STEM CELLS THAT BECOME EMBRYOS
Diane N. Irving, M.A., PhD
STEM CELLS THAT BECOME EMBRYOS: IMPLICATIONS FOR THE NIH GUIDELINES ON STEM CELL RESEARCH, THE NIH STEM CELL REPORT, INFORMED CONSENT, AND PATIENT SAFETY IN CLINICAL TRIALS

Dianne N. Irving, M.A., Ph.D.
Fellow, The Linacre Institute of The Catholic Medical Association
Consultant on Medical and Research Ethics, The Catholic Medical Association USA
Consultant on Medical and Research Ethics, The International Federation of Catholic Medical Associations

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" ... [F]ederally funded research that utilizes hPSCs would not be prohibited by the HHS appropriations law prohibiting human embryo research, because such cells are not human embryos." (DHHS General Counsel)

"Although human pluripotent stem cells may be derived from embryos or fetal tissue, such stem cells are not themselves embryos." (NIH Guidelines for Research Using Human Pluripotent Stem Cells)

 

ANALYSIS: PART I:

I. INTRODUCTION

Question: Can human embryonic and human fetal "pluripotent" stem cells become living human embryos?

The very scientific and legal basis for the NIH Guidelines for Research Using Human Pluripotent Stem Cells (November 21, 2000), as well as for the recent NIH report, Stem Cells: Scientific Progress and Future Research Directions, is the claim that such human stem cells "are not themselves embryos". Hence, the use of such "stem cells" would not violate the Congressional ban on human embryo research.

However, it if could be demonstrated that human embryonic and human fetal stem cells, once separated from the whole intact human embryo, not only can but indeed naturally tend to become new living whole human embryos per se (which would then also be cultivated and killed in research), then these accurate objective scientific facts alone would render both the NIH Guidelines and the recent NIH Report null and void. NIH would in fact illegally be allowing the "creation of a human embryo or embryos for research purposes." (Sec. 511(a)(1)).

If such objective scientific facts could be demonstrated, they should be responsibly and swiftly acknowledged by this administration, including the DHHS and the NIH. The NIH Guidelines should be rescinded, and the moratorium on the use of "pluripotent stem cells" should be reinstated, since even their use would constitute human embryo research per se, and thus automatically violate the Congressional ban.

The purpose of this scientific analysis is to demonstrate empirically, scientifically, and beyond any shadow of a doubt, that indeed, once separated from the whole intact human embryo, human embryonic and fetal "pluripotent" stem cells can become new living human embryos themselves, new living human beings -- as we already know happens even naturally in monozygotic twinning.

The implications for this simple scientific fact on the scientific integrity of the NIH Guidelines, the recent NIH stem cell report, informed consent procedures and documents, as well as on scientifically responsible and safe applications of "stem cell therapies" to potentially millions of vulnerable human patients in subsequent required clinical trials, will be summarized in this analysis.

II. SCIENTIFIC PROOF: STEM CELLS BECOME EMBRYOS

Answer: Yes -- human embryonic and human fetal "pluripotent" stem cells (even as defined in the NIH guidelines and report) can become living human embryos.

There have already been extensive arguments against the NIH Guidelines -- arguments which have thoroughly demonstrated that the Congressional ban on human embryo research would be violated because of the source of the "stem cells". That is, in order to "retrieve" these "stem cells", living human embryos would be, in the words of the Congressional ban, "destroyed, discarded, or knowingly subjected to risk of injury or death..." (Sec. 511(a)(2)). Such "retrieval" processes themselves would thus violate the ban.

But what has not been included in the public debates so far, nor addressed by the NIH, is the fact that in addition to human embryos being destroyed as the source of these "stem cells", these "stem cells" themselves can naturally become living embryos which could also be cultivated and then destroyed during experimentation. That is, once separated from the whole intact human embryo, these separated cells naturally tend to undergo "regulation" -- i.e., to "heal" themselves from any injuries, and they then revert to being new living whole embryos -- human beings -- themselves. We know this from our own observations of natural monozygotic twinning, as well as by simply looking in the human embryology textbooks (emphases added):

"The embryo enters the uterine cavity after half a week, ... . Each cell (blastomere) is considered to be still totipotent (capable, on isolation, of forming a complete embryo), and separations of these early cells is believed to account for one-third of cases of monozygotic twinning." [Ronan O'Rahilly and Fabiola Muller, Human Embryology & Teratology (New York: Wiley-Liss, 1994), p. 23]

"Monozygotic twinning: If the splitting occurred during cleavage -- for example, if the two blastomeres produced by the first cleavage division become separated -- the monozygotic twin blastomeres will implant separately, like dizygotic twin blastomeres, and will not share fetal membranes. Alternatively, if the twins are formed by splitting of the inner cell mass within the blastocyst, they will occupy the same chorion but will be enclosed by separate amnions and will use separate placentae, each placenta developing around the connecting stalk of its respective embryo. Finally, if the twins are formed by splitting of a bilaminar germ disc, they will occupy the same amnion." [William J. Larsen, Essentials of Human Embryology (New York: Churchill Livingstone, 1998), p. 325]

"Early mammalian embryogenesis is considered to be a highly regulative process. Regulation is the ability of an embryo or an organ primordium to produce a normal structure if parts have been removed or added. At the cellular level, it means that the fates of cells in a regulative system are not irretrievably fixed and that the cells can still respond to environmental cues. ... Of the experimental techniques used to demonstrate regulative properties of early embryos, the simplest is to separate the blastomeres of early cleavage-stage embryos and determine whether each one can give rise to an entire embryo. This method has been used to demonstrate that single blastomeres, from two- and sometimes four-cell embryos can form normal embryos, ... . ... Another means of demonstrating the regulative properties of early mammalian embryos is to dissociate mouse embryos into separate blastomeres and then to combine the blastomeres of two or three embryos. The combined blastomeres soon aggregate and reorganize to become a single large embryo, which then goes on to become a normal-appearing tetraparental or hexaparental mouse.... Blastomere removal and addition experiments have convincingly demonstrated the regulative nature (i.e., the strong tendency for the system to be restored to wholeness) of early mammalian embryos. Such knowledge is important in understanding the reason exposure of early human embryos to unfavorable environmental influences typically results in either death or a normal embryo. ... Some types of twinning represent a natural experiment that demonstrates the highly regulative nature of early human embryos, ... . ... Monozygotic twins and some triplets, on the other hand, are the product of one fertilized egg. They arise by the subdivision and splitting of a single embryo. Although monozygotic twins could ... arise by the splitting of a two-cell embryo, it is commonly accepted that most arise by the subdivision of the inner cell mass in a blastocyst. Because the majority of monozygotic twins are perfectly normal, the early human embryo can obviously be subdivided and each component regulated to form a normal embryo." [Bruce Carlson, Human Embryology & Developmental Biology (St. Louis, MO: Mosby, 1999), 2nd ed., pp. 44-49.]

