Finally, and inexorably, a true professional scientist poses clearly challenging questions to his research colleagues, and to the scientific enterprise in general, about the dubious "scientific" justification for the current rush to clone human beings - for both "therapeutic" and for "reproductive" purposes. Ethically, since eventually all such "research" will be applied to people, he cautions against the abuse of women "egg" donors, and against the premature use of vulnerable sick human patients for testing supposedly "patient-specific" stem cells in supposed "therapies", pointing to the obvious violations of standard international research ethics guidelines such clinical trials would necessarily entail. [See Neville Cobbe, "Why the apparent haste to clone humans?", Journal of Medical Ethics 2006;32:298-302), at: http://jme.bmjjournals.com/cgi/content/full/32/5/298, copied below)]
As any decent genuine scientist knows, nature really has an obstinate way of sticking to the truth. Sooner or later that truth will out - like it or not. The scientific enterprise itself will suffer greatly, and society along with it, once the massive fraud and deception to hide the truth -- the objective scientific facts -- are outed. Perhaps this is what was really on Dr. Cobbe's mind, and justifiably so.
It is not that Dr. Cobbe is pointing out anything new and unknown to his research colleagues; they know the accurate objective scientific facts and the studies to which he refers. And if they don't know them, then even the international research ethics guidelines would preclude them from performing such research. Rather, it is that finally Dr. Cobbe is publishing (for the world to see) the problems that his colleagues have refused to articulate or admit to all these many years. It will be interesting to see just how articulate the answers from his colleagues, and from the scientific enterprise, will be to his hard-hitting questions.
Below please find a brief account of the major points Dr. Cobbe makes in this very important article. For a more detailed explanation, along with excellent hyperlinks to his extensive bibliography, please see the original article in the JME itself. [Emphases used to aid those unfamiliar with the science. Any errors in interpretation are mine alone.]
In his introductory sentence, Dr. Cobbe states clearly and concisely what is on his mind:
"The recent desperation to clone human embryos may be seriously undermining accepted ethical principles of medical research, with potentially profound wider consequences."
Those "accepted ethical principles of medical research" he clarifies later in the article as the Nuremberg Code and the Declaration of Helsinki. He understands that the very first ethical principle involving the use of human subjects in research includes the use of accurate science, by those with the proper academic degrees and experience, solid previous animal studies, and legitimate "informed consent". The rest of his questioning essentially applies these research standards to the current "rush to clone humans".
Agreeing with the premise of an earlier article in the same journal, he agrees that we "must not let our debate get completely derailed by vested interests, whether politically or economically motivated", and that the failure to find global agreement on human cloning at the U.N. could result in "reproductive" human cloning [and all the abuses of women that would entail]. And he also agrees that if we don't find global agreement on human cloning, "we can probably expect dire consequences for the future of biomedical research and its impact on society at large."
But he is equally concerned about the unethical aspects inherent in the rush to perform "therapeutic" human cloning research, including the abuses to all vulnerable human patients who would be required to participate in clinical trials. In a caution that I have tried to make innumerable times myself, he points out, for example, a glaring problem in the current Human Fertilisation and Embryology Authority (HFEA) policy in Great Britain:
"Bizarrely, the ultimate aim of this cloning licence was ostensibly to use patient matched embryonic stem cells to treat people with diseases such as type 1 diabetes, despite the recognition that 'transfer of immunologically identical cells to a patient is expected to induce the same rejection' in such autoimmune diseases." (emphases added)
As he has questioned the HFEA before, would not the use of vulnerable human patients in clinical trials be premature, dangerous, and unethical given the already acquired knowledge in the research community that such supposed "patient-specific" stem cells would most probably cause serious immune rejection reactions in these patients? And what about the research community's claim of supposed "superior qualities" of such human embryonic "stem cells":
"Among the various questions raised, I had specifically asked to know the justification for performing research of a preliminary nature with cloned human embryos before conclusively demonstrating the superior therapeutic prowess of embryonic stem cells derived by nuclear transfer or validating the rationale for the proposed work in animal studies." (emphases added)
That is, has the supposed "superior therapeutic prowess" of embryonic stem cells derived by nuclear transfer been conclusively empirically demonstrated? And has this "theory" about "patient-specific" human embryonic stem cells been adequately tested on non-human animals before being applied to vulnerable human patients? This is what the standard international research ethics guidelines require: the use of documented and accurate science, and previous testing on non-human animals.
