Millions of people who until only a few decades ago had no chance of genetic parenthood, now have children of their own. Even for professionals in the field, the progress achieved in the understanding of basic physiological processes relating to female and male infertility and basic human embryology over the last few decades, at times, appear futuristic.
Though, as previously discussed in this series of articles IVF, especially during its early stages, confronted considerable skepticism and ethical scrutiny, it, and other innovative infertility treatments), have been facing progressively declining ethical scrutiny, when almost unimaginable progress over recent years actually calls for more scrutiny. As the only specialty field in human medicine capable of producing “new life,” reproductive medicine has an innate responsibility of pursuing clinical practice at highest possible ethical standards. In parallel, reproductive biology, including embryology, has the same responsibility in research and laboratory practices involved with reproductive medicine. As research and clinic practice increasingly entered controversial and ethically challenging areas, we on some occasions appear, indeed, to have crossed certain lines that should not be breached yet. Here is some material for further thought and consideration
Using in vivo raised human blastocysts for research purposes
In December of 2019 Human Reproduction published a paper by 14 authors, many well known researchers, clinicians, academics, and even past officers of major professional organizations. The study reported on women who underwent ovarian stimulation with fertility drugs and intrauterine inseminations. Their uteri then were lavaged at time points when embryos after fertilization in fallopian tubes were expected to have reached the endometrial cavity. The only purpose was to flush them out before implantation, so that they could undergo preimplantation genetic testing for aneuploid (PGT-A) in a more cost-effective way. But PGT-A is considered controversial, previously repeatedly subject of discussion in The VOICE.
This concept of embryo harvesting was initially pioneered by John E. Buster, MD, in 1985, (2) leading to the development (and patenting) of a special instrument for embryo recoveries (Previvo Genetics) (3). Already in 1989, the technique was reported to allow chromosomal analysis of so-obtained embryos;(3) it, however, despite attempts by the inventors to popularize it as an alternative to standard IVF, for several reasons never received practical acceptance in routine clinical IVF. The group of investigators, indeed, did not publish a single study between 1993 and above cited study in 2019 (1).
Not unanticipated, publication of this study in Human Reproduction raised substantial ethical concerns, well demonstrated by dueling editorials of editors of the same journal (5,6) and a very detailed commentary in the Journal of Assisted Reproduction and Genetics by a highly regarded ethicist (7). As one would predict, not all embryos are successfully flushed out using this method of embryo retrieval. Some of the women participating in the study found themselves, indeed, pregnant against their will and underwent termination of pregnancy with methotrexate or even dilatation & curettage. Lambalk et al (Lambalk is the editor-in-chief of Human Reproduction) correctly noted in their editorial that, “all of these interventions are potentially harmful to the women who did not benefit directly from participation – other than through financial compensation" (5).
Laudably, the journal verified that IRB approval had been obtained appropriately by the U.S.-based Western Institutional Review Board and the Ministry of Health of the State of Nayarit in Mexico (which really cannot be considered an IRB), where, interestingly, all interventions were carried out. Patient information sheets, moreover, appropriately informed participants in the study of all potential risks, including unwanted pregnancies and that participants in the study would receive a payment of $1,400. This, “convinced the Editorial Team that all necessary steps were truly taken for ethical approval,”(5) and the paper was only at this point sent out for peer review. As Lambalk et al further report, “during full external peer review, several reviewers raised serious concerns with regard to the ethical aspects and some recommended outright rejection based on these concerns” but a majority of the team,(5) “did not take the easy way out” (5) (as the editors rather shamelessly lauded their own actions) to reject the paper, while only one loan associate editor, Israel-based fertility specialist Galia Oron, MD, dissented,(6) and so did a leading ethicist, Ronald Michael Green, PhD, the Eunice and Julian Cohen Professor for the Study of Ethics and Human values in Religion (Emeritus) in the Department of Community and Family Medicine at the Dartmouth Medical School(7) and, as shamefully so-far the only professional society, the leadership of the Italian Society of Embryology, Reproduction and Research (SIERR)(8).
Details of all their criticism would fill the whole length of this newsletter. We, therefore, present here only an abbreviated summary of their criticism intermingled with some proprietary CHR opinions; we, however, strongly recommend that readers interested in the subject to look up the below listed citations.
