animals such as sheep and pigs have to be cloned from adult cells, not embryonic stem cells. These should have a full and correct set of imprinted genes, Colman says. He adds that they are less prone to losing their imprinting in culture. Jaenisch is also pessimistic about stem cells being repaired before cloning. Embryonic stem cells used for therapeutic transplantation into mice don't have this problem; being surrounded by normal cells seems to put the cells back on track. Difficulties arise when a single cell is used to make a whole organism. Colman points out that it would be useful to know whether stem cells taken from adults have similar difficulty in reprogramming.