Clone Study Casts Doubt on Stem Cells
Variations in Mice Raise Human Research Issues

URL: http://www.washingtonpost.com/wp-dyn/nation/specials/science/cloning/A24840-2001Jul5.html

Date accessed: 02 August 2001

By Rick Weiss
Washington Post Staff Writer
Friday, July 6, 2001; Page A01

Mice cloned from embryonic stem cells may look identical, but many of them actually differ from one another by harboring unique genetic abnormalities, scientists have learned.

The presence of these subtle and previously undetected genetic glitches could help explain why so many clones do not survive to birth. It also adds credence to scientists' fears that even apparently healthy clones are not as normal as they seem – a consideration relevant to the debate over the safety and morality of human cloning.

The work also shows for the first time that embryonic stem cells – which are at the center of an escalating political and ethical debate as President Bush decides whether federal funds should be spent to study them – are surprisingly genetically unstable, at least in mice.

If the same is true for human embryonic stem cells, researchers said, then scientists may face unexpected challenges as they try to turn the controversial cells into treatments for various degenerative conditions.

In an unusual move reflecting the politically sensitive nature of the research, the scientists who conducted the study deleted at the last minute part of a sentence in their published report that had alluded to this potential ramification, and added a sentence emphasizing the cells' therapeutic promise. It is true that genetic instability in human embryonic stem cells may complicate efforts to turn the cells into cures, the lead researcher said yesterday. But he said he was afraid that any mention of that potential problem in the article might be exaggerated by political factions that oppose the research on religious and ethical grounds.

"A non-scientist could really misinterpret the words," said Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Mass., who led the research with Ryuzo Yanagimachi of the University of Hawaii. "It does need to be checked to see if human [embryonic stem] cells are also so unstable. But even if they are, we don't think it will be a problem."

The new work, published in today's issue of the journal Science, focused on cloned mice, each created from a single cell. But rather than making the clones from a single adult skin cell, as is common in the field, scientists made these from single embryonic stem cells, a special kind of cell of interest to cloners because they produce live clones at 10 times the efficiency of other kinds of cells.

Surprisingly, tests indicated that although every cloned mouse had exactly the same genes as every other – a hallmark of cloning – they varied considerably from one to the next in terms of which of their genes were active and which were dormant, a result of aberrant gene regulation.

The apparently random variation in the way genes were regulated in the clones suggests that the cloning process itself can sometimes scramble the molecular "switches" inside cells that tell various genes when to turn on and when to turn off. Considering what a delicately orchestrated process fetal development is, such regulatory mayhem in a developing clone could help explain why the vast majority of cloned animals die long before they are born, and why live-born clones often suffer from serious malformations.

Moreover, none of the abnormally regulated genes was predictive by itself of whether a clone was healthy. That means it won't be easy to come up with a genetic test to determine which developing clones will be healthy – a strike against some advocates of human cloning who have claimed they could avoid creating genetically aberrant human clones by testing developing fetuses and aborting those whose genes seem abnormal.

To see if the genetic variation found in the mouse clones was entirely a result of the cloning process or was in part "inherited" from the originating stem cells, the team did molecular tests on individual mouse embryonic stem cells. They found that even stem cells that should have been identical displayed very different patterns of gene activation, an indication that gene switches are inherently unstable in this class of cells.

Such varying patterns could have big effects on how cells behave, scientists said. Imagine that a score for a piece of music is photocopied many times, but the notation saying which instruments should actually play their parts is different from one copy to the next – the equivalent to some genes being on and others off. The sequence of notes would be identical in each copy – the scores would be clones – but each would sound very different when played.

If human embryonic stem cells prove to be as variable in this way as their mouse counterparts apparently are, then a political compromise floated by the Bush administration in the stem cell debate may not be as practical as some had hoped. That possible compromise would limit the number of embryonic stem cell lines, or colonies, that scientists could work on, thus limiting the number of embryos destroyed. But if seemingly identical cell lines are subtly different from each other, then some may have particular promise for certain uses – such as to make new brain cells for Parkinson's patients – and others may excel at other tasks, such as becoming cardiac tissue for heart attack patients.

"You may have to establish hundreds of lines to get the few you'd want to have," said John Gearhart, a stem cell researcher at Johns Hopkins University.

Gearhart said he agreed with Jaenisch that the newly discovered genetic instability in embryonic stem cells will probably not interfere with scientists' goal of turning the cells into therapies. Proper "on-off" patterns of gene activity in stem cells are crucial for the coordinated development of an entire fetus, he said, but are less crucial if all that is wanted is to make the cells grow into pure tissues, such as cardiac muscle.

In the original draft of their paper, the authors called for research to see if genetic instability in stem cells might "limit their use in clinical applications." A spokesman for Science said editors there allowed Jaenisch to eliminate that language just days before publication because the change did not involve scientific data, only the authors' interpretation of their data.

Jaenisch said no one knows yet if so-called adult stem cells, which are retrieved from adults instead of from embryos, are more genetically stable than embryonic stem cells. Some opponents of embryo research have advocated focusing solely on adult stem cells.

Categories: 31. Stem Cells, 33. Cloning