The ASRM recently published very timely guidance regarding research involving human embryos. Among several other important points this guidance reemphasized that, in consideration of human embryos’ unique ethical standing, they should be used in research only if there is no other way of receiving the desired research answer; and should that be the case, only the smallest possible number of human embryos should be used to get to those answers(9). What the principal purpose of the Munné study1 was, is, however, unclear: (i) That embryos could be flushed out of the uterus, the authors have repeatedly before demonstrated since 1985;(2-4) (ii) That PGT-A could be performed on such embryos, the authors also already demonstrated in 1989 (3). (iii) Does it really take 134 attempts to determine that euploidy/ aneuploidy are not different between IVF embryos and in vivo-produced embryos? (iv) Does it, indeed, require that many human embryos answer this question?
Because we do not believe the last two points to apply, one must wonder how most of the Editorial Team at Human Reproduction could conclude that the authors had fulfilled ethical requirements in a way that warranted publication of this study. Moreover, that they published a study in which investigators created an unwanted risk of human pregnancies requiring induced abortions of these human pregnancies without any medical gain for these women who financially were obviously coerced, is beyond astonishing.
Lambalk et al, indeed themselves, raised the question of whether payments of $1400 to Mexican participation, in that country the “equivalent of a 71-working-day wage,” 5 may not have to be considered coercive? Why would U.S. investigators (and U.S. economic interests), indeed, conduct such a study in Mexico and not in the U.S.? The reason, of course, was that such a study in the U.S. only unlikely would attract “takers,” willing to risk pregnancy and pregnancy termination in return for a $1400 payment. One also must wonder about the “naiveté” of the Editorial Team in describing the Ministry of Health of the State of Nayarit in Mexico as a “second IRB.” That is, of course, not the function of any government organization. Moreover, government “permissions” are often, of course, relatively easily “purchased” in Mexico.
We have in these pages repeatedly pointed out the shared responsibilities of editors and editorial boards for the ethical practice of medicine and, yes, that includes, if needed, the overruling of ethics boards. Especially if organized as for-profit enterprises (as many regional ethics boards are), their self-interest often favors applicants over other interests. The Editorial Team of Human Reproduction in this case seriously erred in its decision to publish this manuscript. Their arguments were not too dissimilar to those of the Editorial Board of another prominent journal in the field several years ago when publishing a case of spindle transfer to prevent transmission of a terminal mitochondrial genetic disease from mother to offspring (10). Coincidentally, that manuscript also involved treatment in Mexico and serious ethical (as well as legal) transgressions,(11) with the appropriate criticism voiced at the time(12). Simply because of the sheer number of participants involved, ethical concerns regarding the recent Munné paper,(1) however, clearly exceed those of the earlier paper by Zhang et al(11). Reaffirming the increasing influence of the genetic testing industry on some of the ethical excesses infertility practice, Munné, interestingly, shared authorship in both of these manuscripts.
Editors and editorial boards have been increasingly overextended by the explosive growth in numbers of submitted papers but also by the increasing competition from growing numbers of new medical and science journals. Medical research, however, depends on the final judgment of the peer review process in not only determining what represents scientifically valid studies but also whether studies are ethically appropriate and do not, in the name of science, exceed ethical boundaries. Such boundaries, unfortunately, are, however, often easily breached by zealous scientists when they consciously or subconsciously put self-aggrandizement and/or commercial self-interests ahead of ethical conduct of science.
Likely that most outrageous such ethical transgression in recent years was the use of CRISPR-Cas9 by the Chinese scientist He Jiankui in trying to eliminate the CCR5 gene in human embryos in an attempt to make offspring immune to the HIV virus (no reference can be offered since this attempt was never published in a medical journal. Clinical outcomes of these experiments, therefore, to this day are unknown). A recent opinion article by a lawyer from the Faculty of Law at the University of Macao in Macao, China, is, however, already in its title reflective of the ambiguity with which China treats ethical issues in medicine and science, when headlining the article, “The First Chinese Edited babies: A Leap of Faith in Science" (13). Opinions of what represents ethical conduct, therefore, very obviously vary in today’s world!
