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To clone or not to clone, that IS the question!

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You can always be sure of a heated debate about almost anything to do with stem cells but few topics seem to inflame opinions more than the possibility of human cloning.  Until a few days ago we might have been forgiven for thinking that such things had been consigned to the recycle bin of history but an article appearing in Nature [1] on April 28, 2014, may be set to reignite the debate. 

Before 2006, the prospects for making patient, disease or individual specific stem cells cheaply and easily seemed remote and that the only way that this could be achieved at all would be to reprogram somatic cells such as fibroblasts by transferring their nuclei into human oocytes.  This method would in effect “hijack” the mechanism the oocyte normally uses to prepare the two gamete genomes for the task of constructing a new organism.  The plan was to harvest embryonic stem cells from the resulting embryos that would be genetically similar to those of the person who donated the fibroblasts. This turned out to be a lot harder than imagined and it was not until Shoukrat Mitalipov published his study in May 2013 [2] that the feasibility of SCNT-derived ESC was confirmed. However, by 2013, the stem cell world had become largely committed to the idea that induced pluripotent stem cells (iPSC) were the best way forward, if not for regenerative medicine then at least for disease modelling and possibly drug discovery.   The urge to embrace iPSC was very powerful.  SCNT was expensive and technically demanding and no one was really comfortable with the necessity of destroying the cloned embryo to harvest ESC; iPSC on the other hand, are relatively easy to make and are relatively free of ethical concerns, so, game, set and match to iPSC perhaps?

Well, maybe not.  Not all the data coming from the iPSC camp is encouraging.  Both SCNT and iPSC generation require epigenetic reprogramming of a genome that was never really designed to be reprogrammable.  The protocols developed from Yamanaka’s original method can achieve this to a large degree but there are data suggesting that the reprogramming may be incomplete and, even worse, many iPSC lines harbour chromosomal abnormalities and show significant genomic instability.  Furthermore, iPSC have to make do with the mitochondria that came with the somatic cell from which they were derived (along with all the mutations they have acquired).   SCNT-derived ESC get a completely new set from the oocyte.

Now, we must understand that SCNT is not perfect either.  There are suggestions that problems with the meiotic spindle can lead to genome instability in some cloned embryos and that epigenetic reprogramming may not have been complete in earlier attempts at cloning whole organisms but the papers from Mitalipov and the latest offering from Dieter Egli’s team at the New York Stem Cell Foundation suggest that some of these problems may have been solved, at least in part.  If these ESC, made from type I diabetic patients can be used to model the disease, they could be a valuable resource for drug discovery without the problems of inter-clone and/or inter-patient variability that seems to plague some ongoing studies using iPSC.  

It is not yet clear if SCNT derived ESC offer any real advantage over iPSC.  SCNT is still expensive and difficult and not very pleasant for the women who donate the oocytes but if significant differences are shown, we can be sure that the re-emerging debate will intensify.  For those interested, we are including the link to Egli’s paper in this month’s journal club and comments/ questions are invited.

References

M. Yamada et al.,
"Human oocytes reprogram adult somatic nuclei of a type 1 diabetic to diploid pluripotent stem cells,"
Nature, doi:10.1038/nature13287, 2014

S. Mitalipov et al.,
"Human embryonic stem cells derived by somatic cell nuclear transfer,"
Cell, doi:10.106/j.cell.2013.05.006, 2013