Monday, May 30, 2005

An Explainer Regarding Cloning

Grand Rounds
South Korean scientists announced an advance in the development of stem cells, and Congress has been working on legislation that would broaden federal funding for such research in the USA.  These developments have brought the controversy to the forefront of the national consciousness.

The South Korean team created stem cells using a technique known as somatic-cell nuclear transfer (SCNT).  SCNT is performed by taking the nucleus, which contains the genetic material, from one cell from a donor.  The nucleus is then transferred to an egg cell that has had its own nucleus removed.  The resulting cell then can be coaxed into dividing, much as a fertilized egg cell divides.  

This method sometimes is referred to as cloning, or more precisely as therapeutic cloning.  It is different than reproductive cloning, which is done with the intent of producing a fully developed human, or other animal, or even a plant.  SCNT results in a cells that is genetically identical to the cells of the person who donated the somatic cell.  However, the stem cells that result from SCNT are not  identical to cells that would have been present in the donor, when the donor was an embryo.  That is, they are not the same as embryonic stem cells.

To explain: the purpose of a gene is to serve as a template for the production of a protein.  Genes consist of a sequence of parts known as nucleotides.  Proteins consist of a sequence of amino acids.  It is the sequence that determines what function the protein will serve.  When a protein is made in the cell, the sequence of the nucleotides in the gene determines the sequence of amino acids in the protein.  However, not all genes in any particular cell are used to make protein.  Some of the genes are turned on, some off.  Those that are turned on, are turned on to various degrees.  That is, some produce a little bit of protein, some a lot.  The gene is said to be expressed  when it is used to make a protein.  The fact that different genes produce different amounts of protein can be referred to as differential expression.  The processes that result in differential expression are referred to as programming, since they direct the function of a cell much the way that a computer program directs the function of the computer.

A computer is capable of doing a wide range of things.  Once a particular program has been loaded, the computer can do only those things that are directed by the program.  Once a cell has been programmed, it is limited in what it can do.

The factors that control differential expression are not well understood.  Part of the mechanism, at least for some of the genes, involves interaction between the DNA that genes are made of, and small molecules of RNA.  The genes in each individual cell are regulated differently, so that some cells produce the proteins needed for muscle cells, some for skin cells, and so forth.  

Scientists do not have the ability to control differential expression in all ~25,000 genes, which is why we cannot turn ordinary cells into stem cells, and cannot turn skin cells into muscle cells.  Stem cells derived from anything other that a very early embryo have undergone some programming.  Some stem cells are part of the way along the process of turning into specialized cells.  For example, hematopoietic stem cells are able to turn into various types of blood cells, but not nerve cells.  

The cells produced via SCNT can be used to produce an entity that looks very much like a zygote (an early stage in the development of an embryo).  However, the genes already have undergone some programming.  To underscore the differences between the zygotes produced by SCNT, and the zygotes produced by normal fertilization, some scientists refer to the product of SCNT as a clonote.

A more detailed explanation of SCNT can be found here.  The link goes to a transcript of a presentation conducted by the President's Council on Bioethics (PCOB).

One of the Council members, Paul McHugh, has written an article about the subject of SCNT.  The article was published in the New England Journal of Medicine, which is arguably the most prestigious medical journal in the USA.  Dr. McHugh explains his own position on the distinction between therapeutic and reproductive cloning:  
I, however, see a distinction between the two procedures that sanctions different practices involving their products. In my view, SCNT resembles tissue culture, whereas in vitro fertilization represents instrumental support for human reproduction. Specifically, SCNT is an engineered culturing of the nucleus of a somatic cell, accomplished by implanting this nucleus into an enucleated ovum, thereby forming a new diploid cell with the genetic characteristics of the "donor" of the nucleus. [...]

I argue that this process of SCNT, by causing the expression of an intrinsic potential for growth and replication that is found in every somatic cell, can extend and expand a donor's cellular mass into extracorporeal space, as any form of tissue culture does. The stem cells that issued from the process would, in this view, be licitly used as the donor allowed. To specify this fundamental difference between in vitro fertilization and SCNT, I suggested that, since we call the first cell produced by fertilization the zygote, we dub the combination of nucleus and enucleated ovum that launches SCNT the "clonote."
Dr. McHugh states that SCNT results in clonotes rather than zygotes, and points out the distinction is not merely a semantic one.  Clonotes are fundamentally, biologically, different than zygotes.
My distinction rests on the origin of cells in SCNT, not on the process's vaunted potential for producing a living replica (clone) of the donor, as with Dolly the sheep. My confidence in making origins rather than potential the crux of the argument rests first on a reductio ad absurdum: if one used the notion of "potential" to protect cells developed through SCNT because with further manipulation they might become a living clone, then every somatic cell would deserve some protection because it has the potential to follow the same path. But I became more sure of this opinion when strong testimony was presented to the council3 indicating that SCNT performed with primate cells produces embryos with such severe epigenetic problems that they cannot survive to birth.
His footnote (3) is linked to the PCOB discussion that I linked to earlier.  The "epigenetic problems" that he is referring to, are the problems that result from programming of the genes.  

In various media reports, those epigenetic problems usually are not mentioned.  This leaves the public with the misperception that SCNT could be used to produce a normal, viable human adult: reproductive cloning.  Such an outcome is hypothetically possible, but highly unlikely.  To do so, it would be necessary for us to learn how to program, in a suitable manner, all of the genes in the donor nucleus.  

One way to do that might be to produce two cells via SCNT, coax one into becoming a sperm cell, then coax the other into becoming an egg cell; then combining the two via in vitro fertilization.  Nobody knows if that would work with human cells.

Ethicists considering the issue of SCNT may be repulsed by the notion that the process could, hypothetically, lead to the development of a viable human.  They also may be attracted to the idea that SCNT could be used to treat serious illnesses.  At this point, both possibilities remain hypothetical, although research into the therapeutic application has progressed to the point that one might reasonably conclude that SCNT is likely to result in therapeutic techniques.  Thus, the hypothetical therapeutic applications are much closer to reality that the hypothetical application of reproductive cloning.  

Some persons may argue, as Dr. McHugh does, that the seemingly imminent maturation of therapeutic SCNT outweighs the more distant possibility that SCNT could be used for reproductive cloning.  Others may say that SCNT is always wrong, because there is a possibility -- however remote it may be -- that SCNT could be used for reproductive cloning.

Following their investigation into the issue, the President's Council on Bioethics was not able to come to full agreement on many of the issues raised by SCNT.  If they cannot reach agreement, it is unlikely that the general population could reach any kind of consensus.  We will have to travel on the path of discovery, in the light provided by the scientists, while knowing that the available light does not extend to the end of the path.

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