Cobbe proceeds immediately to document the basis for his concerns about adequate knowledge of the science involved in human "therapeutic" cloning by asking some hard questions concerning the purported justification for such research:
"From what I can gather, it appears that the support for human cloning rather than animal research has been primarily based on the results of only two papers. However, the full implications of both of these papers with regard to purported therapeutic applications may be readily questioned, so the insistence that 'no further animal work is needed' is therefore hard to substantiate." (emphases added)
Cobbe first derails the all-important "proof of principle" supposedly used to justify any "therapeutic" cloning for so-called "patient-specific" stem cells. In the case of the paper by Rideout et al, he points out that the authors were "unable to perform therapeutic cloning according to their own definition of the procedure" -- because adult or tissue stem cells cured the mice with the original disorder, not embryonic stem cells derived by nuclear transfer. Indeed, "the [stem] cells derived from cloned embryos were attacked by white blood cells called natural killer cells in the recipient mice". That is, the host mice's immune systems attacked the "patient-specific" embryonic "stem cells" as foreign. Further, the authors used genetically engineered mutant host mice without such natural killer immune cells, which calls into question the general applicability to human patients. Nor did the authors provide any data to explain their observed increase in killer immune cells in these mutant host mice anyway, although such data is readily available.
The implications for applications to human patients is obvious: "To artificially create new humans without natural killer cells is clearly out of the question in terms of treating existing human patients, while it seems few people would currently advocate reproductive cloning for [such] spare parts." Hence Cobbe's challenge to the authors' "proof of principle":
"So, aside from further demonstrating that cloned animals must at least reach a fetal stage of development before they can be dependably used as compatible tissue donors, exactly what principle did this prove?" (emphases added)
Furthermore, the authors of this study insist that the immune rejection problems were associated with the host mice, and not with the transplanted mouse embryonic stem cells. But Cobbe points out that "abundant evidence" already exists to show that the cloning process itself used to derive embryonic "stem cells" could indeed result in cells that would cause immune rejection reactions in the host. He concludes that
" ... various questions regarding the 'proof of principle' paper describing therapeutic cloning should make one exceedingly cautious about extrapolating its implications for future [human patient] therapies without further confirmatory evidence."
Cobbe also points out that, although the paper by Barberi et al was able to demonstrate successful engraftment in parkinsonian mice of dopaminergic neurons derived from embryonic stem cells following nuclear transfer, "it appears that similarly successful engraftment was achieved with neurons derived from regular embryonic stem cells." This is probably because such cells were transplanted into the brain, "an organ that is already well known to be an immune privileged site." (emphases added)
"Since the embryonic stem cells derived by nuclear transfer appeared no more effective therapeutically than other embryonic stem cells, and the derivation of the few embryonic stem cell lines by nuclear transfer that proved to be suitable for use in this study was itself highly inefficient, the support for cloning provided by this paper appears questionable." (emphases added)
Even Ian Wilmut subsequently commented that "in the treatment of diseases within the central nervous system, cells from cloned embryos seem likely to offer less advantage".
