Potentiality switches and epistemic uncertainty: the Argument from Potential in times of human embryo-like structures.

Recent advancements in developmental biology enable the creation of embryo-like structures from human stem cells, which we refer to as human embryo-like structures (hELS). These structures provide promising tools to complement-and perhaps ultimately replace-the use of human embryos in clinical and fundamental research. But what if these hELS-when further improved-also have a claim to moral status? What would that imply for their research use? In this paper, we explore these questions in relation to the traditional answer as to why human embryos should be given greater protection than other (non-)human cells: the so-called Argument from Potential (AfP). According to the AfP, human embryos deserve special moral status because they have the unique potential to develop into persons. While some take the development of hELS to challenge the very foundations of the AfP, the ongoing debate suggests that its dismissal would be premature. Since the AfP is a spectrum of views with different moral implications, it does not need to imply that research with human embryos or hELS that (may) have 'active' potential should be completely off-limits. However, the problem with determining active potential in hELS is that this depends on development passing through 'potentiality switches' about the precise coordinates of which we are still in the dark. As long as this epistemic uncertainty persists, extending embryo research regulations to research with specific types of hELS would amount to a form of regulative precaution that as such would require further justification.

Advances in prenatal screening: the ethical dimension.

Prenatal screening strategies are undergoing rapid changes owing to the introduction of new testing techniques. The overall tendency is towards broadening the scope of prenatal testing through increasingly sensitive ultrasound scans and genome-wide molecular tests. In addition, non-invasive prenatal diagnosis is likely to be introduced in the near future. These developments raise important ethical questions concerning meaningful reproductive choice, the autonomy rights of future children, equity of access and the proportionality of testing.

Prenatal screening: an ethical agenda for the near future.

Prenatal screening for foetal abnormalities such as Down's syndrome differs from other forms of population screening in that the usual aim of achieving health gains through treatment or prevention does not seem to apply. This type of screening leads to no other options but the choice between continuing or terminating the pregnancy and can only be morally justified if its aim is to provide meaningful options for reproductive choice to pregnant women and their partners. However, this aim should not be understood as maximizing reproductive choice per se. Only if understood as allowing prospective parents to avoid suffering related to living with (a child with) serious disorders and handicaps can prenatal screening be a publicly or collectively funded programme. The alternative of moving prenatal testing outside the healthcare system into the private sector is problematic, as it makes these tests accessible only to those who can afford to pay for it. New developments in prenatal screening will have to be assessed in terms of whether and to what extent they either contribute to or undermine the stated aim of providing meaningful options for reproductive choice. In the light of this criterion, this article discusses the introduction of the new non-invasive prenatal test (NIPT), the tendency to widen the scope of follow-up testing, as well as the possible future scenarios of genome-wide screening and 'prenatal personalised medicine'. The article ends with recommendations for further debate, research and analysis.

Microarrays as a diagnostic tool in prenatal screening strategies: ethical reflection.

Genomic microarray analysis is increasingly being applied as a prenatal diagnostic tool. Microarrays enable searching the genome at a higher resolution and with higher sensitivity than conventional karyotyping for identifying clinically significant chromosomal abnormalities. As yet, no clear guidelines exist on whether microarrays should be applied prenatally for all indications or only in selected cases such as ultrasound abnormalities, whether a targeted or genome-wide array should be used, and what these should include exactly. In this paper, we present some ethical considerations on the prenatal use of microarrays. There is a strong consensus, at least in Western countries, that the aim of prenatal screening for foetal abnormalities should be understood as facilitating autonomous reproductive choice for prospective parents. The tests offered should be valid and useful to reach that purpose. Against this background, we address several ethical issues raised by the prenatal application of microarrays. First, we argue that the general distinction between a targeted and a genome-wide microarray needs to be scrutinised. Then we examine whether microarrays are 'suitable tests' to serve either a screening or a diagnostic purpose. Given the wide range of findings possibly generated by microarrays, the question arises whether microarrays actually promote or interfere with autonomous reproductive decision-making. Moreover, if variants of unknown clinical significance are identified, this adds to the burden and complexity of reproductive decision-making. We suggest a qualified use of microarrays in the prenatal context.

