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• W4294190384 abstract "Organ transplantation is limited due to the scarcity of donor organs. In order to expand the supply of organs for transplantation, interspecies chimeras have been examined as a potential future source of humanized organs. Recent studies using gene editing technologies in combination with somatic cell nuclear transfer technology and hiPSCs successfully engineered humanized skeletal muscle in the porcine embryo. As these technologies progress, there are ethical issues that warrant consideration and dialogue. Organ transplantation is limited due to the scarcity of donor organs. In order to expand the supply of organs for transplantation, interspecies chimeras have been examined as a potential future source of humanized organs. Recent studies using gene editing technologies in combination with somatic cell nuclear transfer technology and hiPSCs successfully engineered humanized skeletal muscle in the porcine embryo. As these technologies progress, there are ethical issues that warrant consideration and dialogue. Relatively few chronic or terminal diseases have curative therapies. Consequently, these chronic diseases are permanently debilitating and negatively impact patients’ quality of life, their survival, as well as their families and communities. According to a report from the Milken Institute, chronic disease costs are more than $1 trillion, which is equivalent to 5.8% of the US gross domestic product.1Waters H, Graf M. The costs of chronic disease in the US. Milken Institute 2018.Google Scholar The only curative therapy for many of these chronic diseases is organ transplantation.2Bhagra SK Pettit S Parameshwar J Cardiac transplantation: indications, eligibility and current outcomes.Heart (British Cardiac Society). 2019; 105: 252-260Google Scholar Transplantation medicine is limited due to the scarcity of human organs. The disparity between those that need life-saving cures and those that receive these therapies drives the pursuit of alternative curative therapies. Volumetric muscle loss (VML), sarcopenia and other myopathies are examples of chronic diseases that are debilitating and life threatening. Previous studies have used gene therapy, pharmacotherapies, cell therapy, or reconstructive surgery for the treatment of VML with mixed long-term results.3Greising SM Corona BT McGann C Frankum JK Warren GL Therapeutic Approaches for Volumetric Muscle Loss Injury: A Systematic Review and Meta-Analysis.. Tissue engineering Part B, 2019Google Scholar,4Abujarour R Valamehr B Generation of skeletal muscle cells from pluripotent stem cells: advances and challenges.Frontiers in Cell and Developmental Biology. 2015; 3: 29Crossref Scopus (15) Google Scholar Therefore, new treatment strategies are warranted for these debilitating and/or terminal muscle diseases. Chimerism-related research using human cells, tissues, and organs delivered into animal models has an extensive history. The term chimera refers to an organism that is derived from two or more intra or interspecies parents. For example, chimeric (intraspecies) mice have been used extensively for genetic research.5Devolder K Yip LJ Douglas T The ethics of creating and using human-animal chimeras.ILAR J. 2020; 60: 434-438Crossref Scopus (6) Google Scholar These mice contain cell populations from the same species (cells where all the mouse genes are intact and those cells where one specific murine gene has been deleted or knocked out). Similarly, large animal interspecies chimeras (contains cells from two different species) or hybrids (each cell has a mixture of chromosomes from two different species)6Robert JS Baylis F Crossing species boundaries.Am J Bioeth. 2003; 3: 1-13Crossref Scopus (204) Google Scholar have been established including the geep (a goat-sheep chimera), mules (the product of horse and donkey breeding and, therefore, a hybrid), Labradoodles (a hybrid that is the product of Labrador retrievers and poodles), the beefalo (a domestic cattle-bison hybrid), the dzo (domestic cattle-yak hybrid), a zorse (zebra-horse hybrid), or wholphin (whale-dolphin hybrid). These and other animal models provide a platform for the generation of human–animal chimeras. Human–animal chimeras (interspecies chimeras) have been extensively used to model human diseases and test the pluripotency of human stem cell populations. For example, the SCID-hu mouse has been extensively used in research studies focused on hematopoiesis, cancer biology, and HIV-1-related research for more than 30 years.7McCune J Namikawa R Kaneshima H Shultz L Lieberman M Weissman I The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function.Science (New York, NY). 1988; 241: 1632-1639Crossref Google Scholar This SCID-hu mouse harbors a human thymus, lymph nodes, and liver, but all other organs are murine.7McCune J Namikawa R Kaneshima H Shultz L Lieberman M Weissman I The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function.Science (New York, NY). 