"Any Human Cell - iPS, Direct Programmed, Embryonic, Fetal or Adult - Can Be Genetically Engineered to Asexually Reproduce New Human Embryos for Purposes of Reproduction ('Infertility')"

2. Artificial Sex Gametes Derived From iPS, Human Embryonic, and Adult Cells

One might even take any human cell, deprogram it back to a primitive germ cell, or an iPS cell, allow those cells to mature into sperm and oocytes, then use them in fertilization to reproduce a new embryo for reproductive purposes.

a) Documentation 2000 - 2008

The Hinxton Group has been tracking and documenting research in which any human cell can be deprogrammed back to a primitive germs cell for quite a while now. To see their extensive listing of what is termed "pluirpotent stem cell-derived gametes" (PSCDG) research for the years 2000 - 2008, see this endnote summary.36 More recently, there has been an acceleration of such research.

b) PSCDG Documentation 2008 - 2011

** There are already several books on the use of stem cells and tetraploid complementation for human reproductive purposes. Bongso and Lee describe many of them in their book, Stem Cells: From Bench to Bedside.37 Interestingly, by the time the book was published much of the research involving the production of human sperm and oocytes from HE and iPS cells was already accomplished. But one of the articles in that book by Burley constitutes a good link between the use of these techniques to reproduce human embryos for reproductive purposes and their use to derive human sex gametes from adult cells.

As Burley writes in his contribution to the book:

iPS cells have been combined with a tetraploid embryo (the fusion of two cultured blastomeres) to produce baby mice that are genetically identical to the iPS cells used. This raises the specter of human reproductive cloning in a new guise, assuming that the technique of tetraploid complementation could be replicated using human cells. In addition, as noted above, it is predicted that iPS technology may one day enable researchers to produced gametes from pluripotent stem cells. Two methods have been suggested: the combination of iPS-derived male and female gametes, and the combination of an iPS-derived gamete, such as a sperm with an egg of in vivo natural origin. ... iPS technology could allow the production of artificial gametes from the cells of living or dead people (frozen tissue in tissue banks) of known identity. When the implications of artificial gamete creation are more fully appreciated, it is inevitable that some will argue that it should not be allowed at all because too much scope for abuse exists. ... Artificial gametes would be very easy to make from a person's cells without his/her knowledge, and could be used to create an embryo for research or an embryo for implantation. These worries are, I think, well founded. However, there is no hard and fast causal relationship between a technology and all of its possible uses.38

** In 2008, the editor of Science noted in his article, "Sperm cells created from female embryo", that British scientists, headed by Prof. Nayernia, who had already coaxed human male bone marrow cells to develop into primitive sperm cells, had just repeated the feat with human female embryonic stem cells. As the editor wrote, "Sperm cells have been created from a female human embryo in a remarkable breakthrough that suggests it may be possible for lesbian couples to have their own biological children." The University of Newcastle team that had achieved the feat was applying for permission to turn the bone marrow of a woman into sperm. The editor noted that the research raises the possibility of lesbian couples one day having children who share both their genes as sperm created from the bone marrow of one woman could be used to fertilize an egg from her partner. Prof Nayernia showed the potential of the method in 2006, when he used sperm derived from male embryonic stem cells to fertilize mice to produce seven pups, six of which lived to adulthood, though the survivors did suffer problems.39

** In 2009, researchers from Spain and Australia published a review study, "Differentiation of germ cells and gametes from stem cells".40 Marques-Mari et al note that advances in stem cell research have opened new perspectives for regenerative and reproductive medicine, and that several groups have reported their ability to differentiate stem cells into germ line cells. Some of them have been successful in obtaining male and female gamete-like cells by using different methodologies. Marque-Mari et al highlighted studies reporting development of germ cell-like cells from murine and human embryonic (ESC) and somatic stem cells They noted that published studies indicate that germ cells can be consistently differentiated from mouse and human ESC, "although certain differentiation obstacles remain to be resolved". Their conclusion was that differentiation of germ cells from both iPS and HE stem cells "has the potential of becoming a future source of gametes for research use, and if genetic and epigenetic methodological limitations could be solved, therapeutic opportunities could be also considered."41

** In 2009, Amander Clark, a developmental biologist at the University of California, Los Angeles, and her research team created human egg and sperm precursors using an existing line of human induced pluripotent stem (iPS) cells. "For couples who can't seem to get pregnant, one of the more common causes is egg or sperm quality", the article noted.42 Researchers had previously shown that embryonic stem cells could produce egg- and sperm-cell precursors. But infertile couples would need to use donor eggs or sperm obtained from infertility clinics. "The benefit of using a human iPS cell is that it has the donor's own genetics," Clark says. The study also highlights the differences between embryonic stem cells and iPS cells. When Clark compared the developmental potential of iPS cells to that of embryonic stem cells, she found that the latter resulted in egg and sperm precursors that were substantially healthier, with fewer chromosomal abnormalities.

