William B. Hurlbut

Altered nuclear transfer.

The present conflict over the moral status of the human embryo reflects deep differences in our basic convictions and is unlikely to be resolved through deliberation or debate. While there are currently no federally legislated constraints on the use of private funds for this research, there is a consensus opinion in the scientific community that without NIH support for newly created embryonic stem cell lines, progress in this important realm of research will be severely constrained. A May, 2005, report by the President’s Council on Bioethics, “Alternative Sources of Pluripotent Stem Cells,” outlines several proposals for obtaining pluripotent stem cells without the destruction of human embryos. One of these methods, Altered Nuclear Transfer, proposes to use the technology of somatic cell nuclear transfer (SCNT), but with a preemptive genetic or epigenetic alteration that precludes the integrated and coordinated organization essential for natural embryogenesis. Drawing on insights from systems biology, the distinction between totipotency (capacity to form a whole organism) and pluripotency (capacity to form all the cell types) is explored. The implications of this distinction are used to discuss the moral arguments for the inviolability of nascent human life and the moral standing of entities with only partial and unorganized developmental potential. A way forward is proposed that may open positive a venues of advance in both stem cell research and a broader arena of research in developmental biology.

Altered Nuclear Transfer as a Morally Acceptable Means for the Procurement of Human Embryonic Stem Cells

Perspectives in Biology and Medicine, volume 48, number 2 (spring 2005):211–28

CDX2 in the formation of the trophectoderm lineage in primate embryos

The first lineage decision during mammalian development is the establishment of the trophectoderm (TE) and the inner cell mass (ICM). The caudal-type homeodomain protein Cdx2 is implicated in the formation and maintenance of the TE in the mouse. However, the role of CDX2 during early embryonic development in primates is unknown. Here, we demonstrated that CDX2 mRNA levels were detectable in rhesus monkey oocytes, significantly upregulated in pronuclear stage zygotes, diminished in early cleaving embryos but restored again in compact morula and blastocyst stages. CDX2 protein was localized to the nucleus of TE cells but absent altogether in the ICM. Knockdown of CDX2 in monkey oocytes resulted in formation of early blastocyst-like embryos that failed to expand and ceased development. However, the ICM lineage of CDX2-deficient embryos supported the isolation of functional embryonic stem cells. These results provide evidence that CDX2 plays an essential role in functional TE formation during primate embryonic development.

Ethics and Embryonic Stem Cell Research

Ethical controversy in stem cell research arises because current methods to produce embryonic stem cell lines require the destruction of living human embryos. For this reason, there is increasing interest in developing alternative, non-embryonic sources of pluripotent stem cells. This effort is especially important in the US due to the prevailing policy against federal funding of embryo-destructive research.Altered nuclear transfer (ANT) is one of several potential methods to develop alternative sources of pluripotent stem cells. This approach employs the technique of somatic cell nuclear transfer, but the somatic cell nucleus or egg cytoplasm (or both) are first altered before the somatic cell nucleus is transferred into the oocyte. This alteration precludes the coordinated organization and developmental potential that is necessary for the resulting biological entity to be an embryo, but it still allows the entity to generate pluripotent stem cells.Proof-of-principle for one variant of ANT has been established in mice by silencing the functional expression of the gene Cdx2 in the somatic cell nucleus prior to its transfer into an enucleated egg. From the resulting non-embryonic laboratory construct, fully functional pluripotent stem cells were procured. Other more recent studies have suggested the possibility of achieving the same results by preemptively silencing maternally derived Cdx2 messenger RNA in the egg before the act of nuclear transfer. The procedure would produce the equivalent of a tissue culture of pluripotent stem cells.In contrast to the use of embryos ‘left over’ from clinical in vitro fertilization, ANT could produce pluripotent stem cell lines with an unlimited range of specifically selected and controlled genotypes. Such flexibility would greatly facilitate the study of disease, drug development, and toxicology testing, and may allow the production of therapeutically useful pluripotent stem cells that are immune-compatible. If developed to the point of scientific reliability, ANT would be a valuable research tool for the study of other aspects of cell development and differentiation, including gene expression patterns, imprinting, and cell-cell signaling. ANT would also help to clarify definitions and boundaries that distinguish true organisms from ‘biological artifacts’ and, thereby, provide moral precedent to guide future progress in developmental biology.