Comprehensive embryo testing. Experts' opinions regarding future directions: an expert panel study on comprehensive embryo testing.

STUDY QUESTION: What do scientists in the field of preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS) consider to be the future direction of comprehensive embryo testing? SUMMARY ANSWER: Although there are many biological and technical limitations, as well as uncertainties regarding the meaning of genetic variation, comprehensive embryo testing will impact the IVF/PGD practice and a timely ethical reflection is needed. WHAT IS KNOWN ALREADY: Comprehensive testing using microarrays is currently being introduced in the context of PGD and PGS, and it is to be expected that whole-genome sequencing will also follow. Current ethical and empirical sociological research on embryo testing focuses on PGD as it is practiced now. However, empirical research and systematic reflection regarding the impact of comprehensive techniques for embryo testing is missing. STUDY DESIGN, SIZE AND DURATION: In order to understand the potential of this technology and to be able to adequately foresee its implications, we held an expert panel with seven pioneers in PGD. PARTICIPANTS/MATERIALS, SETTING, METHODS: We conducted an expert panel in October 2011 with seven PGD pioneers from Belgium, The Netherlands, Germany and the UK. MAIN RESULTS AND THE ROLE OF CHANCE: Participants expected the use of comprehensive techniques in the context of PGD. However, the introduction of these techniques in embryo testing requires timely ethical reflection as it involves a shift from choosing an embryo without a particular genetic disease (i.e. PGD) or most likely to result in a successful pregnancy (i.e. PGS) to choosing the best embryo based on a much wider set of criteria. Such ethical reflection should take account of current technical and biological limitations and also of current uncertainties with regard to the meaning of genetic variance. However, ethicists should also not be afraid to look into the future. There was a general agreement that embryo testing will be increasingly preceded by comprehensive preconception screening, thus enabling smart combinations of genetic testing. LIMITATIONS, REASONS FOR CAUTION: The group was composed of seven participants from four Western Europe countries. As willingness to participate in this study may be connected with expectations regarding the pace and direction of future developments, selection bias cannot be excluded. WIDER IMPLICATIONS OF THE FINDINGS: The introduction of comprehensive screening techniques in embryo testing calls for further ethical reflection that is grounded in empirical work. Specifically, there is a need for studies querying the opinions of infertile couples undergoing IVF/PGS regarding the desirability of embryo screening beyond aneuploidy. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the CSG, Centre for Society and Life Sciences (project number: 70.1.074). The authors declare no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

The new genetics and informed consent: differentiating choice to preserve autonomy.

The advent of new genetic and genomic technologies may cause friction with the principle of respect for autonomy and demands a rethinking of traditional interpretations of the concept of informed consent. Technologies such as whole-genome sequencing and micro-array based analysis enable genome-wide testing for many heterogeneous abnormalities and predispositions simultaneously. This may challenge the feasibility of providing adequate pre-test information and achieving autonomous decision-making. At a symposium held at the 11th World Congress of Bioethics in June 2012 (Rotterdam), organized by the International Association of Bioethics, these challenges were presented for three different areas in which these so-called 'new genetics' technologies are increasingly being applied: newborn screening, prenatal screening strategies and commercial personal genome testing. In this article, we build upon the existing ethical framework for a responsible set-up of testing and screening offers and reinterpret some of its criteria in the light of the new genetics. As we will argue, the scope of a responsible testing or screening offer should align with the purpose(s) of testing and with the principle of respect for autonomy for all stakeholders involved, including (future) children. Informed consent is a prerequisite but requires a new approach. We present preliminary and general directions for an individualized or differentiated set-up of the testing offer and for the informed consent process. With this article we wish to contribute to the formation of new ideas on how to tackle the issues of autonomy and informed consent for (public) healthcare and direct-to-consumer applications of the new genetics.

