Friday, November 17, 2006

ES Cells: Conundrums and Cures

Embryonic stem (ES) cells (self-renewing, pluripotent cells derived from embryos) are often hailed for their potential in regenerative medicine and just as often at the centre of controversy. The minefield of ES cell research has become something of a celebrity deathmatch with heavyweights weighing in both praising (e.g. Michael J. Fox, Christopher Reeve) and condemning (e.g. George W. Bush, Pope Benedict XVI) the field. One possible solution is the use of adult stem cells - pluripotent cells from adult tissues. However these cells are more rare, less robust and more difficult to culture than their embryonic counterparts (for a good primer on ES cells, adult stem cells and the differences visit the NIH resource page particularly the section on stem cell basics).

While conscientious researchers and philosophers argue ethics, some researchers are trying to sidestep the debate by developing techniques and creating 'ethical stem cell' lines. One example is the the 'de-differentiation' of fibroblast cells into ES-like cells by expression of defined factors (Cell 126:663-676). These cells could differentiate into multiple cell types and when injected into a blastocyst, contributed to embryo development. This method has the advantages of not involving an embryo at all -- a patient's own somatic cells could be used, which would also skirt problems of rejection when transplanted. However, one of the factors used in de-differentiation is the oncogene, c-myc, which may limit clinical application and the advantages over naturally occuring adult stem cells.

Another approach is the creation of stem cells of embryonic origin that don't involve desctruction of the embryo. In a recent letter to Nature, ES cells were derived from single blastomeres using a technique similar to that used in preimplantation genetic diagnosis (PGD) where single cells are extracted for genetic analysis at an early (8-10 cell) developmental stage. In this case, the cells were cultured to develop new ES cell lines. This paper has been the centre of some controversy since it's publication and is unlikely to offer a complete solution to the ethical dilemmas. In this study, all the embryos used were still destroyed (the authors claim this was so they wouldn't be wasted) and the success rate for establishing lines was low. (More recently, a group has show that using older embryos makes the process more efficient in mice) Additionally, while the technique used for PGD gives rise to healthy babies, subtle long-term effects of removing cells at such an early developmental stage hasn't been determined.

But once those kind of issues are resolved, where do we go from there? Are stem cells the cure-all they're made out to be? In one case, sight was restored in blind mice through retinal cell transplants. Because human ES cells can be coaxed into the same cell type, this offers some promise for future regenerative therapy using autologous transplantation. In another situation, a vaccine made from stem cells protected mice from lung cancer under various conditions. The vaccine exploits similarities between ES and tumour cells, protecting 20 of 25 mice from tumours in a xenograft model and 8 of 9 mice in a simulated smoking chemical carcinogenesis model, both with no obvious side effects. Safety issues aside, this again demonstrates the potential for stem cells if applied to a human disease.

Parkinson disease (PD) is one of the conditions most often held up as the disease most likely to benefit from stem cell therapies. Indeed, if all the promise holds true, most neurodegenerative and many other illnesses stand to gain from stem cell research. It's not all so rosy, though. Recent studies have demonstrated substantial recovery in a rat model of Parkinson disease. In this paper, human ES-cells were differentiated into dopaminergic neurons (using new techniques to enrich this cell population, which is lost in Parkinson disease) which were then transplanted into PD model rats. These rats showed significant recovery of motor function. The downside? Incompletely differentiated cells in the transplant showed persistant proliferation after engraftment. Among other problems described in the paper, these proliferating undifferentiated cells could potentially lead to the unfortunate side-effect of tumour formation.

So where are we on stem cell research? Limitless possibilities? Highway to Hell? As Steve Goldman, senior author on the Parkinson study, puts it, "Neither gene therapy nor stem cells are ready for primetime." But I wouldn't change the channel just yet.