Friday, February 16, 2007

Stem Cells Part VII: Why is cloning necessary?

Last week we saw the distinction between somatic cell nuclear transfer (SCNT) used for reproductive cloning, and SCNT used for therapeutic cloning, and that the difference lies not in the embryo produced, but the fate of that embryo. In reproductive cloning, the embryo is implanted in a uterus, where it will, perhaps, grow to birth. In therapeutic cloning, the embryo is not implanted in a womb; rather, it destroyed for research.

"What happens to clones depends on decisions made by the researchers in question; if they want a clone to grow, it is implanted in the uterus of a woman, and if its stem cells are to be used for research, it is destroyed. Thus, the terms of common usage (reproductive cloning vs. therapeutic cloning - TPC) refer to the applications for which the technology is to be used, which is to say, the intentions of the researchers involved, and not the cloned embryo itself."[1]

We also saw that the name, therapeutic cloning, is a lie: there are no therapies at this time from human embryonic stem cell (hES cell) research, nor are there any therapies on the horizon. However, that is the term which is used and so, to avoid confusion, we'll use it, too. So, why is therapeutic cloning so necessary to a mature hES cell R&D program?

The answer is: "immune mediated tissue rejection".

Our immune systems function by being able to recognize self from non-self. All the cells in my body have unique molecular identifiers, defined by my genome, tagging them as part of me, so that my immune system will recognize them as such, and not destroy them. Conversely, other cells - bacteria, fungi and, these days, transplanted tissues and organs, have tags which identify them as "from away", and the immune system goes after them. Because of this tagging, in a conventional tissue or organ transplant, a search is made to find donor material as immunologically similar as possible. Outside of autologous (self-sourced) donations or donations from identical twins, exact matches are rare. Thus, the transplant recipient generally needs to be on some sort of immune suppression regimen for the rest of his life, so that his own immune system doesn't reject the transplant. As you might imagine, chronic immune suppression carries its own set of problems. The theoretical ideal would be to have an unlimited supply of tissues and organs which were exact immunologic matches to the original equipment. The immune system wouldn't attack them, and there would be no need for chronic suppression.

Recall that the stated near term goal of hES cell research is to generate replacements for diseased systems. When - or if - this will ever actually come to fruition is anybody's guess[2] (I am among the unbelievers) but it is, nevertheless, on the basis of these incessantly repeated claims that the dollars flow. In addition, the less clearly stated goal is ... is what? Immortality, with each and every one of us having his own garage full of spares? Who knows. Regardless, hES cells are pushed as the best theoretical route to this brave new medical world. As we saw in the previous essays, ES cells, human or otherwise, will differentiate, but currently this differentiation cannot be controlled. Instead, they just grow into globs unorganized mature tissues (the box of spare parts in last week's essay) like embryoid bodies and teratomas. Suppose, for sake of argument, the ability to direct hES cell differentiation were a reality instead of a fantasy. Could a patient receive them?

Yes, but. The but is that the patient would still need to be immunosuppressed, to keep from rejecting the hES-derived replacements. True, in this hypothetical brave new world of hES therapy there would (presumably) be a wide selection of cell line genotypes to select from. Large banks of genetically diverse hES cells are envisioned by the National Academies of Science[3], which increases the possibilities of an exact match. This is one of the rationales given for "generating additional hES cell lines from a wider spectrum of the population."[4] However, an exact match would still be rare. The best alternative, from the point of view of the stem cell therapist (a medical qualification I just invented) would be to have replacement tissues which are genetic clones of the patient. Schemata abound as to how this might be accomplished; a representative one goes like this[5]: first, the patient needing replacement tissue is biopsied to obtain somatic cells. For discussion, any somatic cells will do, skin is a good example. Next, SCNT is performed using nuclei from the patient's biopsy and oocytes from some woman donor[6]. The new embryo, currently described as a "created entity with and undefined status",[7] would be grown to the blastocyst stage, and then destroyed to harvest the cells of the inner cell mass. These cells - now cultured and known as hES cells - are then "engineered" using methods not extant, to produce the desired replacement material, which is then implanted in the patient. Since the created entity of an undefined status was, in fact, a clone of the patient, he (she?) was a genetic match, as would be the tissues derived from him (her?). Hence, the patient would not need chronic immunosuppression and the cloned tissue, in theory, gets around the immune rejection problem.

Over the past few essays, we have seen that human embryonic stem cell research requires (1) the creation of viable human embryos, either specifically for research or as cast-offs from IVF procedures, and (2) the destruction of those embryos to obtain their inner cell masses ("harvest"). We have also seen that a mature, fully developed hES program will require cloning, as well as the production of chimeras. All of this is, of course, hopelessly evil. The question we will next take up is whether there are any alternatives which are not immoral.

[1] Bobbert, M. Ethical questions concerning research on human embryos, embryonic stem cells and chimeras. Biotechnology Journal 2006, 1:1352-1369. cf. pg 1354, my emphasis.
[2] ibid, pg. 1357.
[3] "Guidelines for Human Embryonic Stem Cell Research." National Research Council and Institute of Medicine of the National Academies National Academy Press, Washington, D.C. 2005 Pg. 34
[4] ibid
[5] Hipp J & Atala A: Tissue engineering, stem cells, cloning, and parthenogenesis: new paradigms for therapy. Journal of Experimental & Clinical Assisted Reproduction 2004:1:3
[6] The topic of women being paid for their oocytes is an essay in itself. Suffice it so say that egg sales are already a big, big subcomponent of the IVF industry, and young, attractive college coeds with high SAT score can be tens of thousands of dollars for their eggs in California.
[7]de Wert G & Mummery, C. Human embryonic stem cells: research, ethics and policy. Human Reproduction 18(4):672-682, 2003 pg. 679.

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