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Is Oocyte Assisted Reprogramming (OAR) A Moral Procedure To Retrieve Embryonic Stem Cells? 

August 15, 2005
updated September 22, 2005

See: Introductory Notes by Helen Hull Hitchcock --- Michaelmas 2005

In response to the continuing controversy over embryonic stem cell (ESC) research, 35 ethicists and scientists support a new research proposal which they believe may overcome the Catholic Church’s prohibition of research involving the “creation” or destruction of human embryos. Their joint statement, issued June 20, 2005, is accessible on the Ethics and Public Policy Center web site. (http://www.eppc.org/publications/pubID.2374/pub_detail.asp) The joint statement was also published in Origins, the official publication of the US bishops’ conference (July 7, 2005, p 126ff).

This research proposal is called Oocyte Assisted Reprogramming (OAR), and the initial research would involve experiments with mice. OAR is a form of Altered Nuclear Transfer (ANT).  Both OAR and ANT use a modified cloning procedure called somatic cell nuclear transfer (SCNT) previously named therapeutic cloning. 

The procedures

In SCNT the nucleus of an oocyte (egg cell) containing the genetic instructions or genome is removed.  A somatic cell (e.g. skin cell) is then obtained from an adult animal or from a human person.

The nucleus containing the genome of the donor somatic cells is transferred into the egg cell.  The egg cell “reprograms” the genome of the somatic cell such that the combination of egg cell plus somatic cell genome becomes a totipotent zygote.

If this is done with human cells and the zygote is implanted into a uterus, the zygote could develop into a fully grown human infant.  In fact, according to Catholic Church teaching, the zygote itself is a human person.1  

In both ANT and OAR the donor somatic cell’s genome is altered before it is transferred to the egg cell.

In ANT the alteration of the genome involves knocking out (i.e. removing) one of the 30,000 human genes in the donor cell genome.  This particular gene is required for the early development of the zygote

In normal development a zygote cell divides into two cells called blastomeres.  These cells continue to divide such that at the 12 cell stage the developing person is called a morula and at about 60-150 cells a stage called the blastocyst is reached

The blastocyst contains two types of cells:2  

1) Embryonic cells in the inner cell mass (ICM) of the blastocyst will develop into all tissues in the body of the human infant.  These ICM cells are the type of cells used in ESC research. Normally ICM cells would become the epiblast, from which further stages of the embryo body-proper develop.  

2)  The second type of cells in the blastocyst are called trophoblasts. These cells develop into extra embryonic tissues (e.g., the placenta or umbilical cord of the infant).  

In ANT the zygote (i.e. human person) cannot develop past the blastocyst stage due to the removal of the gene (CDX2) required for development of the trophoblasts.

The ANT procedure has received harsh criticism from scientists and at least one ethicist.3 One scientist said, “It will be a sad day when scientists use genetic manipulation to deliberately create crippled embryos to please the Church.” Another scientist said, “We thought some would see this as creating a defective human for purposes of exploitation.”  The ethicist said, “A short lived embryo is still an embryo.”  As a result of these criticisms this ANT procedure was abandoned as a proposal for research that could be ethically funded, and the OAR procedure was proposed in its place as a morally acceptable alternative.

How does OAR differ from ANT? The biological basis for claiming that the OAR procedure is moral is the fact that all cells in the human body contain the entire genetic code for a human being; however, not all genes are expressed in each cell.  For instance, in a skin cell only the genes responsible for the characteristics of a skin cell are turned on.

The specific set of genes which are turned on or off in a particular cell type is the function of certain proteins in the cell called transcription factors (TRF).  The TRF, which specify the cell type, bind to certain genes in the genome and either turn the gene on or off.  The proponents of OAR used a technique called immunocytochemistry to look for the transcription factors which they claim were absent in the zygote but present in the morula and in ICM cells of the blastocyst.  They found one of these, called “Nanog”, which they said was absent in the zygote but present in the morula and in higher amounts in the ICM cells.4,5  From this data they claim they can distinguish the totipotent single cell zygote (i.e., human person) from the morula and ICM cells which they called pluripotent. They assume that because they found Nanog in cells they call pluripotent and not in the totipotent zygote that Nanog can convert a totipotent zygote (human person) into a pluripotent cell.

With this hypothesis in mind, they proposed to alter the donor cell genome by activating the gene producing Nanog before they transfer it into the enucleated egg cell (oocyte) and/or cause the egg cell to produce Nanog before the transfer. According to their hypothesis the transfer of this altered donor cell genome into the “reprogrammed” egg cell would not produce a totipotent zygote (i.e. human person) but only a pluripotent stem cell.

This theory provides the basis for the ethical judgment that a totipotent zygote is never present in OAR and does not precede the formation of so-called pluripotent cells.

The problems

There are serious problems with the hypothesis, however; which prevent the moral certainty required to make the judgment that the proposed OAR procedure overcomes the principal ethical dilemma involved in ANT or other means of producing “embryonic-like” stem cells. Examples follow:

1.     The oocyte (egg cell) is a very powerful reprogramming cell itself. The enucleated oocyte can reprogram a skin cell genome, with all of its specifying transcription factors, to become a totipotent zygote.  We have Dolly the sheep as proof of this fact.  Therefore, the OAR proponents’ claim that just one more transcription factor, i.e., Nanog, will prevent the oocyte from reprogramming the donor cell to totipotency seems doubtful.  

