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Reproductive biotechnologies can separate concepts of parenthood into genetic, gestational and social dimensions, often leading to a fragmentation of heteronormative kinship models and posing a challenge to historical methods of establishing legal and/or moral parenthood. Using fictional cases, this article will demonstrate that the issues surrounding the intersection of current and emerging reproductive biotechnologies with definitions of parenthood are already leading to confusion regarding social and legal family ties for offspring, which is only expected to increase as new technologies develop. Rather than opposing these new technologies to reassert traditional concepts of the family, however, this article will explore the opportunities that these technologies represent for re‐imagining various culturally cherished values of family‐making in a way that is inclusive of diverse genders, sexualities and cultures. It will consider IVF, gametogenesis, mitochondrial donation, surrogacy, artificial gestation, CRISPR‐Cas9 gene editing, foster care and adoption as some of many possible pathways to parenthood, including for members of the LGBTIAUQ+ community. [ABSTRACT FROM AUTHOR]

Background: Recent studies have proved the role of autophagy in mesenchymal stem cell (MSCs) function and regenerative properties. How and by which mechanism autophagy modulation can affect the juxtacrine interaction of MSCs should be addressed. Here, the role of autophagy was investigated in the formation of tunneling nanotubes (TNTs) and homotypic mitochondrial donation. Methods: MSCs were incubated with 15 µM Metformin (Met) and/or 3 µM 3-methyladenine (3-MA) for 48 h. The formation of TNTs was assessed using bright-field and SEM images. The mitochondria density and ΔΨ values were monitored using flow cytometry analysis. Using RT-PCR and protein array, the close interaction and shared mediators between autophagy, apoptosis, and Wnt signaling pathways were also monitored. The total fatty acid profile was assessed using gas chromatography. Result: Data indicated the increase of TNT length and number, along with other cell projections after the induction of autophagy while these features were blunted in 3-MA-treated MSCs (p < 0.05). Western blotting revealed the significant reduction of Rab8 and p-FAK in 3-MA-treated MSCs (p < 0.05), indicating the inhibition of TNT assembly and vesicle transport. Likewise, the stimulation of autophagy increased autophagic flux and mitochondrial membrane integrity compared to 3-MA-treated MSCs. Despite these findings, protein levels of mitochondrial membrane Miro1 and 2 were unchanged after autophagy inhibition/stimulation (p > 0.05). We found that the inhibition/stimulation of autophagy can affect the protein, and transcription levels of several mediators related to Wnt and apoptosis signaling pathways involved in different cell bioactivities. Data confirmed the profound increase of mono and polyunsaturated/saturated fatty acid ratio in MSCs exposed to autophagy stimulator. Conclusions: In summary, autophagy modulation could affect TNT formation which is required for homotypic mitochondrial donation. Thus, the modulation of autophagy creates a promising perspective to increase the efficiency of cell-based therapies. [ABSTRACT FROM AUTHOR]

In this article, we explore the legalisation of mitochondrial donation in the UK as the latest iteration of an established sociotechnical imaginary of permissive yet highly scrutinised human embryo research in the country. The focus of our analysis is the work of the UK House of Commons Science and Technology Select Committee as it contributed to the debates and ultimately played a role in enabling the UK to become the first country in the world to legalise clinical use. Mitochondrial donation is a reproductive technology which could allow women with mitochondrial disease to have healthy, genetically related children. From 2011, an extensive process of inquiry was launched in the UK to assess safety, ethics and public attitudes. We analyse video and transcripts of the meeting, and interviews with panellists to explore three themes: contesting scientific interpretation, the labour of alignment and resolution. We demonstrate how micro-interactions during the meeting, and the broader structure of the meeting itself, aligned with the UK sociotechnical imaginary of a permissive but scrutinising approach to human embryo regulation. We conclude that the event was one element of a larger process of review that together worked to render mitochondrial donation as knowable, ethical, desirable and sanctionable. [ABSTRACT FROM AUTHOR]

Mitochondrial donation is an assisted reproductive technology used to minimize the risk of transmitting serious mitochondrial diseases from mother to child. The aim of this research is to examine the Australian legal landscape regarding mitochondrial donation. This research uses a literature review research method. The data collection technique in this research is literature study. The data that has been collected is then analyzed in three stages, namely data reduction, data presentation and drawing conclusions. The results show that Western Australian legislation (external site) currently prohibits the use of embryos containing the genetic material of more than two people, and this is one of the reasons why mitochondrial donation is not currently legal in Western Australia. In 2021, following a Senate Committee Review and Community Consultation, the Commonwealth Government introduced the Mitochondrial Donation Law Reform Bill (Maeve's Law) (2021) which proposes a phased approach to amending Commonwealth laws that currently make mitochondrial donation illegal. The bill was passed on 30 March 2022. Assisted reproductive technology legislation is under review in Western Australia and the Western Australian Government has committed to engaging in national consultation on new technologies, including mitochondrial donation. [ABSTRACT FROM AUTHOR]

