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Altered nuclear transfer (ANT)
- Framing the Future: Embryonic Stem Cells, Ethics and the Emerging Era of Developmental Biology


The foregoing ethical analysis not only explains what is morally troubling about CBR but it also points toward a resolution to our national policy impasse over its use. What CBR produces and then destroys to harvest ESCs is, when fully constituted, a human embryo. According to the perspective presented here, such an entity is an inviolable living being, not a mere laboratory product available for instrumental use. But if the CBR process could be altered so as to produce ESCs from a biologic construct having only partial developmental potential, no embryo would be created or destroyed. Such a proposal, known as altered nuclear transfer (ANT), has been described in a recently released white paper by the President's Council on Bioethics (13). As the author of the ANT proposal (14), I will discuss it in light of the previous ethical analysis as an approach that may lead to a technological solution to our conflict over ESC research.

As discussed above, natural conception signals the activation of the organizing principle for the self-development and self-maintenance of the full human organism. In the language of stem cell biology, this capability is termed totipotency, the capacity to form the complete organism. A naturally fertilized egg, the one cell embryo, is totipotent. In contrast, the term pluripotency designates the capacity to produce all the cell types of the human body but not the coherent and integrated unity of a living being. ESCs are merely pluripotent. This is a difference between the material parts and the living whole.

In standard nuclear transfer, the cell nucleus is removed from a somatic cell and transferred into an oocyte that first has its own nucleus removed. The oocyte then has a full complement of DNA and after it is electrically stimulated, starts to divide like a naturally fertilized egg. This is how Dolly the sheep was produced. ANT uses the technology of nuclear transfer but with a pre-emptive alteration that assures that no embryo is created. The somatic cell nucleus or the enucleated oocyte's contents (or both) are first altered before the somatic cell nucleus is transferred into the egg. The alterations cause the somatic cell DNA to function in such a way that no embryo is generated, but pluripotent stem cells are produced.{ddagger} The laboratory construct that is produced by ANT has only partial developmental potential. It lacks the integrated unity that characterizes a human embryo so the above ethical analysis would permit harvesting its ESCs.

ANT is a broad concept with a range of possible approaches and there may be many ways this technique can be used to accomplish the same end. As described in a January 2006 paper in Nature magazine, stem cell biologist Rudolf Jaenisch has established the scientific feasibility of one example of the ANT approach in a series of dramatic experiments in which he procured fully functional ESCs from a construct that is radically different in developmental potential than a human embryo (15). Unfortunately, the news reports have emphasized the inability of the ANT entity Dr. Jaenisch produced to form the placenta. The alteration he used, however, results in a failure of formation that is earlier and far more fundamental than simply an inability to implant in the womb. Due to the alteration, the first division into different cell lineages does not occur, the body axes (top/bottom, front/back) cannot form and the basic human body plan is never established. At this stage a critical deficiency is more rightly considered an insufficiency, not a defect in a being, but an inadequacy at such a fundamental level that it precludes the coordinated coherence and developmental potential that are the defining characteristics of an embryonic organism. In preliminary discussions, a broad range of moral philosophers and religious authorities (including some of the most conservative evangelical and Catholic leaders) have expressed strong encouragement for further exploration of this project.

ANT-OAR. Another variation of ANT called oocyte assisted reprogramming (ANT-OAR) has been put forward by Markus Grompe, Director of the Stem Cell Center at Oregon Health Science University. In this variation of ANT, alterations of the nucleus of the adult body cell and the enucleated egg's contents before nuclear transfer would force early expression of genes characteristic of a later and more specialized cell type that is capable of producing pluripotent stem cells. Such a creation, from its very beginning, would never have the actual configuration or potential for development that characterizes a human embryo. As documented on the Ethics and Public Policy Center website this proposal has drawn wide endorsement from leading scientists, moral philosophers and religious authorities (16).

The pre-emptive nature of ANT. The crucial principle of any technical variation of ANT, however, must be the pre-emptive nature of the intervention. This process does not involve the creation of an embryo that is then altered to transform it into a non-embryonic entity. Rather, the proposed genetic alteration is accomplished ab initio: the laboratory construct is brought into its very existence with a genetic structure insufficient to generate a human embryo. From the beginning and at every point along its development, it cannot be designated a living being. If such a limited biologic construct were accorded a certain cautionary respect—as with all human tissues—this project would not compromise any fundamental moral principles. Moreover, such techniques could be developed using animal models and confidently extended to work with human cells without engaging in research that involves the destruction of human embryos.

The advantages of ANT. ANT would provide a uniquely flexible tool for embryonic stem cell research. Embryos left over from IVF procedures represent a limited pool of genotypes. Furthermore, the genomes of these embryos have never proven their capacity to form an organism and, due to mutations, recombinations and re-assortment of alleles in gametogenesis, may carry unrecognized genetic defects. Embryonic stem cells produced by ANT, however, would have genotypes of proven potential. Furthermore, ANT could provide a full range of genotypes, including specific genetic types for tissue-compatible transplantation. In addition, this technique would offer a far wider range of scientific and medical possibilities than ESC lines derived from left over IVF embryos, including generation of diverse and pre-designed ESC lineages for disease modeling and pharmaceutical development. Indeed, in allowing controlled and reproducible experiments, ANT might serve as a temporary bridge to technologies such as direct nuclear reprogramming. Furthermore, in establishing a morally acceptable means for the procurement of ESCs, this important realm of scientific investigation would be opened to federal funding and the advantages of both broad public support and cooperative research collaboration on a national level.

ANT would also unburden ESC research from the additional ethical concerns of the ‘left over' IVF embryos, including the attendant clinical and legal complexities in a realm of great personal and social sensitivity. The one remaining link with IVF, the procurement of oocytes, is a subject of intense scientific research and there appear to be several prospects for obtaining eggs without the morally dubious and expensive super-ovulation of female patients.

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