Markus Grompe, Oregon Stem Cell Center

In the difficult debate over human embryonic stem-cell research, the concept of the soul is sometimes invoked to defend the dignity and inviolability of human life even in its earliest beginnings. Although a complete exploration of this idea is beyond the scope of this essay, some reflection on the classical philosophical meaning of ensoulment may provide the understanding essential to find a solution to our current conflict. Specifically, this consideration may delineate criteria to define a human embryo and to know which methods for generating pluripotent stem cells destroy embryos and which do not.

In literature and the arts, the human soul is often depicted as a translucent copy of a person's body that floats away towards heaven upon death. This naive image has little to do with the concept of the soul put forward by St Thomas Aquinas (1225–1274) in the Christian tradition and by Aristotle (384–322 BCE) before him1,2. The central meaning of the important philosophical idea of the soul is that the true nature of a thing can be known by what it does and what it can become. Thus, a human embryo does not gradually 'become' human — it 'is' human, a living organism of the human species, a concrete instance of an actual, individualized human nature. This true nature of a human being embraces two intricately interconnected dimensions: matter and soul. The concept of soul describes the 'form' of the body — in the sense of the unifying principle of its formation or organization — and expresses the idea that something more than the material from which it is constructed governs the nature of a being. The soul is intricately dependent on and interwoven with its distinctive physical/material basis. In the case of the human zygote, the soul is the source of the integral ordering of the properly disposed matter that was present in the sperm and the egg, what the tradition would call the materia apta, or appropriate matter1. Without the appropriate matter, there can be no 'ensoulment', and no living being.

It is factually wrong to state that limitations on ES cell research are preventing life-saving cures, and it is equally false to claim that ES cells have no therapeutic potential. At this point, we simply don't know.

To me, the very fact that embryos produced in IVF clinics become babies and eventually adult humans means that they are human (and have a human soul) from the very beginning. It also means that they have a special moral status and should not be destroyed for any reason, even for the creation of ES cell lines. In contrast, an entity that by its very constitution cannot develop as a human organism does not have a soul (or its proper or 'substantial' form) and hence is not an embryo, not a human organism at all.

My laboratory started working with murine ES cell lines in 1991 and I have a clear appreciation of the enormous power of this system. I see the primary and short-term use of ES cells as a tool to do 'developmental biology in a dish' and obtain insights into organogenesis and pathogenesis that are otherwise not possible. And I also think that ES cell derivatives could eventually become therapeutically useful. Thus, I have found myself in a conflict between my philosophical convictions on the one hand and the desire to exploit pluripotent stem cells for research and clinical applications on the other. I have also found myself in the cross fire in the public debate between the pro-ES cell and anti-ES cell camps. Unfortunately, this discussion has aroused intense passions and has been full of half-truths, exaggeration and outright disinformation on both sides.

The pro-ES cell side has accused their opponents of being anti-science, but at the same time has been guilty of public campaigns that have twisted scientific fact in sometimes grotesque ways. Examples include the advertisements for Proposition 71 in California or for the pro-cloning Amendment 2 in Missouri. Overstating the promise of ESC is a major tactic of this camp, especially in the arena of national politics. The very name of the pro-ES cell advocacy group Coalition For Lifesaving Cures, based in Clayton, Missouri, misrepresents what is currently known about the therapeutic potential of ES cells. On the other side, anti-ESC proponents continue to insist that adult stem cells can do everything ES cells can do and there is no valid scientific/medical reason to pursue ES research. Another frequently repeated mantra is something along the lines of “adult stem cells have cured over 70 diseases, whereas no one has been cured by embryonic stem cells”.

The anti-ES cell faction conveniently omits mention that the vast majority of those 70 diseases are blood-related, and that ongoing research with adult stem cells is in many cases as tenuous and speculative as research on ES cells. The fact that there are hundreds of untreatable diseases that cannot at present be treated by either adult stem cells or ES cells is conveniently omitted by both sides.

The truth is that the potential of ES cells for curing human diseases is unknown. It is therefore factually wrong to state that limitations on ES cell research are preventing life-saving cures, and it is equally false to claim that ES cells have no therapeutic potential. At this point, we simply don't know — and without the appropriate research, we will never know.