Ironically, even the recent NIH stem cell report itself acknowledges this innate and natural capacity of these "pluripotent stem cells" from early human embryos to naturally form whole living embryos themselves (emphases added):

"If these cells separate, genetically identical embryos result, the basis of identical twinning." (NIH stem cell report, p. A-3)

Three things should be noted from these direct quotations from the human embryology textbooks. First, the tendency of separated individual cells—or even separated groups of cells—to undergo "regulation" and become whole embryos themselves is a natural tendency or property inherent in these separated cells or groups of cells. Second, this ability to "heal" and form new living embryos applies not only to the earliest embryo (e.g., from the 2-16 cell stage embryo which involves "blastomere separation"), but also to the embryo at the blastocyst stage (5-7 days post fertilization which involves "blastocyst-splitting"), as well as to the bilaminar embryo which has already implanted (up to 16 days post fertilization). Third, virtually all of these stages of the early human embryo—from fertilization to just before the formation of the mesoderm (gastrulation)— are included in the definition of "pluripotent" as found in both the NIH guidelines and the NIH stem cell report.

These objective scientific facts are also known by IVF researchers and clinicians, who consider exploiting this natural "healing" tendency in order to produce more embryos for cultivation, implantation and research purposes (emphases added):

"If these cells separate, genetically identical embryos result, the basis of identical twinning." (NIH stem cell report, p. A-3)

Three things should be noted from these direct quotations from the human embryology textbooks. First, the tendency of separated individual cells—or even separated groups of cells—to undergo "regulation" and become whole embryos themselves is a natural tendency or property inherent in these separated cells or groups of cells. Second, this ability to "heal" and form new living embryos applies not only to the earliest embryo (e.g., from the 2-16 cell stage embryo which involves "blastomere separation"), but also to the embryo at the blastocyst stage (5-7 days post fertilization which involves "blastocyst-splitting"), as well as to the bilaminar embryo which has already implanted (up to 16 days post fertilization). Third, virtually all of these stages of the early human embryo—from fertilization to just before the formation of the mesoderm (gastrulation)— are included in the definition of "pluripotent" as found in both the NIH guidelines and the NIH stem cell report.

These objective scientific facts are also known by IVF researchers and clinicians, who consider exploiting this natural "healing" tendency in order to produce more embryos for cultivation, implantation and research purposes (emphases added):

" ... (2) the fertilized egg, which has not yet divided, is now known as a zygote; (3) the egg begins to divide and is now known as an embryo; at this point each blastomere, or cell, within the embryo, is capable of developing into an identical embryo." [Geoffrey Sher, Virginia Davis, and Jean Stoess, In Vitro Fertilization: The A.R.T. of Making Babies (copyright 1998 by authors; information by contacting Facts On File, Inc., 11 Penn Plaza, New York, NY 10001), pp. 20]

"In such cases, patients may benefit from embryo multiplication, as discussed in the study by Massey and co-workers. ... Since each early embryonic cell is totipotent (i.e., has the ability to develop and produce a normal adult), embryo multiplication is technically possible. ... In humans, removal of less than half of the cells from an embryo have been documented. No adverse effects were reported when an eighth to a quarter of the blastomeres were removed from an embryo on day 3 after insemination. ... Further evidence supporting the viability and growth of partial human embryos is provided by cryopreservation. After thawing four-cell embryos, some cells may not survive, leaving one-, two-, or three-cell embryos. These partial embryos survive and go to term, but at a lower rate than whole embryos. ... Based on the results observed in lower order mammals, the critical period of development to ensure success in separating human blastomeres should be at the time of embryonic gene expression, which is reported in humans to be between the four- and eight-cell stages. .... The second potential method of embryo multiplication is blastocyst splitting. ... For couples who have less than three quality embryos for transfer, blastomere separation could be of benefit." [Prof. Dr. Mithhat Erenus, "Embryo Multiplication".

Two things should be noted in these direct quotations from IVF sources. First, after separating off the blastomeres of either the earliest cleaving embryo, of the morula, or of the later blastocyst, obviously neither the IVF clinician nor the woman undergoing IVF "therapy" consider that what is being implanted in her uterus are just "stem cells". At least the assumption is that they are living human embryos. Second, most "excess" human embryos produced by IVF are usually frozen down between the 4-8 cell stage (emphasis added):

"Successful transfer of four- to eight-cell embryos ... to the uterus after thawing is now a common practice (Fugger et al., 1991) ..." [Moore and Persaud, p. 39]

Thus most of these "frozen IVF human embryos" are clearly not 5-7 day old "blastocysts" —the term used in the debates and in the NIH documents. "Blastocysts" are composed of about 30-150 cells and have distinct inner and outer cell layers; it is from their inner cell layers that researchers supposedly want to "retrieve" these "pluripotent stem cells". However, most of these frozen embryos are at the cleavage and the morula stages and thus have no inner cell masses It is impossible to derive "stem cells" from frozen IVF embryos which have no inner cell masses.

In fact, the term "pluripotent stem cells" would seem to be nothing more than the latest reincarnation of the now-rejected and scientifically false term "pre-embryo", used for decades by NIH officials and her researchers to justify the use of these youngest of vulnerable living human beings in destructive research. And like the term "pre-embryo", there is virtually no scientific basis for the current term "pluripotent stem cells" as used in these NIH documents.

In short, yes—"stem cells" derived from the early human embryofrom the 2-cell stage through the germ line stage (gastrulation)are not only capable, but are even inherently driven by regulation to "heal" themselves and to form new whole living embryos themselves. Not only do human embryologists know this empirical fact, so also do IVF researchers, clinicians, and their patients.

It is thus difficult to understand why the former DHHS General Counsel did not know these empirical facts, nor the NIH officials who drafted the NIH Guidelines, nor the majority of NIH officials and scientific "consultants" who drafted the recent NIH report on stem cell research (most of whom receive NIH funding for this research). It is also thus difficult to square the incessant discussions in the NIH Guidelines and the recent NIH report about the use of "frozen human embryos" from which to derive "stem cells" (supposedly from their inner cell masses) when by far the majority of these frozen embryos have no inner cell masses.

It is ironically curious, to say the least, that both NIH documents, which already eschew ethical and legal considerations, purport to be presenting and explaining "scientific" facts as their justification, while simultaneously ignoring, or redefining, these most basic and indisputable of scientific facts of human embryology. What possible purpose would they have for knowingly and methodically doing this?

If the scientific and legal basis for the NIH Guidelines is that human "pluripotent stem cells" are "not themselves embryos", but if it has been empirically and scientifically demonstrated here that all of these "pluripotent stem cells" naturally strive to become and succeed in becoming embryos themselves (which will then also be cultivated and killed), then there is absolutely no scientific or legal basis for the existing NIH Guidelines. Indeed, the very use of such cells would in fact constitute the "creation of a human embryo or embryos for research purposes", and thus automatically violate the Congressional ban.

The implications of the simple and fundamental scientific facts of human embryology presented in this part of the analysis are quite grave and extensive. The impact on individual sections of the NIH Guidelines, the recent NIH report on stem cell research, informed consent processes and documents, and human patient safety in up-coming clinical trials for "stem cell therapies" will be addressed in subsequent "parts" to follow.