Recently, Australia became the second jurisdiction worldwide to legalize the use of mitochondrial donation technology. The Mitochondrial Donation Law Reform (Maeve's Law) Bill 2021 allows individuals with a family history of mitochondrial disease to access assisted reproductive techniques that prevent the inheritance of mitochondrial disease. Using inductive content analysis, we assessed submissions sent to the Senate Committee as part of a programme of scientific inquiry and public consultation that informed drafting of the Bill. These submissions discussed a range of bioethical and legal considerations of central importance to the political debate. Significantly, submissions from those with a first-hand experience of mitochondrial disease, including clinicians and those with a family history of mitochondrial disease, were in strong support of this legislation. Those in support of the Bill commended the two-staged approach and rigorous licencing requirements as part of the Bill's implementation strategy. Submissions which outlined arguments against the legislation either opposed the use of these techniques in general or opposed aspects of the implementation strategy in Australia. These findings offer a window into the ethical arguments and perspectives that matter most to those Australians who took part in the Senate inquiry into mitochondrial donation. The insights garnered from these submissions may be used to help refine policy and guidelines as the field progresses. [ABSTRACT FROM AUTHOR]

Angiogenesis is a complex process that involves the expansion of the pre‐existing vascular plexus to enhance oxygen and nutrient delivery and is stimulated by various factors, including hypoxia. Since the process of angiogenesis requires a lot of energy, mitochondria play an important role in regulating and promoting this phenomenon. Besides their roles as an oxidative metabolism base, mitochondria are potential bioenergetics organelles to maintain cellular homeostasis via sensing alteration in oxygen levels. Under hypoxic conditions, mitochondria can regulate angiogenesis through different factors. It has been indicated that unidirectional and bidirectional exchange of mitochondria or their related byproducts between the cells is orchestrated via different intercellular mechanisms such as tunneling nanotubes, extracellular vesicles, and gap junctions to maintain the cell homeostasis. Even though, the transfer of mitochondria is one possible mechanism by which cells can promote and regulate the process of angiogenesis under reperfusion/ischemia injury. Despite the existence of a close relationship between mitochondrial donation and angiogenic response in different cell types, the precise molecular mechanisms associated with this phenomenon remain unclear. Here, we aimed to highlight the possible role of mitochondria concerning angiogenesis, especially the role of mitochondrial transport and the possible relation of this transfer with autophagy, the housekeeping phenomenon of cells, and angiogenesis. [ABSTRACT FROM AUTHOR]

Mitochondrial replacement therapy (MRT) utilises nuclear transfer technology to replace defective mitochondria with healthy ones and thereby minimise the risk of a mitochondrial disease passing from a mother to her child. It promises much but comes with ethical controversy, significant risk of harm and many unknowns. Forming a position on MRT requires accurate information about the current state of knowledge, and an appreciation of the ethical issues at stake. Ethical deliberations will vary depending on the framework used. There are in principle objections to MRT on the grounds of direct harm to human embryos and germline genetic modification. But even without these objections MRT can be weighed in terms of the balance between risks and benefits, alternatives and uncertainties. This paper explores the evidence and lays out the relevant issues to assist such a deliberation. [ABSTRACT FROM AUTHOR]

There seems to be a consensus that enucleated oocyte donation (EOD) should only be used to reduce the risk of having a child with mitochondrial disorders. However, this paper argues that in the initial phase in which we are at the moment, EOD should first be used to remedy infertility caused by poor oocyte quality or poor embryonic development. That learning period will allow researchers to improve their technical skills and the knowledge of the best procedure before starting on high-risk cases. Mitochondrial carryover of pathologic mtDNA is the main cause of concern for the offspring. That risk does not exist in infertility cases. The application of EOD to treat infertility should at present be performed in a clinical research setting to obtain more evidence about efficacy and safety. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate if cytoplasmic transfer can improve fertilization and embryo quality of women with oocytes of low quality. During ICSI, 10–15% of the cytoplasm from a fresh or frozen young donor oocyte was added to the recipient oocyte. According to the embryo quality, we defined group A as patients in which the best embryo was evident after cytoplasmic transfer and group B as patients in which the best embryo was evident after a simple ICSI. We investigated in the period of 2002–2018, 125 in vitro fertilization cycles involving 1011 fertilized oocytes. Five hundred fifty-seven sibling oocytes were fertilized using ICSI only and 454 oocytes with cytoplasmic transfer. Fertilization rates of oocytes were 67.2% in the cytoplasmic transfer and 53.5% in the ICSI groups (P < 0.001). A reduction in fertilization rate was observed with increased women age in the ICSI but not in the cytoplasmic transfer groups. The best embryo quality was found after cytoplasmic transfer in 78 cycles (62.4%) and without cytoplasmic transfer in 40 cycles (32%, P < 0.001). No significant differences were detected between the age, hormonal levels, dose of stimulation drugs, number of transferred embryos, pregnancy rate and abortion rate between A and B groups. Cytoplasmic transfer improves fertilization rates and early embryo development in humans with low oocyte quality. All 28 children resulting from cytoplasmic transfer are healthy. [ABSTRACT FROM AUTHOR]