[Is germ-line genome modification ethically justified?] / Is kiembaanmodificatie ethisch verantwoord?

As the normative objections to (human) germline genome editing cannot convincingly justify a categorical prohibition of such editing, its present prohibition should be replaced by a strict regulation, i.e. a conditional allowance. If safe and effective, germline genome editing may become a useful reproductive option.

[Broadening NIPT needs more care]. / Zoeken naar 'nevenbevindingen'?

In a research setting (TRIDENT-2), Dutch pregnant women undergoing prenatal screening for trisomies 21, 18 and 13 with the Non-Invasive Prenatal Test (NIPT), are offered the choice to also receive information about incidental findings. In a recent report, the Health Council of the Netherlands has recommended to retain this option, but to only report those incidental findings that very probably will lead to serious health outcomes for the child. A working group has been appointed to draw up a guideline for this. In this article we argue that actively searching for desired 'incidental findings' in fact amounts to broadening the scope of the screening and that a justification of this choice is still lacking. A core issue is whether the benefits of such broader screening outweigh the drawback of inevitably also generating findings that do not fit in with the aim of the screening: providing meaningful reproductive choices.

Non-invasive prenatal diagnosis for aneuploidy: toward an integral ethical assessment.

The great promise of the pending introduction of non-invasive prenatal diagnosis (NIPD) for trisomy 21 (18 and 13) is that it enables one-step, early and safe testing for these abnormalities. The ethical debate so far has been limited to possible drawbacks of routine access to this type of testing: normalization of testing and abortion and adverse effects on autonomous decision-making. We address the ethical implications of the fact that routine NIPD affects the scope and strategy of current prenatal screening cascades. A decision is needed whether complementary (invasive) testing remains in place in order to avoid a loss of information as compared with current practice. If so, the supposed advantages of NIPD may be less significant than generally assumed. Accumulation of tests challenges informed consent and proportionality. Therefore, an ethical evaluation of the implications of NIPD for the prenatal screening strategy as a whole is needed.

Towards a Responsible Transition to Learning Healthcare Systems in Precision Medicine: Ethical Points to Consider.

Learning healthcare systems have recently emerged as a strategy to continuously use experiences and outcomes of clinical care for research purposes in precision medicine. Although it is known that learning healthcare transitions in general raise important ethical challenges, the ethical ramifications of such transitions in the specific context of precision medicine have not extensively been discussed. Here, we describe three levers that institutions can pull to advance learning healthcare systems in precision medicine: (1) changing testing of individual variability (such as genes); (2) changing prescription of treatments on the basis of (genomic) test results; and/or (3) changing the handling of data that link variability and treatment to clinical outcomes. Subsequently, we evaluate how patients can be affected if one of these levers are pulled: (1) patients are tested for different or more factors than before the transformation, (2) patients receive different treatments than before the transformation and/or (3) patients' data obtained through clinical care are used, or used more extensively, for research purposes. Based on an analysis of the aforementioned mechanisms and how these potentially affect patients, we analyze why learning healthcare systems in precision medicine need a different ethical approach and discuss crucial points to consider regarding this approach.

Modelling human embryogenesis: embryo-like structures spark ethical and policy debate.

