Ethical considerations on the moral status of the embryo and embryo-like structures†.

The current article provides an ethical reflection on the moral status of the human embryo, which is a crucial factor in determining permissible actions involving embryos and the extent of their protection. It advocates for the extension of the research period for embryos to 28-days post fertilization. It also states that integrated embryo-like structures (ELSs) should not currently be given the same moral status as natural embryos. However, if they pass the relevant tests, they should be subject to the same rules as natural embryos.

IVF embryos in the bin, embryo-like structures in the spotlight.

Embryo-like structures (ELS) are intended for the study of embryonic development without the use of human supernumerary embryos. Scientists working in countries that do not allow research on embryos hope that these structures will replace natural embryos. The interest in ELS is largely based on two misconceptions: the belief that there is a shortage of research embryos and the belief that research on ELS will make research on natural embryos redundant. This paper argues that research efforts should be refocused on natural embryos.

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.

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.

Heritable human genome editing is 'currently not permitted', but it is no longer 'prohibited': so says the ISSCR.

The Guidelines for Stem Cell Research and Clinical Translation, recently issued by the International Society for Stem Cell Research (ISSCR), include a number of substantive revisions. Significant changes include: (1) the bifurcation of 'Category 3 Prohibited research activities' in the 2016 Guidelines into 'Category 3A Research activities currently not permitted' and 'Category 3B Prohibited research activities' in the 2021 guidelines and (2) the move of heritable human genome editing research out of the 'prohibited' category and into the 'currently not permitted' category. These changes are noteworthy because of the absence of a clear demarcation line between the two categories insofar as, by definition, that which is 'prohibited' is 'currently not permitted', and vice versa. Permanence is not part of the definition of 'prohibition'. In principle, a prohibition can be rescinded at any time. This begs the question 'Why make a policy change that has no apparent practical effect?' One hypothesis is that the recategorisation of specific 'prohibited' research activities as 'currently not permitted' is meant to seed intuitions about which prohibited research activities should 'soon' be permitted subject to specialised scientific and ethics review and approval.

Going high and low: on pluralism and neutrality in human embryology policy-making.

Formulating sound and acceptable embryo research policy remains challenging especially in a pluralistic world. This challenge has acquired a new dimension of complexity with the advent of so-called embryo models, which are derived from stem cells. In this article, we present a normative strategy to facilitate the process of sound policy-making in the field of human embryology. This strategy involves seeking neutral agreements on higher level theories and doctrines as well as seeking agreements on the level of concrete policy proposals. We call this strategy: going high and low. By going high and low, the plurality of reasonable moral and epistemic convictions of stakeholders involved in the domain of human embryology is respected while the process of policy-making in this area is improved.

Two kinds of embryo research: four case examples.

There are ethical obligations to conduct research that contributes to generalisable knowledge and improves reproductive health, and this should include embryo research in jurisdictions where it is permitted. Often, the controversial nature of embryo research can alarm ethics committee members, which can unnecessarily delay important research that can potentially improve fertility for patients and society. Such delay is ethically unjustified. Moreover, countries such as the UK, Australia and Singapore have legislation which unnecessarily captures low-risk research, such as observational research, in an often cumbersome and protracted review process. Such countries should revise such legislation to better facilitate low-risk embryo research.We introduce a philosophical distinction to help decision-makers more efficiently identify higher risk embryo research from that which presents no more risks to persons than other types of tissue research. That distinction is between future person embryo research and non-future person embryo research. We apply this distinction to four examples of embryo research that might be presented to ethics committees.Embryo research is most controversial and deserving of detailed scrutiny when it potentially affects a future person. Where it does not, it should generally require less ethical scrutiny. We explore a variety of ways in which research can affect a future person, including by deriving information about that person, and manipulating eggs or sperm before an embryo is created.

Gamete and embryo donation for research: what might shape the willingness to donate among gamete donors and recipients?

