By Dr Zoe Bolton, published 23rd November 2023

The development of human stem cell based embryo models is progressing at pace, but what are these models, why are scientists creating them, and are they a cause for concern? Read our explainer to find out more.

What are human stem cell based embryo models?

Human stem cell based embryo models (SCBEMs) are embryo-like structures created in a laboratory in vitro using human stem cells rather than eggs and sperm. These models mimic the processes that occur in early human embryo development.

Human SCBEMs have also been termed artificial embryos, embryoids, synthetic embryos with embryo-like features (SHEEFs) and synthetic embryos. Terminology such as ‘synthetic’ has been recognised as misleading in this context because the spontaneous developmental progress of these models is similar to that which takes place in human embryo development.

The stem cells that are used to form human SCBEMs can be derived either from human embryonic stem cells (hESCs) or from reprogrammed body (somatic) cells, known as human induced pluripotent stem cells (hIPSCs). ‘Pluripotent’ means that these cells have the potential to develop into any type of human body cell. Both hESCs and hIPSCs have this potential.

Human embryos require both embryonic and extraembryonic tissue, such as the yolk sac, amniotic cavity and placenta, to fully form. There are two main categories of human SCBEMs, which are distinguished by the tissues that they are capable of developing. Non-integrated models can develop embryonic tissue but not extraembryonic tissue; while integrated models mimic the development of the entire embryo, including both the embryonic and extraembryonic tissues.

SCBEMs are not considered as embryos in the biological definition of the term because they are not currently able to develop into the equivalent of fetuses. In any case, it is illegal in the UK (and in many other jurisdictions) to implant these structures into a human womb because they have not been created through fertilisation.

Why are scientists developing human SCBEMs?

More research is needed into the early stages of human embryo development because not enough is known about why so many early embryos fail to implant or develop. Evidence shows that only 50-60% of pregnancies advance beyond 20 weeks of gestation and 75% of these are not clinically recognised as pregnancies because they fail prior to the implantation stage. Furthermore, an estimated eight-million children globally are born with a birth defect each year and many of these defects originate during the 14-28 day phase of embryo development.

Access to human embryonic materials for research purposes is difficult because of the range of technical challenges that researchers face, including the scarcity of high-quality embryos. There are also ethical and regulatory restrictions. For example, in many jurisdictions, including the UK, there is a 14-day limit on the in vitro cultivation of embryos for research purposes.

These technical and regulatory limitations mean that not enough is yet known about early embryo development to enable us to understand why so many pregnancies fail during this period and why birth defects develop. The period between 14-28 days, often referred to as the ‘black box’ of human development because so little is known about it, is particularly critical and there is a gap in access to research materials: no human embryos can be used after day 14 and tissue derived from aborted or miscarried fetuses, which is permitted for use in research in the UK under specific conditions, is not available until after 28 days.

Human SCBEMs can enable scientists to learn more about the crucial early stages in human embryo development. These models are also highly reproducible, which means that multiple embryo models can be generated for research purposes.

What happens during the first 28 days of human embryo development?

During the pre-implantation stage (~ days 0-7), embryo development starts with the creation of a single cell, the zygote, following the fusion of sperm and egg. The zygote phase lasts around three days after which its cells rapidly divide and assume a spherical shape called a morula. By day five, a cavity forms within the morula creating a hollow structure called a blastocyst. Within the blastocyst, an internal tissue known as the epiblast develops. This is the primitive cell layer from which the three primary cell layers of the fetus are formed during a process known as gastrulation (see below). The rest of the blastocyst contains extraembryonic cells, which protect and support the epiblast and assist with implantation.

Once implantation has occurred (~ days 8-10), the amniotic cavity and yolk sac are formed from extraembryonic tissues and the placenta also begins to form. Around day 14 of the implantation stage, the primitive streak emerges whereby the cells in the epiblast undergo a transition in preparation for gastrulation.

Gastrulation (~ days 14-21) is the most critical point in embryo development when the primary germ, or cell, layers are formed beginning the process of organogenesis (the development of organs and tissues). The three primary germ layers that develop during gastrulation are: the endoderm, which gives rise to key organs, such as the colon, stomach, intestines, lungs, liver, and pancreas; the mesoderm, which forms connective tissues and muscles; and the ectoderm, which creates the skin and nervous system.

