Failure of cloning from embryonic stem cells may spell the end of embryonic stem cell research and 'therapeutic' human cloning, Dr. Mae-Wan Ho reports.
"Cloning by nuclear transfer (NT) is an inefficient process in which most clones die before birth and survivors often display growth abnormalities" [1] This is now admitted by an international team of animal cloners who have examined mice cloned using donor nuclei from embryonic stem cells.
They found the epigenetic state - the state of gene imprinting and expression - of the ES cells "extremely unstable". Similar variations were found in the mice cloned from them. Many of the cloned animals survived to adulthood "despite widespread gene dysregulation" compared with controls. The researchers warn, "Our results indicate that even apparently healthy cloned animals can have gene expression abnormalities that are not severe enough to impede development to birth but that may cause subtle physiological abnormalities which could be difficult to detect."(p.97)
The research findings have implications not just for cloning but for ES cell research. The extreme instability of ES cells is not surprising, as such 'somaclonal' variations in cell culture is well known for both plant and animal cells, and we have drawn attention to this for ES cells [2]. Cell biologist Harry Rubin spent 20 years documenting the endless variation of mammallian cells arising in successive passages in culture, despite their supposed genetic uniformity [3].
The present authors state,
"Because ES cells are a potential in vitro source of many cell types for transplantation medicine, it will be important to assess whether the epigenetic state of human ES cells is as unstable as that of murine ES cells" ( ref. 1, p.97)
If human ES cells are just as unstable, it would be foolhardy to expect them not to cause problems in the transplant recipient.
It transpires that in the original draft of their paper, the authors had called for research to see if genetic instability in stem cells might "limit their use in clinical applications". But Jaenisch was allowed by the editor of Science to eliminate the sentence days before publication [4].
Now, the researchers are claiming that the variability may even be put to good use. For, if seemingly identical cell lines are subtly different from each other, then some may have particular promise for making "new brain cells for Parkinson's patients", and others may become cardiac tissue for heart attack patients. And "You may have to establish hundreds of lines to get the few you'd want to have," said John Gearhart, a pioneer stem cell researcher at Johns Hopkins University. Gearhart said he agreed with Jaenisch that the newly discovered genetic instability in embryonic stem cells probably will not interfere with the project of turning the cells into therapies.
This claim is fallacious, because somaclonal variation is uncontrollable and unpredictable. In other words, if human ES cells turn out to be just as unstable, there is no way to get useful stable lines out of them at all.
Another observation is that there is no significant correlation between abnormal fetal development and the abnormal expression of any single imprinted gene. "It is possible that the disturbance of placental and fetal growth is due to the cumulative action of many abnormally expressed genes which may have opposing influences on fetal growth.." (ref. 1, p.97)
They should have checked the ES cells for chromosomal abnormalities, which are also frequently found in cultured cells. In fact, largescale genomic instability may be present in addition to epigenetic instability. That should well and truly consign embryonic stem cells to the dustbin.
Article first published October 2001