Since mitochondrial replacement techniques (MRT) were developed and clinically introduced in the United Kingdom (UK), there has been much discussion of whether these lead to children borne of three parents. In the UK, the regulation of MRT has dealt with this by stipulating that egg donors for the purposes of MRT are not genetic parents even though they contribute mitochondrial DNA (mtDNA) to offspring. In this paper, I examine the way that the Human Fertilisation and Embryology Act in the UK manages the question of parentage. I argue that the Act breaks the link typically made between genetic causation and genetic parenthood by redefining genetic causation solely in terms of nuclear genetics. Along with this, mtDNA is construed as a kind of supplement to the nuclear family. Drawing on the account of the supplement developed by Jacques Derrida, I argue that mtDNA and the women who donate it are seen as both essential to establishing the nuclear family but also exterior to and insignificant for it. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA (mtDNA), as its name implies, is an embodiment of the mitochondrial genetic information that constitutes about 1% of the mammalian genome. It fills a vital niche in tracing matrilineality; the mtDNA is inherited solely from the mother and plays a crucial role in genealogical research. Even a single mutation in the mtDNA can have debilitating and life-altering consequences. Mothers carrying mtDNA mutations will inevitably pass it on to the future generation. Three-parent In vitro fertilization (IVF), a breakthrough technique, shows promising potential to prevent mothers with mtDNA defects from passing it on to their future generation, while also maintaining the genetic link to their posterity. In this review, I delve into the intricacies of this technique, compare and analyze the difference between maternal spindle transfer and pronuclear transfer, discuss the prospective therapeutic effects, and highlight the ethical concerns surrounding this procedure. Considering the various challenges and ethics of this contentious technique, the paper seeks to answer the rousing question - Is three-parent IVF the answer to preventing mitochondrial defects?. [ABSTRACT FROM AUTHOR]

Sperm, eggs and embryos are made up of more than genes, and there are indications that changes to non‐genetic structures in these elements of the germline can also be inherited. It is, therefore, a mistake to treat phrases like 'germline inheritance' and 'genetic inheritance' as simple synonyms, and bioethical discussion should expand its focus beyond alterations to the genome when considering the ethics of germline modification. Moreover, additional research on non‐genetic inheritance draws attention to a variety of means whereby differences can be inherited in offspring generations that do not rely on differences in germline structures. Research on these diverse forms of inheritance challenges the notion that there is some special form of ethical concern that falls on germline interventions in general, and on interventions to the nuclear genome within the germline in particular. [ABSTRACT FROM AUTHOR]

Study Question: Does an informed group of citizens endorse the clinical use of mitochondrial donation in a country where this is not currently permitted?Summary Answer: After hearing balanced expert evidence and having opportunity for deliberation, a majority (11/14) of participants in a citizens' jury believed that children should be able to be born using mitochondrial donation.What Is Known Already: Research suggests that patients, oocyte donors and health professionals support mitochondrial donation to prevent transmission of mitochondrial disease. Less is known about public acceptability of this novel reproductive technology, especially from evidence using deliberative methods.Study Design, Size, Duration: This study comprised a citizens' jury, an established method for determining the views of a well-informed group of community members. The jury had 14 participants, and ran over one and a half days in 2017.Participants/materials, Setting, Methods: Jurors were members of the public with no experience of mitochondrial disease. They heard and engaged with relevant evidence and were asked to answer the question: 'Should Australia allow children to be born following mitochondrial donation?'Main Results and the Role Of Chance: Eleven jurors decided that Australia should allow children to be born following mitochondrial donation; 7 of whom added conditions such as the need to limit who can access the intervention. Three jurors decided that children should not (or not yet) be born using this intervention. All jurors were particularly interested in the reliability of evidence, licensing/regulatory mechanisms and the rights of children to access information about their oocyte donors.Limitations, Reasons For Caution: Jurors' views were well informed and reflected critical deliberation and discussion, but are not intended to be representative of the whole population.Wider Implications Of the Findings: When presented with high quality evidence, combined with opportunities to undertake structured deliberation of novel reproductive technologies, members of the public are able to engage in detailed discussions. This is the first study to use an established deliberative method to gauge public views towards mitochondrial donation.Study Funding/competing Interest(s): This study was funded by a University of Sydney Industry and Community Collaboration Seed Award (2017), which was awarded contingent on additional funding from the Mito Foundation. Additional funding was provided by the Mito Foundation. The Foundation was not involved in jury facilitation or deliberation, nor analysis of research data.Trial Registration Number: Not applicable. [ABSTRACT FROM AUTHOR]

Abstract: The Institute of Medicine has recently endorsed arguments put forward by John Appleby calling for mandatory sex selection against female offspring in the initial trials of mitochondrial replacement techniques. In this paper I argue that, despite this endorsement, the reasons offered by Appleby for mandatory sex selection are inadequate. I further argue that plausible revisions to Appleby's arguments still fail to convincingly defend such an intrusive policy. While I remain neutral about whether intending parents making use of mitochondrial replacement techniques ought to have access to sex selection, I conclude that to date the case for mandatory sex selection has not been satisfactorily made. [ABSTRACT FROM AUTHOR]