2.     Nanog keeps the cell in which it is present in the undifferentiated state.  The most undifferentiated state is totipotency.  Therefore, Nanog’s presence cannot be interpreted as overcoming totipotency to produce mere pluripotency.  What Nanog does is to prevent the zygote from differentiating past a certain stage of development.  That is, Nanog is said to keep the ES cells in an undifferentiated state. Therefore, OAR, like ANT, would produce a crippled embryo incapable of fully developing into a human infant.  

3.     The term pluripotent used to describe morula and ICM cells is ambiguous and not used by all scientists.  For instance, John Shea, MD, of Toronto, states, “All cells of the early human embryo are totipotent until shortly after the blastocyst stage (6).”  This same view is described in the “Embryology” chapter of Gray’s Anatomy:  “This [ICM cells] represents the residue of totipotential cells, some of which (the embryogenic cells) are destined to form the body of the embryo proper”.2  The only cells which ICM cells cannot form are the trophoblasts which produce extraembryonic tissues like the placenta.  In fact, because Nanog is present in morula cells, it cannot prevent these cells from forming trophoblasts.  Therefore, Nanog will not prevent the zygotes from forming trophoblasts or the blastocyst. Thus the zygote, even in the presence of Nanog, is totipotent in the strictest sense.  In addition, if cultured ICM cells replace ICM cells in the blastocyst, a normal embryo is formed.   Calling ICM cells pluripotent instead of totipotent appears to be a distinction without an essential difference.

4.     Finally, one must consider the limits of biological science, which relies on only statistical certainty, to produce the moral certainty required to make the key ethical judgment that OAR can produce a pluripotent cell first, without ever producing the totipotent zygote (human person). In this regard, the immunocytochemical method used to detect Nanog has a biological limit which depends on the potency and specificity of the antibodies used in the procedure.5  The lack of detection of Nanog in the zygote does not mean that it is not present.  Thus the biological underpinning of the OAR hypothesis, namely that the zygote differs from the morula or ICM cells of the blastocyst because it lacks Nanog, cannot be proven with moral certainty.

A simple analogy may help illustrate the essential point that neither Altered Nuclear Transfer nor Oocyte Assisted Reprogramming procedures can truly bypass the production of a zygote, which, if human cells are used, is a human person at its earliest stage of development.

Let's consider that the zygote is a complete book containing 30,000 pages, one page for each gene in the genome. If you remove a single page — let's say, page 61, for the gene that directs development of the embryo after the blastocyst stage, as in ANT — would you have created something that is not a book (human person)? Or would you call it a defective book (crippled embryo)?

Carrying this analogy one step further: If you also remove page 200 (that is, alter the gene required for development of the epiblast, as in OAR), would you have an entirely new thing or would you have a defective book (crippled embryo)?

Furthermore, these problems with the OAR hypothesis prescind from the overarching and complex moral and ethical questions that surround these procedures that would involve “harvesting” from women the egg cells that would be required for the purpose of producing the desired stem cells.

William Burke, M.D., Ph.D.
Professor of Neurology, Associate Professor in Medicine
Associate Professor in Anatomy and Neurobiology
Saint Louis University Health Sciences Center
3635 Vista Avenue at Grand Blvd, Saint Louis, Missouri 63110

Ph: 314-577-8026

 

Patrick Pullicino, MD, PhD.
Chair, Department of Neurology and Neurosciences
UMDNJ-New Jersey Medical School.
MSB H506, 185 South Orange Avenue, Newark, New Jersey 07103

Ph: 973-972-5208 - fax: 973-972-5059

 

The Rev. Edward J. Richard, MS, DThM, JD
Vice-Rector, Dean of Students
Associate Professor of Moral Theology
Kenrick Glennon Seminary
5200 Glennon Drive, St. Louis MO 63119

Ph: 314-792-6107

------

REFERENCES:

1. Instruction on Bioethics, Donum Vitae, 1.2. Congregation for the Doctrine of the Faith, Feb. 22, 1987.

2. R. Warwick and P.L. Williams, eds. “Embryology”. Gray’s Anatomy Philadelphia (PA): W.B. Saunders Co. 1973, pp. 54-198.

3. Constance Holden and Gretchen Vogel. “A technical fix for an ethical bind?” Science 306:2174-2176, 2004.

4. President's Council on Bioethics. “The moral retrieval of ES cells”. Ethics and Medics 30(7): 2005.

5. S.Y. Hatano, M. Tada, et al.  “Pluripotential competence of cells associated with nanog activity”. Mechanics of Development 122(1):67-79, 2005.

6. John B. Shea, MD. “The pre-embryo question”. Catholic Insight, January:18-21, 2005.


Link to Communio web site - Critiques of ANT and OAR:
http://www.communio-icr.com/ant.htm


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