Cobbe also addresses the biostatistical and carcinogenic implications of the Rideout et al study. Biostastically, the study lasted only eight weeks, and used only six mice for each of the two cell lines examined [which presumably would not pass a "t-test"]. This is also insufficient time to "eliminate recognisable risks of teratoma formation or carcinogenesis", especially given such cancer risks already known in the use of embryonic stem cells, e.g., those associated with epigenetic aberrations. And even though previous studies were performed to test the "developmental competence" of the cloned mouse embryonic stem cells, those tests provide little evidence of possible mutations, and used chimeric progeny. Finally, Cobbe points out:
"Moreover, work with embryonal carcinoma cells has shown that studies in which cells are injected into preimplantation embryos would still fail to address the potential of such cells to form aggressive tumours when injected into mature animals." (emphases added)
Corresponding work in adult humans would be unethical, he notes again.
Cobbe then turns to the second of the two papers, the one used to justify cloning with genetic modification, for both therapeutic and reproductive purposes -- a single report of successful gene targeting in human embryonic stem cells by Thomas Zwaka and James Thomson. He notes that again in this study, random insertions with potential pathological consequences in the host might not have been detected:
"I am therefore unsure why it is concluded elsewhere that 'there is little chance of a gene landing in the wrong place and causing problems' based on the data in this paper."
Cobbe notes that more efficient gene targeting has been described using human adult stem cells, and adds that "Zwaka and Thomson have subsequently urged caution in the use of embryonic stem cells, based on their observations of aneuploid cells in culture." Cobbe pointedly asks:
"This begs the question of why anyone would want to propose using stem cells from cloned embryos as the preferred route for gene therapy." (emphases added)
So, he wonders, where might this recent urgency to clone human embryos come from?
Cobbe questions the very rationale behind "research cloning", i.e., the use of "nuclear transfer" with patient cells to produce their cloned human embryos for research purposes only. It is argued that "research cloning" would avoid invasive and risky biopsies of patients to study how their cells could be affected in disease, or how the patients might respond to drugs. But this claim is seriously flawed, Cobbe argues, because of the significant variation in gene expression between clones - as reported in cow fetuses cloned from the same nuclear donor compared to half siblings from IVF or artificial insemination. Wilmut has also described cloned offspring as being more variable than siblings, and asserted that "there is no currently available or foreseeable way to reliably predict the developmental performance of cloned embryos or determine beforehand how their gene expression patterns might be altered." Wilmut also noted that aberrant gene expression caused by cloning could actually invalidate studies that are aimed at identifying subtle differences in drug metabolism between patients with different geneotypes. As Cobbe points out, the additional variation in gene expression resulting from nuclear transfer is likely to "confound interpretation of such experiments," as would studies involving non-congenital genetic diseases of relatively late onset conditions (as distinct from those that are truly congenital in nature). Wilmut has also highlighted the epigenetic instability inherent in embryonic stem cell lines, and stressed the importance of studies to detect possible defects "throughout a life span". With classic understatement, Cobbe concludes:
"As I am presently unaware of any animal studies that demonstrate the feasibility of such research with human embryos, I am therefore left wondering what the real rationale behind such work might be." (emphases added)
Cobbe expresses "surprise" that these scientific difficulties "have subsequently been overlooked by some advocates of cloning in their writing for the general public." He gives the example of lobbying efforts at the United Nations before a final decision on human cloning: It was claimed that cells from cloned embryos would not have the same developmental defects as cloned animals. However, Cobbe notes, "[T]his paradoxical assertion conflicts with numerous published studies showing that the potential for cloned embryos to develop normally is limited by epigenetic defects in the embryos themselves." Thus the few individuals which make it to term and present abnormalities are likely to represent merely a minority of embryos in which nuclear reprogramming is more successful, and epigenetic dysregulation is least severe. [That is, they could hardly be considered the "norm".]