** Another focus on "infertility" treatments involved a study concerned with male infertility. In 2009, Neri et al pointed out in their study, "Treatment options for impaired spermatogenesis: germ cell transplantation and stem-cell based therapy", that men diagnosed with germ cell aplasia can only be treated by donor or de novo generated human gametes. In the past several years there have been attempts to manufacture gametes by inducing haploidization of somatic cells and more recently, by generating sperm-like cells through embryonic stem cell differentiation.43

** In early 2011 a French journal published another review study concerning "infertility" treatments.44 The article by Assou et al, "Generation of artificial gametes from human pluripotent stem cells: Is this possible?", noted how both human embryonic stem cells and iPS stem cells are both "pluripotent", and therefore "they have remarkable properties of self-renewal and differentiation into the three cellular lineages, somatic as well as germinal". The article also notes that the formation of putative gametes from mouse pluripotent stem cells has been shown, the apparent derivation of functional mouse male gametes has also been described, and that "in vitro production of [human] gametes by differentiation of human iPS has become a very immerging aspect of the actual research constituting an alternative tool for infertility treatment."

** Recently, a bioethical panel at Japan's Keio University in Japan announced its approval for research to create human reproductive cells (sperm and ova) using iPS cells to treat infertility and other congenital diseases.45 Prof. Hideyuki Okano of the university's School of Medicine and the Tokyo-based Kato Ladies Clinic will lead the research. The research team will try to transform human iPS cells into human reproductive ones by injecting reagents into human stem cells created from human skin cells.

** Another review study, "Application of iPS in assisted reproductive technology: sperm from somatic cells?", was published in September 2011 by Yao and his research team.46 Noting that "infertility is an emotionally charged problem, and it is a condition of increasing incidence", they present a hypothesis for a cure for infertile men with non-obstructive azoospermia (NOA) (caused by testis failure or impaired spermatogenesis). They suggest that "induced pluripotent stem (iPS) cell-derived spermatozoa can be a potential source for male gametes for patients with NOA",. They cite the evidence already established: the generation of viable, live-born, fertile mature organism from iPS cells; the successful induced differentiation of male gametes from pluripotent cells in vitro; and the wide use of intracytoplasmic sperm injection (ICSI) in human assisted reproduction.

** Finally, in November 2011 a Federal Government-appointed panel in Australia has recommended the use of the controversial "in vitro-derived gametes" in its final report to the review of national cloning and embryo research laws, "opening the door for a woman to produce a baby by creating her own sperm from skin cells."47 The technology - if proven - "could allow same-sex couples, or those who cannot produce their own eggs or sperm, to have genetically related children from both parents." It could also wipe out genetically linked diseases from one partner, and allow a man to develop his own eggs to fertilize his sperm in a surrogate. The panel points out that scientists have proven they can produce mice from natural egg and artificial sperm, and Britain's national fertility and embryology authority estimates eggs and sperm could be developed within five years to be potentially used in infertility treatment. Though the proposed legislation bans using artificial gametes for reproduction for now, bringing Australia in line with Britain, the report warns the community that the "development should be anticipated".

3. Embryo Splitting ("Twinning")

A team of reproductive researchers just recently discovered for in vitro work what had long been acknowledged in in vivo human reproduction - that the early human embryo has a natural inherent biological capacity to both heal itself when damaged and to convert totipotent cells (or blastomeres) that had separated from the original embryo to new embryos - called monozygotic or identical "twinning" (also called embryo splitting, blastomere separation, blastocyst splitting, embryo multiplication). In their July 2011 report, "Early embryos can correct genetic abnormalities during development: findings have significant implications for fertility treatment and stem cell therapies",48 William Kearns, director of the Shady Grove Center for Preimplantation Genetics in Rockville, Maryland, and his team decided to take advantage of this practice to see if the embryos maintained their genetic defects as they developed.

Using SNP microarrays, they reassessed abnormal 3-day-old IVF embryos, which patients had consented to donate to science, two days later. While only a fraction of these abnormal embryos survived those two days, many that did appeared normal.

What is happening - and what is hardly new to human embryologists - involves natural biological processes such as "methylation" and "regulation".49 In short, a human cell has the natural capacity to both "heal" a damaged cell or organism as is reported here, as well as revert any totipotent cell that has split off from the original embryo back to a new whole embryo (who is now the identical "twin" of the original embryo).