 

ANALYSIS: PART II:

One comment seems to be in order before applying the foregoing scientific considerations to the NIH Guidelines and the recent NIH report on stem cell research. The massive confusion over the scientific facts that has resulted from the stem cell and cloning debates is not simply a reflection of some debilitating lack of scientific consensus on the correct scientific facts all, but rather more the result of extensive efforts, extending over decades, on the part of some unscrupulous scientists and their proponents flooding the market place with erroneous "scientific facts" in order to advance and achieve their own agendas, many having significant financial conflicts of interest in these debates. Given that much is still not known about the intricate details of the development of the early human embryo, much is.

This analysis is an effort to "reconstruct" the well-known, well-documented, well-established, and most current and relevant scientific facts involved in these related issues, in order to bring some sense of clarity and integrity back to these critical scientific debates. Surely public policy should begin with and be based on the most accurate, current and documented scientific facts available. If not, the rationale of not so doing should be presented to and defended before the American people themselves. Why base public policy on false science?

The issues addressed in this report have been fully referenced by the most current human embryology and human molecular textbooks, written by eminent human embryologists whose work is well known and well respected internationally, and who have been publishing these excellent textbooks for decades now -- texts which have been fully peer-reviewed by dozens of others in their specialties from around the world. If any "scientific expert" wishes to refute the work of the authors of these textbooks referenced in this analysis, the minimum professional requirement would be to legally require that these "experts" submit xerox copies from the pages of the human embryology and human molecular genetics textbooks from which they are quoting, or which they are using as the basis upon which they are proffering their "expert scientific opinions." In addition, they should be legally required to defend their "scientific opinions" before the largest assembly of their own professional scientific peers with academically credentialed expertise in these fields, as well as before the American people. To require less, at this stage of these debates, would be inexcusable and negligent. Far too much is at stake.

The same should thus apply to this analysis. If any scientific facts presented here are incorrect, scientifically documented corrections are requested, and would be greatly appreciated.

III. CULTURE-PRODUCED HUMAN EMBRYOS FROM HUMAN EMBRYONIC STEM CELLS WOULD BE HUMAN CLONES

As documented in Part I of this analysis, when human embryonic stem cells are removed or separated from the intact embryo—called "blastomere separation" and "blastocyst splitting"—they naturally tend to undergo "regulation", and can revert to new human embryos in culture. This is called "twinning", and we have empirical examples of natural twinning in vivo with human monozygotic twins. "Twinning" is the classic example of "cloning"—i.e., the duplication or replication of genetic materials in which genetic "copies" of a progenitor are formed. Repeating some of the references on in vivo human "twinning" (emphases added):

"Monozygotic twinning: If the splitting occurred during cleavage -- for example, if the two blastomeres produced by the first cleavage division become separated -- the monozygotic twin blastomeres will implant separately, like dizygotic twin blastomeres, and will not share fetal membranes. Alternatively, if the twins are formed by splitting of the inner cell mass within the blastocyst, they will occupy the same chorion but will be enclosed by separate amnions and will use separate placentae, each placenta developing around the connecting stalk of its respective embryo. Finally, if the twins are formed by splitting of a bilaminar germ disc, they will occupy the same amnion." [William J. Larsen, Essentials of Human Embryology (New York: Churchill Livingstone, 1998), p. 325]

" Monozygotic twins and some triplets, on the other hand, are the product of one fertilized egg. They arise by the subdivision and splitting of a single embryo. Although monozygotic twins could ... arise by the splitting of a two-cell embryo, it is commonly accepted that most arise by the subdivision of the inner cell mass in a blastocyst. Because the majority of monozygotic twins are perfectly normal, the early human embryo can obviously be subdivided and each component regulated to form a normal embryo." [Bruce Carlson, Human Embryology & Developmental Biology (St. Louis, MO: Mosby, 1999), 2nd ed., pp. 44-49.]

However, do we have empirical proof that human twinning in vitro could also produce human twins that could be implanted and allowed to develop in vivo, and go to term as well? The evidence is not yet overwhelming. Yet it has already been suggested in a referenced used in Part I that human twinning in vitro can result in the production of born human twins:

"In humans, removal of less than half of the cells from an embryo have been documented. No adverse effects were reported when an eighth to a quarter of the blastomeres were removed from an embryo on day 3 after insemination. ... Further evidence supporting the viability and growth of partial human embryos is provided by cryopreservation. After thawing four-cell embryos, some cells may not survive, leaving one-, two-, or three-cell embryos. These partial embryos survive and go to term, but at a lower rate than whole embryos." {Prof. Dr. Mithhat Erenus, "Embryo Multiplication" (<http://www.hekim.net/~erenus/20002001/asistedreproduction/
micromanipulation/embryo_multiplication.htm>)]

The fact that one group of cells that had been separated from the whole embryo in vitro survived—i.e., the "partial embryo"—would, it would seem, be some empirical evidence that at least one group of separated cells did go through regulation in vitro, became a twin in vitro, was implanted, was allowed to developed in vivo, and was born.

Thus it is at least plausible that new culture-produced human embryos, or twins, could be produced in vitro. If they were, these twins would also be clones, i.e., identical genetic "copies" of their progenitor cells. Therefore their production would constitute human cloning (emphases added):

"The term 'clones' indicates genetic identity and so can describe genetically identical molecules (DNA clones), genetically identical cells or genetically identical organisms. Animal clones occur naturally as a result of sexual reproduction. For example, genetically identical twins are clones who happened to have received exactly the same set of genetic instructions from two donor individuals, a mother and a father. A form of animal cloning can also occur as a result of artificial manipulation to bring about a type of asexual reproduction. The genetic manipulation in this case uses nuclear transfer technology: a nucleus is removed from a donor cell then transplanted into an oocyte whose own nucleus has previously been removed. The resulting 'renucleated' oocyte can give rise to an individual who will carry the nuclear genome of only one donor individual, unlike genetically identical twins. The individual providing the donor nucleus and the individual that develops from the 'renucleated' oocyte are usually described as "clones", but it should be noted that they share only the same nuclear DNA; they do not share the same mitochondrial DNA, unlike genetically identical twins. ... Nuclear transfer technology was first employed in embryo cloning, in which the donor cell is derived from an early embryo, and has been long established in the case of amphibia. ... Wilmut et al (1997) reported successful cloning of an adult sheep. For the first time, an adult nucleus had been reprogrammed to become totipotent once more, just like the genetic material in the fertilized oocyte from which the donor cell had ultimately developed. ... Successful cloning of adult animals has forced us to accept that genome modifications once considered irreversible can be reversed and that the genomes of adult cells can be reprogrammed by factors in the oocyte to make them totipotent once again." [Tom Strachan and Andrew P. Read, Human Molecular Genetics 2 (New York: John Wiley & Sons, Inc, 1999), pp. 508-509]

"Clone describes a large number of cells or molecules identical with a single ancestral cell or molecule." [Benjamin Lewin, Genes VII (New York: Oxford University Press, 2000), p. 955)]

Therefore, if culture-produced human embryos are formed in the process of the derivation of human embryonic stem cells, then that process would be cloning, and those culture-produced human embryos would be clones.

In short, if the derivation of human embryonic stem cells is achieved by "blastomere separation" and "blastocyst splitting", and if "blastomere separation" and "blastocyst splitting" are twinning, and if twinning is cloning, then the process of deriving human embryonic stem cells would be cloning if culture-produced human embryos are formed in the process. The NIH Guidelines do not acknowledge that "twinning" is cloning.

