Embryonic Stem Cell Research: Two Responses to My Post

In response to my post yesterday (here), I have received these two very informative/helpful responses.  Thanks so much to Robby George and Carter Snead (Notre Dame, Law) for their messages.

Dear Michael:

 

If we lay aside the profound ethical issues pertaining to the deliberate destruction of human embryos, there are good reasons to prefer stem cells derived from embryos created by somatic cell nuclear transfer (cloning) to those obtainable from IVF "spare" embryos being stored in assisted reproduction clinics.  First, the spare embryos are stored in a frozen condition (cryopreservaion). It is possible that the freezing has a negative impact on the embryos and the cells harvested from their inner cell mass.  ("Embryonic" stem cells are produced in the lab by culturing these inner cell mass cells.  Pluripotency appears to be induced by the culturing process.) Second, very few IVF cryopreserved embryos are actually available for use in biomedical research.  Even if President Bush's restrictions on federal funding of embryo-destructive research were lifted, there would be fewer than 12,000 embryos available for funded research.  If embryonic stem cells were ever to become useful in regenerative medicine (as Senators Kerry and Edwards and Ron Reagan Jr. said they would be in the last campaign), this would be only a tiny fraction of the number needed for the treatment of even a single disease (Juvenile Diabetes, Parkinson's, what have you).  The IVF spares would quickly be used up and it would be necessary to produce a massive number of additional embryos.  But the most important reason is the third:  the IVF spare embryos are of very limited utility in regenerative medicine because they are not a genetic match to the person needing treatment. They are, after all, products of the genetic lottery.  Cloned embryos, by contrast, are a genetic match to the somatic cell donor.  So scientists could produce a cloned embryo using a somatic cell from the patient needing treatment, then treat the patient with stem cells produced by "disaggregating" the embryo.

 

Given the advantages of cloned embryos over the IVF spares, I have been trying to persuade people who support the use of the spares (whether or not they are willing to go along with cloning) to shift their allegiance to alternative methods of producing pluripotent stem cells---methods that give us the advantages of cloning, but without creating or killing embryos.  There are two leading possibilities.  In the first, known as "altered nuclear transfer," the basic cloning technology is used, but genetic and or epigenetic alterations to the somatic cell nucleus (and possibly the oocyte cytoplasm) are made prior to its transfer to the enucleated ovum to ensure that embryogenesis cannot occur.  What is produced is a nonembryonic entity that is the biological (and thus the moral) equivalent of a teratoma or a complete hydatidiform mole. Rudolf Jaenisch's research at MIT has shown that pluripotent stem cells (indistinguishable from those obtained from embryos) can be produced from these entities.  (I should note here that some pro-lifers object to altered nuclear transfer because they believe--mistakenly in my view--that it would produce a damaged or disabled embryo, rather than a truly non-embryonic, tumor or mole-like entity.)   The second alternative method is even more exciting.  In what is known as "dedifferentiation," an ordinary somatic cell is "reprogrammed" to, in effect, return it to its primitive, stem cell state.  The most celebrated work in this area so far is that being done by Kevin Eggan at Harvard.  He used existing embryonic stem cells (I believe they were taken from the presidentially approved lines) as the reprogramming agents.  (Another possibility would be to use egg cytoplasm, which will also effectuate the reprogramming by causing an overexpression of key transcription factors, such as Nanog and Oct 3/4---factors that control other genes.)  Eggan's use of existing embryonic stem cells leaves a problem to be solved, namely, an extra set of chromosomes is left in the stem cells produced by the process.  A way will have to be found to remove them for usable cell lines to be produced.  Dr. Yuri Verlinsky in Chicago says that he has solved this problem, but his research has not been published.  (My understanding it that he is going for a patent.)  A number of other people are working on it, including a very important stem cell researcher in Australia named Alan Trounson.

 

Altered nuclear transfer has a problem that cloning also has, namely, oocytes are needed.  The same is true in forms of dedifferentiation using oocyte cytoplasm as an epigenetic reprogramming agent.  Where will the eggs come from?  Today when eggs are needed (eg., in in vitro fertilization), they are obtained by subjecting women to hormonal stimulation in a procedure known as "superovulation."  This is painful and potentially dangerous.  In my statements in favor of further research on altered nuclear transfer, I have always said that I am absolutely opposed to the use of superovulation.  If we cannot find another way to obtain the needed oocytes, I am for abandoning the project.  My fear is that any strategy requiring hundreds of thousands and eventually millions of eggs will result in the exploitation of poor women -- probably in developing nations where the poor are even more vulnerable than they are in the U.S. and Europe.

 

A couple of weeks ago, a team led by Professor Yamanaka in Japan published research showing that they had dedifferentiated somatic cells using neither embryonic stem cells nor egg cytoplasm.  They immersed the cells in a bath containing factors found in standard reprogramming agents.  I believe their research used mouse cells.  If they can now do it using human cells, it will be a great thing.

 

But even then, our excitement must be tempered by the knowledge that embryonic stem cells and their equivalent cannot now be used in therapies because of their tendency to tumor formation.  No one knows when, if ever, they will have therapeutic utility.  The problem is profound, and no one seems to have much of an idea of how to go about solving it.  That is why there is not a single embryonic stem cell-based therapy even in stage one of FDA clinical trials.  (By contrast, there are about 1,200 adult stem cell-based therapies in trials -- some quite far along.  A few have already been approved.) Cells are stabilized naturally during gestation by an unimaginably complicated process of intercellular communication.   This leads some supporters of embryonic stem cell research to say that the real value of embryonic stem cells is in basic research, the construction of disease models, and the testing of pharaceutical products; not in regenerative medicine.

 

I hope that these comments are responsive to your inquiry (and not more than you wanted to know).

 

Best wishes,

Robby

 

===========================================

Robert P. George

McCormick Professor of Jurisprudence

Director, James Madison Program in American

    Ideals and Institutions

Princeton University

244 Corwin Hall

Princeton, NJ  08544

(609) 258-3270

(609) 258-6837 (fax)

[email protected]


Hi Michael:

I hope you are well.  If you are wondering why someone would support so-called
therapeutic cloning, you might find the following chapter of the PCBE's 2002
cloning report useful:

http://www.bioethics.gov/reports/cloningreport/research.html

This chapter sets forth what I believe to be the most powerful case for cloning
for biomedical research.  It also contains the most powerful case against
cloning for biomedical research.

A few points to keep in mind:  It has been estimated that literally millions of
embryos (preferably of diverse genetic profiles) will be necessary to realize
the aspirations of stem cell researchers.  Such aspirations include the
development of disease/injury-specific (and immune-compatible) ES cell lines
for regenerative therapies (should they ever arrive), as well as the
development of models for study.  Among the 400,000 supernumerary embryos in
cryopreservation, less than 3% have been designated by their caretakers for use
in research.  Thus, there is a problem of scarcity that requires the production
of embryos solely for the sake of research (either by SCNT or IVF).

As always, it's important to be clear-eyed about the state of the science.
Scientists have yet been unable to isolate embryonic stem cells from cloned
human embryos.  The only researcher who claimed success in this regard is the
now-discredited Dr. Hwang, who not only flouted basic principles of ethical
research involving human subjects (by paying poor women, and coercing his lab
assistants into "donating" ova), but also falsified all of his research
findings.  This is not to say that derivation of stem cells from cloned embryos
is impossible in principle, but no one has been able to do it so far despite
many concerted efforts and millions of dollars spent.

Hope this is helpful.

Best,
Carter