When boundaries benefit science and society.

In the rapidly moving field of stem cell and embryo research, research questions often sit at the intersection of scientific inquiry and ethical considerations. The International Society for Stem Cell Research (ISSCR) produces guidelines to help navigate decisions in this area. For Cell's 50th Anniversary Focus on Developmental Biology, scientific editor Sarah Geisler discussed the importance of the ISSCR guidelines on stem cell and embryo research for both the stem cell community and the broader public with Amander Clark, Robin Lovell-Badge, and Janet Rossant, who have been involved in the ongoing evolution of the guidelines. A lightly edited transcript of their conversation is shared here.

An ethical framework for human embryology with embryo models.

A human embryo's legal definition and its entitlement to protection vary greatly worldwide. Recently, human pluripotent stem cells have been used to form in vitro models of early embryos that have challenged legal definitions and raised questions regarding their usage. In this light, we propose a refined legal definition of an embryo, suggest "tipping points" for when human embryo models could eventually be afforded similar protection to that of embryos, and then revisit basic ethical principles that might help to draft a roadmap for the gradual, justified usage of embryo models in a manner that aims to maximize benefits to society.

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 research: toward greater unity in Europe?

There are four major positions on human embryonic stem cell research in the different member states of the European Union, ranging from permissive to very restrictive. This reflects the diversity of research systems within Europe and poses a challenge to developing a common European research policy.

Importance of In Vitro Embryo Model Procedure Standardization.

In vivo studies offer a detailed understanding of organism functioning, surpassing the insights provided by in vitro studies. These experiments are crucial for comprehending disease emergence, progression, and associated mechanisms in humans, as well as for developing treatments. When choosing experimental models, factors such as genomic similarity, physiological relevance, ethical appropriateness, and economic feasibility must be considered. Standardized protocols enhance the reliability, and reproducibility of scientific methods, promoting the assessment of research in the scientific literature. Researchers conducting embryo studies should establish and document standardized protocols for increased data comparability. Standardization is vital for scientific validity, reproducibility, and comparability in both in vivo and in vitro studies, ensuring the accuracy and reliability of experimental results and advancing scientific knowledge.

Species Choice and Model Use: Reviving Research on Human Development.

While model organisms have had many historians, this article places studies of humans, and particularly our development, in the politics of species choice. Human embryos, investigated directly rather than via animal surrogates, have gone through cycles of attention and neglect. In the past 60 years they moved from the sidelines to center stage. Research was resuscitated in anatomy, launched in reproductive biomedicine, molecular genetics, and stem-cell science, and made attractive in developmental biology. I explain this surge of interest in terms of rivalry with models and reliance on them. The greater involvement of medicine in human reproduction, especially through in vitro fertilization, gave access to fresh sources of material that fed critiques of extrapolation from mice and met demands for clinical relevance or "translation." Yet much of the revival depended on models. Supply infrastructures and digital standards, including biobanks and virtual atlases, emulated community resources for model organisms. Novel culture, imaging, molecular, and postgenomic methods were perfected on less precious samples. Toing and froing from the mouse affirmed the necessity of the exemplary mammal and its insufficiency justified inquiries into humans. Another kind of model-organoids and embryo-like structures derived from stem cells-enabled experiments that encouraged the organization of a new field, human developmental biology. Research on humans has competed with and counted on models.

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.

The Warnock report and partial ectogestation: retracing the past to step into the future.

Partial ectogestation continues to move towards human clinical trials. This article draws upon the Report of the Committee of Inquiry into Human Fertilisation and Embryology (Warnock Report) to provide guidance as to what may need to be considered for the future regulation of this technology. While the Warnock Report dates back to 1984, its significance and legacy continue to influence the current regulation of reproductive practices in the UK. By drawing upon specific elements within the report, many of the decisions and recommendations within it could provide direction for the future regulation of partial ectogestation. The role of the public, the social and political context at the time of the Warnock report, the determination of the status of the embryo, and arguments pitted against in vitro fertilisation (IVF) at the time, are all examined. As a result, this article suggests that the inclusion of the general public in the development and implementation of partial ectogestation prior to another Warnock-style inquiry will increase the success of long-standing regulatory and legislative provisions.

The people behind the papers - Madeleine Linneberg-Agerholm, Yan Fung Wong and Josh Brickman.

Our understanding of lineage decisions in early human development has been greatly aided by embryonic stem cell lines, which avoid many of the practical and ethical difficulties of in vivo material. A new paper in Development exploits naïve human embryonic stem cells to generate in vitro models for the extra-embryonic endoderm. We caught up with first authors Madeleine Linneberg-Agerholm and Yan Fung Wong, and their supervisor Josh Brickman, Professor of Stem Cell and Developmental Biology at the Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) in Copenhagen, to hear more about the work.