Positions on human embryonic stem-cell research tend to fall into two camps: Either anything goes, or nothing goes. Proponents of the anything-goes position assert that the potential scientific and medical benefits of embryonic stem-cell research override all other considerations”and therefore restrictions on the funding and scope of this research are unwarranted. Proponents of the nothing-goes position assert that no amount of potential medical and scientific usefulness can justify the intentional creation and destruction of nascent human life.
Attempts have been made to bridge this divide by proposing alternative sources of embryonic stem cells for research and therapeutic purposes. In a recent white paper, the President’s Council on Bioethics outlined four proposals for obtaining embryonic stem cells without destroying living human embryos: obtaining stem cells from embryos that are clinically dead, removing stem cells without harming the embryo, creating non-embryonic entities that produce usable stem cells, and converting adult cells into embryonic stem cells by a process of genetic reprogramming. Each of these proposals has considerable merit as an alternative to the generation and destruction of embryos for research”yet for each there are also significant questions about scientific feasibility and ethical soundness.
One proposal that has received considerable scientific support has been to generate non-embryonic entities that can serve as a source of stem cells through a process termed Altered Nuclear Transfer (or ANT). This would involve three general steps. First, an adult cell would be removed from a patient and the DNA of that cell altered to control and direct the types of gene expression the nucleus is capable of supporting. Then, the DNA would be removed from an oocyte (an egg cell) and this enucleated oocyte fused to the altered adult cell”creating a new cell that is neither an oocyte nor an adult cell but a hybrid exhibiting the properties programmed into it by the alterations made to the adult-cell nucleus. Finally, the newly generated ANT-cell would be allowed to produce stem cells. These stem cells would be genetically identical to the patient from whom the original adult cell was taken and could be used for research and therapeutic purposes.
This ANT approach could take many possible forms. Some researchers have proposed deleting or disabling key genes that are required for early embryonic development. The cell produced following fusion of such an altered adult nucleus with an enucleated oocyte would be capable of generating embryonic stem cells”yet fundamentally incapable of orchestrating an overall embryonic pattern of development.
Such a form of ANT has caused some bioethicists to raise serious moral concerns. While the entity generated by deleting or disabling early embryonic genes would produce only an unorganized collection of stem cells, it would do so after a period of what appears to be relatively normal development. Thus, it is difficult to know with certainty whether such an entity was or was not a human embryo at some point in its development.
Recently, however, a new proposal has been made that takes a novel and scientifically powerful approach by combining the concept of ANT with the fourth alternative discussed in the white paper from the president’s council: reprogramming of an adult nucleus to a stem-cell state. This new proposal, named Altered Nuclear Transfer-Oocyte Assisted Reprogramming (or ANT-OAR), has been endorsed by a number of distinguished scientists and bioethicists in a statement entitled Creation of Pluripotent Stem Cells by Oocyte Assisted Reprogramming.
In contrast to previously proposed forms of ANT that suggested deletion of genetic information as a means of preventing embryo formation, this new proposal actively instructs the adult nucleus to enter directly into an embryonic stem-cell state without passing through any intervening developmental stages. Such a single-step conversion of an adult cell into an embryonic stem cell entirely avoids the question of whether an embryo has been created, since the cell produced by ANT-OAR never exhibits any of the properties of a single-cell embryo.
ANT-OAR makes use of a process known as epigenetic reprogramming to convert an adult cell into an embryonic stem cell. As specialized cells are generated during embryonic development, they are programmed to use only a limited amount of the total genetic information present in the nucleus to produce the proteins required for their particular function. Thus, adult skin cells and adult brain cells contain exactly the same genetic information, yet each cell type uses a different subset of the total genetic information it contains. This process of restricting the use of genetic information during embryonic development is known as epigenetic programming”programming that is not part of the DNA code itself but imposed on that code during embryonic development.
During normal development, epigenetic programming restricts both the genes a cell can use and the cell’s developmental potency. A single-cell embryo is totipotent (capable of producing all the cells of the body), and has full use of all the genetic information required to produce all the cell types of the developing body. As the single-cell embryo divides to generate more cells, genes required for the earliest stages of development are progressively shut off while others are turned on. These later-developing, specialized cells no longer access the full range of genetic information”and as a result, their potency is more limited.