PURPOSE: Research using gametes and embryos donated by reproductive and third-party donors contributed to substantial, albeit contentious achievements. The views of gamete donors and recipients on donation for research and the underpinning role of attitudes towards research have been seldom explored and are yet to be incorporated into ethical, legal, and regulatory landscapes. From a cultural standpoint, this study adapts and explores psychometric properties of the Portuguese version of the Research Attitudes Questionnaire (RAQ), and analyzes the willingness of gamete donors and recipients to donate gametes and embryos for research and its association with sociodemographic, reproductive characteristics, and attitudes towards research. METHODS: Between July 2017 and June 2018, 71 donors and 165 recipients completed a self-administered questionnaire at the Portuguese Public Bank of Gametes. Willingness to donate and attitudes towards research were measured with a 5-point Likert scale. RAQ psychometric characteristics were explored. RESULTS: Two RAQ components were identified: "trustworthiness of research" and "critical perspective". Most participants were willing to donate gametes and embryos: donors more willing to donate gametes and male recipients more willing to donate gametes and embryos. Higher RAQ scores, indicating a more positive attitude towards research, were observed on the component "trustworthiness of research" among those willing to donate gametes and embryos and on the component "critical perspective" among those willing to donate embryos. CONCLUSION: These findings help foster inclusivity, diversity, and responsiveness of research and call for upstream engagement of male and female gamete donors and recipients, promoting a trustworthy, anticipatory, democratic, and people-centered approach to policies, regulations, and practices in human gamete and embryo research.

How Should We Regulate Heritable Human Genome Editing in Australia?

Heritable human genome editing is a form of modification of the human genome that will be inherited by progeny of the person whose DNA has been edited. Editing human genomes in ways that are heritable is currently prohibited in many countries throughout the world, including in Australia. This section starts with an examination of the historical backdrop to Australia's current laws relating to heritable human genome editing, with particular focus on how technological advances and community responses have shaped our legislative environment for innovative artificial reproductive technologies. The section then examines how community responses to current developments in heritable human genome editing might shape future law reform. The aim is to provide a foundation for examining how the future regulatory environment for heritable human genome editing in Australia might be shaped in ways that are responsive both to technological developments and to contemporary ethical norms and social values.

The Beginning of Life Issues: An Islamic Perspective.

Islam gives legal precedence to purity of lineage and known parenthood of all children. In Islam treatment to infertility using IVF is permitted within validity of marriage contract with no genes mixing. The paper shows that the Qur'an, the word of Allah, and science, the deeds of Allah are not in major conflicts in defining the start of human life. The Holy Qur'an provides an elegant description of origin, developmental stages of intra-uterine life. The Hadith explains two positions one that believes human embryo get ensouled at conception and the other after 40 days of conception. The paper aims to find that Islam confers moral respect to human embryo, but it also clarifies the absence of full human rights to a developing foetus. In Islam, human embryonic use is probably permissible for therapeutic and reproductive purpose keeping intact the principles of Shari'ah.

Decisional authority of gamete donors over embryos created with their gametes.

In the ongoing discussion on the rights and obligations of gamete donors, scant attention has been paid to the decisional authority of gamete donors over the disposition of the embryos created with their gametes. This paper analyses four different positions: three cases relate to the disposition options for surplus or unused embryos by the first recipients, and one case relates to the use of the embryos stored by the first recipients for procreation.We conclude that the gamete donor causally contributes to the creation of the embryos and thus becomes indirectly responsible. To avoid that donors would become accomplices to an activity to which they morally object, a qualified generic consent mentioning types of research should be obtained. No consent from the donor is required for the destruction of the embryos.The cancellation of the agreement by anonymous or identifiable gamete donors should not be possible for embryos in storage for reproduction by the recipients. The interests in not becoming a genetic parent against one's wishes do not outweigh the damage done to recipients who would no longer be able to use their embryos. Known donors, on the contrary, should be able to withdraw their consent up to the moment of transfer of the embryos based on the greater harm caused to them as a consequence of attributional parenthood. They should also be able to veto transfer of the embryos to other people than the original recipients.

(Re)Drawing the Line: Australian Regulation of Human-Animal Interspecies Embryos.

The mixing of human and animal cellular and genetic material is a promising area of science, but inherent societal and safety concerns make such mixing in embryos particularly controversial. The sensitive nature of this research, coupled with science's rapid development, creates problems for policymakers responsible for deciding what practices are and are not permitted in Australia. Australia's regulation in this area, last significantly amended in 2006, is in urgent need of reform. This article investigates what is happening in this fast moving area and the regulatory reforms necessary for Australian scientists to participate.