Framing the Future: Embryonic Stem Cells, Ethics and the Emerging Era of Developmental Biology

Throughout the 20th century, advances in biology were accomplished largely through the study of biochemical parts apart from their place within the whole organism. This reductive and analytic approach, which has culminated in the sequencing of the human genome, has now led us back to the study of living beings. When applied to human biology, this inquiry re-opens the most fundamental questions concerning the moral meaning of developing life. The current conflict over ES (embryonic stem) cell research is just the first in a series of difficult controversies that will require us to clearly and precisely define the boundaries of humanity that we seek to defend. Through a careful consideration of the social, political, and scientific foundations of our current debate, we may discern the terms of a possible resolution that can sustain social consensus while opening avenues for scientific advance. Four such proposals were discussed in a May 2005 publication by the Presidents Council on Bioethics, entitled “Alternative Sources of Pluripotent Stem Cells.” One of these methods, altered nuclear transfer, proposes to use the technology of somatic cell nuclear transfer (SCNT), but with a pre-emptive genetic or epigenetic alteration that precludes the integrated and coordinated organization essential for natural embryogenesis. The moral and scientific dimensions of this proposal are discussed as a way forward for embryonic stem cell research as well as a frame for further studies in developmental biology.

Evolutionary Theory and the Emergence of Moral Nature

The views of morality presented by evolutionary psychology and Christian theology are generally considered mutually exclusive. Love is central to the Christian message, but the self-sacrifice of Christian love seems incompatible with an evolutionary paradigm. This incompatibility, however, stems not from irreconcilable differences, but from an overextension and misapplication of the methodology of evolutionary psychology; no acknowledgement of the transcendent is possible, and morality becomes mere functionality. Within human phylogeny there is an evident ascent of freedom, mind, and moral awareness. This freedom, however, leads to greater interpersonal dependence and vulnerability, which both makes possible and makes necessary moral behavior. The crucial significance of moral conviction and motivation receives its complement and completion within the natural order in the revelation of love through the sacrificial death of Christ. The earthly and the transcendent are unified, as humanity is called into communion with a loving God.

Building Capacity for a Global Genome Editing Observatory: Conceptual Challenges

A new infrastructure is urgently needed at the global level to facilitate exchange on key issues concerning genome editing. We advocate the establishment of a global observatory to serve as a center for international, interdisciplinary, and cosmopolitan reflection. This article is the first of a two-part series.

Building Capacity for a Global Genome Editing Observatory: Institutional Design

A new infrastructure is urgently needed at the global level to facilitate exchange on key issues concerning genome editing. We advocate the establishment of a global observatory to serve as a center for international, interdisciplinary, and cosmopolitan reflection. This article is the second of a two-part series.

Stem Cells, Embryos and Ethics: Is There a Way Forward?

A century of advances in molecular and cell biology have brought us at the dawn of the 21st century back to the study of whole living beings. When these studies are applied to human biology, we must once again consider the fundamental questions about the meaning and significance of nascent human life. The current conflict over embryonic stem cell research is only the beginning of a series of difficult controversies concerning scientific manipulation of human life in its early stages of development. What is needed now is a coherent and reasonable definition of the boundaries of humanity that we seek to defend, one that takes into account the vast wealth of human tradition – social, political and scientific. This would facilitate a resolution that would make possible the advance of science while achieving social consensus. Several proposals have been advanced to achieve this end. One of these methods, altered nuclear transfer, proposes to make use of the technology of somatic nuclear cell transfer, but with a pre-emptive genetic or epigenetic alteration that precludes the integrated and coordinated organization necessary for embryogenesis. The moral and scientific aspects of this proposal are discussed as a way forward for embryonic stem cell research.

The Boundaries of Humanity: The Ethics of Human–Animal Chimeras in Cloning and Stem Cell Research

Advances in molecular and cell biology are opening new possibilities for combining human and animal cells, tissues, and organs. These projects could have important scientific and medical benefits, but open ethical dilemmas that challenge our traditional notions of the boundaries of humanity. Beginning with an overview of the goals and likely limitations of this research, we seek a framework of fundamental principles that can at once open avenues of scientific advance and defend human dignity. Reflection on these difficult dilemmas can promote a deeper understanding and appreciation of what defines and distinguishes the human creature.