1988; 241: 1632-1639Crossref Google Scholar Additionally, human neural stem cells have been injected into a mouse brain that ultimately contained 1% human cells.8Chen C Kim W-Y Jiang P Humanized neuronal chimeric mouse brain generated by neonatally engrafted human iPSC-derived primitive neural progenitor cells.JCI Insight. 2016; 1: e88632Crossref Scopus (22) Google Scholar,9Zhou FW Fortin JM Chen HX et al.Functional integration of human neural precursor cells in mouse cortex.PloS One. 2015; 10: e0120281Crossref Scopus (16) Google Scholar This model has been useful for studies focused on neurogenesis and mechanisms of diseases. Chimeric mice having a humanized liver have been engineered and used for metabolic and toxicology studies as well as regenerative medicine studies.10Angarita SAK Truong B Khoja S et al.Human hepatocyte transplantation corrects the inherited metabolic liver disorder arginase deficiency in mice.Mol Genet Metab. 2018; 124: 114-123Crossref Scopus (7) Google Scholar Additionally, the pluripotency of human stem cell populations has been characterized through the generation of teratomas in mice. These teratomas give rise to all the human derivatives of the three germ layers including cardiomyocyte, neuronal, muscle, liver, gut, and other lineages.11Masaki H Kato-Itoh M Umino A et al.Interspecific in vitro assay for the chimera-forming ability of human pluripotent stem cells.Development. 2015; 142: 3222-3230Google Scholar, 12Takahashi K Yamanaka S Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (19040) Google Scholar, 13Yu J Vodyanik MA Smuga-Otto K et al.Induced pluripotent stem cell lines derived from human somatic cells.Science (New York, NY). 2007; 318: 1917-1920Crossref Scopus (8211) Google Scholar, 14Hentze H Soong PL Wang ST Phillips BW Putti TC Dunn NR Teratoma formation by human embryonic stem cells: evaluation of essential parameters for future safety studies.Stem Cell Res. 2009; 2: 198-210Crossref PubMed Scopus (345) Google Scholar Collectively, these human–animal chimera research models have been extensively used by the research community and supported by federal funds. Chimerism-related research has been further advanced as outlined in a recent publication by Maeng et al.15Maeng G Das S Greising SM et al.Humanized skeletal muscle in MYF5/MYOD/MYF6-null pig embryos.Nature Biomedical Engineering. 2021; 5: 805-814Crossref Scopus (18) Google Scholar In these studies, gene editing was used to engineer pig embryos that lacked the skeletal muscle lineage. Human-induced pluripotent stem cells (hiPSCs) that lacked the tumor suppressor gene, TP53 (using CRISPR/Cas9), were used as donors and delivered (complemented) into the MYF5/MYOD/MYF6 null porcine host (or recipient) embryo and implanted in surrogate porcine gilts.15Maeng G Das S Greising SM et al.Humanized skeletal muscle in MYF5/MYOD/MYF6-null pig embryos.Nature Biomedical Engineering. 2021; 5: 805-814Crossref Scopus (18) Google Scholar Human–porcine chimeric embryos were then analyzed (at less than 30 days gestation) using immunohistochemistry and PCR (with sequence confirmation for the human transcript). These studies provided a proof of concept for successful embryonic complementation with a majority of hiPSCs populating the myogenic lineages and not the germline or the neuronal lineages.15Maeng G Das S Greising SM et al.Humanized skeletal muscle in MYF5/MYOD/MYF6-null pig embryos.Nature Biomedical Engineering. 2021; 5: 805-814Crossref Scopus (18) Google Scholar Overall, this study provides concept validation for the engineering of gene edited pigs that harbor human skeletal muscle products, which may serve 1 day as a research model for the testing of devices or the efficacy of treatments for myopathic disorders. Moreover, it is possible that that these technologies may provide an unlimited supply of organs that have a role in the treatment of myopathies, sarcopenia or VML. As with every major scientific advance, there are ethical issues that require discussion within the scientific and lay communities. Ethical issues related to the engineering of human–animal chimeras are no exception.16Wu J Platero Luengo A Gil MA et al.Generation of human organs in pigs via interspecies blastocyst complementation.Reprod Domest Anim. 2016; 51: 18-24Crossref Scopus (22) Google Scholar,17Wu J Platero-Luengo A Sakurai M et al.Interspecies chimerism with mammalian pluripotent stem cells.Cell. 2017; 168 (e415): 473-486Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar Human–animal chimeras have been extensively used in biomedical research and have yielded important discoveries that have impacted patient-related treatments. The studies outlined by Maeng et al.15Maeng G Das S Greising SM et al.Humanized skeletal muscle in MYF5/MYOD/MYF6-null pig embryos.Nature Biomedical Engineering. 