Further, Cobbe continues, Jaenisch et al have clearly demonstrated that cloning by nuclear transfer introduces "a host of new defects in gene expression" in both embryonic and extra-embryonic tissues which defects cannot be accounted for "simply in terms of artefacts resulting from artificial in vitro culture conditions." And although a recent study showed that some embryonic stem cell lines derived from cloned or fertilized mouse embryos may appear to be transcriptionally and functionally indistinguishable, "one should note that the selected cell lines that were described in this study were those already shown previously to support life following injection into chimeric embryos." This study also neglects to highlight the low overall rate at which the resulting chimeric embryos actually survived to term. Needless to say, Cobbe points out, corresponding experiments on humans to assess the behavior of human embryonic stem cells would obviously be considered unethical. His point is clear:
"It is therefore hard to envisage why epigenetic defects might only present problems for reproductive cloning but not therapeutic cloning." (emphases added)
Next Cobbe questions why more preliminary studies using animal cloned embryos and their stem cells have not been done before moving directly to cloned human embryos? Since cloning by nuclear transfer is "still far from efficient," and the limited data available from therapeutic cloning from blastocysts suggest that it is "even less successful than reproductive cloning", then "how explain the exaggerated claims that therapeutic cloning 'can help just about any condition in which there is lost or damaged cells'" and that "the list is almost endless"? Perhaps "something resembling part of the promise of therapeutic cloning may become feasible some time in the distant future," Cobbe says. Yet this would depend on considerable investment in further basic research, and Cobbe questions that this necessarily requires cloning human embryos (rather than those of other animals). The practicality of using the mouse and other animal systems has been well-published and documented. Since especially the mouse system provides a convenient model for studies, "we should be critical of the primary motivation underlying any apparent urgency to use cloned human embryos at this stage in the search for therapies." This is especially important "in light of the barely discussed phenomenon of host dependent turmorigenesis following transplantation of embryonic stem cells" making it clear that the safety of stem cells derived from human embryos cannot be determined by zenotransplantation [cross-species]. Cobbe then states what should have been obvious all along:
"It is therefore vital that significant risks should be properly eliminated in studies from other species before any therapeutic use of human embryonic stem cells can be considered."
If mouse studies won't work, then why not try other animal species? Although he doesn't condone unnecessary or inhumane animal experimentation, Cobbe asks:
" ... shouldn't we be even more critical of any intentional exploitation of human life when the rationale behind the proposed research appears questionable and remains to be validated by corresponding studies in other species? ... [I]f one opposes vivisection on the grounds of its non-consensual nature at an individual level and the assumption that one would not wish to be subjected to similar procedures, then one is unlikely to consider corresponding experiments on humans any more justifiable, even less so where one believes that the latter lives have greater potential value." (emphases added)
And then Cobbe acknowledges what I have also been emphasizing for a long time - the international research guidelines:
"Both the Nuremberg Code and the Declaration of Helsinki stipulate that any allowed experimentation involving human subjects should be capable of being supported by the relevant research literature and preceded by corresponding humane work in animals if necessary. For example, the Declaration of Helsinki states that 'research involving human subjects includes research on identifiable human material' and stipulates that 'medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and on adequate laboratory and, where appropriate, animal experimentation.'" (emphases added)
Cobbe also makes another critical observation concerning "informed consent" - another international research ethics principle. What meaning would "informed consent" really have:
" ... if women are expected to provide eggs for research on the assumption that such work is potentially life saving when the requisite evidence for this from animal studies is still sorely lacking and the risks to a woman's health can be potentially grave." (emphases added)
Cobbe notes the recent Hwang research fraud, questioning the rush to create a World Stem Cell Hub under Hwang's leadership, facilitating global recruitment of patients and exchange of cells derived by nuclear transfer, "when it was still acknowledged that 'preclinical evidence is required' to prove that transplantation of stem cells from cloned embryos 'can be safe, effective, and tolerated.'" He also addresses the impact that so much hype about this research has had on the "informed consent" process:
"Will 'informed consent' embrace correcting the confusion caused to the average patient by the persistent public deception surrounding both procedures for obtaining human eggs for cloning, and fraudulent claims regarding the purported efficiency with which patient specific embryonic stem cell lines could be created by nuclear transfer?" (emphases added)
Cobbe then hits his colleagues hard, and it is worth quoting him word for word:
"Regardless of any potential therapeutic benefits of research using stem cells from embryos otherwise destined for destruction, if we should choose to permit both the creation and destruction of human life and potential exploitation of patients simply for the express purpose of pursuing currently unsubstantiated and questionable research with no obvious or immediate clinical applications, then we should recognise how this risks the crossing of an ethical boundary that was originally drawn to prevent further abuses of human rights previously associated with Nazi doctors. Even in Britain, this would be a striking departure from the presumed intention of the Human Fertilisation and Embryology (Research Purposes) Regulations 2001, that permits limited human embryo cloning in principle. Nevertheless, this does not seem to have deterred proposals to use critically ill patients as test subjects for highly risky and premature experiments, for which the long term consequences remain worryingly uncertain. I therefore pose the question, if we now allow such human experimentation without prior and thorough validation from humane work in other species, do we really know where we are going?" (emphases added)
Here is an honest man who knows that the Nazi Medical Holocaust that ended just 60 years ago was quite real. He seems very worried about what he is currently observing within his own medical research profession today.
