Shifting to a model of donor conception that entails a communication agreement among the parents, donor, and offspring.

BACKGROUND: Some persons conceived with donor gametes react negatively when they found their birth via donor conception. They request access to information about and seek to communicate with the donor. However, some countries mandate donor anonymity. Other countries allow donor-conceived persons to access donor information, but they can only use this access if their parents have disclosed donor conception to them. We investigated a thorny issue of donor conception: whether donor conception should be shifted from an anonymous basis to a non-anonymous basis. METHODS: We review the issues and concerns regarding donor conception. We then consider the impact of direct-to-consumer genetic testing on donor conception, as well as the influence of donor conception on offspring's identity and the potential of different types of donors. To discuss the future policy of donor conception, the policies on the anonymity of gamete donors were investigated using publicly-available documents in 15 countries. RESULTS: The aim of mandating donor anonymity is to protect the privacy of the donor and intended parents. However, the diffusion of direct-to-consumer genetic testing may make it impossible to maintain anonymity. Birth via donor conception shapes the offspring's identity, and the donor may further influence the development of offspring's identity through communications. It remains important to disclose donor conception to donor-conceived offspring and to provide them with donor information. However, that information might be insufficient for some donor-conceived persons. Here are benefits to having open-identity donors and known donors. Such donors can make an agreement with the parents regarding future communication with the offspring, although both sides should respect privacy. Subsequent counseling for all parties involved can result in better tripartite communication agreements. CONCLUSIONS: In sum, ethical and practical issues that complicate donor anonymity are driving a shift to non-anonymous donor conception, in which all parties come to a communication agreement. To pave the way for such a donor conception system, transitional measures can be put into place. For countries that already adopted non-anonymous donor conception, ensuring the communication agreements is important to protect the rights of parents, donor, and offspring.

Proving that a genome-edited organism is not GMO.

A genome-edited agricultural product that is proven to contain no exogenous DNA is not subject to genetically modified organism (GMO) regulations in some countries. However, whether such proof is definitive is often disputed. We discuss the approaches to substantially proving that a genome-edited organism is not GMO, while considering social aspects.

Reactions to the National Academies/Royal Society Report on Heritable Human Genome Editing.

In September 2020, a detailed report on Heritable Human Genome Editing was published. The report offers a translational pathway for the limited approval of germline editing under limited circumstances and assuming various criteria have been met. In this perspective, some three dozen experts from the fields of genome editing, medicine, bioethics, law, and related fields offer their candid reactions to the National Academies/Royal Society report, highlighting areas of support, omissions, disagreements, and priorities moving forward.

Safety of Germline Genome Editing for Genetically Related "Future" Children as Perceived by Parents.

The social acceptability of germline genome editing (GGE) depends on its perceived safety, as well as respect for reproductive autonomy. However, it is doubtful that prospective parents sufficiently understand the risks of GGE. In the future, the use of GGE in specific situations seems plausible, as it offers couples potential means to safeguard genetically related future children from a serious disease and overcome infertility due to a gene mutation. Should GGE fail, however, some couples may be obliged to abort affected fetuses, or give birth to adversely affected children, which would be a tragedy. Some children might develop diseases later in life due to overlooked off-target mutations. Compounding this, some parents are unlikely to inform their offspring about the details of conception, hampering necessary follow-up. Prospective parents, scientists and policy makers should carefully discuss the safety implications of GGE for genetically related future children.

Should Long-Term Follow-up Post-Mitochondrial Replacement be Left up to Physicians, Parents, or Offspring?

UK law permits parents to use mitochondrial replacement (MR) to have genetically-related children without serious mitochondrial disease. However, long-term follow-up is required for each case. Whether this follow-up should be left to physicians, parents, or offspring has not been established. Due to the experimental status of MR, physicians must inform parents of the risks and the importance of follow-up tailored to a specific mitochondrial disease. Given that the use of MR is a responsible exercise of reproductive freedom, parents should ensure that the follow-up is performed properly and in the best interests of their offspring. On becoming legally competent, the resulting children should be entitled to refuse follow-up provided that the prevention of mitochondrial disease with no adverse effects has been evident till then. This offspring-centred long-term follow-up approach might also be applied to the use of MR for infertility treatment, even though the primary endpoint is healthy live births.

Raising Gene Therapy for Unmet Medical Needs in Japan.

Gene therapy has a complicated history. Some early trials resulted in catastrophes, including subjects' deaths. In 2003, the world's first gene therapy product (GTP) was approved in China. More recently, EU and US regulators have successively approved seven GTPs, including chimeric antigen receptor (CAR) T cells for refractory cancers and an adeno-associated vector, for treating serious genetic disease. In Japan, where there are no approved GTPs, some clinics have provided domestically-unapproved GTPs for cancer patients; however, in some cases, bereaved individuals litigated against such clinics. Meanwhile, the advent of GTPs is becoming controversial because of the unprecedentedly high treatment cost. The present article has three aims: 1) Reconsider the ethical legitimacy of gene therapy and its use for serious conditions. 2) Compare the Japanese, EU and US regulatory situations concerning GTPs and underscore Japan's need for clearer and more up-to-date regulatory guidance. 3) Call for social understanding of GTPs and deliberations regarding the appropriate and acceptable cost, while noting that regulatory approval does not necessarily meet genetic disease patients' needs.