Mitochondrial Replacement Therapy is an ethically controversial procedure that allows women with genetically transmitted mutations in their mitochondria to have healthy children. Using this procedure, healthy mitochondria from a third party can be donated in the fertilization process to create a healthy child from three genetic "parents". There is much concern about the safety and ethics of this procedure and presenting the Catholic and Jewish perspectives of Mitochondrial Replacement Therapy can offer insights into the morally complexity of the ethical issues surrounding this innovative medical procedure. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the second most commonly diagnosed cancer in females and the third in males. In this work, we aim to investigate the possible anti-cancer effects of interferon-gamma (IFN-γ) in CRC cells. We observed that IFN-γ induced mitochondria-derived reactive oxygen species (ROS) production in a time-dependent manner in SW480 and HCT116 cell lines. The IFN-γ-induced mitochondrial ROS generation was dependent on the activation of cytosolic phospholipase A2 (cPLA2). In addition, a mitochondria-targeted antioxidant SS31 and/or cPLA2 inhibitor AACOCF3 abolished the IFN-γ-induced ROS production and subsequent autophagy and apoptosis. Moreover, suppression of autophagy by CQ was able to reduce IFN-γ-induced cell apoptosis. Beclin-1 gene silencing resulted in caspase-3 inactivation, decreased Bax/Bcl-2 ratio and less population of apoptotic cells. Collectively, our results suggested that IFN-γ induces autophagy-associated apoptosis in CRC cells via inducing cPLA2-dependent mitochondrial ROS production. [ABSTRACT FROM AUTHOR]

Jurisdictions are beginning to respond to growing demands to begin the clinical use of mitochondrial donation in human embryos. This form of directed modification of human embryos is intended to prevent mitochondrial disease in future members of families with a known history of such disease. At least one child has already been born after the technique was used during his conception. The United Kingdom has legalized such use and the United States has undertaken high level reviews of the legal and ethical issues that arise from it. Other jurisdictions, such as Australia, continue to prohibit the clinical use of the technique. Using these three distinct responses, this article identifies three fundamental issues raised by the clinical use of mitochondrial donation that must be addressed by jurisdictions considering their own governance responses and analyzes the policy and regulatory contexts that impact how these issues are or will be responded to. Drawing on this analysis, the article discusses how the studied frameworks can inform future governance arrangements in other jurisdictions considering clinical mitochondrial donation. [ABSTRACT FROM AUTHOR]

The articles in this issue cover a wide range of topics, including the moral status of human embryos and human-animal chimeras and hybrids, the determination of death, theories of human cognition, and policies on the identity of mitochondrial donors. Despite this variety, there are two underlying questions that tie the articles together: what is a human being? And, what is the basis of moral status? First, I discuss these two questions and why they are important for bioethics. Then I provide summaries of the six articles in this issue and explain how each of them is connected to the questions of human nature and moral status. [ABSTRACT FROM AUTHOR]

Novel technological developments mean that gene editing - making deliberately targeted alterations in specific genes - is now a clinical reality. The inherited metabolic disorders, a group of clinically significant, monogenic disorders, provide a useful paradigm to explore some of the many ethical issues that arise from this technological capability. Fundamental questions about the significance of the genome, and of manipulating it by selection or editing, are reviewed, and a particular focus on the legislative process that has permitted the development of mitochondrial donation techniques is considered. Ultimately, decisions about what we should do with gene editing must be determined by reference to other non-genomic texts that determine what it is to be human - rather than simply to undertake gene editing because it can be done. [ABSTRACT FROM AUTHOR]

The development of any novel reproductive technology involving manipulation of human embryos is almost inevitably going to be controversial and evoke sincerely held, but diametrically opposing views. The plethora of scientific, ethical and legal issues that surround the clinical use of such techniques fuels this divergence of opinion. During the policy change that was required to allow the use of mitochondrial donation in the UK, many of these issues were intensely scrutinised by a variety of people and in multiple contexts. This extensive process resulted in the publication of several reports that informed the recommendations made to government. We have been intrinsically involved in the development of mitochondrial donation, from refining the basic technique for use in human embryos through to clinical service delivery, and have taken the opportunity in this article to offer our own perspective on the issues it raises. [ABSTRACT FROM AUTHOR]

The question whether maternal spindle transfer (MST) and pronuclear transfer (PNT) can be prohibited under EU legislation was examined by the non-governmental organisation European Bioethics Research (EBR). It did so by submitting an official complaint to the EU Commission proposing that the UK Human Fertilisation and Embryology (Mitochondrial Donation) Regulations 2015 breached the prohibition on the modification of a person's germ line genetic identity of the EU Clinical Trials Directive 2001/20/EC and the new Regulation EU 536/2014. A discussion then took place, during 2016, between EBR and the EU Commission whether MST and PNT principally involved a 'medicinal product' in which case the EU Clinical Trials Directive 2001/20/EC and Regulation EU 536/2014 would be applicable or whether the procedures just involved a medical procedure in which case the Tissue and Cells Directive 2004/23/EC was applicable which did not include any prohibition on the intentional modification of a person's germline. [ABSTRACT FROM AUTHOR]

