Australian public perspectives on genomic newborn screening: which conditions should be included?

BACKGROUND: Implementing genomic sequencing into newborn screening programs allows for significant expansion in the number and scope of conditions detected. We sought to explore public preferences and perspectives on which conditions to include in genomic newborn screening (gNBS). METHODS: We recruited English-speaking members of the Australian public over 18 years of age, using social media, and invited them to participate in online focus groups. RESULTS: Seventy-five members of the public aged 23-72 participated in one of fifteen focus groups. Participants agreed that if prioritisation of conditions was necessary, childhood-onset conditions were more important to include than later-onset conditions. Despite the purpose of the focus groups being to elicit public preferences, participants wanted to defer to others, such as health professionals or those with a lived experience of each condition, to make decisions about which conditions to include. Many participants saw benefit in including conditions with no available treatment. Participants agreed that gNBS should be fully publicly funded. CONCLUSION: How many and which conditions are included in a gNBS program will be a complex decision requiring detailed assessment of benefits and costs alongside public and professional engagement. Our study provides support for implementing gNBS for treatable childhood-onset conditions.

Stem cell-derived embryo models: moral advance or moral obfuscation?

Stem cell-derived embryo models (SCEMs) are model embryos used in scientific research to gain a better understanding of early embryonic development. The way humans develop from a single-cell zygote to a complex multicellular organism remains poorly understood. However, research looking at embryo development is difficult because of restrictions on the use of human embryos in research. Stem cell embryo models could reduce the need for human embryos, allowing us to both understand early development and improve assisted reproductive technologies. There have been several rapid advances in creating SCEMs in recent years. These advances potentially provide a new avenue to study early human development. The benefits of SCEMs are predicated on the claim that they are different from embryos and should, therefore, be exempt from existing regulations that apply to embryos (such as the 14-day rule). SCEMs are proposed as offering a model that can capture the inner workings of the embryo but lack its moral sensitivities. However, the ethical basis for making this distinction has not been clearly explained. In this current controversy, we focus on the ethical justification for treating SCEMs differently to embryos, based on considerations of moral status.

The Donation of Human Biological Material for Brain Organoid Research: The Problems of Consciousness and Consent.

Human brain organoids are three-dimensional masses of tissues derived from human stem cells that partially recapitulate the characteristics of the human brain. They have promising applications in many fields, from basic research to applied medicine. However, ethical concerns have been raised regarding the use of human brain organoids. These concerns primarily relate to the possibility that brain organoids may become conscious in the future. This possibility is associated with uncertainties about whether and in what sense brain organoids could have consciousness and what the moral significance of that would be. These uncertainties raise further concerns regarding consent from stem cell donors who may not be sufficiently informed to provide valid consent to the use of their donated cells in human brain organoid research. Furthermore, the possibility of harm to the brain organoids raises question about the scope of the donor's autonomy in consenting to research involving these entities. Donor consent does not establish the reasonableness of the risk and harms to the organoids, which ethical oversight must ensure by establishing some measures to mitigate them. To address these concerns, we provide three proposals for the consent procedure for human brain organoid research. First, it is vital to obtain project-specific consent rather than broad consent. Second, donors should be assured that appropriate measures will be taken to protect human brain organoids during research. Lastly, these assurances should be fulfilled through the implementation of precautionary measures. These proposals aim to enhance the ethical framework surrounding human brain organoid research.

Shaping children through genetic and environmental means.

In 'Parental Genetic Shaping and Parental Environmental Shaping', Anca Gheaus argues there is a normative difference between parents using genetic means to influence the development of their child, and parents using environmental means to achieve the same ends. Genetic shaping but not environmental shaping, it is claimed, introduces a negative asymmetry in the child-caregiver relationship. In this paper, we argue that Gheaus' argument fails as a critique of genetic shaping, and does not establish a moral difference between genetic and environmental shaping. Contrary to Gheaus' arguments in both 'Parental Genetic Shaping and Parental Environmental Shaping' and 'Parental Enhancement and Symmetry of Power in the Parent-Child Relationship', we also argue that even if genetic or prebirth shaping introduces further inequality in the parent-child relationship, this is not necessarily a bad thing, and it is not clear how a parent refraining from taking up the availability of such technology leaves the child better off.

