September 6, 2023

expert reaction to study on a model mimicking the structure of a post-implantation human embryo

A study published in Nature looks at a model of an embryo with a structure similar to that of a human.

Dr James Briscoe, Principal Group Leader – Assistant Research Director, Francis Crick Institute, said:

“The important thing about this research is that it is a step towards opening a window on the period of human development where many pregnancies fail and which has been really difficult to study up until now.  

“Technically, the researchers have created a model of early human embryos – a group of cells that act like an embryo but which can’t grow into one – out of stem cells. What’s interesting is that this so called ‘integrated stem cell-derived embryo” seems to produce all of the different types of cells that form tissues at this early stage of development, without needing to make any genetic changes, which previous attempts at this needed. The process is still very inefficient but it’s an important step.

“Producing embryo models in this way does of course raise profound ethical and legal questions, as it is not clear whether the currently established legal framework, governing the use of embryos arising from in vitro fertilisation (IVF), applies to embryo models produced through this new method. On the one hand, models of human embryos made of stem cells might offer an ethical and more readily available alternative to the use of IVF derived human embryos. On the other hand, the closer stem cell derived models of human embryos mirror human embryos, the more important it is to have clear regulations and guidelines for how they are used.”

Prof Magdalena Żernicka-Goetz FMedSci, Professor of Development and Stem Cells at the University of Cambridge and a Bren Professor of Biology and Biological Engineering at the California Institute of Technology, said:

“What an exciting year for the human embryo field. This study adds to six other similar human embryo-like models published earlier this year. None of these models fully recapitulate natural human development but each adds to ways in which many aspects of human development can now be studied experimentally.

“Generating the diverse models of human embryo is very important as the majority of human pregnancies fail and while we can now finally study human embryos until day 14, embryo-like models will allow us to dissect of reasons behind this developmental failure.

Prof Roger Sturmey, Professor of Reproductive Medicine at the Hull York Medical School, said:

“The work recently published from the Hanna research team describes an impressive series of experiments in which the authors have been able to persuade pluripotent stem cells to self-organise into structures that are remarkably close to early embryos.  The research builds on earlier work from this group and from other teams and shows that it is possible to induce stem cells toward key cell types that closely resemble those in the embryo.  In a step forward however, the team from the Weizmann Institute has been able to show that when these programmed stem cells are mixed together in suitable ratio, they are capable of self-organising into a structure that looks very much like an early embryo at the stage around when they begin to engage in implanting into the womb.  The team have taken further careful steps and confirmed that the cells within the embryo models possess a number of important molecular characteristics seen in natural embryos at equivalent stages.  The work has been performed to a high standard and with great care, however it is important to note that the efficiency of this process is low, with only a very small percentage of structures able to complete the process.  Crucially, these structures are embryo models and the term in the press release of ‘synthetic embryos’ is unfortunate, since these are neither synthetic nor embryos.  The International Society for Stem Cell Research describes this terminology as inaccurate.   In addition, it is not appropriate to consider these models as ‘embryos’ because we have no way of assessing their potential for further development since it remains prohibited to transfer an embryo model into the uterus of an animal or person.  Moreover, they form through very different processes to what happens in natural embryo development and so significant further work is required to understand the degree to which these, and many other embryo models resemble native embryos. Nonetheless, it is important that research in this area continues to be carefully governed.  In the UK, the Governance of Stem-Cell Based Embryo Models (G-SCBEM) project, led by Cambridge Reproduction, has convened academic researchers, legal scholars, bioethicists and research funders to prepare a set of guidelines for working with Stem Cell Based Embryo Models.”

Prof Alfonso Martinez Arias, ICREA Senior Research Professor, Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), said:

“This is a most important piece of research, particularly in the context of the collection of claims over the summer that the equivalent of a ‘complete human embryo’, the complement of embryonic and extraembryonic tissues, had been achieved in the lab. In one instance the claim was associated with alarming headlines that triggered ethical concerns about the science and the scientists. Unfortunately, these claims were not supported by the publication of the work which showed mangled groups of cells rather than anything resembling the structures in vivo. The complete structure is complex and the results of these experiments raised the question of whether it would be possible to assemble the whole. The work of the Hanna’s lab shows that it is possible and this has a number of implications.