Embryonic stem cells are produced during development by the same process of epigenetic programming that later will produce adult cells such as skin and brain. Embryonic stem cells are scientifically and medically interesting because they are pluripotent (capable of generating many cell types), but they are not the same as totipotent single-cell embryos. Rather, embryonic stem cells have already undergone epigenetic restriction and cannot produce an organized body with all of its required parts. There are clear differences between totipotent single-cell embryos and pluripotent stem cells on a molecular level as well. Recent work has identified a number of genes expressed only in pluripotent stem cells. Thus, unlike totipotent single-cell embryos, pluripotent embryonic stem cells are specialized cells that have limited developmental capabilities.
The epigenetic programming established during development is normally quite stable (skin cells do not spontaneously turn into brain cells during adult life), but it is not irreversible. Indeed, the ability to clone animals, such as Dolly the sheep, by fusion of an adult cell to an enucleated oocyte demonstrates that the epigenetic programming responsible for maintaining an adult cell in a stable state can be erased by factors present in the cytoplasm of the oocyte. When cloning is successful, the adult nucleus is stripped of its epigenetic programming, and is restored to a totipotent state that can use all the genetic information present in the nucleus to orchestrate the complete program of embryonic development.
Human cloning has been proposed as a means of generating human embryos that can be destroyed to obtain embryonic stem cells. Proponents of human cloning assert that this is the only method of producing pluripotent stem cells with the same genetic make-up as adult patients. ANT-OAR accomplishes this same goal, however, by using an approach that does not involve the generation and destruction of human embryos. In this proposal, specific master genes that are required for the pluripotent stem-cell state would be turned on in an adult cell. Experiments in animal cells have shown that although these genes are required to form pluripotent stem cells during development, they are not powerful enough on their own to overcome the epigenetic programming of a mature cell and convert it to a pluripotent stem cell directly. ANT-OAR would use the cytoplasm of the oocyte to assist with the required reprogramming of the adult nucleus.
Both ANT-OAR and cloning rely on the oocyte cytoplasm to strip the epigenetic programming from the adult-cell nucleus. What happens next is entirely different. During cloning, the adult nucleus is converted to a totipotent state that will then proceed through a clear progression of developmental steps to yield pluripotent stem cells at a later time. Should the ANT-OAR proposal work, the alterations made to the adult nucleus will ensure that the cell produced by ANT-OAR enters immediately into a restricted, pluripotent state, without ever generating a totipotent embryo.
The cell produced by ANT-OAR would have all of the positive properties of a pluripotent stem cell”as well as all of the restrictions in developmental potency such cells normally exhibit. The ANT-OAR cell would not undergo any type of development to produce stem cells and would only divide to generate other cells identical to itself. Thus, if successful, ANT-OAR would produce only a single type of cell, and that cell would be unambiguously distinct from a single-cell embryo”in its molecular properties, its behavior, and its developmental potency. Moreover, the cell produced by ANT-OAR would be exactly the type of cell that is most useful to basic research and medical science: a pluripotent stem cell with the same genetic information as an adult patient.
The scientific feasibility of ANT-OAR must first be established by research in animal cells. With a relatively modest, focused scientific effort, such testing could be done rapidly. While there are no guarantees that any scientific proposal will work as predicted, this proposal is exceptionally well supported by a large body of established scientific evidence. Meanwhile, the generation of human pluripotent stem cells via ANT-OAR raises no significant moral issues, so long as human eggs and adult human cells are obtained in a medically safe and ethically sound manner.
The ANT-OAR proposal represent a scientifically and morally sound means of obtaining human pluripotent stem cells that does not compromise either the science or the deeply held moral convictions of those who oppose the destructive use of human embryos for research”which is a creative approach that can be embraced by both the anything-goes camp and the nothing-goes.
Maureen L. Condic is an associate professor of neurobiology and anatomy at the University of Utah School of Medicine and conducts research on the development and regeneration of the nervous system.
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