The biological and legal definitions of “embryo” don’t match, and that will become a problem, according to Nicolas Rivron, PhD, of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences. Advances in embryo models eventually will blur the distinction between those models, which are created for research, and embryos created for reproduction.

Writing in Cell, Rivron and colleagues from the Catalan Institution for Research and Advanced Studies, the Jackson Laboratory in Maine, the Francis Crick Institute in London, and University Medical Center in Rotterdam called for a new ethical framework governing the use of embryo models. At its heart is a proposed new definition that removes much of the ambiguity.

“Based on basic ethical principles that are widely shared in science and medicine (e.g., proportionality, subsidiarity, etc.), we propose that permission from an ethics committee to culture human embryo models for a specified period of time should take into account the quality of the model, the justification of the objectives, the technical feasibility, and the consistency of the practice with local and international values,” Rivron tells GEN.

“Our interpretation of these basic principles also suggests that, for a specific goal, forming an embryo model that is more complete than necessary might yield equal benefits but cause more concerns. Therefore, if possible, less complete models should be preferred.

“For example,” he continues, “if the goal is to form a specific organ, the minimal required features (e.g., progenitors and supporting tissues) could be formed without promoting the development of a more complete embryo model (e.g., blastoids). This can be achieved by channeling development, as seen in assemblies of organoids and non-integrated embryo models (e.g., gastruloids). Consequently, while the use of human integrated embryo models is justified in the early stages of development, alternatives might make their use less justified at later stages.”

Clear definitions needed

The biological definition aims to describe an embryo scientifically, and the legal definition aims to protect it. The distinction, the paper noted, should be the potential of cells to form a neonate rather than how an embryo or embryo model was formed.

What is most needed is “more clarity around how we are defining the limits of integrated embryo modeling research,” Insoo Hyun, PhD, director, Center for Life Sciences and Public Learning at Boston’s Museum of Science and a member of Harvard Medical School’s Center for Bioethics, tells GEN.

“Right now, there is a reasonably good definition of embryo models offered by the International Society for Stem Cell Research (ISSCR), which draws a distinction between integrated and non-integrated embryo models. Integrated models strive to model the embryo proper, along with all the support tissues necessary for embryonic growth. Non-integrated models strive to model just one part of an embryo, not the whole thing.

“I think the policy definition of an embryo model, for federal funding and oversight reasons, should focus now on integrated models only,” Hyun continues. “Right now, integrated models are not capable of supporting the development of fetal human life, but as the authors [of the Cell paper] suggest, there may come a time when this becomes the case.”

Far from tipping point

That time is still some way away, Hyun and Rivron agree.

“We are far from a tipping point, but it is important that we think ahead and clarify the path forward,” Rivron says. That entails recognizing what constitutes that tipping point and how to evaluate whether it has been passed.

Currently, he points out, “No animal embryo model has ever formed a neonate. Even the most complete mouse embryo models failed to form newborn mice when transferred to a mouse uterus. That shows that these models are not embryos and also that we have limited knowledge of what is important for embryogenesis.”

Similar knowledge is unavailable for humans. Transferring human embryo models into a human or animal uterus is prohibited throughout the world. While embryo models reflect some aspects of the first two weeks of development, they also develop genetic defects that prevent them from developing into fetuses, Rivron explains.

Legally, he says, an embryo is defined as “a group of human cells supported by elements fulfilling extraembryonic and uterine functions that, combined, have the potential to form a fetus.” Watershed moments in the development of human embryos that may merit legal protection are:

  • Fertilization and implantation
  • Gastrulation and the formation of specialized cells
  • Organogenesis
  • Pregnancy

Because embryonic models lack the necessary extraembryonic and uterine support to develop into a fetus, “They should not, therefore, legally be considered embryos,” Rivron and colleagues wrote. However, if embryonic models had those supports, they could develop into a fetus, they acknowledge, substantially blurring distinctions between an embryo and an embryo model.

Research ramifications

 “The latest guidelines from the ISSCR already set out very useful concepts and distinctions in relation to this field of research. But with the science advancing rapidly, and human embryo models becoming ever more sophisticated, further consideration is warranted,” Sarah Norcross, director of Progress Educational Trust and a member of the University of Cambridge’s Governance of Stem-Cell-Based Embryo Models project, said in a statement.

Nonetheless, Hyun is concerned about the potential for confusion regarding what researchers can and cannot do with embryos created in fertility clinics for the purpose of reproduction.

“These early, pre-implantation embryos are now called embryos and are treated as such by researchers,” Hyun says, “even though these products of fertilization [are not, as the paper says], ‘supported by elements fulfilling extra-embryonic and uterine functions.’ If they don’t fall under this new legal definition of a human embryo, then what would these fertilized eggs be in the eyes of the law?

“This shift,” Hyun says, “could be disruptive to life sciences research that relies on donated pre-implantation human embryos, including human embryonic stem cell research.”

 Scientific support

The evolution of ethical guidelines is commonplace in the scientific community, Rivron says, noting that the ISSCR guidelines on embryo models were updated two years ago. Afterward, he and other members of that task force—scientists and ethicists—continued discussing the issue, recognizing that the models would continue to advance.

“Many others in the community were involved in these discussions, including members of ethical committees in France, the Netherlands and Germany,” he says, in the hope that the guidelines they proposed could provide a blueprint for further discussions within scientific societies.

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