With an increasing number of ways to 'assist' reproduction, some bioethicists have started to wonder what it takes to become a genetic parent. It is widely agreed that sharing genes is not enough to substantiate the parent-offspring relation, but what is? Without a better understanding of the concept of reproduction (and what it means to say that an organism has reproduced), our thinking about parent-offspring relations and the ethical issues surrounding them risk being unprincipled. Here, I address that problem by offering a principled account of reproduction--the Overlap, Development and Persistence account--which I believe best captures the meaning of 'genetic parenthood'. [ABSTRACT FROM AUTHOR]

Mitochondrial replacement therapy is a process whereby a child is created by combining the nuclear DNA of two people wishing to have a child with mitochondrial DNA (mtDNA) donated by a third person. It poses a new question as to the extent of a person’s right to know the identity of those from whom their DNA is inherited. In commentary upon Turkmendag’s paper, I evaluate the consistency of UK regulation of this issue with the European Convention of Human Rights. Under UK law, a person created using donated mtDNA is only entitled to information about the procedure which does not identify the donor. I argue that this approach is consistent with the previous European Court of Human Rights and UK judicial decisions on the rights of individuals to information about their identity and ancestry and with the deeper foundational principle which Kai Möller argues the Convention protects existential self-understanding. I conclude that, as mtDNA has not been proven to affect an individual’s life choices and outward characteristics to the extent that gamete donation does, it is acceptable to prioritize the interests that anonymous donation protects over the desire of the recipient to know the identity of their donor. [ABSTRACT FROM AUTHOR]

This article addresses the child’s right to know their genetic origins in mitochondrial donation. It focuses on the UK’s public debate on mitochondrial replacement techniques and examines the claims-making activities that shaped the donor information regulations. During the public consultation, downplaying the significance of the mitochondria helped distinguish mitochondria donors from gamete donors and determine their relational status with the resulting child. As a result, according to the Mitochondrial Donation regulations, mitochondria donors, unlike gamete donors, will not be required to be identifiable to the resulting child. I argue that, in the UK, similar to donor conception, public understanding of mitochondrial donation is shaped by a “calculus of genes”: simplified accounts of how genes determine the resulting child’s characteristics and identity. While the donor conception regulations ascribe social meaning to the passage of genes, the mitochondria regulations strip the social meaning away from the donation based on the assumption that the genetic contribution made by the donor is quantitatively insignificant in influencing the identity of the resultant offspring. The nature of the genetic material itself should not be considered as a privileged standpoint from which to decide on social meaning of the donation or the rights attached to it. [ABSTRACT FROM AUTHOR]

Mitochondria are present in all human cells and vary in number from a few tens to many thousands. As they generate the majority of a cell's energy supply which power every part of our body, and hence, their number varies in different cells as per the energy requirement of the cell. Mitochondria have their own separate DNA, which carries total 13 genes. All of these 13 genes are involved in energy production. For normal functioning of cells, the mitochondria need to be healthy. Unhealthy mitochondria can cause severe medical disorders known as mitochondrial disease. In case of mitochondrial disease, the most commonly affected organs are the heart, kidney, skeletal muscle, and brain. The diseases related to defects in these organs are quite prevalent in the society. Majority of these mitochondrial diseases are caused by genetic defects (mutations) in the mitochondrial DNA. Unlike nuclear genes, mitochondrial DNA is inherited only from our mother. Mothers can carry abnormal mitochondria and be at risk of passing on the serious disease to their children, even if they themselves show only mild or no symptoms. Due to the complex nature of these diseases, their diagnosis and therapy are very difficult. Hence, till now, only the different methods for management of these diseases are known. However, after understanding the complexity related to the cure of these diseases, alternative methods have been developed to minimize/stop the transfer of mitochondrial diseases from mother to offspring. This latest technique is called mitochondrial replacement or "donation." In the present review, we are discussing the methodological details and issues related to the technique of mitochondrial donation. Our study is also a step toward raising awareness about mitochondrial diseases and advocating for the legalization of mitochondrial donation, a revolutionary in vitro fertilization technique. [ABSTRACT FROM AUTHOR]