The Guidelines also only refer to one method of human cloning i.e., somatic cell nuclear transfer (SCNT). Yet there are other methods of cloning as well. We know, at least, that to be "silent" on an issue in the legislative language means that that issue is not covered by that legislation.

IV. IMPACT OF CORRECT SCIENCE ON NIH GUIDELINES FOR RESEARCH USING HUMAN PLURIPOTENT STEM CELLS

Although the NIH Guidelines acknowledge that the production by IVF of human embryos for use in research would violate the Congressional ban, they argue that the mere use of "stem cells" privately derived from these human embryos would not, "because such stem cells are not human embryos themselves." ["Summary of Public Comments on Draft Guidelines", p. 1; and "I. Scope of Guidelines", p. 7] [NIH Guidelines can be found on-line at: <http://www.nih.gov.news/stem cell/stem cell guidelines.htm>].

However, as demonstrated in Part I of this analysis, the very process of retrieving these "pluripotent stem cells" from IVF-produced embryos normally and automatically triggers in the cell the natural process of "regulation", which could result in these separated "stem cells" becoming new embryos themselves in culture. This would be "the production of human embryos for research purposes", albeit these human embryos would be culture-produced rather than IVF-produced. If this is possible, and if the research were performed, would this not violate the Congressional ban, and thereby render the NIH Guidelines null and void? Indeed, it could set up a perpetual cycle of killing living human embryos for "the advancement of scientific knowledge" and for "curing diseases."

Likewise, any "stem cells" derived from these culture-produced human embryos could also revert to human embryos themselves through regulation, and so on. Would this kind of research also constitute human embryo research, and thus violate the Congressional ban?

Additionally, the phenomenon of natural "regulation" could render most of the research deemed "eligible" by NIH for funding as "ineligible", according to the restrictions in the NIH Guidelines themselves.

A. "Pluripotent Stem Cell" Research Rendered "Ineligible" for NIH funding

Section III (p. 12) of the NIH Guidelines stipulate those areas of research using "human pluripotent stem cells" that are ineligible for NIH funding. [This list does not address research using "fetal stem cells", since, as the Guidelines point out, research using "fetal stem cells" is already legal, given the fact that it is derived from "fetal tissue", and "fetal tissue transplant research" already falls under the protection of federal regulations and statutes]. Given the correct science, most of the research that NIH deems "eligible" in its Guidelines could possibly qualify for inclusion on their "ineligible" list instead, and thus could not receive NIH funding.

For example, (1) the Guidelines state that "research in which human pluripotent stem cells are utilized to create or contribute to a human embryo" is deemed ineligible for NIH funding. However, as scientifically demonstrated in Part I of this analysis, "human pluripotent stem cells" derived from frozen IVF-produced human embryos could revert to being human embryos themselves in culture, containing their own "stem cells" which when separated from these culture-produced human embryos could convert to human embryo themselves, etc. This would constitute research in which human "pluripotent" stem cells "are utilized to create or contribute to a human embryo" -- albeit "stem cells" generated from culture-produced human embryos—and thus would be ineligible for NIH funding according to their own Guidelines.

(2) The Guidelines state that "the derivation of pluripotent stem cells from human embryos" is deemed ineligible for NIH funding—the assumption being that the term "human embryo" being used by NIH refers only to frozen IVF-produced human embryos. But has NIH not considered that these "stem cells" are not all "pluripotent", and could naturally tend to revert to human embryos themselves? And if any "stem cells" were derived from these culture-generated human embryos, this too would constitute research in which "pluripotent stem cells" were derived from human embryos -- albeit culture-generated human embryos—and would thus be ineligible for NIH funding according to their own Guidelines.

(3) The NIH Guidelines state that "research utilizing pluripotent stem cells that were derived from human embryos created for research purposes, rather than for fertility treatment" is deemed ineligible for NIH funding. But again, culture-produced human embryos would contain their own "stem cells" which, when separated from these culture-produced human embryos, could revert to being human embryos themselves in culture, and their "stem cells" could be derived from them and used, etc. This would in fact constitute the "creation of human embryos for research purposes". Thus wouldn't the use of such "stem cells" derived from culture-produced human embryos would be deemed ineligible for NIH funding according to their own Guidelines?

(4), (5), and (6) The NIH Guidelines state that research utilizing human pluripotent stem cells that were derived or used by means of somatic cell nuclear transfer, i.e., the transfer of a human somatic cell nucleus into a human or animal egg, is ineligible for NIH funding. Many questions need to be answered:

First, couldn't one perform somatic cell nuclear transfer (SCNT) with private funding to create a human embryo, and then have that SCNT-produced human embryo's stem cells removed, cultivated, and allowed to revert to culture-produced human embryos? Those culture-produced human embryos could then have their own stem cells removed, and used in research. These NIH Guidelines do not address this very real possibility.

Second, the NIH statement refers only to the prohibition of using "somatic" cells in nuclear transfer cloning. But there is another category of "diploid" cells in the body other than "somatic" cells, i.e., germ-line cells, or the primitive sex cells -- precisely those referred to in these debates as "fetal stem cells". Because these non-somatic germ-line or primitive sex cells are also diploid, they too can be cloned by means of SCNT, or by any other method of cloning, producing human embryos for research. Those culture-produced human embryos' stem cells could be removed, and used in research. Would such research be "eligible" for NIH funding? These Guidelines do not seem to recognize this very real possibility either.

Third, would this "silence" in the Guidelines also allow research involving the transfer of a human germ-line cell nucleus into a "human or animal egg"? The issue of the use of germ-line cells, referred to in these debates as "fetal stem cells", will be addressed in more detail below. However, within this context of "ineligible research", it is important to recognize that these "fetal stem cells" could be used for cloning by means of "twinning", by means of SCNT, as well as by means of DNA-recombinant human gene germ line transfer—a form of "positive eugenics". In DNA-recombinant gene transfer, the "foreign" DNA is transferred into a gamete or early embryo, and that "foreign" DNA is then replicated throughout succeeding generations of humans. DNA-recombinant gene transfer is considered by human molecular geneticists as a form of cloning of molecules of foreign DNA (emphases added):

"[A] cloning vector is a plasmid or phage that is used to 'carry' inserted foreign DNA for the purposes of producing more material or a protein product." (p. 956) ... [Used in "clonal analysis"]: "Clonal analysis identifies a group of cells descended from a single ancestor in which a transposition-mediated event altered the phenotype. Timing of the event during development is indicated by the number of cells; tissue specificity of the event may be indicated by the location of the cells." (p. 474) ) [Benjamin Lewin, Genes VII (New York: Oxford University Press, 2000)]

Fourth, and relatedly, the Guidelines only make a restriction on one method of cloning—i.e., SCNT. But what about other forms of cloning, e.g., parthenogenesis, the transfer of mitochondrial DNA, "twinning", or DNA-recombinant gene transfer to germ line cells or early embryos? The Guidelines do not address the possibility of using cloning methods other than SCNT to produce human embryos whose "stem cells" could then be harvested.