Although Cobbe agrees with the earlier journalist that bioethics should be more concerned about fair access to health-care for adults, rather than about cloning and embryos, he counters that perhaps the difficulty in achieving international consensus on the use of cloning reflects the extent to which the immediate benefits might only be for the wealthy. Public reaction in Britain also show how insistence on such experimentation might be more influenced primarily by economic interests, rather than genuine concern for patient welfare. Cobbe notes that reproductive cloning of non-human animals involves considerable sums of money, and that both therapeutic and reproductive cloning in humans won't be cheaper - especially given the high price of eggs. He relates how this concern even caused a European Parliament resolution that seriously questioned the role of the British cloning authorities in facilitating a trade of human eggs from vulnerable Romanian women. Other concerns include the elevated risks of ovarian hyperstimulation syndrome, and the surgical risks associated with oocyte retrieval. Such real risks to women might not be given adequate attention "when money become a dominant motive." Proposals to acquire human eggs for cloning by subsidizing fertility treatments in developing countries, he adds, "will appear highly suspicious wherever more pressing health issues than infertility predominate." Additionally, the demand for human eggs of the highest quality for cloning research could further reinforce concerns, especially with egg donors from IVF in short supply.
Wilmut himself acknowledged that "therapeutic cloning is unlikely to be practical for routine use" because the process would require an inordinate supply of eggs. Cobbe also reminds his colleagues that Hwang's fraudulent research claimed to have used at least 242 fresh oocytes donated by healthy women, from which only one embryonic stem cell line was purportedly derived. Yet we now know that as many as 2061 eggs from 129 women were used - without deriving any "patient-specific" stem cells from any cloned human embryos.
Cobbe acknowledges that modified protocols using fresh eggs from younger donors might help. But even still, development to the blastocyst stage to derive stem cells is not equivalent to full reprogramming; and we can't predict which of the few embryos produced might have relatively few gene mutations -- thus probably indicating the need for even more eggs to be sure. It is also possible, he agrees, to either use eggs from other animals or eggs differentiated from embryonic stem cells in the nuclear transfer process, but "the currently available data fails to support either of these proposals as feasible at present." Thus the shortage of human eggs required remains "a considerable obstacle that poses a potential threat to the welfare of poorer women (as pointed out by Nigeria's representative to the United Nations on 18th February 2005)."