That He’s scientific pursuits have not been published by any medical journal reemphasizes that medical journals are meant to serve as the ultimate authority in controlling the scientific truth of the moment and the ethical conduct of research. To see them kowtow to governments and/or commercial interests like the rapidly growing genetic testing industry is, however, disturbing and, in itself, often unethical.
Munné et al., First PGT-A using human in vivo blastocysts recovered by uterine lavage: comparison with matched IVF embryo controls. Hum Reprod 2019;35(1):70-80.
Buster JE. Embryo donation by uterine flushing and embryo transfer. Clin Obstet Gynecol. 1985;12(4):815-824
Sauer MV, .... Buster JE. An instrument for the recovery of preimplantation uterine ova. Obstet Gynecol 1988;71(5):804-806.
Buster JE, Carson SA. Genetic diagnosis of the preimplantation embryo. Am J Med Genet 1989;34(2):211-216
Lambalk et al., Ethics beyond ethics. Hum Reprod 2020;35(1):1-2
Oron G. How far should we go in the name of science? Hum Reprod 2020;35(1):3-4
Green RM. When pregnancy is a research risk. J Assist Reprod Genet 2020;37:2687-2690
De Santis et al., IUI and uterine lavage of in vivo-produced blastocysts for PGT purposes: is it a technically and ethically reasonable perspective? Is it actually needed? J Assist Reprod Genet 2020;37(7):1579-1582
ASRM Ethics Committee. Ethics in embryo research: a position statement by the ASRM Ethics in Embryo Research Task Force and the ASRM Ethics Committee. Fertil Steril 2020;113(2):270-294
Alikani et al., First birth following spindle transfer for mitochondrial replacement therapy: hope and trpidation. Reprod Biomed Online 2017;34(4):333-336
Zhang et al., Live birth derived from oocyte spindle transfer to prevent mitochondrial disease. Reprod Biomed Online 2017;34(4):361-368
What is success in advancing medicine?
The preceding section already demonstrated that progress “at all costs” very easily can lead to ethical transgressions that must be avoided. As above presented examples also demonstrated, such transgressions are relatively easily noticed and, therefore, if truly of ethical importance, will be in most cases discovered and remedied. A very different kind of scientific success is, however, at times more difficult to point out and, ethically, therefore may represent a more complex problem.
A good example is uterine transplantation. Women who either from birth are lacking a uterus and/or had their uteri removed for medical reasons, quite obviously can no longer conceive, and carry a pregnancy. Assuming they still have their ovaries, until recently, their only chance of becoming genetic mothers was, use of a gestational carrier.
CHR investigators attempted to tackle this problem already in the mid 1980s in small animal models but quickly gave up because transplanted uteri got severely infected.1 Several years later a Swedish friend of The CHR, Prof. Mats Brännström, MD, initiated what likely represents one of the most remarkable research effort in the history of modern infertility: Through sequentially small animal experiments, large animal experiments, cadaver surgeries and ultimately, human surgeries in a prospective clinical trial that started in 2013 and in 2014 resulted in the first live births of a newborn raised in a transplanted human uterus, he truly created a revolutionary treatment from scratch2 Brännström’s effort, unquestionably, must be recognized as one of the great achievement in reproductive medicine in the last 50 years and it happened scientifically as well as ethically in exemplary form, meeting and exceeding all expectations. Moreover, his and his team’s efforts have spawned worldwide copycats, with multiple births reported by now from multiple centers all around the world.
Yet, despite all this success, colleagues from Salt Lake City recently astutely asked in association with uterine transplantation surgeries, “what is success?”3 Among other issues they raised the question whether patients undergoing uterine transplants really were receiving appropriate informed consent? They questioned whether the admirable goals of scientific advancements are properly tempered by honest enough considerations of possible iatrogenic harm.
Physicians, of course, know that informed consent always depends on how information is provided to patients and, often, also by whom. We here at CHR, therefore, strongly feel that deference to IRBs in approving clinical trials is essential. Physicians, in addition, or even better beforehand, must decide whether in working toward a new treatment goal potential benefits will outweigh potential risks because using a treatment that causes more harm than it brings benefits can never be considered ethical.