In October 2015 the UK enacted legislation to permit the clinical use of two cutting edge germline-altering, IVF-based embryonic techniques: pronuclear transfer and maternal spindle transfer (PNT and MST). The aim is to use these techniques to prevent the maternal transmission of serious mitochondrial diseases. Major claims have been made about the quality of the debates that preceded this legislation and the significance of those debates for UK decision-making on other biotechnologies, as well as for other countries considering similar legislation. In this article we conduct a systematic analysis of those UK debates and suggest that claims about their quality are over-stated. We identify, and analyse in detail, ten areas where greater clarity, depth and nuance would have produced sharper understandings of the contributions, limitations and wider social impacts of these mitochondrial interventions. We explore the implications of these additional considerations for (i) the protection of all parties involved, should the techniques transfer to clinical applications; (ii) the legitimacy of focussing on short-term gains for individuals over public health considerations, and (iii) the maintenance and improvement of public trust in medical biotechnologies. We conclude that a more measured evaluation of the content and quality of the UK debates is important and timely: such a critique provides a clearer understanding of the possible, but specific, contributions of these interventions, both in the UK and elsewhere; also, these additional insights can now inform the emerging processes of implementation, regulation and practice of mitochondrial interventions. [ABSTRACT FROM AUTHOR]

Mitochondrial donation (or mitochondrial replacement techniques, MRT) is a special form of in vitro fertilisation involving the mitochondrial DNA (mtDNA) of a third (donor) party. This technique eliminates the risk of severe mitochondrial pathologies, genetically inherited from the mother, by replacing part of her mtDNA with healthy mtDNA from another woman, the donor. This paper explores the ethical dimensions of this technique and their impact upon policy decisions. In particular, it is argued that despite the spectacular fact that a child might have three genetic sources, the bi-parental paradigm is not truly challenged. The most important issue surrounding mitochondrial donation is the fact that it involves germline modification. To this extent, approval of such a technique sets a precedent. There is a wide and traditional international consensus on prohibiting human germ-line modification, and this paper examines whether the specific procedure of mitochondrial donation falls within this logic. [ABSTRACT FROM AUTHOR]

Reproductive rights in South Africa have traditionally focused on the rights of individuals to avoid reproduction. However, with an increase in the use of assisted reproductive technologies (ART), there has been a shift in the focus on reproductive rights from the rights of individuals to avoid reproduction to the rights of individuals to reproduce noncoitally. With the emergence of new technologies, reproduction by noncoital means and the right to engage in these new technologies is becoming more prevalent. This raises two questions. The first question is whether such a right exists. The recent Constitutional Court decision in AB v Minister of Social Development 2017 3 BCLR 267 (CC) suggests that it does, but only if the person claiming this right is physically involved in the reproductive process. Ostensibly this excludes those who cannot contribute to the reproduction of a child. The second question raised pertains to the impact of this right on specific forms of ART, namely mitochondrial transfer, posthumous reproduction and embryo donation. While the first two forms of ART would meet the criteria set down in AB, embryo donation would not. Individuals denied access to embryo donation could thus not rely on either the right to reproductive autonomy or the right to privacy to aid them. Fortunately the existing legal framework provides some assistance to these individuals, although sadly the same legislative framework does not support the use of mitochondrial transfer and posthumous reproduction. In this respect there is incongruence between rights and legislation, which has only been exacerbated by the recent Constitutional Court decision. What is thus needed is clarity on the meaning of certain rights in respect of certain forms of ART as well as legislative reform to reflect the clarified position. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Mitochondrial replacement techniques (MRT) are intended to avoid the transmission of mitochondrial diseases from mother to child. MRT represent a potentially powerful new biomedical technology with ethical, policy, economic and social implications. Among other ethical questions raised are concerns about the possible effects on the identity of children born from MRT, their families, and the providers or donors of mitochondria. It has been suggested that MRT can influence identity (i) directly, through altering the genetic makeup and physical characteristics of the child, or (ii) indirectly through changing the child's experience of disease, and by generating novel intrafamilial relationships that shape the sense of self. In this article I consider the plausibility and ethical implications of these proposed identity effects, but I focus instead on a third way in which identity may be affected, through the mediating influence of the wider social world on MRT effects on identity. By taking a narrative approach, and examining the nature and availability of identity narratives, I conclude that while neither direct genetic nor indirect experiential effects can be excluded, social responses to MRT are more likely to have a significant and potentially damaging influence on the generation of MRT children's narratives of identity. This conclusion carries some implications for the collective moral responsibility we hold to ensure that MRT, if implemented, are practised in ethically justifiable ways. [ABSTRACT FROM AUTHOR]

Jürgen Habermas is regarded as a central bioconservative commentator in the debate on the ethics of human prenatal genetic manipulations. While his main work on this topic, The Future of Human Nature, has been widely examined in regard to his position on prenatal genetic enhancement, his arguments regarding prenatal genetic therapeutic interventions have for the most part been overlooked. In this work I do two things. First, I present the three necessary conditions that Habermas establishes for a prenatal genetic manipulation to be regarded as morally permissible. Second, I examine if mitochondrial replacement techniques meet these necessary conditions. I investigate, specifically, the moral permissibility of employing pronuclear transfer and maternal spindle transfer. I conclude that, according to a Habermasian perspective on prenatal genetic manipulation, maternal spindle transfer (without using a preselected sperm and egg) and pronuclear transfer are morally impermissible. Maternal spindle transfer is, in principle, morally permissible, but only when we have beforehand preselected a sperm and an egg for our reproductive purpose. These findings are relevant for bioconservatives, both for those who hold a Habermasian stance and for those who hold something akin to a Habermasian stance, because they answer the question: what should bioconservatives do regarding mitochondrial replacement techniques? In fact, the answer to this question does not only normatively prescribe what bioconservatives should do in terms of their personal morality, but it also points towards what kind of legislation regulating mitochondrial replacement techniques they should aim at. [ABSTRACT FROM AUTHOR]

