A donor animal and its clone are not genetically identical, and in fact, the clones sometimes exhibit dangerously different patterns of gene expression. So says a team of researchers from the Whitehead Institute at the Massachusetts Institute of Technology and the University of Hawaii in today's issue of the journal Science. Their findings, which are based on a group of mice they cloned from embryonic stem cells, confirm the fear that reproductive cloning could prove unsafe.

The scientists first cloned the animals by way of nuclear transfer, removing the genetic material from embryonic stem cells and placing it inside emptied egg cells for development. Then they monitored the activity of so-called imprinted genes. Unlike other developmental genes, these genes are controlled by special tags. They hoped to discover why animals cloned from embryonic stem cells have such a poor survival rate and why some are much bigger at birth than their natural counterparts.

The team found that the tags that switch imprinted genes on or off were not faithfully reproduced from donor cell to cloneand the problem lay not in the cloning procedure but with the embryonic stem cells. As these cells divided in culture, they lost tags to such a degree that even sister cells gave rise to clones with dramatically different patterns of gene expression. Despite this instability, many embryos survived to adulthood. "This suggests that even apparently normal clones may have subtle aberrations of gene expression that are not easily detected in the cloned animal," M.I.T.'s Rudolf Jaenisch remarks.

Confirming that nuclear transfer was not to blame, the researchers showed that clones derived by a different techniquenamely directly from embryonic stem cellsexhibited the same irregular gene expression. "It is important to remember that embryonic stem cells when combined with normal cells as in making chimeras or when used in transplantation may function fine," Jaenisch concludes. "In other words, ES cells might work fine when used as cell therapy, but when they are used to make whole animals would likely produce organisms that are abnormal."