Human embryos in a dish – modeling early embryonic development with pluripotent stem cells

Stem cell-based embryo models present new opportunities to study early embryonic development. In a recent study, Kagawa et al. identified an approach to create human pluripotent stem cell-based blastoids that resemble the human blastocysts. These blastoids efficiently generated analogs of the EPI, TE, PrE lineages with transcriptomes highly similar to those found in vivo. Furthermore, the formation of these lineages followed the same sequence and pace of blastocyst development, and was also dependent on the same pathways required for lineage specification. Finally, the blastoids were capable of attaching to stimulated endometrial cells to mimic the process of implantation. While more comprehensive analysis is needed to confirm its validity and usefulness, this new blastoid system presents the latest development in the attempt to model early human embryogenesis in vitro.

Mechanics of human embryo compaction

The shaping of the human embryo begins with compaction, during which cells come into close contact and form a tighter structure. Assisted reproductive technology (ART) studies suggest that human embryos fail compaction primarily because of defective adhesion. Based on our current understanding of animal morphogenesis, other morphogenetic engines, such as cell contractility, could be involved in shaping the human embryo. However, the molecular, cellular and physical mechanisms driving human embryo morphogenesis remain uncharacterized. Using micropipette aspiration on human embryos donated to research, we have mapped cell surface tensions during compaction. This reveals a 4-fold increase of tension at the cell-medium interface while cell-cell contacts keep a steady tension. Comparison between human and mouse reveals qualitatively similar but quantitively different mechanical strategies, with human embryos being mechanically least efficient. Inhibition of cell contractility and cell-cell adhesion in human embryos reveal that only contractility controls the surface tension responsible for compaction. Interestingly, if both cellular processes are required for compaction, they exhibit distinct mechanical signatures when faulty. Analyzing the mechanical signature of naturally failing embryos, we find evidence that non-compacting embryos or partially compacting embryos with excluded cells have defective contractility. Together, our study reveals that an evolutionarily conserved increase in cell contractility is required to generate the forces driving the first morphogenetic movement shaping the human body.

Mitochondrial DNA Copy Number in Cleavage Stage Human Embryos—Impact on Infertility Outcome

A retrospective case control study was undertaken at the molecular biology department of a private center for reproductive medicine in order to determine whether any correlation exists between mitochondrial DNA (mtDNA) content of cleavage-stage preimplantation embryos and their developmental potential. A total of 69 couples underwent IVF treatment (averaged women age: 36.5, SD 4.9) and produced a total of 314 embryos. A single blastomere was biopsied from each embryo at the cleavage stage (day-3 post-fertilization) subjected to low-pass next generation sequencing (NGS), for the purpose of detecting aneuploidy. For each sample, the number of mtDNA reads obtained after analysis using NGS was divided by the number of reads attributable to the nuclear genome. The mtDNA copy number amount was found to be higher in aneuploid embryos than in those that were euploid (mean mtDNA ratio ± SD: 6.3 ± 7.5 versus 7.1 ± 5.8, p < 0.004; U Mann–Whitney test), whereas no statistically significant differences in mtDNA content were seen in relation to embryo morphology (6.6 ± 4.8 vs. 8.5 ± 13.6, p 0.09), sex (6.6 ± 4.1 vs. 6.2 ± 6.8, p 0.16), maternal age (6.9 ± 7.8 vs. 6.7 ± 4.5, p 0.14) or its ability to implant (7.4 ± 6.6 vs. 5.1 ± 4.6, p 0.18). The mtDNA content cannot serve as a useful biomarker at this point in development. However, further studies investigating both quantitative and qualitative aspects of mtDNA are still required to fully evaluate the relationship between mitochondrial DNA and human reproduction.

‘Focusing and Unfocusing’—Cognitive, Evaluative, and Emotional Dynamics in the Relationship with Human Embryos among ART Beneficiaries

This article uses data gathered from a study conducted in Portugal to examine the (plural and composite) conceptions that doctors, embryologists, and beneficiaries of Assisted Reproductive Technology (ART) have of the in vitro human embryo. Taking the sociology of engagements, developed by Thévenot, as its theoretical lens, the article draws on a total of 69 interviews with ART patients to analyse the plurality of fluid meanings produced about this biological entity, whose status is neither static nor universal. ART beneficiaries are likely to produce plural conceptions of the lab-generated embryo within the framework of different regimes of engagement, understood as cognitive and evaluative formats. These various pragmatic regimes, in turn, entail distinct emotional investments. When speaking about their relationship with embryos, beneficiaries therefore express plural emotional experiences, which are articulated using terms such as affection, love, detachment, loss, frustration, hope, mourning, and anguish. Using the theoretical framework of the sociology of engagements, we propose an approach that enables us to produce a detailed record of the connections between the cognitive, evaluative, and emotional dimensions in beneficiaries’ relationship with—and decision-making processes about—the embryos, accounting for the plasticity of emotional states linked to the (re)configuration of attributed meanings.