2021; 5: 805-814Crossref Scopus (18) Google Scholar used blastocyst complementation and demonstrated the plasticity of human stem cell populations when delivered into a porcine embryo. From an ethical perspective, we believe this study15Maeng G Das S Greising SM et al.Humanized skeletal muscle in MYF5/MYOD/MYF6-null pig embryos.Nature Biomedical Engineering. 2021; 5: 805-814Crossref Scopus (18) Google Scholar should be compared to the published studies performed in the adult mouse following delivery of human stem/progenitor cells as these cells were observed to contribute to neurogenesis, liver and thymus formation, and blood or teratoma formation.18Yin L Wang X-J Chen D-X Liu X-N Wang X-J Humanized mouse model: a review on preclinical applications for cancer immunotherapy.Am J Cancer Res. 2020; 10: 4568-4584Google Scholar, 19Kenney LL Shultz LD Greiner DL Brehm MA Humanized mouse models for transplant immunology.American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2016; 16: 389-397Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 20Walsh NC Kenney LL Jangalwe S et al.Humanized mouse models of clinical disease.Annu Rev Pathol. 2017; 12: 187-215Crossref PubMed Scopus (348) Google Scholar, 21Grompe M Strom S Mice with human livers.Gastroenterology. 2013; 145: 1209-1214Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar In these previously reported chimeric mouse studies, human stem cells have formed entire organs (thymus or liver) and have contributed significantly to the brain (1% of all neurons).7McCune J Namikawa R Kaneshima H Shultz L Lieberman M Weissman I The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function.Science (New York, NY). 1988; 241: 1632-1639Crossref Google Scholar,8Chen C Kim W-Y Jiang P Humanized neuronal chimeric mouse brain generated by neonatally engrafted human iPSC-derived primitive neural progenitor cells.JCI Insight. 2016; 1: e88632Crossref Scopus (22) Google Scholar,10Angarita SAK Truong B Khoja S et al.Human hepatocyte transplantation corrects the inherited metabolic liver disorder arginase deficiency in mice.Mol Genet Metab. 2018; 124: 114-123Crossref Scopus (7) Google Scholar,21Grompe M Strom S Mice with human livers.Gastroenterology. 2013; 145: 1209-1214Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar,22Krieger LM. Treading new ethical ground, scientists put a bit of man into a mouse. San Jose Mercury News. 2022.Google Scholar In spite of the fact that federal (NIH)5Devolder K Yip LJ Douglas T The ethics of creating and using human-animal chimeras.ILAR J. 2020; 60: 434-438Crossref Scopus (6) Google Scholar,23Greely HT Human brain surrogates research: the onrushing ethical dilemma.Am J Bioeth. 2021; 21: 34-45Crossref Scopus (26) Google Scholar dollars have been used for the delivery of human stem cells in adult mice (a human–animal chimera) for the purpose of generating humanized mouse models, ethical arguments have been raised regarding large animal human–animal chimera research. A range of ethical concerns have been articulated to include the possible violation of species’ boundaries, the undermining of human dignity, the potential to enhance the moral status of the chimeric organism (by humanizing a non-human animal), or general concerns about the unnaturalness of chimera research.6Robert JS Baylis F Crossing species boundaries.Am J Bioeth. 2003; 3: 1-13Crossref Scopus (204) Google Scholar,24Streiffer R At the edge of humanity: human stem cells, chimeras, and moral status.Kennedy Inst Ethics J. 2006; 15: 347-370Crossref Scopus (75) Google Scholar,25Streiffer R. Human/Non-Human Chimeras.in: The Stanford Encyclopedia of Philosophy. July 21, 2014 ed:. Johns Hopkins University Press, 2009Google Scholar The issue of violating species’ boundaries presents itself in the practice of xenotransplantation. A xenotransplant is defined by any introduction of any animal product (fluids, cells, tissues, or organs) into a human recipient. A recent example, is the transplant of a porcine heart from a gene edited pig into a patient with endstage heart failure.26Shah AM Han JJ First successful porcine to human heart transplantation performed in the United States.Artif Organs. 2022; 46: 543-545Crossref PubMed Scopus (6) Google Scholar,27Kotz D. University of Maryland Schol of Medicine Faculty Scientist and Clinicians Perform Historic First Successful Transplant of Porcine Heart into Adult Human with End-Stage Heart Disease.. University of Maryland News, 2022Google Scholar This life-saving technology in combination with gene editing to modify the immunogenicity of the porcine heart has reinvigorated the use of xenotransplantation for the treatment of endstage, terminal diseases. Likewise, gene-edited porcine kidneys have recently been transplanted into decedent humans.28Porrett PM Orandi BJ Kumar V et al.First clinical-grade porcine kidney xenotransplant using a human decedent model.Am J Transplant. 2022; 22: 1037-1053Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar,29Cooper DKC Genetically engineered pig kidney transplantation in a brain-dead human subject.Xenotransplantation. 