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• W2931402074 abstract "On March 1, 2019, Japan’s Ministry of Education, Culture, Sports, Science and Technology (MEXT) deregulated human-animal chimeric embryo (HACE) research for the production of human organs in animals. The MEXT’s newly released guidelines effectively approved the production of human-animal chimeras, or chimeric individuals (Ministry of Education CultureSportsScience and Technology (MEXT), 2019Ministry of Education Culture, Sports, Science and Technology (MEXT)Guidelines for the Handling of Specified Embryos.http://www.lifescience.mext.go.jp/files/pdf/n2163_03.pdfDate: 2019Google Scholar). Despite the very recent nature of these developments, research groups are already beginning to move forward. Most notably, Hiromitsu Nakauchi’s laboratory is preparing a new proposal for HACE research in Japan (Jiji Press, 2019Jiji PressJapanese team plans to grow human pancreases in pigs.https://jen.jiji.com/jc/eng?g=eco&k=2019030101178Date: 2019Google Scholar). Since 2010, significant research has leveraged the blastocyst complementation method toward the goal of creating pluripotent stem cell (PSC)-derived xeno organs (Kobayashi et al., 2010Kobayashi T. Yamaguchi T. Hamanaka S. Kato-Itoh M. Yamazaki Y. Ibata M. Sato H. Lee Y.S. Usui J. Knisely A.S. et al.Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells.Cell. 2010; 142: 787-799Abstract Full Text Full Text PDF PubMed Scopus (417) Google Scholar, Wu et al., 2017Wu J. Platero-Luengo A. Sakurai M. Sugawara A. Gil M.A. Yamauchi T. Suzuki K. Bogliotti Y.S. Cuello C. Valencia M.M. et al.Interspecies Chimerism with Mammalian Pluripotent Stem Cells.Cell. 2017; 168: 473-486 e415Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). Moreover, it is expected that this platform can improve investigations of disease mechanisms, drug discovery, and organ transplantation. Accordingly, there have been active global discussions about how the blastocyst complementation method should be regulated and how it should be applied to generate xeno organs. For example, in 2016, the United Kingdom Home Office issued new guidance for scientific research involving the use of human material in animals (see the Home Office report, “Guidance on the use of human material in animals,” published in January 2016; see The Academy of Medical Sciences report, “Animals containing human material,” published in July 2011). This guidance divides human-animal chimera and hybrid research into three categories and specifies how to regulate each category accordingly. In contrast, in 2015, the United States’ National Institutes of Health (NIH) announced the suspension of federal research funding for studies involving the introduction of human pluripotent cells into vertebrate embryos. The NIH’s goal during this moratorium period was to understand the current status of HACE research and examine the ethical issues related to the research and animal welfare (see NIH notice number NOT-OD-15-158). The following year, the NIH created a draft revision of its Guidelines for Human Stem Cell Research that would lift its moratorium on funding, and they solicited public comments on it (see NIH notice number NOT-OD-16-128; for the results, see NIH Office of Extramural Research site, “Mail and fax submissions to the ‘Proposed Changes to the NIH Guidelines for Human Stem Cell Research and the Proposed Scope of an NIH Steering Committee’s Consideration of Certain Human-Animal Chimera Research’”); however, no official revision has been made thus far. It is noteworthy that the moratorium does not include other ethically sensitive human-animal chimera research (Hyun, 2018Hyun I. The Ethics of Chimera Creation in Stem Cell Research.Current Stem Cell Reports. 2018; 4: 235-239Crossref Scopus (8) Google Scholar). Meanwhile, in Japan, the Guidelines for the Handling of Specified Embryos (hereafter, Embryo Guidelines) have been in effect under the Act on Regulation of Human Cloning Techniques (2000) since 2001 (http://www.lifescience.mext.go.jp/files/pdf/30_226.pdf; amended in 2009). The previous Embryo Guidelines permitted the introduction of human PSCs into animal embryos if the embryo culture was limited to 14 days after the introduction or until the primitive streak appears, and only for basic research aimed at producing human organs for transplantation. However, in 2013, the Expert Panel on Bioethics (Japan Cabinet Office) altered its stance toward HACE research and requested the MEXT to reconsider the guidelines. Following this request, from 2013 to 2016, the MEXT investigated the scientific aspects of HACE research and concluded that there are scientifically valid objectives for the research. By 2018, they had approved the production of human-animal chimeras for any scientifically valid research aimed at not only organ transplantation but also the elucidation of disease mechanisms and drug discovery (http://www.lifescience.mext.go.jp/files/pdf/Report-AnimalHumanChimericEmbryo180330r2.pdf). The MEXT’s discussions did not include the clinical use of human organs generated in animals, since the scope of the MEXT’s regulations is limited to basic research. The Ministry of Health, Labour, and Welfare is expected to discuss the ethical acceptability and translational pathway of using these organs in the future. During their deliberations, the MEXT identified animals with human-like appearance, animals with higher brain functions, and hybrids generated via the fertilization of animals with human gametes as “individuals with ambiguous boundaries between humans and animals,” which could possibly cause ethical concerns. The MEXT then scientifically investigated the possibility of generating such animals and concluded that the likelihood that they could gain human characteristics is extremely