論人體胚胎研究“軟法”修改之正當性

LANGUAGE NOTE | Document text in Chinese; abstract also in English. This commentary briefly discusses the substantive and procedural justifications for amending the longstanding 14-day rule, a soft-law limitation on the culturing of human embryos. The 14-day rule was established on the basis of general recognition of the human embryo's special status, accompanied by widespread public conversation and engagement. In principle, amending this rule would require the same substantive and procedural justifications. However, such justifications were absent prior to the lifting of the rule by the ISSCR in its 2021 guidelines. This article also discusses the value and importance of the 14-day rule to the development of human embryo research in the last three decades. Discarding the rule without the proper substantive and procedural justifications is likely to damage public trust and confidence in future human embryo research.

放棄人類胚胎“14天限制” 的倫理反駁

LANGUAGE NOTE | Document text in Chinese; abstract also in English. This article explores prominent arguments in favor of and against extending the current 14-day statutory limit on the maintenance of human embryos. I discuss the history of the 14-day limit and the reasons behind the decision to opt for a compromise between competing moral views. I then argue that the ISSCR's guidelines for extending the 14-day limit are not a valuable tool, despite their potential to contribute scientific knowledge. The importance of respecting the 14-day rule should be acknowledged by ethics committees in the current research ethics climate of mainland China.

生物醫學技術發展應該改變14天法則限制嗎？

LANGUAGE NOTE | Document text in Chinese; abstract also in English. Developments in research have made culturing human embryos beyond the 14-day limit seem technologically feasible. In the article “Emerging Human Embryo Research Technologies, the 14-day Rule, and the Special Status of the Embryo,” the authors examine a proposal for new human embryo and embryoid research guidelines by reviewing the history of the 14-day limit and emerging areas of research that are impacted by these guidelines. However, as noted by the authors, changes in science policy should not be developed solely by scientists. Instead, policy development should reflect the reality of science as a public endeavor. After 40 years of consensus, any attempts to revoke the 14-day limit on the in vitro culturing of human embryos should rely on public and stakeholder engagement.

Human embryos arrest in a quiescent-like state characterized by metabolic and zygotic genome activation problems

Around 60% of in vitro fertilized (IVF) human embryos irreversibly arrest before compaction between the 3-8-cell stage, posing a significant clinical problem. The mechanisms behind this arrest are unclear. Here, we show that the arrested embryos enter a quiescent-like state, marked by cell cycle arrest, the downregulation of ribosomes and histones and downregulation of MYC and p53 activity. Mechanistically, the arrested embryos can be divided into three types. Type I embryos fail to complete the maternal-zygotic transition, and type II/III embryos have erroneously low levels of glycolysis and variable levels of oxidative phosphorylation. Treatment with resveratrol or nicotinamide riboside (NR) can partially rescue the arrested phenotype. The mechanism of reactivation involves the upregulation of SIRT1, and activation of glycolysis and fatty acid oxidation which forces the embryos out of a quiescent state. Overall, our data reveal how human embryo arrest can be overcome by modulating metabolic pathways.

Right to life and possible interference in its implementation: Constitutional and legal aspect

Introduction. The problems of realizing the right to life are relevant to varying degrees in all countries of the world. Their importance can hardly be overestimated, since the preservation of a full-fledged family, society and the state as a whole depends on their solution. The article examines the problems associated with abortion, surrogacy, the development of biotechnology, death penalty, and analyzes the legislative experience of various states and Russia in these areas. The purpose of the study is to conduct a comprehensive analysis of the problems arising in connection with the realization of the right to life and its possible restrictions. In the course of studying the problems, both general scientific and special legal methods were used: historical and dialectical methods, methods of analysis and synthesis, as well as the comparative legal method. Theoretical analysis. Russia (RSFSR) was the first country in the world to legislate in 1920 to allow abortion. According to the author, artificial termination of pregnancy solely at the request of a woman (without taking into account medical and social factors) causes irreparable harm to society, especially given the difficult demographic situation in modern Russia. In addition, this does not correspond to the guiding thesis of responsibility to future generations, enshrined in the preamble to the Constitution of the Russian Federation. In the context of realizing the right to life, each state faces a problem related to death penalty. Can a state, where the right to life is guaranteed, take the life of criminals? Apparently, each state should decide this issue based on the extent to which a particular crime poses a threat to society, a threat to life and health of people. Results. In our opinion, in countries with liberal legislation in relation to abortion, such as Russia, it is necessary to prohibit abortion at the request of a woman, since in this case the woman’s desire violates the right to life of an unborn child. The state should protect the right to life from the moment of conception, not birth, but this is a long process that should lead to an extensive interpretation of Part 2 of Art. 17 of the Constitution of the Russian Federation by the Constitutional Court of the Russian Federation. In addition, Russia needs to pay attention to the legislative experience of Germany and France in relation to surrogacy. In these countries, the legislator has clearly substantiated why surrogacy is in fact a crime against the family. In these countries, surrogacy is criminalized. Also, with the development of biotechnology all over the world, the problems of IVF and cryopreservation of human embryos are acute. This problem can also be solved at the level of legislation by allowing IVF only to married couples (man and woman) who cannot give birth to a child, and by limiting the number of fertilized eggs to a minimum, so that later the issue of destroying unclaimed embryos is not resolved. In general, it seems that in a mature society that wants to develop and tries to prevent the destruction of its state, it is necessary to protect the right to life by all possible legislative methods.