Despite the apparently irreconcilable differences between the two camps, I see a clear way forward with the emergence of alternative methods for producing pluripotent human stem cells with properties virtually identical to embryo-derived stem-cell lines. In 2005, the US President's Council on Bioethics produced a white paper3 outlining four general approaches by which pluripotent stem cells could be generated. This paper triggered almost immediate ridicule from some of the proponents of unlimited ES cell research, who suggested that such methods were far off in the future or would never work at all. As it turned out, experimental support for the feasibility of several of these approaches was published very quickly thereafter. I think that two of the proposed methods are particularly promising, because they not only seek to avoid the destruction of embryos, but would also generate pluripotent stem cells from specific individuals. The ability to control the genetic origin of pluripotent stem cells is a clear scientific advantage both for the in vitro study of development and therapeutic cell transplantation.

The method of directly reprogramming adult cells back to the pluripotent state (method 4 of the white paper) was initially pioneered by Shinya Yamanaka at Kyoto University, Japan, who was able to show that a combination of only four genes introduced by retroviral gene transfer is sufficient to generate murine pluripotent stem cells4. Several papers published this summer5 demonstrated that these cells are truly equivalent to ES cells and can even be used for germline transmission —that is, to produce a new generation of animals. Direct reprogramming has not yet been demonstrated for human cells, however, and the requirement for retroviral integration of the reprogramming genes would pose a significant problem for any clinical use of such cells. Thus, direct reprogramming of human cells may become a true alternative only in the future.

Another method (method 3 in the white paper), called altered nuclear transfer (ANT), was initially proposed by William Hurlbut at Stanford University, California, and is based on the philosophical understanding of a human embryo described above. Contrary to some claims that this approach generates 'disabled embryos', it is reasonable to expect — based on studies with mice — that ANT attempted with human cells would not produce a living member of the human species. The idea is to use genetic modification in combination with somatic cell nuclear transfer into oocytes to directly produce cells capable of generating pluripotent stem cells, but without making an embryo.

A thought experiment will illustrate the general concept of ANT. If you were to introduce messenger RNA for the potent myogenic transcription factor myoD into an oocyte before nuclear transfer, the resulting cell would probably express a muscle phenotype and would certainly not be an embryo. As the goal of ANT is not to make muscle cells, but pluripotent stem cells, the proposed genetic alterations would ensure that only the inner cell mass, but not the trophectoderm lineage, develops after nuclear transfer. The differentiation of the embryo into trophectoderm, which gives rise to the placenta, and inner cell mass, which produces the embryo proper, is the first indication that a human organism is present. Conversely, the absence of this step indicates that this cell was not a human embryo. Again, the basic feasibility of this approach has already been demonstrated by knocking down the gene CDX2, a gene required for trophectoderm development, in nuclei used for somatic cell nuclear transfer6. Other alterations, perhaps in combination with the inactivation of CDX2, might include the induction of an inner-cell-mass fate using positive factors. Genetic alterations of this kind may also be useful in the production of pluripotent stem cells from parthenogenotes (zygotes produced by parthenogenesis), because for the purposes of federal funding, parthenogenetic entities may still be considered “embryos” under the Dickey Amendment. This legislation, signed by President Clinton in 1995, bars federal funding for the creation and destruction of human embryos. Because ANT has the aim of directly producing inner cell mass cells, its successful application is likely to also have the scientific advantage of making the production of pluripotent stem cells more efficient than in routine somatic cell nuclear transfer. Thus, one might call ANT enhanced nuclear transfer. This approach might also represent a powerful experimental system for studying reprogramming factors.

As the generation of pluripotent stem cells from somatic cell nuclear transfer embryos and parthenogenesis now appears feasible7, it is my opinion that ANT and altered parthenogenesis have the best potential in the short term to provide us with patient-matched, ethically noncontentious pluripotent stem cells. In the long term, I am optimistic that direct reprogramming will provide us with an abundant source of pluripotent stem cells.

In the meantime, I believe that the ethical concerns regarding the destruction of human life — however tiny and fragile — outweigh the potential benefits of producing new embryo-derived cell lines. This is a view shared by many of the general public. Clearly, the best way forward would be to find a technological solution that at once sustains social consensus and opens up biomedical advances.