(7) Other supposedly "ineligible research" in the NIH Guidelines is chimera research—i.e., research in which intra- or inter-species of embryos are formed. Virtually any of the kinds of research listed above could be used—sooner or later—for chimera research, other than the one kind of cloning specified in these Guidelines. The NIH restrictions on funding would not preclude any of that research from NIH funding.

(8) Finally, the NIH Guidelines state that "research in which human pluripotent stem cells are used in combination with somatic cell nuclear transfer for the purposes of reproductive cloning of a human" is "ineligible" for NIH funding. However, again, virtually all of the research listed above could be used to create human embryos, "stem cells", or even human or animal chimeras, for the purposes of reproductive cloning, without the use of the SCNT technique. Yet the NIH Guidelines are silent on those kinds of research as well. Thus those kinds of research could receive NIH funding. Since these Guidelines do not address any other form of cloning except SCNT, all other forms of cloning which could produce embryos, "pluripotent stem cells", and chimeras for the purposes of reproductive cloning of a human" would be eligible for NIH funding, according to their own Guidelines.

In sum, it would seem that most of the research listed by the NIH Guidelines as "eligible for NIH funding" would in reality be ineligible for NIH funding, even according to their own Guidelines. In addition, much of the research listed by the NIH Guidelines as "ineligible for NIH funding" would be eligible for NIH funding —even according to their own Guidelines—because the Guidelines remain silent on them.

B. The Case of the Vanishing Embryo #1: "Just Stem Cells"

Regardless, if NIH is determined to pursue these goals, the linguistic means of doing so could be identified in NIH's peculiar definitions of the relevant biological terms, "stem cell" and "pluripotent".

In 1999, then-Director of NIH, Dr. Harold Varmus, came up with an astounding definition of the early human "embryo". In his testimony before a U.S. Senate sub-committee hearing on stem cell research, Dr. Varmus defined the early developing human embryo itself—from fertilization on—as "just stem cells"! Voila—the early human embryo has verbally vanished. That is, according to the Director of NIH, from fertilization on there are only stem cells present—no embryo (emphases added):

"Totipotent stem cellssuch as the product of fertilization of an ovum and its progeny—are stem cells that have total potency, which means that they have the ability to form an entire mature organism, e.g., a human being, although only if placed in a woman's uterus. In contrast, human pluripotent stem cells, which are under discussion today, do not have total potency, and hence cannot form an entire organism under any known condition. But pluripotent stem cells can give rise to all of the different types of specialized cells in the body. " [http://www.nih.gov/news/stemcell/statement.htm]

So, according to Dr. Varmus, then-Director of the NIH: the product of fertilization is just totipotent stem cells; human beings do not exist until they are adults; and "pluripotent" stem cells can "give rise to all of the different types" of cells in the body—a definition usually reserved for the term "totipotent". Nowhere is the term "embryo" even mentioned. The embryo has simply vanished from any and all considerations.

Contrary to the then-Direct of NIH, and according to any basic human embryology textbook, "the product of fertilization of an ovum" is a human being, a human organism, a human zygote—a human embryo (emphases added):

"Human pregnancy begins with the fusion of an egg and a sperm." (p. 2); " ... finally, the fertilized egg, now properly called an embryo, must make its way into the uterus ...." (p. 2). [Carlson (1999)]

" ... but the embryo begins to develop as soon as the oocyte is fertilized. (p. 2); ... Zygote: this cell results from the union of an oocyte and a sperm. A zygote is the beginning of a new human being (i.e., an embryo). (p. 2); ... Human development begins at fertilization, the process during which a male gamete or sperm ... unites with a female gamete or oocyte ... to form a single cell called a zygote. This highly specialized, totipotent cell marks the beginning of each of us as a unique individual." (p. 18). [Moore and Persaud (1994)]

" ... the male and female sex cells or gametes, which will unite at fertilization to initiate the embryonic development of a new individual. ... Fertilization takes place in the oviduct ... resulting in the formation of a zygote containing a single diploid nucleus. Embryonic development is considered to begin at this point. (p. 1); ... This moment of zygote formation may be taken as the beginning or zero time point of embryonic development." (p. 17). [Larsen (1997)]

"Fertilization is an important landmark because, under ordinary circumstances, a new, genetically distinct human organism is thereby formed. (p. 5); ... Fertilization is the procession of events that begins when a spermatozoon makes contact with a secondary oocyte or its investments. (p. 19); ... The zygote ... is a unicellular embryo. (p. 19); ... The ill-defined and inaccurate term pre-embryo, which includes the embryonic disc, is said either to end with the appearance of the primitive streak or ... to include neurulation. The term is not used in this book." (p. 55). [O'Rahilly and Mueller (1994)]

These scientific facts could not be clearer. The product of fertilization is a human being, a human embryo—not "just stem cells".

C. The Case of the Vanishing Embryo #2: "Just Pluripotent"

As demonstrated in Part I of this analysis, separated "stem cells" from the 2-cell stage through the blastocyst-stage embryo could be totipotent, undergo "regulation" and become whole embryos themselves. This is an established scientific fact in animal studies. These human "stem cells", therefore, are probably not all "pluripotent". Once separated from the intact embryo these cells are capable of being "totipotent".

Yet if the correct scientific term were to be used to describe some of these separated stem cells, i.e., "totipotent", then it could be argued that they should not be used in research precisely because they can undergo regulation and produce embryos themselves. That would constitute human embryo research and violate the Congressional ban. However, if the term "pluripotent" were used instead, then the implication would be that these cells could not possibly revert to embryos themselves, but rather could only form "some" of the cells and tissues of the adult organism. Culture-produced human embryos (i.e., those that might be produced from separated "human embryonic stem cells") would vanish as well. That would not constitute human embryo research, and therefore would not violate the Congressional ban. This could be what the NIH Guidelines have accomplished.

IV. APPLICATION TO NIH GUIDELINES

[I.] Scope of NIH Guidelines

The term "pluripotent" is used in the very title of the NIH Guidelines to describe all of these separated "stem cells" that are to be cultured and used in research and "therapy" (emphases added):

"For purposes of these Guidelines, 'human pluripotent stem cells' are cells that are self-replicating, are derived from human embryos or human fetal tissue, and are known to develop into cells and tissues of the three primary germ layers. ... NIH research funded under these Guidelines will involve human pluripotent stem cells derived 1) from human fetal tissue; or 2) from human embryos that are the result of in vitro fertilization, are in excess of clinical need, and have not reached the state at which the mesoderm is formed." (p. 7)

So the term "pluripotent", rather than the term "totipotent", is used to refer to all of the separated "stem cells" from the developing human embryo from fertilization until the formation of the "mesoderm". New stem-cell-culture-produced human embryos that might have been produced have now completely vanished from sight, and therefore from all considerations and debates.