“The 14^th day of human development is a crucial landmark associated with the moment in which a human embryo earns its right to legal protection. An important feature of this moment is the ability of the embryonic cells to develop into a human being and this depends, to a large extent, on their ability to associate with the mother who will provide nurture and protection. This in turn requires what are called extraembryonic tissues; a complex web of membranes, developed from the same initial cell as the embryo and that will be used to build both attachments to the womb and a niche for the development human being. The organization of these membranes and the embryo is neigh impossible to carry out as it takes place inside the womb within very small structures. Being able to study the emergence and organization of these complex structures would provide a window and a tool to understand the pregnancy failures associated with the maternal embryo-interface.  Although it is possible to culture embryos during this very important time, current techniques do not allow normal development. The work from the Hanna lab just published has, for the first time, achieved a faithful construction of the complete structure from stem cells, in vitro, thus opening the door for studies of the events that lead to the formation of the human body plan.

“The last few years have seen great progress in the use of embryonic stem cells to reconstruct the early stages of human development. This takes advantage of the ability of these cells to organize and orient themselves in space and some laboratories have exploited this to engineer the embryonic part of around day 14. It is surprising that this works but, in any event, the resulting structures lack extraembryonic tissues and collapse shortly after this time. This raises the question of whether the addition of extraembryonic tissues to the embryonic cells would maintain the structure and allow it to progress.

“The work of Hanna shows the assembly, starting with embryonic stem cells, of a structure that evolves in time and reaches a configuration  uncannily similar to the ensemble of embryonic and extraembryonic cells that configure the embryo at day 14. It is true that the numbers of structures per experiment is low but their configuration is so much like that of the ones derived from sperm and egg, to suggest that the scientists have tapped into an experimental system that can be made more efficient. The work also sets up standards for this field that one hopes can be implemented so that one can put to rest exaggerated claims that promote hype rather than hope. It is also important to remark that the structures described here assemble without the need of any genetic modification of the component cells.

“The work opens up an avenue to study the interaction between embryonic and extraembryonic tissues up to the all important day 14 and the start of the building of the human body plan. It also will allow the study of the early stages of the process of gastrulation, a most significant event that lays down the blueprint of the human body, and where the origin of many pathologies lies.

“I expect the work to raise ethical issues but, unlike earlier claims, this time with a real basis to think about the questions that emerge. Nevertheless, it is important to state that surprising as the emergence of the structure is, this work is not unexpected and the scientific community has been anticipating these developments for the last few years and have ongoing discussions on the subject geared towards regulation of this type of research.

“From my point of view, the issue to emphasize is that the system reproduces the natural situation remarkably well and, unlike all the other reports that have appeared during the summer, this is a landmark study that opens up new avenues for research into human development and the study several aspects of fertility and disease.”

Prof Darius Widera, Professor of Stem Cell Biology and Regenerative Medicine, University of Reading, said:

“This interesting study, conducted by Oldak and others in the Jacob Hanna lab at the Weizmann Institute, presents a sophisticated new model of the early human embryo formed through the self-organisation of human embryonic stem cells without genetic modifications. These structures, resembling early human embryos, could generate valuable insights into the processes governing early human development and potentially provide new insights into certain factors that contribute to miscarriages in humans.

“In contrast to similar studies published earlier this year, these embryo-like structures contained most of the cell types found in developing embryos and exhibited a high degree of organisation, mirroring what is typically observed in early human embryos during normal development.

“Despite being a significant stepping stone, this study is focused on early embryo development, and the protocols have a relatively low efficacy. Importantly, although the embryo-like structures resemble early human embryos, they are not identical.

“This research and other recent reports on models of the early human embryo show that models of human embryos are getting more sophisticated and closer to events that occur during normal development, highlighting that a robust regulatory framework is more needed than ever before.”

‘Complete human day 14 post-implantation embryo models from naïve ES cells’ by Bernardo Oldak et al. was published in Nature at 16:00 UK time on Wednesday 6 September.

DOI: https://doi.org/10.1038/s41586-023-06604-5

Declared interests

Prof Magdalena Żernicka-Goetz: “I am an inventor of patents that utilise embryonic and extra-embryonic stem cells to generate mouse and human embryo models and direct academic research laboratories in this field.”

Prof Roger Sturmey: “Roger Sturmey is a Professor of Reproductive Medicine at the Hull York Medical School and chairs the Guideline Working Group of the Governance of Stem-Cell Based Embryo Models project; a project led by Cambridge Reproduction that is developing a governance framework for the use of SCBEMS in the UK.”

Prof Alfonso Martinez Arias: “Have two patents on gastruloids, stem cell based embryo of mammalian development.”

Prof Darius Widera: “I have no conflict of interest to disclose.”

For all other experts, no reply to our request for DOIs was received.