** In 2000 and 2001 a series of studies were published by J. P. Geradts and G. M. Wert on the technical and ethical considerations of human cloning. Technically, they explain how human cloning is not only possible, but has application in human reproductive cloning:

The successful cloning experiments in mammals such as the sheep and mouse prompted speculations on clinical application in humans. Cloning is possible by nucleus transplantation and by embryo splitting. Nucleus transplantation does not result in a genetically completely identical individual because the mitochondrial DNA originates from the ovum donor. Embryo splitting may be regarded as the artificial production of a monozygotic multiplet. Possible applications of cloning in humans belong in the context of reproduction (treatment of couples with subfertility, with genetic problems or with a 'replica motive'), transplantation of genetically identical tissue, and scientific research.50

Note the acknowledgement of the researchers that: (1) in cloning by nuclear transfer (either using donor somatic cells or donor germ cells), the resulting embryo is not "genetically identical to an existing or previously existing human being", nor is it a "twin" of the donor, since the new embryo's mitochondrial DNA is from the enucleated oocyte, and thus is genetically unique; and (2) it is possible to use "twinning" to reproduce new human embryos.

As for the "ethical" considerations, Geradts and Wert acknowledge the "unfavorable reactions" of some against human reproductive cloning, citing fears that cloning is unnatural, that it affects human dignity and violates the individual's right to genetic uniqueness. Other objections include unjustified health risks for the progeny, unjustified psychosocial risks for the clone child and the risk of cloning for eugenic purposes. Their "ethical" analysis of the reproductive cloning of human embryos, however, is reduced to "the purposes and applications" of such experiments. That is, if the purpose or intention is good, then it should be done. Reproductive cloning may be yet unsafe and inefficient; but "therapeutic" cloning should be acceptable "if alternatives are lacking".51

** In his 2001 article "Embryo splitting: A role in infertility?", Wood echoes and agrees with the counsel of Geradts and Wert on human reproductive cloning:

Embryo splitting may be used to increase the potential fertility of couples requiring IVF. ... The 30-40% greater chance of conception would reduce costs for the government, health authorities and patients, and reduce stress, time and complications for women having IVF treatment. Embryo splitting may also provide donor embryos for infertile couples that cannot conceive naturally or with IVF. The shortage of children for adoption and donor embryos may be overcome by the production of demi-embryos.52

** In 2008, Van de Velde et al "proved" what has been already scientifically documented for decades - that the "twinning" of a new human embryo in order to asexually reproduce new human embryos is possible. In their scientific study, "The four blastomeres of a 4-cell stage human embryo are able to develop individually into blastocysts with inner cell mass and trophectoderm", the researchers noted that:

Early mammalian blastomeres are thought to be flexible and totipotent allowing the embryo to overcome perturbations in its organization during preimplantation development. In the past, experiments using single blastomeres from 2-, 4- and 8-cell stage mammalian embryos have provided evidence that at least some of the isolated cells can develop into healthy fertile animals and therefore are totipotent. We investigated whether isolated blastomeres of human 4-cell stage embryos could develop in vitro into blastocysts with trophectoderm (TE) and inner cell mass (ICM).53

The researchers then split 4-cell stage human embryos, and the blastomeres (cells) were cultured. The result was that "The majority of the blastomere-derived embryos followed the normal pattern of development with compaction on Day 4 and cavitation on Day 5 and developed into small blastocysts". They concluded that "the blastomeres of a 4-cell stage human embryo are flexible and able to develop into blastocysts with ICM and TE."54

** In 2009, Illmensee et al continued the push to asexually reproduce new human embryos for reproductive purposes by "twinning". In their research study, "Human embryo twinning with applications in reproductive medicine", the researchers' purpose was "to assess the efficacy of human embryo twinning by blastomere biopsy at different early embryonic stages (splitting efficiency) and to determine the in vitro developmental capacity of twinned human embryos (developmental efficiency)." The "setting" of the research was "private IVF centers"; the "patients" were couples undergoing IVF who donated their "triploid" embryos. Their "method" was to split embryos at various cell-number intervals (2, 5, 6, and 8 cells) into blastomere cell groupings, and then culture them to the blastocyst stage. "Splitting of 6- to 8-cell embryos yielded superior rates of twin embryos developing to blastocysts (developmental efficiency)"; and "Twinning success was related to the superior morphological quality of embryos used for splitting.". They concluded that "This is the first report on twinned human embryos developing to blastocysts. This study exhibits the potential for novel applications in human assisted reproduction."55

** Also in 2009 Geens et al announced that they had proven that there is a mix of totipotency and pluripotency in the cells of the early intact human embryo. In their research study, "Human embryonic stem cell lines derived from single blastomeres of two 4-cell stage embryos",56 the researchers noted that they had already demonstrated previously that single blastomeres [cells] of a 4-cell stage human embryo are able to develop into blastocysts [embryos] with inner cell mass and trophectoderm [i.e., that some of the blastomeres were totipotent]. To further investigate potency at the 4-cell stage, they aimed in this study to derive pluripotent human embryonic stem cells (hESC) from single blastomeres, using embryo splitting to derive single blastomeres -- some of which went on to form embryos in culture:

[P]luripotency was confirmed by the presence of all three germ layers in the teratoma obtained after injection in immunodeficient mice. ... We report the successful derivation and characterization of two hESC lines from single blastomeres [cells] of four split 4-cell stage human embryos. These two hESC lines were derived from distinct embryos, proving that at least one of the 4-cell stage blastomeres is pluripotent.57

In the same year (2009), the American Medical Association (AMA) again came out with their latest "ethics" report,58 reaffirming their 2004 report endorsing "preembryo splitting" for "infertility" treatments.

** Shortly after that AMA report, researchers Illmensee et al published another study on human "twinning" in Fertility and Sterility, a journal of the American Society of Reproductive Medicine. In this new study, "Human embryo twinning with applications in reproductive medicine", the authors cite the most recent approval of "preembryo splitting" for infertility purposes. Their objectives for this current study were:

... to apply the newly developed technology [in mice] to human embryo splitting to evaluate its efficacy at different early embryonic stages (splitting efficiency) and to determine the best success rates of twin embryo development to the blastocyst stage under in vitro culture conditions (developmental efficiency).59

The researchers found that significantly increased rate for embryo twinning was observed for the more advanced embryos split at the 6- to 8-cell stage than for those split at the 2- to 5-cell stage. Noting the implications for reproductive cloning, they stated that:

For couples with few embryos of good quality available during one IVF cycle, embryo splitting may yield additional embryos to be cryopreserved for subsequent transfer, potentially increasing the likelihood of a pregnancy and even providing time-separated twins. The Ethics Committee of the ASRM has stated in its report that "splitting one embryo into two or more embryos could serve the needs of infertile couples in several ways. As long as a couple is fully informed of the risk of such an outcome, there would appear to be no major ethical objection".60

Thus such research is "ethical" as long as a couple is "fully informed of the risk of such an outcome."

** Just recently Illmensee et al published another related study in the Middle East Fertility Society Journal, entitled "Human embryo twinning with proof of monozygocity" (2011).61 Human embryos were split at the 6-8 cell stage into two groups of cells, and cultured to the blastocyst stage. They were then analyzed and confirmed as individual embryos. The researchers also confirmed that "Embryo splitting exhibits novel potential for future applications in assisted reproductive medicine."

** Of growing concern is the "call" by many researchers and certain organizations to "update" or change the long-documented formal definitions of critical scientific terms - and whether those new "scientific" definitions will simply provide excuses to perform unethical research, therapies and reproductive alternatives. Just one example of such efforts is from a Spanish rsearcher, Beriain I. de Miguel, in his study, "The human embryo after Dolly: new practices for new times."62 De Miguel notes that the possibility of cloning human beings "introduced a lot of issues in our ethical and legal frameworks." By changing the definition of an "embryo" as a whole organism into one of "just cells", presumably such (false) definitions will "help" researchers "face the new situation":

The possibility of cloning human beings introduced a lot of issues in our ethical and legal frameworks. In this paper, we will put the focus into the necessary changes in the concept of embryo that our legal systems will have to implement in order to face the new situation. The description of the embryo as a group of cells able to develop into a human being will be defended here as the best way of doing so.63 (emphases added)

As is already well known, such efforts to deconstruct the accurate human embryology to "justify" various efforts in medicine and research are hardly new. In the old days it used to be called "scientific fraud".

III. "Rogue" Reproductive Researchers and/or "Rogue" Science?

"When _I_ use a word," Humpty Dumpty said in rather a scornful tone, "it means just what I choose it to mean - neither more nor less." "The question is," said Alice, "whether you CAN make words mean so many different things." "The question is," said Humpty Dumpty," which is to be master -- that's all." Through the Looking-Glass, by Lewis Carroll [Charles Dodgson]

As even noted in the UNESCO document cited at the beginning of this article, there has been concern that some of these genetic engineering techniques could be used by "rogue" scientists and others who don't care about infringing any laws or regulations, who are trained in the use of these genetic engineering techniques (most of which are relatively simple), and who find their own private funding and private laboratories. Understandably, such efforts have been at least publicly discouraged by some scientists and organizations.

For example, in 2001, the Gerontology Research Group (GRG), which is fundamentally "pro" all this research, especially if it can lead to "immortality", announced its "position statement" distancing itself from recent reproductive research that had reportedly been executed by "rogue researchers" using private funds, etc. "Respectable scientists must disassociate themselves from those who have gone on record as seeking to accomplish this feat secretly in the near term", and they identified the following "rogue scientists".

Next Page: A. "Rogue Scientists"
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