The choice of the term "mesoderm" here is interesting too. According to current human embryology textbooks, the "mesoderm" is formed "well after the formation of the primitive streak", in the third week of development post-fertilization (emphases added):

"At the end of the second week the embryo consists of two flat layers of cells, the epiblast and the hypoblast. As the third week ... begins, the embryo enters the period of gastrulation, during which the three embryonic germ layers become clearly established. ... The first evidence of gastrulation is the formation of the primitive streak, ... (pp. 60-61) ... After the primitive streak is well established, the majority of cells passing through it spread out between the epiblast and the hypoblast to form the embryonic mesoderm). (p. 62) [Carlson (1999)]

As noted here, gastrulation, the process during which the "mesoderm" is formed, is marked by the beginning of the formation of the primitive streak, usually about day-16 (Carnegie stage 7), and continues to day-18 (Carnegie stage 8) [Larsen (1998), pp. xi, 33; Moore and Persaud (1998), p. 64]. Does this mean that the "mesoderm" to which the NIH Guidelines refer would not even begin to be formed until after the primitive streak is "well-established"—which would be usually closer to day-18? If so, then this "limit" for deriving stem cells from living embryos, a "condition" stated for their use in these NIH Guidelines, would exceed the usual arbitrary 14-day "biological marker" used in many bioethics and governmental studies and discussions to date.

And if by the phrase "the state at which the mesoderm is formed" the NIH Guidelines are referring to that point when the mesoderm of the embryo is completely formed, then the official "limit" for using such embryos could be extended considerably later than day-18. Can't the NIH be more precise than this? Are these official "limits" slowly creeping up the embryological continuum?

Thus, the NIH Guidelines use the term "pluripotent stem cells" to refer to all of these separated "stem cells", which some of which could actually be "totipotent" stem cells because of their strong inherent capacity to revert to human embryos -- regardless of where on a gradient of "totipotency" any particular separated stem cell would happen to fall. "Totipotent" is "totipotent"—i.e., capable of forming new whole human organisms. We know -- from the reality of human monozygotic twinning, as well as from well-documented animal twinning experiments—that this totipotent capacity is inherent to all of these cells. Thus this research could entail the production of living human embryos in laboratory conditions. If such research were performed, and if such human embryos were produced, that would constitute human embryo research per se. Such research would violate the existing Congressional ban, and thus is already prohibited.

The "scope" section of these NIH Guidelines also state that the source of these "pluripotent stem cells" are "human embryos that are the result of in vitro fertilization." [p. 7] However, as noted in Part I of this analysis, most IVF-produced human embryos are frozen down at the 4-8 cell stage—when each of the cells of the embryo are totipotent, not pluripotent. Furthermore, at this stage most of these embryos have no inner cell mass containing purely "pluripotent" stem cells; and it has been scientifically demonstrated that even stem cells from the inner cell mass of a blastocyst can also be "totipotent" and form new whole embryos -- as documented in most natural and experimentally induced monozygotic twinning. Whether IVF-produced human embryos are frozen down until just before the completion of the formation of the mesoderm surely remains to be clarified.

Regardless, because the cells from most of these IVF-produced early human embryos are not all "pluripotent", nor possess inner cell masses containing only "pluripotent" stem cells, these NIH Guidelines could not possibly even apply to these IVF-produced human embryos.

 

[A.] Research Using Cells From Human Embryos

[1.] Submissions By Investigators:

For research that is "eligible" for NIH funding, the NIH Guidelines require an assurance from intramural and extramural investigators who are intending to use existing NIH funds that their "proposed research using human pluripotent stem cells is not a class of research that is ineligible for NIH funding" [p. 8] (emphases added). Yet because many of these separated "pluripotent stem cells" could actually be totipotent and could form human embryos themselves, such research would constitute human embryo research per se, and thus violate the Congressional ban. Therefore, such research could not be "eligible for NIH funding".

And the question needs to be asked: Do investigators know the correct human embryology and human molecular genetics required to submit a scientifically credible assurance to the NIH? Do members serving on the Institutional Review Boards (IRB's) have the required scientific knowledge to evaluate and approve such research? And how is this substantiated by the NIH?

[2.] Conditions for Use of "Human Embryonic Stem Cells"

The scientific fact that these separated "human embryonic stem cells" could actually be totipotent and form new living human embryos themselves, as well as the NIH Guidelines' requirement that only IVF frozen embryos can be used as the source for these "stem cells", has ramifications throughout the rest of the text of these NIH Guidelines. Only a few examples will be presented here.

For example, the NIH Guidelines state (emphases added):

"Studies utilizing pluripotent stem cells derived from human embryos may be conducted using NIH funds only if the cells were derived (without Federal funds) from human embryos that were created for the purposes of fertility treatment and were in excess of the clinical need of the individuals seeking such treatment." [p. 8]

Clearly, not all of the cells "derived from human embryos that were created for the purposes of fertility treatment" -- whether produced by IVF or by any other "fertility treatment" -- would be "pluripotent", but some could be "totipotent" and therefore capable of becoming new whole embryos themselves. Hence it would seem that the "conditions for use" as stipulated in these NIH Guidelines would actually prohibit the use of these cells left over from fertility treatments in federally funded research.

[3.] Informed consent:

"Informed consent" refers to both a process and a document. The purpose of informed consent is to provide a decision maker with the information necessary to make an "informed" decision based on knowledge of the accurate facts involved, as well as to assure that no pressures have been forced on this person's will that would cause him/her to make a decision that was unintended or undesired. The "information" is conveyed to the person by experts who are professionally competent to provide the actual facts that are needed (either orally or in writing), and this informed consent of the person is so documented in writing.

It is of interest that in this section of the "conditions for use" of human embryonic stem cells, the NIH Guidelines note that (emphases added):

"Decisions related to the creation of embryos for fertility treatment should have been made free from the influence of researchers or investigators proposing to derive or utilize human pluripotent stem cells in research." [p. 9]

While it is admirable that NIH seeks to assure the integrity of the informed consent process by separating the "decision to create embryos" of the donors from untoward pressures from researchers or investigators feverishly seeking the use of these very embryos, it is unfortunate that NIH does not appear to be as interested in providing the same level of integrity of the informed consent process when it comes to shielding these donors from these same researchers and investigators in their "decisions to donate embryos". Indeed, the integrity of these informed consent processes and documents should be taken as seriously by NIH and by the donors as the integrity of the informed consent processes and documents required to create these human embryos to begin with.

For example, the NIH Guidelines state (emphases added):

"To ensure that human embryos donated for research were in excess of the clinical need of the individuals seeking fertility treatment, and to allow potential donors time between the creation of the embryos for fertility treatment and the decision to donate for research purposes, only frozen human embryos should have been used to derive human pluripotent stem cells." [p. 9]

"Informed consent should have been obtained from individuals who have sought fertility treatment and who elect to donate human embryos in excess of clinical need for human pluripotent stem cell research purposes." [p. 9]

Again, the Guidelines stipulate that informed consent should have included "a statement that the embryos will be used to derive human pluripotent stem cells for research that may include human transplantation research", that derived cells and/or cell lines "may be kept for many years", and that "embryos donated will not survive the human pluripotent stem cell derivation process." [pp. 9-10] (emphases added)

Given the scientific uncertainties involved in this research and being presented to these potential donors, it would seem to be next to impossible for them to be sufficiently informed to give ethically and legally valid informed consent. Are these decision makers being given the accurate scientific information that these living embryos of theirs are already real whole living human beings—or are they told, or the implication conveyed, that these embryos are just "potential human beings", or "just a bunch of loosely connected undifferentiated 'stem cells' no bigger than the period at the end of this sentence"—as the NIH public relations have actively depicted these tiny living human beings for many years now?