BACKGROUND: Studying the human peri-implantation period remains hindered by the limited accessibility of the in vivo environment and scarcity of research material. As such, continuing efforts have been directed towards developing embryo-like structures (ELS) from pluripotent stem cells (PSCs) that recapitulate aspects of embryogenesis in vitro. While the creation of such models offers immense potential for studying fundamental processes in both pre- and early post-implantation development, it also proves ethically contentious due to wide-ranging views on the moral and legal reverence due to human embryos. Lack of clarity on how to qualify and regulate research with ELS thus presents a challenge in that it may either limit this new field of research without valid grounds or allow it to develop without policies that reflect justified ethical concerns. OBJECTIVE AND RATIONALE: The aim of this article is to provide a comprehensive overview of the existing scientific approaches to generate ELS from mouse and human PSCs, as well as discuss future strategies towards innovation in the context of human development. Concurrently, we aim to set the agenda for the ethical and policy issues surrounding research on human ELS. SEARCH METHODS: The PubMed database was used to search peer-reviewed articles and reviews using the following terms: 'stem cells', 'pluripotency', 'implantation', 'preimplantation', 'post-implantation', 'blastocyst', 'embryoid bodies', 'synthetic embryos', 'embryo models', 'self-assembly', 'human embryo-like structures', 'artificial embryos' in combination with other keywords related to the subject area. The PubMed and Web of Science databases were also used to systematically search publications on the ethics of ELS and human embryo research by using the aforementioned keywords in combination with 'ethics', 'law', 'regulation' and equivalent terms. All relevant publications until December 2019 were critically evaluated and discussed. OUTCOMES: In vitro systems provide a promising way forward for uncovering early human development. Current platforms utilize PSCs in both two- and three-dimensional settings to mimic various early developmental stages, including epiblast, trophoblast and amniotic cavity formation, in addition to axis development and gastrulation. Nevertheless, much hinges on the term 'embryo-like'. Extension of traditional embryo frameworks to research with ELS reveals that (i) current embryo definitions require reconsideration, (ii) cellular convertibility challenges the attribution of moral standing on the basis of 'active potentiality' and (iii) meaningful application of embryo protective directives will require rethinking of the 14-day culture limit and moral weight attributed to (non-)viability. Many conceptual and normative (dis)similarities between ELS and embryos thus remain to be thoroughly elucidated. WIDER IMPLICATIONS: Modelling embryogenesis holds vast potential for both human developmental biology and understanding various etiologies associated with infertility. To date, ELS have been shown to recapitulate several aspects of peri-implantation development, but critically, cannot develop into a fetus. Yet, concurrent to scientific innovation, considering the extent to which the use of ELS may raise moral concerns typical of human embryo research remains paramount. This will be crucial for harnessing the potential of ELS as a valuable research tool, whilst remaining within a robust moral and legal framework of professionally acceptable practices.

Risk Assessment for Huntington's Disease for (Future) Offspring Requires Offering Preconceptional CAG Analysis to Both Partners.

Amongst the main reasons people at risk for Huntington's disease (HD) have for undergoing predictive genetic testing are planning a family and prevention of passing on an expanded CAG-repeat to future offspring. After having received an unfavourable test result, a couple may consider prenatal testing in the foetus or preimplantation genetic diagnostic testing (PGD) in embryos. Testing of the foetus or embryos is possible by means of direct testing of the expanded repeat. Optimal reliability in testing the foetus or embryos requires the establishment of the origin of the repeats of both parents in the foetus. For PGD the analysis is combined with or sometimes solely based on identification of the at-risk haplotype in the embryo. This policy implies that in the context of direct testing, the healthy partner's CAG repeat lengths in the HD gene are also tested, but with the expectation that the repeat lengths of the partner are within the normal range, with the proviso that the partner's pedigree is free of clinically confirmed HD. However, recent studies have shown that the expanded repeat has been observed more often in the general population than previously estimated. Moreover, we have unexpectedly observed an expanded repeat in the non-HD partner in four cases which had far-reaching consequences. Hence, we propose that in the context of reproductive genetic counselling, prior to a planned pregnancy, and irrespective of the outcome of the predictive test in the HD-partner, the non-HD partner should also be given the option of being tested on the expanded allele. International recommendations for predictive testing for HD should be adjusted.

Health-related quality of life of children with a positive carrier status for inherited cardiovascular diseases.