Storing paediatric genomic data for sequential interrogation across the lifespan.

Genomic sequencing (GS) is increasingly used in paediatric medicine to aid in screening, research and treatment. Some health systems are trialling GS as a first-line test in newborn screening programmes. Questions about what to do with genomic data after it has been generated are becoming more pertinent. While other research has outlined the ethical reasons for storing deidentified genomic data to be used in research, the ethical case for storing data for future clinical use has not been explicated. In this paper, we examine the ethical case for storing genomic data with the intention of using it as a lifetime health resource. In this model, genomic data would be stored with the intention of reanalysis at certain points through one's life. We argue this could benefit individuals and create an important public resource. However, several ethical challenges must first be met to achieve these benefits. We explore issues related to privacy, consent, justice and equality. We conclude by arguing that health systems should be moving towards futures that allow for the sequential interrogation of genomic data throughout the lifespan.

Ethical analysis of the first porcine cardiac xenotransplantation.

In this article, we provide an ethical analysis of the first porcine cardiac xenotransplant, performed in Maryland, USA in early 2022. David Bennett was offered the experimental procedure after he was deemed ineligible for human heart transplantation and mechanical circulatory support, based on a history of non-compliance. It was reported that Mr Bennett's previous instances of non-compliance were for medically non-life-threatening conditions years earlier, where the risks of non-compliance were not as high. We argue that, in Mr Bennett's case, a history of non-compliance in a different context, should not necessarily rule him ineligible for a potentially life-saving treatment now. Furthermore, using previous non-compliance to exclude individuals from donor organs may have the unintended effect of placing the burden of testing xenotransplantation on those who are already disadvantaged. We then argue that it is not enough to rely on patient consent to ethically justify xenotransplantation research. Taking a broad ethical perspective is crucial when mapping a clinical pathway for xenotransplantation.

Non-Invasive Prenatal Testing for "Non-Medical" Traits: Ensuring Consistency in Ethical Decision-Making.

The scope of noninvasive prenatal testing (NIPT) could expand in the future to include detailed analysis of the fetal genome. This will allow for the testing for virtually any trait with a genetic contribution, including "non-medical" traits. Here we discuss the potential use of NIPT for these traits. We outline a scenario which highlights possible inconsistencies with ethical decision-making. We then discuss the case against permitting these uses. The objections include practical problems; increasing inequities; increasing the burden of choice; negative impacts on the child, family, and society; and issues with implementation. We then outline the case for permitting the use of NIPT for these traits. These include arguments for reproductive liberty and autonomy; questioning the labeling of traits as "non-medical"; and the principle of procreative beneficence. This summary of the case for and against can serve as a basis for the development of a consistent and coherent ethical framework.

Polygenic risk score for embryo selection-not ready for prime time.

Numerous chronic diseases have a substantial hereditary component. Recent advances in human genetics have allowed the extent of this to be quantified via genome-wide association studies, producing polygenic risk scores (PRS), which can then be applied to individuals to estimate their risk of developing a disease in question. This technology has recently been applied to embryo selection in the setting of IVF and preimplantation genetic testing, with limited data to support its utility. Furthermore, there are concerns that the inherent limitations of PRS makes it ill-suited for use as a screening test in this setting. There are also serious ethical and moral questions associated with this technology that are yet to be addressed. We conclude that further research and ethical reflection are required before embryo selection based on PRS is offered to patients outside of the research setting.

Moving from 'fully' to 'appropriately' informed consent in genomics: The PROMICE framework.

