Ethics of modifying the mitochondrial genome

Recent preclinical studies have shown the feasibility of specific variants of nuclear transfer to prevent mitochondrial DNA disorders. Nuclear transfer could be a valuable reproductive option for carriers of mitochondrial mutations. A clinical application of nuclear transfer, however, would entail germ-line modification, more specifically a germ-line modification of the mitochondrial genome. One of the most prominent objections against germ-line modification is the fear that it would become possible to alter 'essential characteristics' of a future person, thereby possibly violating the child's right to an open future. As only the nuclear DNA would contain the ingredients for individual characteristics, modification of the mtDNA is often considered less controversial than modification of the nuclear DNA. This paper discusses the tenability of this dichotomy. After having clarified the concept of germ-line modification, it argues that modification of the mtDNA is not substantively different from modification of the nuclear DNA in terms of its effects on the identity of the future person. Subsequently the paper assesses how this conclusion affects the moral evaluation of nuclear transfer to prevent mtDNA disorders. It concludes that the moral acceptability of germ-line modification does not depend on whether it alters the identity of the future child-all germ-line modifications do-but on whether it safeguards the child's right to an open future. If nuclear transfer to prevent mtDNA disorders becomes safe and effective, then dismissing it because it involves germ-line modification is unjustified

ESHRE task force on ethics and law 15: Cross-border reproductive care

This paper analyses the ethical aspects of cross-border reproductive care. Ethical questions are raised by some of the main reasons of cross-border travelling, i.e. law evasion and unequal access to treatment. The phenomenon also generates possible conflicts linked to the responsibility of the professionals. Three points are discussed: the moral obligation of the physician to refer the patient, his/her duty to provide information and counselling and the acceptability of fee-splitting. The recommendations focus on measures to reduce or limit the number of patients that have to travel abroad and on steps to guarantee the safety and quality of the treatment wherever it is provided

A leap of faith? An interview study with professionals on the use of mitochondrial replacement to avoid transfer of mitochondrial diseases

STUDY QUESTION: What are the opinions of professionals in the field of genetics, reproductive science and metabolic diseases on the development of mitochondrial replacement technologies to be used in the context of medically assisted reproduction? SUMMARY ANSWER: Although concerns regarding safety remain, interviewees supported the development of nuclear transfer techniques to help women who are at risk of transferring a mitochondrial DNA disease to their offspring conceive a genetically related child. WHAT IS KNOWN ALREADY: Technological developments in the field of nuclear transfer have sparked new interest in the debate on the acceptability of the use of donor oocytes to prevent the transmission of mitochondrial diseases. For example, in the UK, extensive public consultations have been done to investigate whether such techniques would allow the passing of a law that involves making changes to a human oocyte or embryo before transfer to a woman's body. Until now, continental European countries seem to await the outcome of the British debate before themselves considering the arguments for and against this technology. STUDY DESIGN, SIZE, AND DURATION: We interviewed 12 professionals from Belgium and The Netherlands. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: We conducted 12 interviews with fertility specialists, scientists, clinical geneticists, a pediatrician specialized in metabolic diseases and a specialist in metabolic diseases. The profiles of the interviewees varied but all had experience with mitochondrial diseases, either in treating patients or in providing counseling to patients or to prospective parents. The interviews were conducted face-to-face and took 30-45 min. The language of the interviews was Dutch. We analyzed the transcript of these interviews using QSR NVIVO 10 software to extract themes and categories. MAIN RESULTS AND THE ROLE OF CHANCE: This study has shown that, although amongst the professionals we interviewed there was support for the development and deployment of nuclear transfer, this support does not necessarily correspond to uniform opinions about the importance of having a genetically own child or the contribution of mitochondrial DNA to essential characteristics of an individual. LIMITATIONS, REASONS FOR CAUTION: In translating the quotes from Dutch to English some of the linguistic nuances may have been lost. We only interviewed 12 individuals, in two countries, whose view may not be representative of existing values and opinions that may be held by professionals worldwide on this matter. To further explore the issue at hand, a subsequent investigation of the opinions of people affected by mitochondrial diseases and of the general public is necessary. WIDER IMPLICATIONS OF THE FINDINGS: With this study we have demonstrated there is in principle support for the nuclear transfer technique from Dutch and Belgian professionals. Further research, both scientific and ethical, is needed to define the modalities of its possible introduction in the fertility clinic

Dynamics and Ethics of Comprehensive Preimplantation Genetic Testing. A Review of the Challenges

BACKGROUND: Genetic testing of preimplantation embryos has been used for preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS). Microarray technology is being introduced in both these contexts, and is to be expected that also whole genome sequencing of blastomeres will become possible. The amount of extra information such tests will yield may prove to be beneficial for embryo selection, but also raise various ethical issues. We present an overview of the developments and an agenda-setting exploration of the ethical issues. METHODS: The paper is a joint endeavour by the presenters at an explorative 'campus meeting' organized by the European Society of Human Reproduction and Embryology in cooperation with the department of Health, Ethics & Society of the Maastricht University (The Netherlands). RESULTS: The increasing amount and detail of information that new screening techniques such as microarrays and whole genome sequencing offer does not automatically coincide with an increasing understanding of the prospects of an embryo. From a technical point of view, the future of comprehensive embryo testing may go together with developments in preconception carrier screening. From an ethical point of view, the increasing complexity and amount of information yielded by comprehensive testing techniques will lead to challenges to the principle of reproductive autonomy and the right of the child to an open future, and may imply a possible larger responsibility of the clinician towards the welfare of the future child. “Smart combinations” of preconception carrier testing and embryo testing may solve some of these ethical questions but could introduce others. CONCLUSION: As comprehensive testing techniques are entering the IVF clinic, there is a need for a thorough rethinking of traditional ethical paradigms regarding medically assisted reproduction.This article was written by Dr Ainsley Newson during the time of her employment with the University of Bristol, UK (2006-2012). Self-archived in the Sydney eScholarship Repository with permission of Bristol University, Sept 2014

