Clone failures may not be caused by 'reprogramming errors'

The high failure rate of animal cloning may not be caused by faulty 'reprogramming' of the cell's genetic material as previously suspected, an international team of scientists reports. Although 13 different species of mammal - including sheep, cows, cats and dogs - have so far been successfully cloned, only 1-5 per cent of the cloned embryos ever result in a live birth. The researchers, who published their findings in the online edition of the Proceedings of the National Academy of Sciences, say that much more work needs to be done to understand and improve the cloning process.

Cloning, or SCNT (somatic cell nuclear transfer) involves taking the nucleus from a donor body cell and inserting into an unfertilised egg cell emptied of its own genetic material. The resulting cell is then stimulated so that it begins to divide and develop in the same way as a fertilised egg. However, for this to happen, the genetic information from the donor cell must be successfully returned to an embryonic state. This 'reprogramming' process reactivates crucial genes required by the growing embryo, and switches off others that are not required until later in development.

To find out if ineffective reprogramming is responsible for the high failure rate of animal cloning experiments, the researchers compared the activity of 5000 different genes in cow embryos created by either cloning, IVF or artificial insemination (AI).To their surprise, they found that the pattern of gene activity in cloned embryos closely matched that of embryos produced using AI. The activity of less than one per cent of the genes studied differed substantially between the two - making them roughly as similar as two genetically unrelated AI embryos. The patterns of activity in the cloned embryos differed drastically from that of the original donor cells, however, suggesting that they had undergone 'significant' reprogramming.

Team leader Xiangzhong Yang, of the University of Connecticut, said that the findings were 'good news for therapeutic cloning and bad news for reproductive cloning', since they suggest that the abnormalities reported in cloned animals result from errors that occur during pregnancy, rather than during the initial reprogramming of the cloned cell. However, UK researcher Wolf Reik told the Scientist magazine that the results could mean that cloned embryo stem cells used therapeutically may appear perfectly normal initially, but trigger problems later on.

German researcher Heiner Niemann cautions that the findings are preliminary, since a total of 8-10,000 genes could be involved in fetal development. This means that the study may have missed crucial differences between the cloned embryos and their naturally fertilised counterparts. Yang now wants to look at the small number of genes (25) that were switched on only in the cloned embryos, and not the AI or IVF embryos. 'We want to extensively study these genes and see if they are responsible for later reprogramming problems', he told the Scientist.