2021; 28: e12718Crossref Scopus (14) Google Scholar The initial success of these studies prompts the need for further discussion with regard to species boundaries and the ethics of crossing such boundaries. In these cases, as well as in Maeng et al.,15Maeng G Das S Greising SM et al.Humanized skeletal muscle in MYF5/MYOD/MYF6-null pig embryos.Nature Biomedical Engineering. 2021; 5: 805-814Crossref Scopus (18) Google Scholar the engineering of humanized organs in the pig must be considered in the context of species boundaries. Likewise, the use of xenotransplantation (a primarily pig organ to human) versus exotransplantation (a primarily human organ to human15Maeng G Das S Greising SM et al.Humanized skeletal muscle in MYF5/MYOD/MYF6-null pig embryos.Nature Biomedical Engineering. 2021; 5: 805-814Crossref Scopus (18) Google Scholar) must be deliberated. In the latter case, the exotransplantation of a human organ developed in a pig and transplanted into a human patient represents an intra-species chimera as both the donor organ and the recipient are of the same species. It should be noted that intra-species chimeras are produced regularly when human donor organs are transplanted into human recipients.23Greely HT Human brain surrogates research: the onrushing ethical dilemma.Am J Bioeth. 2021; 21: 34-45Crossref Scopus (26) Google Scholar The argument surrounding human dignity may be dependent on which organs or the extent to which an organ(s) is humanized and also how humanization affects the moral status of the pig. Moral status is often assigned based on sentience or the ability to experience feelings, cognition, and sensations. Therefore, one must ask if the development of an organ within a pig can alter the animals’ sentience? If the organ were a brain, then one might predict that the animals’ feelings and sensations could be altered and possibly humanized. In the case of muscle, as well as various other organs, however, this possibility seems more remote as behaviors are less likely to be affected by the humanization of skeletal muscle or other organs such as kidney. Regarding the arguments that human–animal chimeras are unacceptable as they are unnatural, one should consider the common practice of using devices for the treatment of human diseases. Consider the use of prosthestic devices in amputees, metal/ceramic/plastic joints, dental implants, cardiac pacemakers, intracardiac defibrillators and mechanical cardiac assist devices. All of these examples represent life enhancing or life-saving devices that are not natural. Rather, all are artificial devices, which are commonly engineered, deemed socially acceptable as these devices improve quality of life and provide life-saving therapies to patients. Do these devices create a non-human, robotic feature in human beings and do they negatively alter human dignity? Or do they, instead, enhance human dignity by restoring natural function to the human being? The production of humanized animals began in the early 2000s. Humanized mice, for example, are generated by the delivery of human cells into immunodeficient mice. In contrast, human: pig chimeras are produced by introducing human cells into early stage porcine embryos. Much of the criticism of human–animal chimeras have focused on the unintentional (or intentional) contribution of human pluripotent stem cells to the developing animal brain or gametes. The Irving Weissman laboratory proposed the injection of human embryonic stem (HES) cells into the mouse brain to determine the utility of cells to treat human diseases.30Kelly S Bliss TM Shah AK et al.Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex.Proc Natl Acad Sci U S A. 2004; 101: 11839-11844Crossref PubMed Scopus (538) Google Scholar The ethics of this work was rigorously reviewed given the potential for humanized cognitive and emotive function in mice.23Greely HT Human brain surrogates research: the onrushing ethical dilemma.Am J Bioeth. 2021; 21: 34-45Crossref Scopus (26) Google Scholar,31Capps B Do chimeras have minds?.Camb Q Healthc Ethics. 2017; 26: 577-591Crossref Scopus (9) Google Scholar In the study by Maeng et al.,15Maeng G Das S Greising SM et al.Humanized skeletal muscle in MYF5/MYOD/MYF6-null pig embryos.Nature Biomedical Engineering. 2021; 5: 805-814Crossref Scopus (18) Google Scholar the goal was to produce human skeletal muscle in the pig. Any human contribution of human cells to the brain or the germ line would be unintended and unwanted as the goal was to specifically produce human skeletal muscle only. Importantly, Maeng et al.15Maeng G Das S Greising SM et al.Humanized skeletal muscle in MYF5/MYOD/MYF6-null pig embryos.Nature Biomedical Engineering. 