Cobbe finally concludes that:
" ... a host of vested interests may have played a significant role in encouraging potentially profound misrepresentation of both the science surrounding cloning and its foreseeable clinical implications." (emphases added)
This is "considerably more worrying" than previous concerns about the hasty manner some cloning research had been "prematurely publicised before peer review," and leading to fears that the image of science as a whole might be seriously threatened by the recent fraud. Cobbe then concludes with a final hard question for his scientific colleagues, and indeed, the medical research enterprise as a whole:
"Perhaps we would be wise to ask ourselves not so much whether the question of human cloning has deserved so much debate, but rather whether the seemingly biased nature of the debate so far has blinded many of us to its possible wider implications for the practice of medical research and its true beneficiaries." (emphases added)
Hopefully Cobbe's hard analysis of the current irrational "rush to clone humans" won't be in vain.
http://jme.bmjjournals.com/cgi/content/full/32/5/298
Journal of Medical Ethics
2006;32:298-302;
doi:10.1136/jme.2005.011981
(subscription)
RESEARCH ETHICS
N Cobbe
Correspondence to:
N Cobbe
Wellcome Trust Centre for Cell Biology, University of
Edinburgh, Michael Swann Building, King's Buildings,
Mayfield Road, Edinburgh EH9 3JR, UK;
Neville.Cobbe@ed.ac.uk
Original version received 21 February 2005
Revised version received 17 May 2005
Accepted for publication 19 May 2005
The recent desperation to clone human embryos may be seriously undermining accepted ethical principles of medical research, with potentially profound wider consequences.
In her editorial in the February 2005 issue of this journal, Nikola Biller-Andorno questioned whether the effort and resources that have been invested in debates about cloning at the United Nations might have been somewhat disproportionate, if a binding universal agreement on reproductive cloning cannot be reached.1 Although most of the overt disagreement has centred around "therapeutic" cloning, rather than the potential use of nuclear transfer for reproduction, it is none the less clear that the delay and ultimate failure to date in achieving consensus on the former has also increased the likelihood of the latter becoming a foreseeable reality in the absence of a legally binding global convention. Whilst the much heralded promise of therapies has now been severely undermined by scandals of fraud,2 the available evidence from various primate studies3,4,5 and the history of similar work with other mammalian species6,7 have provided little reason to doubt that human reproductive cloning might be possible in principle (albeit grossly inefficient and untenably risky). I completely agree with Dr Biller-Andorno's appeal that we need to "foster a genuine, worldwide discourse on bioethical issues" and not let our debate get completely derailed by vested interests, whether politically or economically motivated. If we don't, we can probably expect dire consequences for the future of biomedical research and its impact on society at large.
Prior to the United Nations' discussions regarding a ban on human cloning in October 2004, the Human Fertilisation and Embryology Authority (HFEA) in Great Britain announced that they had granted their first licence to clone human embryos by nuclear transfer,8 though no other applications had apparently been made following the legalisation of restricted human cloning over three years previously. Bizarrely, the ultimate aim of this cloning licence was ostensibly to use patient matched embryonic stem cells to treat people with diseases such as type 1 diabetes,9 despite the recognition that "transfer of immunologically identical cells to a patient is expected to induce the same rejection" in such autoimmune diseases.10 The granting of their second licence was then announced barely a week before a United Nations working group was expected to begin meeting to finalise the text of a declaration on human cloning. This is curious since Britain's representative to the United Nations had previously made it clear that any attempt to ban or unreasonably restrict cloning for research purposes would not be supported anyway, while asserting that "the United Kingdom is totally opposed to human reproductive cloning". Nevertheless, members of the divided House of Commons Science and Technology Select Committee subsequently questioned whether there should be "a total prohibition of any form of reproductive cloning", despite also acknowledging "that research in developing reproductive cloning would very likely involve experimentation that is highly unethical". Following initial correspondence with the HFEA in which I had raised several questions about the wisdom and timing of their decision to grant even the first of these licences,11 the authority published a report on their website, describing the background to their decision. Among the various questions raised, I had specifically asked to know the justification for performing research of a preliminary nature with cloned human embryos before conclusively demonstrating the superior therapeutic prowess of embryonic stem cells derived by nuclear transfer or validating the rationale for the proposed work in animal studies. Here I attempt to explore broader ethical and scientific issues arising from the response to this question.
Next Page:
Current Progress Towards Therapeutic Cloning
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