When talking about a “successful” treatment the premise, therefore, must be that the treatment offers a favorable risk-benefit ratio. Assessment of such risk-benefit considerations can, however, be complex because while risks can usually be objectively established, benefits can be highly subjective. Uterine transplants are, indeed, a good example. There are many women for whom the ability to experience a pregnancy and delivery will be a potentially lifechanging event. But for a quickly increasing number of women that is not the case, as increasing numbers of gestational carrier pregnancies for social rather than medical reasons convincingly demonstrate. In other words, for many, likely still most women, carrying their own children and delivering them still appears like a substantial benefit and, indeed, may outweigh all known risks. But do these women, as previously noted,3 fully understand their risks?
Do they understand that: (i) the surgery to implant the uterus is major, hours-long surgery (not even considering that, unless cadaver uteri are used, the donors also must undergo major surgery)? (ii) Not every uterine transplantation will “take,” and that some uteri must again be immediately surgically removed because of rejection responses by the immune system.? (iii) While maintaining a uterine transplant, the women must be on major immunosuppressive treatments with considerable side effects (especially during a pandemic a quite risky thing to do)? (iv) Ultimately, every uterus must be removed again in a second major surgery to be able to stop immunosuppressive treatments. (v) Pregnancies while on such drugs may experience additional complications; and, finally, do they understand the costs of such a uterine transplant, of subsequent maintenance treatments and, ultimately, of a high-risk pregnancy on potent immunosuppressive drugs?
In the Swedish live donor trial of Brännström’s group, the cost of the transplant surgery alone, excluding pregnancy care, was reported to be €74,5644 (roughly US$ 90,000), a substantial sum, but laughable in comparison to what the unsponsored costs would be in the U.S. Nevertheless, it is interesting that Sweden is willing to expend this money, when the same country, based on limited resources and a case of distributive justice, denies routine IVF treatments to women above age 41. We would argue existence of a logical incongruity in supporting the former (for a relative few) while denying the latter to a clearly much large patient population. But logical incongruities are unfortunately not uncommon in health care, - and not only in Sweden. Such discrepancies, however, do have ethical relevance if one starts with the assumption that opportunity to achieve pregnancy is a basic right and support to achieve this goal should be offered equally.
No wonder, therefore, that the ethics literature regarding uterine transplants is heating up. Let us imagine, however, what the future may bring on this subject, once a first transgender woman will receive a uterine transplant, a project, we are certain, somebody, somewhere somehow is already working on. A second case of lactation induction in a transgender woman wanting to breast feed was, indeed, just reported.5 That uterine transplantation will be the next step, therefore, appears only logical! Will that be the next big success in reproductive medicine?
- Confino E. .... Gleicher N Non-vascular transplantation of the rabbit uterus. Int J Gynaecol Obstet 1986;24(4):3210325
- Brännström M. Uterus transplantation: transition from experimental to clinical procedure. Minerva Ginecol 2019;71 (6):460-466
- Theilen and Heuser. Uterine transplant: what is success? Am J Obstet Gynecol 2021; PMID: 32976814 https://doi.org/10.1016/j.ajog.2020.09.027
- Davidson et al. The costs of human uterus transplantation: a study based on nine cases of the initial Swedish live donor trial. Hum Reprod 2021;36(2):358-366
- Wamboldt R et al. Lactation induction in a transgender woman wanting to breastfeed: Case report. J Clin Endocrinol 2021; 106(5):e2047-e2052
Are human-monkey embryo chimeras the new laboratory animal?
The final issue we wish to present in Part III in our ethics series involves a recent publication from the laboratory of another old friend and collaborator of The CHR, Prof Juan Carlos Izpisua Belmonte, PhD, from the Salk Institute for Biological Studies in La Jolla, CA with collaborators from Kunmin, Yunnan province, China, that recently received worldwide coverage in professional journals as well as the lay press because the investigators for the first-time produced human-monkey chimeras.1
The term “chimera” stems from Greek mythology, where it described a fire-breathing female monster that had a lion’s head, the body of a goat and the tail of a serpent. Though, of course, nonexistent in nature, this rather negative and frightening connotation of the term has somehow persisted when biological terminology fell back on this term in describing the presence of more than one cell lineage within an organism. Biologically, this fear is, however, unwarranted because, as we learned over recent decades, practically all humans are in one way or the other chimeras. We, for example, all contain cell lineages from our mothers and, sometimes, even from our grandparents which entered our bodies while we still were in utero in our mothers. Similarly, mothers receive cell lineages from their fetuses in a process called microchimerism, now recognized as essential to develop tolerance to the fetus or an organ transplant.