2021; 5: 805-814Crossref Scopus (18) Google Scholar did not observe any human cell derivatives associated with the central or peripheral nervous systems or the gametes in the human–porcine chimera using multiple molecular and morphological techniques. This study prompts a valuable discussion regarding the ethical issues surrounding the unintended humanization of neuronal and gamete lineages and whether or not the development of a chimera that has a human heart or a human lung or a human kidney should be permitted. Whether the generation of a human: pig chimera has greater ethical consequence than a human: rodent chimera is an interesting question. Part of the answer to that question may reside in the method of production, as discussed above. Regardless of the method of production, however, it is important to consider the impact on moral status of the host and whether a humanized brain in a lower vertebrate is more acceptable and more ethical than humanized skeletal muscle in a pig? Issues of regulatory oversight should be considered as well. To frame this discussion, a relevant question may be, do pluripotent hiPSCs have a competitive advantage over the porcine blastomeres during embryogenesis? Specifically, are the hiPSCs able to contribute broadly to unwanted lineages beyond the niche that would contribute, for example, to human like cognition, or allow for unfettered breeding of a new species? The studies to date support the notion that the hiPSC contribution to interspecies chimeras are relatively inefficient and unable to broadly contribute to the porcine (or other large animal species) embryo.17Wu J Platero-Luengo A Sakurai M et al.Interspecies chimerism with mammalian pluripotent stem cells.Cell. 2017; 168 (e415): 473-486Abstract Full Text Full Text PDF PubMed Scopus (311) Google Scholar In Maeng et al.,15Maeng G Das S Greising SM et al.Humanized skeletal muscle in MYF5/MYOD/MYF6-null pig embryos.Nature Biomedical Engineering. 2021; 5: 805-814Crossref Scopus (18) Google Scholar niche development has been demonstrated to allow for the survival of hiPSCs by providing a competition free zone. Their data suggest that hiPSCs are capable of responding to cues within the niche in the native porcine environment to produce specific and desired tissues (skeletal muscle and not connective tissue, nerve, or other organs). Nevertheless, it is conceivable that genetic engineering of the hiPSCs may increase the efficiency of chimerism. As such, this work should have strong, transparent external oversight. Therefore, it would seem reasonable that the field should pursue these human–animal chimera experiments using a phased approach, supervised by Institutional Stem Cell Research Oversight (SCRO) committees and that these committees would monitor the contribution of humanized lineages during embryogenesis.24Streiffer R At the edge of humanity: human stem cells, chimeras, and moral status.Kennedy Inst Ethics J. 2006; 15: 347-370Crossref Scopus (75) Google Scholar,25Streiffer R. Human/Non-Human Chimeras.in: The Stanford Encyclopedia of Philosophy. July 21, 2014 ed:. Johns Hopkins University Press, 2009Google Scholar,32Koplin JJ Savulescu J Time to rethink the law on part-human chimeras.J Law Biosci. 2019; 6: 37-50Crossref Scopus (14) Google Scholar Institutional SCROs are the foundation for oversight, in part, because of a need to have local oversight of ongoing research initiatives. This also follows the pattern and practice for IACUC and IRB oversight of bench and clinical research, respectively, at an institution. But there could be advantages to having an external committee that would be aware and provide available experts for review of selected protocols and share guidelines for institutions. Organization of such an external committee may be challenging due to time-sensitive review of submitted protocols, however. Nonetheless, a step-wise approach to assess the biology pertaining to the use of hiPSCs for the generation of human–animal chimeras using blastocyst complementation is warranted. In addition, future resources may include a national oversight committee, which would serve as a resource for institutional SCRO committees by providing expertise, protocols and recommendations for research proposals. A second oversight issue to consider is where this type of research should be performed? International legislation and recommendations for human chimeric embryos are variable32Koplin JJ Savulescu J Time to rethink the law on part-human chimeras.J Law Biosci. 2019; 6: 37-50Crossref Scopus (14) Google Scholar and, in some cases, relatively little oversight is provided for these research studies. As the development of chimeras is being pursued in countries across the globe, an international assembly of scientists, ethicists, clinicians, and others should be considered to provide consistent oversight to these efforts. Additionally, there should be requirements that scientific studies be peer reviewed prior to press releases to protect and maintain public trust. Since 2015, the NIH has placed, a moratorium on the funding of human–animal chimeras produced by the introduction of human cells into an early stage non-human vertebrate embryo.33NIH research involving introduction of human pluripotent cells into non-human vertebrate animal pre-gastrulation embryos. 