Mitochondrial replacement techniques (MRTs), known in the popular media as 'three-parent' or 'three-person' IVFs, have the potential to enable women with mitochondrial diseases to have children who are genetically related to them but without such diseases. In the debate regarding whether MRTs should be made available, an issue that has garnered considerable attention is whether MRTs affect the characteristics of an existing individual or whether they result in the creation of a new individual, given that MRTs involve the genetic manipulation of the germline. In other words, do MRTs affect the qualitative identity or the numerical identity of the resulting child? For instance, a group of panelists on behalf of the UK Human Fertilisation and Embryology Authority (HFEA) has claimed that MRTs affect only the qualitative identity of the resulting child, while the Working Group of the Nuffield Council on Bioethics (NCOB) has argued that MRTs would create a numerically distinct individual. In this article, I shall argue that MRTs do create a new and numerically distinct individual. Since my explanation is different from the NCOB's explanation, I shall also offer reasons why my explanation is preferable to the NCOB's explanation. [ABSTRACT FROM AUTHOR]

In February 2015 the UK became the first country to legalise high-profile mitochondrial replacement techniques (MRTs), which involve the creation of offspring using genetic material from three individuals. The aim of these new cell reconstruction techniques is to prevent the transmission of maternally inherited mitochondrial disorders to biological offspring. During the UK debates, MRTs were often positioned as a straightforward and unique solution for the 'eradication' of mitochondrial disorders, enabling hundreds of women to have a healthy, biologically-related child. However, many questions regarding future applications and potential users remain. Drawing on a current qualitative study on reproductive choices in the context of mitochondrial disorders, this article illustrates how the potential limitations of MRTs have been obscured in public debates by contrasting the claims made about the future beneficiaries with insights from families affected by mitochondrial disorders and medical experts. The analysis illuminates the complex choices with which families and individuals affected by mitochondrial disorders are faced, which have thus far remained invisible. An argument is presented for improved information for the public as well as an intensification of critical empirical research around the complex and specific needs of future beneficiaries of new reproductive biotechnologies. [ABSTRACT FROM AUTHOR]

The classification of techniques used in mitochondrial donation, including their role as purported germ-line gene therapies, is far from clear. These techniques exhibit characteristics typical of a variety of classifications that have been used in both scientific and bioethics scholarship. This raises two connected questions, which we address in this paper: (i) how should we classify mitochondrial donation techniques?; and (ii) what ethical implications surround such a classification? First, we outline how methods of genetic intervention, such as germ-line gene therapy, are typically defined or classified. We then consider whether techniques of mitochondrial donation fit into these, whether they might do so with some refinement of these categories, or whether they require some other approach to classification. To answer the second question, we discuss the relationship between classification and several key ethical issues arising from mitochondrial donation. We conclude that the properties characteristic of mitochondrial inheritance mean that most mitochondrial donation techniques belong to a new sub-class of genetic modification, which we call 'conditionally inheritable genomic modification' (CIGM). [ABSTRACT FROM AUTHOR]

Background: Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are capable of repairing wounded lung epithelial cells by donating cytoplasmic material and mitochondria. Recently, we characterized two populations of human lung-derived mesenchymal stromal cells isolated from digested parenchymal lung tissue (LT-MSCs) from healthy individuals or from lung transplant recipients' bronchoalveolar lavage fluid (BAL-MSCs). The aim of this study was to determine whether LT-MSCs and BAL-MSCs are also capable of donating cytoplasmic content and mitochondria to lung epithelial cells. Methods: Cytoplasmic and mitochondrial transfer was assessed by co-culturing BEAS2B epithelial cells with Calcein AM or Mitotracker Green FM-labelled MSCs. Transfer was then measured by flow cytometry and validated by fluorescent microscopy. Molecular inhibitors were used to determine the contribution of microtubules/tunnelling nanotubes (TNTs, cytochalasin D), gap junctions (carbenoxolone), connexin-43 (gap26) and microvesicles (dynasore). Results: F-actin microtubules/TNTs extending from BM-MSCs, LT-MSCs and BAL-MSCs to bronchial epithelial cells formed within 45 minutes of co-culturing cells. Each MSC population transferred a similar volume of cytoplasmic content to epithelial cells. Inhibiting microtubule/TNTs, gap junction formation and microvesicle endocytosis abrogated the transfer of cytoplasmic material from BM-MSCs, LT-MSCs and BAL-MSCs to epithelial cells. In contrast, blocking connexin-43 gap junction formation had no effect on cytoplasmic transfer. All MSC populations donated mitochondria to bronchial epithelial cells with similar efficiency. Mitochondrial transfer was reduced in all co-cultures after microtubule/TNT or endocytosis inhibition. Gap junction formation inhibition reduced mitochondrial transfer in BM-MSC and BAL-MSC co-cultures but had no effect on transfer in LT-MSC co-cultures. Connexin-43 inhibition did not impact mitochondrial transfer. Finally, bronchial epithelial cells were incapable of donating cytoplasmic content or mitochondria to any MSC population. Conclusion: Similar to their bone marrow counterparts, LT-MSCs and BAL-MSCs can donate cytoplasmic content and mitochondria to bronchial epithelial cells via multiple mechanisms. Given that BM-MSCs utilize these mechanisms to mediate the repair of damaged bronchial epithelial cells, both LT-MSCs and BAL-MSCs will probably function similarly. [ABSTRACT FROM AUTHOR]