Genomic sequencing technologies (GS) pose novel challenges not seen in older genetic technologies, making traditional standards for fully informed consent difficult or impossible to meet. This is due to factors including the complexity of the test and the broad range of results it may identify. Meaningful informed consent is even more challenging to secure in contexts involving significant time constraints and emotional distress, such as when rapid genomic testing (RGS) is performed in neonatal intensive care units. In this article, we propose that informed consent matters not for its own sake, but because obtaining it furthers a range of morally important goals, such as promoting autonomy, well-being, and trust in medicine. These goals form the basis of a new framework [PROmoting Morally Important Consent Ends (PROMICE)] for assessing the ethical appropriateness of various informed consent models. We illustrate this framework with two examples: (a) a tiered and layered consent model for obtaining consent for GS, and (b) consent for RGS in critically ill newborns. We conclude that appropriately-rather than fully-informed consent provides the correct standard for genomic medicine and research.

Ethics of genomic passports: should the genetically resistant be exempted from lockdowns and quarantines?

Lockdowns and quarantines have been implemented widely in response to the COVID-19 pandemic. This has been accompanied by a rise in interest in the ethics of 'passport' systems that allow low-risk individuals greater freedoms during lockdowns and exemptions to quarantines. Immunity and vaccination passports have been suggested to facilitate the greater movement of those with acquired immunity and who have been vaccinated. Another group of individuals who pose a low risk to others during pandemics are those with genetically mediated resistances to pathogens. In this paper, we introduce the concept of genomic passports, which so far have not been explored in the bioethics literature. Using COVID-19 as an illustrative example, we explore the ethical issues raised by genomic passports and highlight differences and similarities to immunity passports. We conclude that, although there remain significant practical and ethical challenges to the implementation of genomic passports, there will be ways to ethically use them in the future.

Collective Reflective Equilibrium in Practice (CREP) and controversial novel technologies.

In this paper, we investigate how data about public preferences may be used to inform policy around the use of controversial novel technologies, using public preferences about autonomous vehicles (AVs) as a case study. We first summarize the recent 'Moral Machine' study, which generated preference data from millions of people regarding how they think AVs should respond to emergency situations. We argue that while such preferences cannot be used to directly inform policy, they should not be disregarded. We defend an approach that we call 'Collective Reflective Equilibrium in Practice' (CREP). In CREP, data on public attitudes function as an input into a deliberative process that looks for coherence between attitudes, behaviours and competing ethical principles. We argue that in cases of reasonable moral disagreement, data on public attitudes should play a much greater role in shaping policies than in areas of ethical consensus. We apply CREP to some of the global preferences about AVs uncovered by the Moral Machines study. We intend this discussion both as a substantive contribution to the debate about the programming of ethical AVs, and as an illustration of how CREP works. We argue that CREP provides a principled way of using some public preferences as an input for policy, while justifiably disregarding others.

Genetics experience impacts attitudes towards germline gene editing: a survey of over 1500 members of the public.

CRISPR-Cas9 has revolutionised genome engineering and has the potential to radically change our approach to genetic disease. However, the potential for genetic modification of embryos has raised significant and complex ethical and social concerns. The scientific community have called for ongoing stakeholder consultation about Germline Gene Editing (GGE), in particular lay publics, to help guide policy, education, research and regulatory priorities. In response, we conducted a survey to gauge public support for GGE and describe the demographic, experiential and contextual factors that influence individual attitudes. Respondent support was measured across nine hypothetical medical and enhancement GGE applications. We received responses from 1537 participants across 67 countries. Respondents were generally supportive of GGE, particularly for medical applications. While the most opposition observed was among religious respondents, those with work experience in genetics or genomics also reported greater resistance to GGE. Personal or family-related experience with genetics or genomics, identifying as female and tertiary education were also associated with less support for GGE. Further research needs to explore a diverse range of community and group attitudes towards GGE; the reasons underlying demographic and experiential differences; and to determine where the public and genetics professionals draw the line on ethical implementation respectively.

Sex selection and non-invasive prenatal testing: A review of current practices, evidence, and ethical issues.