2015.Google Scholar,34Schneider D The five: chimeras created by science.The Guardian. 2019; Google Scholar This moratorium has effectively stalled meaningful discussion regarding the regulation of human–animal chimeras in large animals. Additionally, such a ban may encourage US-based investigators to seek product development in other countries35Cyranoski D Japan approves first human-animal embryo experiments.Nature. 2019; Crossref Google Scholar; some of which may have little or no regulatory oversight. Not only does this raise concerns regarding the need for the coordination of international regulation between countries, it draws into question the ability of the United States to compete in the biotechnology market place by developing these chimeras as useful research models and meaningful patient therapeutics. Again, proper regulation both in the United States and abroad would benefit the field. A third issue pertains to the type of human stem cell population that would be used in human–animal chimera studies. hiPSCs, given their mature, somatic cell, and non-invasive derivation lack many of the ethical issues associated with HES cells. The hiPSCs also have the advantage of being donor derived. Therefore, engineered hiPSCs or specified human progenitors may have utility and serve as an effective donor source to generate personalized humanized organs thus limiting the use of immunosuppressive agents. It is also possible that hiPSCs can be produced as an off-the-shelf tool and may be universal in their utility. These possibilities would warrant further discussion of the ethics pertaining to the democratization of organ allocation. A fourth issue is the time period whereby human–animal embryonic cultures can be evaluated and examined. While previous guidelines stated that human–animal embryonic cultures could be maintained up to the pregastrulation stage (differentiation to the derivatives of the three germ layers), the updated (2021) human stem cell research guidelines by the International Society for Stem Cell Research removed the 14 day limit for culturing human embryos or human–animal chimeras.29Cooper DKC Genetically engineered pig kidney transplantation in a brain-dead human subject.Xenotransplantation. 2021; 28: e12718Crossref Scopus (14) Google Scholar These guideline modifications underscore the ongoing research initiatives that are focused on the human embryonic and human–animal chimeric lineage specification and differentiation.29Cooper DKC Genetically engineered pig kidney transplantation in a brain-dead human subject.Xenotransplantation. 2021; 28: e12718Crossref Scopus (14) Google Scholar Advanced culturing of humanized chimera beyond 14 days should also be approached in a stepwise fashion to provide check points for the extent of the humanization of the non-human embryo. Furthermore, these guideline modifications emphasize the importance of the definition of the germ layer contribution of human cells to non-human embryos, and this will likely require evaluation in multiple settings to fully comprehend the capacity of the human cells in a foreign embryo. Lastly, consideration should be given to placing a moratorium on the breeding of any human–animal chimeras to prevent an unwanted phenotype or the generation of new species. This would allow for the development of human–animal chimeras yet would serve to prevent the propagation of these chimeric models and any recombinant events that would occur in multiple breedings. Society should collectively agree not to pursue the breeding of human–animal chimeras and impose strict penalties for doing so. Such a step will build confidence and trust between the lay and scientific communities in chimeric research. In summary, human–animal chimeras in large animals have the potential for revolutionizing the field of transplantation and research of human disease. The safe utility of these chimeras is attainable with clear guidelines and proper oversight and establishing regulations surrounding these important technologies should be a priority for all countries using these technologies. DJG is supported by grants from RMM and the DoD. MGG is supported by grant funding from the DoD. The authors have no other financial disclosures as described by the American Journal of Transplantation. The data that support the findings of this study are available from the corresponding author upon reasonable request. The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. DJG and MGG are co-founders of NorthStar Genomics." @default.
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• W4294190384 title "Emerging technologies and ethics—exogenic chimeric humanized organs" @default.
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