In 2015, the UK became the first country permitting the clinical application of mitochondrial replacement techniques (MRT). Here, we explore how MRT have led to diverging international policy. In response, we recommend focused regulatory efforts coupled with United Nations (UN) leadership to build international consensus on the future of MRT. [ABSTRACT FROM AUTHOR]

Mitochondrial DNA diseases are rare genetic disorders, which can have a devastating effect on the patients' health and well-being. There is no cure for such diseases, although recent experiments suggest that there may be a way to prevent them by genetically altering the eggs or embryos through a procedure known as mitochondrial donation. However, such a procedure not only raises serious safety and ethical concerns, but legal challenges as well, since it involves germline gene modification, which until recently was not legal in the UK or elsewhere. In February 2015, the British Parliament amended the relevant legislation to allow such. a procedure, making the UK the first state to openly challenge the global policy on germline gene modification. The article presents the scientific background to the procedure and discusses the regulatory challenges brought by the first case of its legalisation. [ABSTRACT FROM AUTHOR]

The British Parliament has recently approved regulations to allow techniques ‘to prevent the transmission of serious mitochondrial disease from a mother to her child’. The regulations term these techniques ‘mitochondrial donation’, but in the popular media, the issue has been discussed under the heading of ‘three parent’ babies or ‘three parent’ embryos. This paper examines the language of the debate, with particular reference to one of the techniques approved. It concludes that the terminology of ‘mitochondrial donation’ is scientifically inaccurate and ethically misleading, while the popular media description of ‘three parent’ embryos is broadly accurate, at least for one technique. This latter phrase also has the great merit, from an ethical perspective, of drawing attention to the ‘other woman’, the egg donor. She takes risks with her health in order to provide the egg which supplies the body of the embryo. Without her, this embryo simply would not exist. [ABSTRACT FROM AUTHOR]

The article offers the author's insights on a study concerning the mitochondrial replacement in human oocytes with pathogenic DNA mutations. The author discusses the ruling issued by the British Human Fertilisation and Embryology Authority, approving the in vitro fertilization (IVF) and mitochondrial donation. The author also discusses the mutations in mitochondrial DNA (mtDNA), the presence of genomes in human cells, and importance of mitochondrial genotype in embryonic stem-cell propagation.

The article discusses the potential benefit of in-vitro fertilization techniques in preventing the spread of inherited genetic diseases. Topics include the effect of the pathogenic mitochondrial DNA (mtDNA) mutations on the fertility rates of affected women in Great Britain and the U.S., the assumptions made by the authors, and their views on the Human Fertilisation and Embryology Regulations of 2015.

Background: Mitochondrial DNA (mtDNA) diseases are a group of maternally inherited genetic disorders caused by a lack of energy production. Currently, mtDNA diseases have a poor prognosis and no known cure. The chance to have unaffected offspring with a genetic link is important for the affected families, and mitochondrial replacement techniques (MRTs) allow them to do so. MRTs consist of transferring the nuclear DNA from an oocyte with pathogenic mtDNA to an enucleated donor oocyte without pathogenic mtDNA. This paper aims to determine the efficacy, associated risks, and main ethical and legal issues related to MRTs. Methods: A bibliographic review was performed on the MEDLINE and Web of Science databases, along with searches for related clinical trials and news. Results: A total of 48 publications were included for review. Five MRT procedures were identified and their efficacy was compared. Three main risks associated with MRTs were discussed, and the ethical views and legal position of MRTs were reviewed. Conclusions: MRTs are an effective approach to minimizing the risk of transmitting mtDNA diseases, but they do not remove it entirely. Global legal regulation of MRTs is required. [ABSTRACT FROM AUTHOR]

The article discusses the Human Fertilization and Embryo Authority (HFEA) licensing requirements for mitochondrial donation which stipulate that it should be used in situations in which there is substantial risk of transmitting serious mitochondrial DNA (mtDNA) disease. It states that the estimated average number of births per year among women at risk for the disease is 152 in Great Britain and 778 in the U.S. and mitochondrial donation will have an immediate and direct effect on the births.

The article reports on the amendments to the 2008 Human Fertilization and Embrology Act in the U.S. Topics covered include the focus of the changes on allowing mitochondrial donation, the importance of the changes to address the issue of mitochondrial disease in some babies and the controversy raised by the issue.