Alternatives to Human Pluripotent Stem Cell Derivation

Recently, three alternatives have been proposed to supposedly circumvent embryo destruction, and to derive human embryonic stem cell lines. Drs. Landry and Zucker (Columbia University), hypothesizing that thawed embryos failing to divide past 24 hours in culture can be considered ‘organismically dead’, propose that harvesting hESC from such embryos is akin to harvesting organs from a brain-dead organ donor. Dr Hurlbut (Stanford University) proposes ‘Altered Nuclear Transfer’, where an embryo is created through nuclear transfer, after having inactivated a gene (for example cdx2) that is crucial for trophectoderm formation. Such an embryo would eventually die and would be ‘a biological entity that, by design and from its very beginning, lacks the attributes and capacities of a human embryo’, and could thus be used to derive hESC. The third alternative is suggested by work of Rogers et al., United Kingdom, who described a method to induce parthenogenetic division in unfertilized human eggs. The thus created embryos underwent cleavage division and some formed blastocysts, but no derivation of hESC lines was described.

While it is commendable to seek ways to pursue human embryonic stem cell research without the destruction of embryos, several points have to be made.

First, the only method to derive human pluripotent stem cell lines that has been successfully developed to date, and this after long years of fruitless attempts, is the current method of extracting pluripotent cells from the ICM of blastocyst stage embryos.

Second, many opinion polls have now shown that in the United States a majority of the public supports derivation of human embryonic stem cells and its funding, provided surplus embryos from IVF treatments are used that are otherwise destroyed if not used for fertility treatment or donated to research. Moreover, many countries have now enacted favorable legislation, among them Spain and France, two catholic countries, reversing their prior stifling laws. Globally, the United States once a scientific leader, becomes more and more isolated with its position on human embryonic stem cell research.

Third, while all three proposals have merit and certainly could pique scientific curiosity, all three would require massive research efforts to potentially yield cell lines equivalent to those derived from blastocyst ICMs. There is however a distinct possibility that after many years of efforts in manpower and funding, those attempts may fail, as it is not certain that a) ‘dead’ embryos can yield viable pluripotent stem cells, b) that the transient knock-down of cdx2 (or other genes) will not have unwanted downstream effects on viability and pluripotentiality of the derived cells, and c) that parthenogenetically derived cells will be pluripotent due to problems with epigenetic regulation and genomic imprinting.

And last, before withdrawing scarce resources from an underfunded field it may be worthwhile to discuss the ethicality of such a step. Would it not be more ethical towards the 100 million of Americans that could potentially benefit from therapies emerging from stem cell research to step up efforts to bring hESC successfully into the clinic, rather than to waste precious time and resources? The decision to use human embryos to harvest pluripotent stem cells is supported by the majority of Americans. The debate now needs to shift towards how to ensure rapid and ethical progress towards clinical applications in order to come true on the immense promises of the stem cell field.

Posted: February 2, 2005