Non-invasive prenatal testing (NIPT) can determine the sex of the fetus very accurately and very early in gestation. There are concerns that the ease, timing, and accuracy of NIPT sex determination will facilitate sex-selective termination of pregnancy (TOP). Here, we review current practices, the evidence for a link between NIPT and sex-selective TOP, and associated ethical issues. Sex-selective TOP, usually motivated by son preference, has had serious demographic consequences in countries such as India and China. Currently, ultrasound is the primary method by which parents determine the sex of the fetus. The diffusion of ultrasound technology has had a direct impact on the rates of sex-selective TOP. Although NIPT is currently more costly, it is feasible that increased uptake of this technology could have a similar effect. Partly because NIPT is a relatively recent development in prenatal screening, there is little data on the impact of NIPT on sex selection practices. Evidence that NIPT is playing a role in sex-selective TOP remains largely anecdotal. Further research is required to assess and quantify TOP resulting from NIPT sex determination. The use of these technologies for sex selection raises a number of ethical issues, in addition to practical demographic consequences.

Germline gene editing and the precautionary principle.

The precautionary principle aims to influence decision-making in contexts where some activity poses uncertain but potentially grave threats. This perfectly describes the controversy surrounding germline gene editing. This article considers whether the precautionary principle should influence how we weigh the risks and benefits of human germline interventions, focusing especially on the possible threats to the health of future generations. We distinguish between several existing forms of the precautionary principle, assess their plausibility and consider their implications for the ethics of germline modification. We also offer a novel form of the precautionary principle: the sufficientarian precautionary principle. Some plausible versions of the precautionary principle recommend placing somewhat greater weight on avoiding threats to future generations than on achieving short-term benefits. However, no plausible versions of the precautionary principle entail that we should outright reject the use germline gene editing in human reproduction and some, such as the sufficientarian version, might endorse its use.

Great minds think different: Preserving cognitive diversity in an age of gene editing.

It is likely that gene editing technologies will become viable in the current century. As scientists uncover the genetic contribution to personality traits and cognitive styles, parents will face hard choices. Some of these choices will involve trade-offs from the standpoint of the individual's welfare, while others will involve trade-offs between what is best for each and what is good for all. Although we think we should generally defer to the informed choices of parents about what kinds of children to create, we argue that decisions to manipulate polygenic psychological traits will be much more ethically complicated than choosing Mendelian traits like blood type. We end by defending the principle of regulatory parsimony, which holds that when legislation is necessary to prevent serious harms, we should aim for simple rules that apply to all, rather than micro-managing parental choices that shape the traits of their children. While we focus on embryo selection and gene editing, our arguments apply to all powerful technologies which influence the development of children.

Drawing the line on in vitro gametogenesis.

In vitro gametogenesis (IVG) might offer numerous research and clinical benefits. Some potential clinical applications of IVG, such as allowing opposite-sex couples experiencing infertility to have genetically related children, have attracted support. Others, such as enabling same-sex reproduction and solo reproduction, have attracted significantly more criticism. In this paper, we examine how different ethical principles might help us to draw lines and distinguish between ethically desirable and undesirable uses of IVG. We discuss the alleged distinction between therapeutic and non-therapeutic uses of assisted reproduction in the context of IVG, and show how it is both problematic to apply in practice and theoretically dubious. We then discuss how the ethical principles of reproductive justice and beneficence apply to IVG for opposite-sex reproduction, same-sex reproduction, and solo reproduction. We suggest that these principles generate strong reasons for the use of IVG for opposite-sex and same-sex reproduction, but not for solo reproduction.

Drugs, genes and screens: The ethics of preventing and treating spinal muscular atrophy.