Familial hypercholesterolemia, hypertrophic cardiomyopathy, and long QT Syndrome are genetic cardiovascular conditions which may lead to sudden cardiac death at a young age. Preventive measures include lifestyle modifications, medications, and/or cardiac devices. Hence, identification of carrier children can protect them for the potentially life threatening consequences at a young age. Yet, informing children about their genetic risk status and subjecting them to treatment may have negative consequences. This preliminary study aimed to explore (1) how the health-related quality of life of carrier children compares to the quality of life of Dutch children in general; and (2) to what extent the carrier children's quality of life and their parents' perception thereof concur. Our method involved carrier children (n = 35), aged between 8 and 18 years, and their parents (n = 37) who completed a self-report questionnaire. Children's health-related quality of life was assessed with a children and parent version of the KIDSCREEN. Dutch reference data were available from a representative national sample. Our results show no statistically significant differences in scores between carrier children and the reference group. Also, no differences were found between carrier children and their parents' ratings, with the exception of the scale "psychological well being". Parents rated their child's psychological well being significantly lower. We identified no problems with the well-being of carrier children as compared to a representative sample of peers. This may offer some initial reassurance to those who have concerns about the implications of genetically testing children for one of these cardiovascular conditions. Yet, attention to possible problems in these children remains warranted.

Predictive genetic testing for cardiovascular diseases: impact on carrier children.

We studied the experiences of children identified by family screening who were found to be a mutation carrier for a genetic cardiovascular disease (Long QT Syndrome (LQTS), Hypertrophic Cardiomyopathy (HCM), Familial Hypercholesterolemia (FH)). We addressed the (a) manner in which they perceive their carrier status, (b) impact on their daily lives, and (c) strategy used to cope with these consequences. Children (aged 8-18) who tested positive for LQTS (n=11), HCM (n=6) or FH (n=16), and their parents participated in semi-structured audiotaped interviews. Interview topics included illness perception, use of medication, lifestyle modifications, worries, and coping. Each interview was coded by two researchers. The qualitative analysis was guided by Leventhal's model of self-regulation. The children were overall quite articulate about the disease they were tested for, including its mode of inheritance. They expressed positive future health perceptions, but feelings of controllability varied. Adherence and side-effects were significant themes with regard to medication-use. Refraining from activities and maintaining a non-fat diet were themes concerning lifestyle modifications. Some children spontaneously reported worries about the possibility of dying and frustration about being different from peers. Children coped with these worries by expressing faith in the effectiveness of medication, trying to be similar to peers or, in contrast, emphasizing their "being different." Children generally appeared effective in the way they coped with their carrier status and its implications. Nevertheless, dealing with the daily implications of their condition remains difficult in some situations, warranting continued availability of psychosocial support.

Advantages and Disadvantages of Different Implementation Strategies of Non-Invasive Prenatal Testing in Down Syndrome Screening Programmes.

BACKGROUND: Implementation of non-invasive prenatal testing (NIPT) in Down syndrome screening programmes requires health policy decisions about its combination with other tests and its timing in pregnancy. AIM: Our aim was to aid health policy decision makers by conducting a quantitative analysis of different NIPT implementation strategies. METHODS: Decision trees were created to illustrate all plausible alternatives in a theoretical cohort of 100,000 pregnant women in five screening programmes: classical screening by the first-trimester combined test (FCT), pre-selection of high-risk women prior to NIPT by the FCT, NIPT as the first screening test at 10 weeks and at 13 weeks, and the simultaneous conductance of NIPT and the FCT. RESULTS: Pre-selection by FCT prior to NIPT reduces the number of amniocenteses to a minimum because of a reduction of false-positive NIPT results. If NIPT is the first screening test, it detects almost all fetal Down syndrome cases. NIPT at 10 weeks reassures women early in pregnancy, while NIPT at 13 weeks prevents unnecessary tests due to spontaneous miscarriages and allows for immediate confirmation by amniocentesis. CONCLUSION: Every implementation strategy has its advantages and disadvantages. The most favourable implementation strategy may be NIPT as the first screening test at 13 weeks, offering the most accurate screening test for Down syndrome, when the risk for spontaneous miscarriage has declined remarkably and timely confirmation by amniocentesis can be performed.