Crop Gene-Editing: Should We Bypass or Apply Existing GMO Policy?

Recent advances in crop gene-editing technologies allow for efficient site-specific mutagenesis without introducing exogenous DNA, potentially bypassing product-based genetically modified organism (GMO) regulations. Conversely, such plants can be subject to process-based GMO regulations. However, it is important to tailor existing GMO regulations with the aim to ensure social acceptance of gene-edited crops.

Mitochondrial manipulation in fertility clinics: Regulation and responsibility.

The clinical uses of cytoplasmic transfer and pronuclear transfer for infertility treatment have raised concerns, leading to restrictive regulatory responses in both the USA and China. In 2015, the UK legalized nuclear transfer from oocytes and zygotes to prevent the onset of serious mitochondrial disease in the children of affected mothers. A research team in the USA then performed egg nuclear transfer, with subsequent embryo transfer in Mexico, to prevent mitochondrial disease. A live birth resulted, but the cross-border activity attracted attention from regulatory authorities. In order to respond appropriately to the likelihood of the wider use of such mitochondrial manipulation techniques (MMT), the present study first surveyed countries where MMT have been clinically implemented or where such experimental procedures are advertised on the internet. Sixteen countries were selected for an analysis of the legal position regarding germline genetic modification and egg donation. It was found that regulation of the clinical use of MMT could be broken down into three categories: (i) largely prohibited (USA and China), (ii) not regulated (Northern Cyprus and Ukraine), and (iii) insufficiently regulated (the remaining 12 countries, including Mexico). The reasons for no or insufficient regulation included no intention to oversee experimental procedures, no consideration of the manipulation in eggs, unclear technical terms and ambiguous medical purposes. To protect future children, this study underscores the pressing need for regulatory frameworks with policies that cover MMT. Wider implications regarding the responsible implementation of procedures in experimental reproductive medicine are discussed.

Promoting In Vitro Gametogenesis Research with a Social Understanding.

Recent advances in in vitro gametogenesis (IVG), including in humans, have raised ethical concerns regarding the potential misuse and manipulation of 'artificial embryos'. However, basic research on IVG is expected to be of immense scientific and social value provided that the ethical, legal, and social issues are carefully considered.

The ethics of creating genetically modified children using genome editing.

PURPOSE OF REVIEW: To review the recent ethical, legal, and social issues surrounding human reproduction involving germline genome editing. RECENT FINDINGS: Genome editing techniques, such as CRISPR/Cas9, have facilitated genetic modification in human embryos. The most likely purpose of germline genome editing is the prevention of serious genetic disease in offspring. However, complex issues still remain, including irremediable risks to fetuses and future generations, the role of women, the availability of alternatives, long-term follow-up, health insurance coverage, misuse for human enhancement, and the potential effects on adoption. Further discussions, a broad consensus, and appropriate regulations are required before human germline genome editing is introduced into the global society. SUMMARY: Before germline genome editing is used for disease prevention, a broad consensus must be formed by carefully discussing its ethical, legal, and social issues.

Mitochondrial Replacement Techniques: Genetic Relatedness, Gender Implications, and Justice.

In 2015 the United Kingdom (UK) became the first nation to legalize egg and zygotic nuclear transfer procedures using mitochondrial replacement techniques (MRTs) to prevent the maternal transmission of serious mitochondrial DNA diseases to offspring. These techniques are a form of human germline genetic modification and can happen intentionally if female embryos are selected during the MRT clinical process, either through sperm selection or preimplantation genetic diagnosis (PGD). In the same year, an MRT was performed by a United States (U.S.)-based physician team. This experiment involved a cross-border effort: the MRT procedure per se was carried out in the US, and the embryo transfer in Mexico. The authors examine the ethics of MRTs from the standpoint of genetic relatedness and gender implications, in places that lack adequate laws and regulation regarding assisted reproduction. Then, we briefly examine whether MRTs can be justified as a reproductive option in the US and Mexico, after reassessing their legalization in the UK. We contend that morally inadequate and ineffective regulations regarding egg donation, PGD, and germline genetic modifications jeopardize the ethical acceptability of the implementation of MRTs, suggesting that MRTs are currently difficult to justify in the US and Mexico. In addition to relevant regulation, the initiation and appropriate use of MRTs in a country require a child-centered follow-up policy and more evidence for its safety.

A future scenario of the global regulatory landscape regarding genome-edited crops.

The global agricultural landscape regarding the commercial cultivation of genetically modified (GM) crops is mosaic. Meanwhile, a new plant breeding technique, genome editing is expected to make genetic engineering-mediated crop breeding more socially acceptable because it can be used to develop crop varieties without introducing transgenes, which have hampered the regulatory review and public acceptance of GM crops. The present study revealed that product- and process-based concepts have been implemented to regulate GM crops in 30 countries. Moreover, this study analyzed the regulatory responses to genome-edited crops in the USA, Argentina, Sweden and New Zealand. The findings suggested that countries will likely be divided in their policies on genome-edited crops: Some will deregulate transgene-free crops, while others will regulate all types of crops that have been modified by genome editing. These implications are discussed from the viewpoint of public acceptance.