Neurulation (~ days 21-28) follows on from gastrulation and marks the beginning of the process of forming the brain and the spinal cord.

For the reasons described above, scientists have not been able to research early embryo development effectively using human embryos and so have instead been developing human embryo models.

Which human SCBEMs have already been developed?

Human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hIPSCs) have already been successfully developed in vitro. These are the biological building blocks that can be used to create human embryo models. More progress has been made so far with human SCBEMs derived from hESCs.

Following the successful development of a number of stem cell based embryo models in mice, researchers have been working to replicate this using human pluripotent stem cells. The models that have been developed focus on different stages in early embryo development and fall into three broad categories: blastoids, gastruloids and post-implantation embryo models.

Blastoids
As the name suggests, blastoids are SCBEMs that mimic the blastocyst. A blastoid is an integrated embryo model containing both embryonic and extraembryonic tissues. Since 2021, a number of different research groups have reported the generation of blastoids from hESCs. For example, in 2021, a team from Austria, Belgium and France reported the creation of human blastoids that model blastocyst development and implantation and, in early 2023, some of the same members of that team announced the development of a more sophisticated model of the blastocyst. The scientists view these models as a scalable and ethical alternative to the use of embryos.

Gastruloids
Gastruloids are three dimensional models that can form derivatives of the three cell layers that are formed during the gastrulation stages of human embryo development. Gastruloids are non-integrated SCBEMs because they do not contain extraembryonic tissue. There are already well-established embryo models of human gastrulation, including the ones reported here in 2020.

Post-implantation embryo models
Up until now, blastoids have demonstrated limited capacity for post-implantation development, and gastruloids lack extraembryonic tissue which means they cannot be used to explore key peri-gastrulation events such as the formation of the primitive streak, amniotic cavity and yolk sac. In response, more complete human SCBEMs that mimic the period post-implantation up to the start of gastrulation (~ days 7-14) have been developed.

In June 2023, a team of researchers from the University of Cambridge and the University of Washington reported that they had created SCBEMs of the post-implantation human embryo. This was followed in August 2023 when a group from the US announced that they had developed a robust method to generate an integrated model of human peri-gastrulation. Then, in September 2023, an Israeli-led team reported that they had also created complete human post-implantation embryo models.

These are all integrated SCBEMs which contain embryonic and extraembryonic tissues but, while they can mimic aspects of post-implantation human embryo development, they cannot develop to the equivalent of postnatal stage humans.

What recommendations are there about the use of human SCBEMs?

In 2023, in light of the rapid rate of progress in the development of integrated human SCBEMs, the International Society for Stem Cell Research (ISSCR) published a statement on new research with embryo models. This makes it clear that, while these models are not embryos, research with SCBEMs should only proceed under certain conditions: (i) there should be a compelling scientific rationale for conducting the research; (ii) there should be a dedicated scientific and ethical oversight process for approving research using SCBEMs; (iii) integrated embryo models should be maintained in culture for the minimum time necessary to achieve the scientific objective; and (iv) researchers must also comply with local laws and policies.

Given the increasing sophistication of human SCBEMs, there may come a point when these models should be regulated in the same way as embryos. This issue is explored in some detail in an article published in Cell in August 2023, which argues for a revised legal definition of the term ‘embryo’ to incorporate these models and identifies a series of ‘tipping points’ for when human SCBEMs should be afforded similar protection to that of embryos.

In fact, the Health Council of the Netherlands has just published recommendations that a 28-day rule should be applied to integrated SCBEMs and that these models should be regarded as ‘non-conventional embryos’ under the Dutch Embryo Act. While, in the UK, Cambridge Reproduction is in the process of developing the first governance framework for research using SCBEMs.

As is so often the case with new reproductive technologies, there are concerns about whether regulatory frameworks will be able to keep pace with the rapid developments in human SCBEMs. However, the work already underway in this area is an encouraging first step to ensuring that these models are used ethically to further advance understanding of early human embryo development.