Exogenous glutathione improves intracellular glutathione synthesis via the γ-glutamyl cycle in bovine zygotes and cleavage embryos.

Excess reactive oxygen species (ROS) generated in embryos during in vitro culture damage cellular macromolecules and embryo development. Glutathione (GSH) scavenges ROS and optimizes the culture system. However, how exogenous GSH influences intracellular GSH and improves the embryo developmental rate is poorly understood. In this study, GSH or GSX (a stable GSH isotope) was added to the culture media of bovine in vitro fertilization embryos for 7 days. The cleavage rate, blastocyst rate, and total cell number of blastocysts were calculated. Similarly to GSH, GSX increased the in vitro development rate and embryo quality. We measured intracellular ROS, GSX, and GSH for 0-32-hr postinsemination (hpi) in embryos (including zygotes at G1, S, and G2 phases and cleaved embryos) cultured in medium containing GSX. Intracellular ROS significantly decreased with increasing intracellular GSH in S-stage zygotes (18 hpi) and cleaved embryos (32 hpi). γ-Glutamyltranspeptidase ( GGT) and glutathione synthetase ( GSS) messenger RNA expression increased in zygotes (18 hpi) and cleaved embryos treated with GSH, consistent with the tendency of overall GSH content. GGT activity increased significantly in 18 hpi zygotes. GGT and GCL enzyme inhibition with acivicin and buthionine sulfoximine, respectively, decreased cleavage rate, blastocyst rate, total cell number, and GSH and GSX content. All results indicated that exogenous GSH affects intracellular GSH levels through the γ-glutamyl cycle and improves early embryo development, enhancing our understanding of the redox regulation effects and transport of GSH during embryo culture in vitro.

Dual consent? Donors' and recipients' views about involvement in decision-making on the use of embryos created by gamete donation in research.

BACKGROUND: Reasonable disagreement about the role awarded to gamete donors in decision-making on the use of embryos created by gamete donation (EGDs) for research purposes emphasises the importance of considering the implementation of participatory, adaptive, and trustworthy policies and guidelines for consent procedures. However, the perspectives of gamete donors and recipients about decision-making regarding research with EGDs are still under-researched, which precludes the development of policies and guidelines informed by evidence. This study seeks to explore the views of donors and recipients about who should take part in consent processes for the use of EGDs in research. METHODS: From July 2017 to June 2018, 72 gamete donors and 175 recipients completed a self-report structured questionnaire at the Portuguese Public Bank of Gametes (response rate: 76%). Agreement with dual consent was defined as the belief that the use of EGDs in research should be consented by both donors and recipients. RESULTS: The majority of participants (74.6% of donors and 65.7% of recipients) were willing to donate embryos for research. Almost half of the donors (48.6%) and half of the recipients (46.9%) considered that a dual consent procedure is desirable. This view was more frequent among employed recipients (49.7%) than among non-employed (21.4%). Donors were less likely to believe that only recipients should be involved in giving consent for the use of EGDs in research (25.0% vs. 41.7% among recipients) and were more frequently favourable to the idea of exclusive donors' consent (26.4% vs. 11.4% among recipients). CONCLUSIONS: Divergent views on dual consent among donors and recipients indicate the need to develop evidence-based and ethically sustainable policies and guidelines to protect well-being, autonomy and reproductive rights of both stakeholder groups. More empirical research and further theoretical normative analyses are needed to inform people-centred policy and guidelines for shared decision-making concerning the use of EGDs for research.

Organs, embryos, and part-human chimeras: further applications of the social account of dignity.

In their recent paper in this journal, Zümrüt Alpinar-Sencan and colleagues review existing dignity-based objections to organ markets and outline a new form of dignity-based objection they believe has more merit: one grounded in a social account of dignity. This commentary clarifies some aspects of the social account of dignity and then shows how this revised account can be applied to other perennial issues in bioethics, including the ethics of human embryo research and the ethics of creating part-human chimeras.

A 14-day limit for bioethics: the debate over human embryo research.