Spinal muscular atrophy (SMA) is the most common genetic disease that causes infant mortality. Its treatment and prevention represent the paradigmatic example of the ethical dilemmas of 21st-century medicine. New therapies (nusinersen and AVXS-101) hold the promise of being able to treat, but not cure, the condition. Alternatively, genomic analysis could identify carriers, and carriers could be offered in vitro fertilization and preimplantation genetic diagnosis. In the future, gene editing could prevent the condition at the embryonic stage. How should these different options be evaluated and compared within a health system? In this paper, we discuss the ethical considerations that bear on the question of how to prioritize the different treatments and preventive options for SMA, at a policy level. We argue that despite the tremendous value of what we call 'ex-post' approaches to treating SMA (such as using pharmacological agents or gene therapy), there is a moral imperative to pursue 'ex-ante' interventions (such as carrier screening in combination with prenatal testing and preimplantation genetic diagnosis, or gene editing) to reduce the incidence of SMA. There are moral reasons relating to autonomy, beneficence and justice to prioritize ex-ante methods over ex-post methods.

Moral reasons to edit the human genome: picking up from the Nuffield report.

In July 2018, the Nuffield Council of Bioethics released its long-awaited report on heritable genome editing (HGE). The Nuffield report was notable for finding that HGE could be morally permissible, even in cases of human enhancement. In this paper, we summarise the findings of the Nuffield Council report, critically examine the guiding principles they endorse and suggest ways in which the guiding principles could be strengthened. While we support the approach taken by the Nuffield Council, we argue that detailed consideration of the moral implications of genome editing yields much stronger conclusions than they draw. Rather than being merely 'morally permissible', many instances of genome editing will be moral imperatives.

'Is it better not to know certain things?': views of women who have undergone non-invasive prenatal testing on its possible future applications.

Non-invasive prenatal testing (NIPT) is at the forefront of prenatal screening. Current uses for NIPT include fetal sex determination and screening for chromosomal disorders such as trisomy 21 (Down syndrome). However, NIPT may be expanded to many different future applications. There are a potential host of ethical concerns around the expanding use of NIPT, as examined by the recent Nuffield Council report on the topic. It is important to examine what NIPT might be used for before these possibilities become consumer reality. There is limited research exploring views of women on possible future uses of NIPT, particularly those of women who have undergone NIPT. In this study, we examined the views of women who undertook NIPT previously on the acceptability of and interest levels in using NIPT for a number of current and possible future applications. These included several medical conditions encompassing psychiatric, neurodevelopmental and adult-onset conditions as well as non-medical traits such as intelligence. One thousand women were invited to participate and 235 eligible surveys were received. Women generally reported an interest in using NIPT for medical conditions that severely impacted quality of life and with an onset earlier in life and stressed the importance of the accuracy of the test. Concerns were raised about the use of NIPT for non-medical traits. Respondents indicated that termination of pregnancy was not their only reason for testing, particularly in the case of sex. These results can further inform the ethical debate around the increasing integration of NIPT into healthcare systems.

'Small cost to pay for peace of mind': Women's experiences with non-invasive prenatal testing.

BACKGROUND: Non-invasive prenatal testing (NIPT) has been available in Australia on a user-pays basis since 2012. Since its introduction, it has grown in popularity as a screening method for fetal aneuploidy and may become publicly funded. AIMS: To assess the motivations and experiences of women who have undergone NIPT in a user-pays system in Australia. MATERIALS AND METHODS: One thousand women who had undergone NIPT through the Victorian Clinical Genetics Services in Melbourne, Australia were contacted and asked to complete a mixed-methods survey. The number of eligible responses received was 235. Quantitative data analysis was performed in STATA IC 15.1, and qualitative data were examined using content analysis. RESULTS: Women reported generally positive experiences with NIPT and 95% of respondents indicated they would undergo NIPT in a future pregnancy. Most respondents received a low-risk result, with 2.2% receiving a high-risk result. Respondents viewed NIPT favourably compared to invasive testing and cited reassurance as a key reason they sought it. However, a small minority of women reported negative experiences with the testing process. Women were also supportive of NIPT becoming publicly funded, with 93% of respondents indicating support. Pre- and post-test counselling were identified as possible areas for improvement to ensure informed consent. CONCLUSION: In support of the existing literature, these results indicate that Australian women generally report positive experiences with NIPT. As NIPT becomes more common, with possible integration into public healthcare, further qualitative research would be valuable to examine the motivations and experiences of women undergoing NIPT.