Are these potential donors informed that the separated "stem cells" that would be derived from their own donated IVF-embryos could in fact totipotent, and therefore could naturally try to revert to new living embryos themselves, to be perpetuated in a continuous laboratory system in which even more laboratory-derived embryos could be produced, cultured, and killed for experimentation and "therapy"? Would these donors really not care if their own living progeny—created out of a sincere yet desperate and almost panicky desire to have their own children—were reproduced over and over again for years in laboratories around the world, cultivated in vitro or even in vivo in other women or even animal surrogate wombs, and used for whatever compelling research projects await science in the future? Can scientists document empirically that these scenarios could or would not take place?

Do these informed consent forms advise the potential donors that embryos derived from their embryos could be produced, possibly kept in cultures for many years, and also used in "human transplant research", and that untold numbers of these embryos would not survive later derivation processes either? Are these potential donors informed that any culture-produced progeny (or their "stem cells") could be used to form human or animal chimeras, or used in "positive eugenics" research in which their progeny could be permanently genetically altered for generations to come? Or could these donors just go into denial and pretend they didn't understand this information, or refuse it—and would this constitute true ethically and legally valid informed consent?

Should every consideration be given to the fact that so much of the same scientific "misinformation" is often disseminated by these "same researchers and investigators" themselves—especially through the media, press—indeed possibly through these official NIH Guidelines themselves? Wouldn't such public-generated "misinformation" be prejudicial to the donor's decision making as well?

Don't all involved in the informed consent processes and documentations bear serious moral and legal responsibilities for producing, conveying, disseminating, attaining, or accepting scientific "misinformation" in these donor "informed consents"?

What possible scientific, moral, ethical, legal or social merit would such "informed consent" processes and documents possess? And who is morally and legally accountable and responsible for such "uninformed consents"?

It would seem that the use of so much questionable science, and the pressures and influences to which confused and anxious potential donors of human embryos have been subjected, would preclude these potential donors from giving any ethically or legally valid informed consent.

[B.] Research Using "Human Fetal Stem Cells"

Among the "pluripotent stem cells" identified in the NIH Guidelines are what they refer to as "fetal tissue stem cells". The use of such "fetal tissue stem cells" in research, the NIH Guidelines state, is already legal because such research falls under the Federal statutory restrictions regulations regarding fetal tissue research [42 U.S.C. Sec. 289g-2(a); Federal regulations at 45 CFR Sec. 46.210; 42. U.S.C. Sec. 289g-1 and 42. U.S.C. Sec. 289g-2(b)]. But are "fetal tissue stem cells" just some vague blob of "fetal tissue" -- like, for instance, the kind used in the celebrated Parkinson's research we've all heard so much about? Not quite.

[1.] What "fetal stem cells" really are:

"Fetal stem cells" are the primitive sex cells, the "germ line" cells, which when they finally mature decades later can take part in fertilization as sperms and secondary oocytes to produce new human beings/embryos.

These primitive sex cells begin to develop very early in the developing human embryo—some human embryologists claim as early as the blastocyst stage (emphases added):

"Gametogenesis is the production of germ cells (gametes), i.e., spermatozoa and oocytes. These cells are produced in the gonads, i.e., the testes and ovaries respectively. The gametes are believed to arise by successive divisions from a distinct line of cells (the germ plasm), and the cells that are not directly concerned with gametogenesis are termed somatic. ... The reduction of chromosomal number from 46 (the diploid number) to 23 (the haploid number) is accomplished by a cellular division termed meiosis. ... Primordial germ cells ... are difficult to recognize in very young human embryos. Claims for them have been made as early as in the blastocyst, and they are believed to be segregated at latest by 2 weeks and possibly much earlier." [O'Rahilly and Muller (1994), pp. 13-14]

In addition, these "fetal stem cells" are usually removed from early developing aborted human embryos, not from fetuses (the embryonic period begins at fertilization and extends to the end of 8 weeks; the fetal period begins at 9 weeks and continues until birth). One wonders, then, why they are referred to as "fetal stem cells", rather than as "embryonic stem cells"? Could it be in order to "qualify" them as "fetal tissue", the use of which in "fetal tissue transplant research" is already legally valid in our federal statutes and regulations?

These "fetal stem cells" are also not somatic cells (which are defined as all the cells of the body with the exception of the germ-line cells). Nor are germ-line cells in the haploid state. They are diploid (contain the full complement of human DNA) during the decades of years required to mature them, the significance being that because they are still diploid they too may be cloned, just as somatic cells may be cloned, by any of several cloning techniques. These primitive sex cells—both male and female—may also be matured and then used in IVF or other reproductive methods to produce new living human embryos (emphases added):

"A subset of the diploid body cells constitute the germ line. These give rise to specialized diploid cells in the ovary and testis that can divide by meiosis to produce haploid gametes (sperm and egg). ... The other cells of the body, apart from the germ line, are known as somatic cells ... most somatic cells are diploid ...". [Tom Strachan and Andrew Read, Human Molecular Genetics: Second Edition (New York: Wiley-Liss, 1999), p. 28] "Meiosis is a special type of cell division that involves two meiotic cell divisions; it takes place in germ cells only. Diploid germ cells give rise to haploid gametes (sperms and oocytes)." [Moore and Persaud (1998), p. 18]

"In a mitotic division, each germ cell produces two diploid progeny that are genetically equal." [Carlson (1999), p. 2]

"Like all normal somatic (i.e., non-germ cells), the primordial germ cells contain 23 pairs of chromosomes, or a total of 46." [Larsen, (1998), p. 4]

Of significance too is that these germ-line cells are the cells used for "positive" eugenic purposes (emphases added):

There are serious concerns, therefore, that a hidden motive for germline gene therapy is to enable research to be done on germline manipulation with the ultimate aim of germline-based genetic enhancement. The latter could result in positive eugenics programs, whereby planned genetic modification of the germline could involve artificial selection for genes that are thought to confer advantageous traits." [Tom Strachan and Andrew Read, Human Molecular Genetics: Second Edition (New York: Wiley-Liss, 1999), pp. 539-541]

(See other discussions of human germ line "therapy" using DNA-recombinant human gene germ line "transfer" in: Carlson (1999), pp. 46-47; Larsen (1997), pp. 22-28; Benjamin Lewin (ed.), Genes III (New York: John Wiley & Sons, 1987), pp. 353-354.]