BACKGROUND: This article explores the reasons in favour of revising and extending the current 14-day statutory limit to maintaining human embryos in culture. This limit is enshrined in law in over a dozen countries, including the United Kingdom. In two recently published studies (2016), scientists have shown that embryos can be sustained in vitro for about 13 days after fertilisation. Positive reactions to these results have gone hand in hand with calls for revising the 14-day rule, which only allows embryo research until the 14th day after fertilisation. MAIN TEXT: The article explores the most prominent arguments in favour of and against the extension of the 14-day limit for conducting research on human embryos. It situates these arguments within the history of the 14-day limit. I start by discussing the history of the 14-day limit in the United Kingdom and the reasons behind the decision to opt for a compromise between competing moral views. I then analyse the arguments that those who are generally in favour of embryo research put forward in support of extending the 14-day rule, namely (a) the argument of the beneficence of research and (b) the argument of technical feasibility (further explained in the article). I then show how these two arguments played a role in the recent approval of two novel techniques for the replacement of faulty mitochondrial DNA in the United Kingdom. Despite the popularity and widespread use of these arguments, I argue that they are ultimately problematic and should not be straightforwardly accepted (i.e. accepted without further scrutiny). I end by making a case for respecting value pluralism in the context of embryo research, and I present two reasons in favour of respecting value pluralism: the argument of public trust and the argument of democracy. CONCLUSION: I argue that 14-day limit for embryo research is not a valuable tool despite being a solution of compromise, but rather because of it. The importance of respecting value pluralism (and of respecting different views on embryo research) needs to be considered in any evaluation concerning a potential change to the 14-day rule.

[Relationship between mitochondrial DNA copy number, membrane potential of human embryo and embryo morphology].

Objective: To explore the relationship between the embryo with the different morphological types in the third day and its mitochondrial copy number, the membrane potential. Methods: Totally 117 embryos with poor development after normal fertilization and were not suitable transferred in the fresh cycle and 106 frozen embryos that were discarded voluntarily by infertility patients with in vitro fertilization-embryo transfer after successful pregnancy were selected. According to evaluation of international standard in embryos, all cleavage stage embryos were divided into class Ⅰ frozen embryo group (n=64), class Ⅱ frozen embryo group (n=42) and class Ⅲ fresh embryonic group (not transplanted embryos; n=117). Real-time PCR and confocal microscopy methods were used to detect mitochondrial DNA (mtDNA) copy number and the mitochondrial membrane potential of a single embryo. The differences between embryo quality and mtDNA copy number and membrane potential of each group were compared. Results: The copy number of mtDNA and the mitochondrial membrane potential in class Ⅲ fresh embryonic group [(1.7±1.0)×10(5) copy/µl, 1.56±0.32] were significantly lower than those in class Ⅰ frozen embryo group [(3.4±1.7)×10(5) copy/µl, 2.66±0.21] and class Ⅱ frozen embryo group [(2.6±1.2)×10(5) copy/µl, 1.80±0.32; all P<0.05]. The copy number of mtDNA and the mitochondrial membrane potential in classⅠ frozen embryo group were significantly higher than those in classⅡ frozen embryo group (both P<0.05). Conclusion: The mtDNA copy number and the mitochondrial membrane potential of embryos of the better quality embryo are higher.

Factors associated with willingness to donate embryos for research among couples undergoing IVF.

Between 2011 and 2012, 213 heterosexual couples undergoing fertility treatments in a Portuguese public fertility centre were systematically recruited to assess factors associated with willingness to donate embryos for research. Data were collected by questionnaire. Most couples (87.3%; 95% CI 82.1 to 91.5) were willing to donate embryos for research, citing benefits for science, health and infertile patients. Almost all couples (94.3%; 95% CI 89.8 to 96.7) reached consensus about the decision. Willingness to donate was more frequent in women younger than 36 years (adjusted OR 3.06; 95% CI 1.23 to 7.61) and who considered embryo research to be very important (adjusted OR: 6.32; 95% CI 1.85 to 21.64), and in Catholic men (adjusted OR 4.16; 95% CI 1.53 to 11.30). Those unwilling to donate reported conceptualizing embryos as children or living beings and a lack of information or fears about embryo research. Men with higher levels of trait anxiety (adjusted OR 0.90; 95% CI 0.84 to 0.96) were less frequently willing to donate. Future research on embryo disposition decision-making should include the assessment of gender differences and psychosocial factors. Ethically robust policies and accurate information about the results of human embryo research are required.