Reproductive medicine involving genome editing: clinical uncertainties and embryological needs.

Genome editing based on site-directed nucleases facilitated efficient and versatile genetic modifications in human cells. However, recent reports, demonstrating CRISPR/Cas9-mediated genome editing in human embryos have raised profound concerns worldwide. This commentary explores the clinical justification and feasibility of reproductive medicine using germline genome editing. Despite the perceived utility of reproductive medicine for treating intractable infertility, it is difficult to justify germline genome editing from the perspective of the prospective child. As suggested by the UK legalization regarding mitochondrial donation, the prevention of genetic disease in offspring by genome editing might be acceptable in limited cases of serious or life-threatening conditions, where no alternative medicine is available. Nonetheless, the mosaicism underlying human embryos as well as the off-target effect by artificial nucleases will likely hamper preimplantation genetic diagnosis prior to embryo transfer. Such considerations suggest that this type of reproductive medicine should not be developed toward a clinical application. However, the clinical uncertainties underscore the need for embryology that can address fundamental questions regarding germline aneuploidy and mosaicism using genome editing.

Germ line genome editing in clinics: the approaches, objectives and global society.

Genome editing allows for the versatile genetic modification of somatic cells, germ cells and embryos. In particular, CRISPR/Cas9 is worldwide used in biomedical research. Although the first report on Cas9-mediated gene modification in human embryos focused on the prevention of a genetic disease in offspring, it raised profound ethical and social concerns over the safety of subsequent generations and the potential misuse of genome editing for human enhancement. The present article considers germ line genome editing approaches from various clinical and ethical viewpoints and explores its objectives. The risks and benefits of the following three likely objectives are assessed: the prevention of monogenic diseases, personalized assisted reproductive technology (ART) and genetic enhancement. Although genetic enhancement should be avoided, the international regulatory landscape suggests the inevitability of this misuse at ART centers. Under these circumstances, possible regulatory responses and the potential roles of public dialogue are discussed.

Consumer acceptance of food crops developed by genome editing.

One of the major problems regarding consumer acceptance of genetically modified organisms (GMOs) is the possibility that their transgenes could have adverse effects on the environment and/or human health. Genome editing, represented by the CRISPR/Cas9 system, can efficiently achieve transgene-free gene modifications and is anticipated to generate a wide spectrum of plants. However, the public attitude against GMOs suggests that people will initially be unlikely to accept these plants. We herein explored the bottlenecks of consumer acceptance of transgene-free food crops developed by genome editing and made some recommendations. People should not pursue a zero-risk bias regarding such crops. Developers are encouraged to produce cultivars with a trait that would satisfy consumer needs. Moreover, they should carefully investigate off-target mutations in resultant plants and initially refrain from agricultural use of multiplex genome editing for better risk-benefit communication. The government must consider their regulatory status and establish appropriate regulations if necessary. The government also should foster communication between the public and developers. If people are informed of the benefits of genome editing-mediated plant breeding and trust in the relevant regulations, and if careful risk-benefit communication and sincere considerations for the right to know approach are guaranteed, then such transgene-free crops could gradually be integrated into society.

Providing Appropriate Risk Information on Genome Editing for Patients.

Genome editing, represented by CRISPR/Cas9, facilitates somatic and germline gene modifications in many species, including humans. However, one of key issues, off-target mutation deserves special consideration prior to clinical applications. We herein discuss the importance of risk information on genome editing for obtaining legitimate patient consent and social acceptance.

Germline genome-editing research and its socioethical implications.

Genetically modifying eggs, sperm, and zygotes ('germline' modification) can impact on the entire body of the resulting individual and on subsequent generations. With the advent of genome-editing technology, human germline gene modification is no longer theoretical. Owing to increasing concerns about human germline gene modification, a voluntary moratorium on human genome-editing research and/or the clinical application of human germline genome editing has recently been called for. However, whether such research should be suspended or encouraged warrants careful consideration. The present article reviews recent research on mammalian germline genome editing, discusses the importance of public dialogue on the socioethical implications of human germline genome-editing research, and considers the relevant guidelines and legislation in different countries.

Towards social acceptance of plant breeding by genome editing.

Although genome-editing technologies facilitate efficient plant breeding without introducing a transgene, it is creating indistinct boundaries in the regulation of genetically modified organisms (GMOs). Rapid advances in plant breeding by genome-editing require the establishment of a new global policy for the new biotechnology, while filling the gap between process-based and product-based GMO regulations. In this Opinion article we review recent developments in producing major crops using genome-editing, and we propose a regulatory model that takes into account the various methodologies to achieve genetic modifications as well as the resulting types of mutation. Moreover, we discuss the future integration of genome-editing crops into society, specifically a possible response to the 'Right to Know' movement which demands labeling of food that contains genetically engineered ingredients.