That is, these human germ-line cells, both male and female, can be injected with new foreign genes (human or animal, forming "chimeras"), and cloned to produced new living human embryos. Or they can be matured to the haploid state, and subsequently used in fertilization to produce new human beings/embryos. In either case, all of the cells of these new human embryos are therefore also permanently genetically changed—including their primitive sex cells. Thus, when these human beings grow up and later take part in reproduction—sexual or asexual—all subsequent new human beings or progeny will carry the new foreign genes as well, and perpetuate those genetic changes down through the generations. The genetic changes may be for "curing diseases", for "genetic enhancements only", or for "the advancement of scientific knowledge." It is worth repeating that human germ line gene transfer is a distinctive form of human cloning by means of genetic transfer of identical "copies" of human or animal genetic materials, using asexual and then sexual reproduction through the generations. The "foreign" genetic materials are transferred by using cloning vectors (emphases added):

"Clone describes a large number of cells or molecules identical with a single ancestral cell or molecule." (p. 955)... [A] cloning vector is a plasmid or phage that is used to 'carry' inserted foreign DNA for the purposes of producing more material or a protein product." (p. 956) ... Used in "clonal analysis": "Clonal analysis identifies a group of cells descended from a single ancestor in which a transposition-mediated event altered the phenotype. Timing of the event during development is indicated by the number of cells; tissue specificity of the event may be indicated by the location of the cells." (p. 474) ) [Benjamin Lewin, Genes VII (New York: Oxford University Press, 2000)]

"The term 'clones' indicates genetic identity and so can describe genetically identical molecules (DNA clones), genetically identical cells or genetically identical organisms." [Tom Strachan and Andrew P. Read, Human Molecular Genetics 2 (New York: John Wiley & Sons, Inc, 1999), pp. 508-509]

It is also of peculiar interest that some of these "fetal stem cells" would seem to be capable of being totipotent—at least if derived from the early human embryo—IVF-produced or culture-produced—from the blastocyst stage until the "formation of the mesoderm", as already scientifically documented in this analysis. As with "human embryonic stem cells", these "fetal stem cells" derived from the early human embryo could also revert to being new human embryos due to regulation. If this research were performed,this would constitute human embryo research, which would violate the Congressional ban. It would also violate the NIH Guidelines themselves.

Germ-line cells, aka "fetal stem cells", could also apparently be derived from IVF-produced or culture produced human embryos from the blastocyst stage until before the "formation of the mesoderm", and then cloned, producing new living human embryos, since they would still be diploid. Or, they could be allowed to mature to the haploid state, and then used in fertilization to produce new living human embryos. The production of living human embryos, by both cloning or by fertilization, would constitute human embryo research per se, and would violate the existing Congressional ban.

Nor, it would seem, would the use of most of these cells, by definition, accurately fall under protection of the various human fetal tissue transplant statutes and regulations as claimed in these NIH Guidelines, because they are mostly derived from embryos, not from fetuses, and therefore they would not be derived from "fetal tissue"; they would be derived from "embryonic tissue". Nor could such research be justified by referring to our federal OPRR regulations for the use of human subjects in research. Those federal regulations quite erroneously define the "fetus" as beginning at implantation (5-7 days post fertilization). However, the accurate scientific definition of "fetus" is the developing human being from the 9th week post-fertilization until birth. Therefore any tissue retrieved before 9 weeks would be embryonic tissue, not fetal tissue. Besides, these IVF-produced and culture-produced human embryos would not be implanted yet.

Thus, human "fetal stem cells" are really mostly human "embryonic stem cells", and their use, it seems, should not properly fall under the federal statutes and regulations dealing with "fetal tissue transplant research." Furthermore, to use the immature human germ line cells for cloning to produce human embryos, to mature and use these "fetal stem cells" in fertilization to produce living human embryos, or to derive them from IVF-produced or culture-produced human embryos for similar purposes, would surely constitute "human embryo research" per se, and therefore would violate the Congressional ban, as well as be prohibited by the NIH Guidelines themselves.

[2.] Submissions by investigators:

For research that is eligible for NIH funding, the NIH Guidelines require an assurance from intramural and extramural investigators who are intending to use existing NIH funds that "the pluripotent stem cells were derived from human fetal tissue in accordance with the conditions set forth in Section II.B.2 of these Guidelines" (which refers to the existing federal regulations and statutes pertaining to "fetal tissue transplant research") (p. 10). However, since these "fetal stem cells" are mostly "embryonic stem cells", it would seem that they could not fall under the protection of these federal regulations and statutes, because most of them are not derived from "fetuses". If they do, then perhaps those federal regulations and statutes are in need of serious reconsideration and revision.

Also, because some of these "fetal stem cells"—whether derived from frozen IVF human embryos or from culture-produced human embryos—could be "totipotent" rather than "pluripotent". Thus it is difficult to understand how such research using "pluripotent" stem cells could be "eligible" for NIH finding.

Once again, do investigators know the correct scientific facts of human embryology and human molecular genetics required to submit a scientifically credible assurance to the NIH? Do members serving on the institutional Review Boards (IRB's) have the required scientific knowledge to evaluate and approve such "fetal stem cell research". How does NIH assure that?

[3.] Informed consent:

As noted in the previous discussion concerning "human embryonic stem cells", the purpose of "informed consent" is to provide a decision maker with the information necessary to make an "informed" decision based on knowledge of the accurate facts involved, as well as to assure that no pressures have been forced on this person's will that would cause him/her to make a decision that was unintended or undesired. Most of the concerns for ethically and legally valid informed consent already mentioned with respect to the use of "human embryonic stem cells" apply to the use of "fetal stem cells" as well.

But in addition to those concerns, one wonders if the donors of "fetal tissue", from which these "fetal stem cells" are derived, are informed that this tissue also consists of the primitive sex cells, the germ line cells? Do they realize that these "fetal tissues" are mostly derived from their embryos, not from their fetuses, and therefore might not be protected by the federal regulations and statutes on "fetal tissue transplant research", or by the OPRR regulations? Are they told that these germ line cells may be totipotent, and therefore could form new living human embryos themselves, with derivable totipotent "stem cells" themselves? Are they informed that their "fetal stem cells" could be cloned to produce new living human embryos, matured and then fertilized to produce new living human embryos, or used in DNA-recombinant human gene germ line research and "therapy" for both "positive" and "negative" eugenic purposes, creating new living human beings with foreign genetic changes from their progeny, and from their progeny, down through the generations? Are the donors of frozen IVF-produced human embryos informed that their embryos, from the blastocyst stage until before the formation of the mesoderm, might also contain these primitive sex cells, or germ line cells? And that these germ line cells could be used in all of the same kinds of research as are "fetal stem cells"? Would these donors not care, or not want to know this critical scientific information, and if not, is that really ethically and legally valid informed consent?

And once again, who is ethically and legally responsible for any "uninformed consents"?

[IV.] Oversight:

Finally, in addition to the IRB's that NIH relies on to evaluate and approve the submissions and assurances from investigators for this research, the NIH Guidelines state that the "NIH Human Pluripotent Stem Cell Review Group (HPSCRG) will review documentation of compliance with the Guidelines for funding requests that propose the use of human pluripotent stem cells" (p. 12), and that a Scientific Review Group will review "cases of new or competing (renewal) or competing supplement applications" (p. 13). The obvious but very valid question is whether the members of this HPSCRG or the Review Group themselves know the required established facts of human embryology and human molecular genetics to be able to competently review documentation of compliance with the Guidelines, or to review new applications.

Far too many unanswered questions remain concerning "human pluripotent stem cell research"—both scientific and ethical. Perhaps the decision to allow such research, and to fund it—privately or publicly—would be premature.

[Part III will follow, consisting in the application of the correct science to the recent NIH stem cell report, the informed consent and safety of human patients who would participate in the use of human "pluripotent" stem cell "therapy" in clinical trials, and a summary of the entire analysis.]


Copyright, Dianne N. Irving, M.A., Ph.D, Bethesda, MD., July 22, 2001


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