A Brief Commentary on the Nanog Gene And Its Proposed Importance To Stem Cell Research

C. Ward Kischer
July 2006
Reproduced with Permission

The objections to human embryonic stem cell research (hescr) lie in the fact that to obtain the so - called "stem cells" destroys the embryo, and, thus, human life. This is predicated on the known scientific fact that human life begins, by sexual reproduction, with fertilization, or, by asexual reproduction, when a cloning procedure would be used. To avoid the moral problem of destroying human life, Professor William B. Hurlbut, a member of The President's Council on Bioethics, has proposed a rather novel approach by altering a gene, which, according to him, would redefine the initiation of human life. To fully understand Hurlbut's idea we must first cite some preliminary studies which have been made in mice.

The Nanog Gene

The idea which Hurlbut has presented has been termed Altered Nuclear Transfer - Oocyte Assisted Reprogramming (ANT-OAR). This approach has centered on a gene called Nanog. It is a regulator gene and was named after the mythologcal Celtic land of the ever-young "Tir nan Og" [Cavaleri and Scholer, 2003. Cell, 113:551-556]. It has been extensively characterized in mice [ Chambers, et al. Cell, 113:643-655].

In mice the action of this gene appears in the early embryo about 5 days post - fertilization. It promotes proliferation of the blastomeres. A few days later the action of Nanog is lost, thereby, and, presumably, allowing for differentiation into the trilaminar embryo.

The early embryonic blastomeres (cells) are assummed to be totipotent. The action of Nanog promotes proliferation; but, the fact that it disappears prior to the 14th day post - fertilization suggests that the lack of its action allows for differentiation and progression into the "pluripotent" state. Totipotent means able to form the complete individual; but, pluripotent means the cell no longer can do this, but it can proceed to form the more than 200 different tissues of the body.

The experiments in mice suggested that an overexpression of Nanog, that is, adding or triggering the Nanog action, sustained the pluripotency of the blastomeres and prevented their differentiation into the three germ layered embryo. Therefore, the thinking is as long as Nanog is active it would keep the embryo "ever-young".

This led to Hurlbut's idea that if the gene Nanog could be altered so that it would not be deactivated, and through a cloning procedure (presumably) the nucleus containing the sustained Nanog would be introduced into an enucleated oocyte, a true embryo would not be formed.

Certain Questions

Certain questions must be asked. For instance, if the Nanog gene is overexpressed in a donor nucleus, would the expression of the gene be immediate or not until 5 days later? And, if not until 5 days later, would not the early embryo up to that time be individual human life? Would ALL of the progeny cells carry the overexpression? Also, if so, what would this mean for so-called stem cells generated from such a mass used therapeutically? Also, if this would mean that any cell carrying the excess or altered Nanog must be altered to restore the inactive Nanog, would that cell resort to a totipotent state, and, if so, would it then be a living human being?

Further, most genes do not act alone. Within the cascade system, genes have effects on other genes, some of which are distanced greatly from the original gene or gene action.

With overexpression of Nanog, how would this affect other genes within the cascade system?

Another Example of ANT-OAR

Now we hear of another gene, called CDX2, which apparently promotes the formation of the trophoblast. If this gene is knocked out the trophoblast will not form and thus the embryo will not progressively develop. However, if this gene is knocked out and so-called stem cells derived later, what effect would these cells have therapeutically? The CDX2 gene also promotes intestinal epithelial cell proliferation. So, very likely, this would have degenerative effects theapeutically down the road.


Professor Hurlbut has proposed an idea, not an experimental protocol. The approach through ANT - OAR is simply an idea and, so far, has not been well thought out.

I agree that the early human embryo which would carry the overexpression of Nanog, or the knockout of CDX2, would be "a damaged human embryo", but nonetheless a living human embryo, and, therefore, a human life. There are unanswered questions, as per above.

Further, there is no such cell as the human embryonic stem cell. Meissner and Jaenisch (Nature, 2006. 439:212-215) claim they were able to culture CDX2 - depleted blastomeres to intestinal cells. I assume they were definitive. That is not what is wanted. If they could have controlled the cultures to produce intestinal "stem cells" that would have redeemed their research.

These examples of ANT - OAR do not resolve the moral issue and do not resolve the scientific issue of the continuum of human life.