low. Nevertheless, the MEXT stipulated that prior to beginning any research, the research ethics committees and the MEXT should confirm that there is sufficient scientific rationale for the research as well as precautionary protocol measurements, such as differentiation control and step-by-step observation of the developmental process in the womb. Although the revised Embryo Guidelines permit the production of human-animal chimeras when it is deemed scientifically rational and necessary, they prohibit the mating of the chimeric individuals with human gametes or any in vitro fertilization using human gametes generated by the research (Ministry of Education CultureSportsScience and Technology (MEXT), 2019Ministry of Education Culture, Sports, Science and Technology (MEXT)Guidelines for the Handling of Specified Embryos.http://www.lifescience.mext.go.jp/files/pdf/n2163_03.pdfDate: 2019Google Scholar; see also http://www.lifescience.mext.go.jp/files/pdf/Report-AnimalHumanChimericEmbryo180330r2.pdf; http://www.lifescience.mext.go.jp/files/pdf/n2071_01.pdf). Currently, some researchers present scientific arguments for creating human PSC-derived brains in non-human primates using blastocyst complementation for animal models of degenerative disorders, such as Alzheimer’s disease and Parkinson’s disease (De Los Angeles et al., 2018De Los Angeles A. Hyun I. Latham S. Elsworth J. Redmond E. Human-Monkey Chimeras For Modeling Human Disease: Opportunities and Challenges.Stem Cells Dev. 2018; https://doi.org/10.1089/scd.2018.0162Crossref PubMed Scopus (7) Google Scholar). In the future, even in Japan, scientific rationale and necessity may create a case for producing and using human-monkey chimeras with humanized brains as animal models of neurodegenerative diseases. The revised Embryo Guidelines do not prohibit studies that produce such chimeric individuals, so the production of non-human primate models containing humanized brains may be permitted following scientific verification that there is no chance of producing animals with human-like higher brain function that may raise reasonable ethical concerns (Crane et al., 2019Crane A.T. Voth J.P. Shen F.X. Low W.C. Concise Review: Human-Animal Neurological Chimeras: Humanized Animals or Human Cells in an Animal?.Stem Cells. 2019; 13https://doi.org/10.1002/stem.2971Crossref Scopus (13) Google Scholar). Others argue that the production and use of human PSC-derived gametes derived in animals is necessary (Palacios-González, 2017Palacios-González C. Chimeras intended for human gamete production: an ethical alternative?.Reprod. Biomed. Online. 2017; 35: 387-390Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). Currently in Japan, the 2010 Guidelines on Research Producing Germ Cells from Human iPS Cells or Human Tissue Stem Cells prohibit the fertilization of human PSC-derived gametes (http://www.lifescience.mext.go.jp/files/pdf/n1492_01r2.pdf; amended in 2015). Based on future research advances, however, the debate as to whether to allow embryo production from germ cells will likely resume (https://www8.cao.go.jp/cstp/tyousakai/life/chukanmatome_150909.pdf). If the guidelines are amended to allow the fertilization of human PSC-derived gametes in the future, for consistency, researchers may argue that this amendment should also grant permission for in vitro fertilization using humanized gametes produced in animals. The recent revision of the guidelines permits researchers to produce and use HACEs for basic research and disease modeling and for an alternative for organ transplantation in the future. Our survey results revealed that although the Japanese public is generally supportive of the production of human-animal chimeras, they are very concerned about the contribution of human cells into the brains and gametes of animals (Sawai et al., 2017aSawai T. Hatta T. Fujita M. Public attitudes in Japan towards human-animal chimeric embryo research using human induced pluripotent stem cells.Regen. Med. 2017; 12: 233-248Crossref PubMed Scopus (15) Google Scholar, Sawai et al., 2017bSawai T. Hatta T. Fujita M. The Japanese generally accept human-animal chimeric embryo research but are concerned about human cells contributing to brain and gametes.Stem Cells Transl. Med. 2017; 6: 1749-1750Crossref PubMed Scopus (5) Google Scholar). So if researchers would like to pursue the production of chimeric animals with humanized brains and human gametes, public ethical debates should be conducted. Moreover, as the research progresses, safety risk assessments and further ethical analyses for the transplantation of human organs produced by HACE research and its regulations will be required. The authors would like to thank Dr. Peter Karagiannis (Center for iPS Cell Research and Application, Kyoto University, Japan) for proofreading an earlier draft of this article. T.S. was funded by the Grant-in-Aid for Young Scientists (B) (Grant Number: 17K13843) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). T.S., T.H., and M.F. were funded by the Uehiro Foundation on Ethics and Education. T.S. conducted the initial research, drafted the initial manuscript, and made revisions. M.F. and T.H. provided feedback on drafts. T.S. and M.F. prepared the manuscript for submission. All authors approved the final manuscript as submitted. M.F. is a reviewer (i.e. panel member) of the project evaluation panel for Leading Advanced Projects for Medical Innovation (AMED) that is currently evaluating, “Generation of functional organs using developmental niche,” by Dr. Hiromitsu Nakauchi at The University of Tokyo." @default.
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• W2931402074 title "Japan Significantly Relaxes Its Human-Animal Chimeric Embryo Research Regulations" @default.
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