Preimplantation genetic testing for more than one genetic condition:clinical and ethical considerations and dilemmas

STUDY QUESTION: Which clinical and ethical aspects of preimplantation genetic testing for monogenic disorders or structural rearrangements (PGT-M, PGT-SR) should be considered when accepting requests and counselling couples for PGT when applied for more than one condition (combination-PGT; cPGT-M/SR)? SUMMARY ANSWER: cPGT is a feasible extension of the practice of PGT-M/SR that may require adapting the criteria many countries have in place with regard to indications-setting for PGT-M/SR, while leading to complex choices that require timely counselling and information. WHAT IS KNOWN ALREADY: Although PGT-M/SR is usually performed to prevent transmission of one disorder, requests for PGTM/SR for more than one condition (cPGT-M/SR) are becoming less exceptional. However, knowledge about implications for a responsible application of such treatments is lacking. STUDY DESIGN, SIZE, DURATION: Retrospective review of all (40) PGT-M/SR applications concerning more than one genetic condition over the period 1995-2018 in the files of the Dutch national PGT centre. This comprises all relevant national data since the start of PGT in the Netherlands. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Data regarding cPGT-M/SR cases were collected by means of reviewing medical files of couples applying for cPGT-M/SR. Ethical challenges arising with cPGT-M/SR were explored against the background of PGT-M/SR regulations in several European countries, as well as of relevant ESHRE-guidance regarding both indications-setting and transfer-decisions. MAIN RESULTS AND THE ROLE OF CHANCE: We report 40 couples applying for cPGT-M/SR of which 16 couples started their IVF treatment. Together they underwent 39 IVF cycles leading to the birth of five healthy children. Of the couples applying for cPGT, 45% differentiated between a primary and secondary condition in terms of perceived severity. In the light of an altered balance of benefits and drawbacks, we argue the 'high risk of a serious condition' standard that many countries uphold as governing indications-setting, should be lowered for secondary conditions in couples who already have an indication for PGT-M/SR. As a consequence of cPGT, professionals will more often be confronted with requests for transferring embryos known to be affected with a condition that they were tested for. In line with ESHRE guidance, such transfers may well be acceptable, on the condition of avoiding a high risk of a child with a seriously diminished quality of life. LIMITATIONS, REASONS FOR CAUTION: We are the first to give an overview of cPGT-M/SR treatments. Retrospective analysis was performed using national data, possibly not reflecting current trends worldwide. WIDER IMPLICATIONS OF THE FINDINGS: Our observations have led to recommendations for cPGT-M/SR that may add to centre policy making and to the formulation of professional guidelines. Given that the introduction of generic methods for genomic analysis in PGT will regularly yield incidental findings leading to transfer requests with these same challenges, the importance of our discussion exceeds the present discussion of cPGT

Human germline gene editing: Recommendations of ESHG and ESHRE

Technological developments in gene editing raise high expectations for clinical applications, first of all for somatic gene editing but in theory also for germline gene editing (GLGE). GLGE is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if GLGE would become safe and effective. What were the arguments behind this legislation, and are they still convincing? If a technique can help to avoid serious genetic disorders, in a safe and effective way, would this be a reason to reconsider earlier standpoints? The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates. After consulting its membership and experts, this final version of the Recommendations was endorsed by the Executive Committee and the Board of the respective Societies in May 2017. Taking account of ethical arguments, we argue that both basic and pre-clinical research regarding GLGE can be justified, with conditions. Furthermore, while clinical GLGE would be totally premature, it might become a responsible intervention in the future, but only after adequate pre-clinical research. Safety of the child and future generations is a major concern. Future discussions must also address priorities among reproductive and potential non-reproductive alternatives, such as PGD and somatic editing, if that would be safe and successful. The prohibition of human germline modification, however, needs renewed discussion among relevant stakeholders, including the general public and legislators

Responsible innovation in human germline gene editing: Background document to the recommendations of ESHG and ESHRE

Technological developments in gene editing raise high expectations for clinical applications, including editing of the germline. The European Society of Human Reproduction and Embryology (ESHRE) and the European Society of Human Genetics (ESHG) together developed a Background document and Recommendations to inform and stimulate ongoing societal debates. This document provides the background to the Recommendations. Germline gene editing is currently not allowed in many countries. This makes clinical applications in these countries impossible now, even if germline gene editing would become safe and effective. What were the arguments behind this legislation, and are they still convincing? If a technique could help to avoid serious genetic disorders, in a safe and effective way, would this be a reason to reconsider earlier standpoints? This Background document summarizes the scientific developments and expectations regarding germline gene editing, legal regulations at the European level, and ethics for three different settings (basic research, preclinical research and clinical applications). In ethical terms, we argue that the deontological objections (e.g., gene editing goes against nature) do not seem convincing while consequentialist objections (e.g., safety for the children thus conceived and following generations) require research, not all of which is allowed in the current legal situation in European countries. Development of this Background document and Recommendations reflects the responsibility to help society understand and debate the full range of possible implications of the new technologies, and to contribute to regulations that are adapted to the dynamics of the field while taking account of ethical considerations and societal concerns