How sensitive the subject of producing human chimeras for research purposes can, however, become for the public, was witnessed years ago by CHR’s Medical Director and Chief Scientist, Norbert Gleicher, MD, who in 2003 submitted an abstract to the annual ESHRE meeting (in that year in Barcelona, Spain) reporting on a study of human embryos donated to research, where his team of investigators attempted to determine whether embryos diagnosed with single gene diseases could be potentially “cured” by turning them into chimeras through introduction of a small number of genetically normal cells into an abnormal embryos that would integrate and start multiplying, thereby curing that embryo. It had by that time point been determined that, to cure certain single gene diseases that were missing an enzyme, not all abnormal cells had to necessarily receive substitution; even if only a relatively small percentage received a missing enzyme, the disease could be cured.
The abstract was chosen as one of four finalists for the Best Presentation Award and Dr. Gleicher with three other finalists was invited by ESHRE to participate in a press conference on the day before the final winner was to be chosen. Once the media, however, became aware of Dr. Gleicher’s pending oral presentation, all hell broke loose in newspaper articles and other media all over the world because to determine whether embryos would accept cells from normal sibling embryos, the study implanted individual blastomeres from male embryos into female embryos, allowing tracing of transplanted cells and their offspring cells simply by fluorescence studies for the X and/or Y chromosome. ESHRE, of course, immediately caved in to the public uproar and removed the abstract from presentation as well as from consideration for the Best Presentation Award, even though, even today, the study in all respects would still fulfill all ethical criteria for research on human embryos. Fortunately, the official medical journal of the ASRM, Fertility & Sterility, was more level-headed and published the study in full length in 2004.2
We are retelling this rather traumatic story for CHR investigators to point out the emotional response human chimera studies can elicit even from professionals in the field. Even though nobody conducting such studies would ever consider transferring such embryos into a uterus and. therefore, creating the chance of birth for such embryos, as we in Part I of this article series noted, the public’s false association of all embryos with “life,” even if never really given the chance of implantation, pregnancy, delivery and, therefore, real “life” [LINK March issue], mandates carefully detailed and transparent information to the public whenever such studies are reported. Izpisua Belmonte et al have attempted to do so by explaining to the press the potential benefits mankind may derive from such studies.3 But even though he4 and other investigators, including the Brivanlou laboratory at Rockefeller University,5 have previously published research on human-animal chimera with less uproar, the monkey-human chimera appears to have elicited especially strong emotions.
Because of the closeness in the evolutionary tree between apes and humans, such enhanced sensitivities should not surprise and are even expressed in leading science journals.6 At the same time one, however, also has to acknowledge that these chimeras do not experience pain and are not conscious in any way and that insights from these kinds of studies could boost efforts to grow replacement human organs in livestock7 but also clearly deserve close ethical supervision.8
- Tan et al., Chimeric contribution of human extended pluripotent stem cells to monkey embryos ex vivo. Cell 2021;184(8):2020-2032
- Gleicher N, Tang XY. Blastomere transplantation in human embryos may be a treatment for single gene diseases. Fertil Steril 2004;81(4):977-981
- Hotz RL. First human-monkey embryos bring advance, ethics worries. The Wall Street Journal, Tuesday, April 27, 2021, pA11
- Zhong et al., Pig chimeric model with human pluripotent stem cells. Methods Mol Biol 2019;2005:101-124
- Martyn et al. Chick models and human-chick organizer grafts. Methods Mol Biol 2019;2005:77-89
- Subbaraman N. First monkey-human embryos spark debate over hybrid animals. Nature 2021;592:497
- Leslie M. Lab-grown embryos mix human and monkey cells. Science 2021;372:223
- Greely HT, Farahany NA. Advancing the ethical dialogue about monkey/human chimeric embryos. Cell 2021;184(8):1962-1963
Norbert Gleicher, MD, FACOG, FACS
Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.
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