Human embryo-like models have been created in the laboratory for the first time by reprogramming embryonic stem cells, according to research described at the International Society for Stem Cell Research's annual meeting in Boston this week, and reported in The Guardian.
Prof Magdalena Żernicka-Goetz, of the University of Cambridge and the California Institute of Technology, told the meeting that the synthetic embryos could be cultivated to a stage just beyond the equivalent of 14 days' development for a natural embryo, to reach the developmental milestone of gastrulation. This is the point when the embryo transforms from a continuous sheet of cells to forming distinct cell lines and setting up the basic axes of the body.
The current UK legal limit for scientists to grow human embryos in the lab is set at 14 days. Therefore during the period between 14 days and subsequent stages of pregnancy, when development can be studied through in vivo scans and embryos donated for research, embryo development remains largely hidden to scientific enquiry. The Cambridge research, which has not yet been published or peer reviewed, aimed to overcome this.
Commentators cautioned that the science was outpacing the law, and urged that a clear governance framework for such research was needed.
Model Created Entirely from Stem Cells Described as 'Beautiful'
"Our human model is the first three-lineage human embryo model that specifies amnion and germ cells, precursor cells of egg and sperm," Prof Żernicka-Goetz told the newspaper before her presentation to the meeting. "It's beautiful, and created entirely from embryonic stem cells."
Scientists say synthetic embryos could further study of genetic disorders and recurrent miscarriage during the crucial post-14 day window. They include cells that would typically go on to form the placenta, yolk sac, and the embryo itself, though have not yet developed a beating heart or rudimentary brain, and it remains unknown whether they have the potential to continue maturing beyond this earliest stage of development.
After parallel research in mice in Prof Żernicka-Goetz's lab, synthetic embryos grown from mouse cells appeared almost identical to natural embryos. They underwent gastrulation and began formation of a brain and a beating heart structure. However, when implanted into female mice they failed to develop. It would be illegal under current legislation to implant synthetic human embryos into a woman's uterus.
Also commenting to The Guardian, Dr Robin Lovell-Badge PhD, head of the laboratory of stem cell biology and developmental genetics at the Francis Crick Institute in London, said: "The idea is that if you really model normal human embryonic development using stem cells, you can gain an awful lot of information about how we begin development, [and] what can go wrong, without having to use early embryos for research."
However, he cautioned that if the intention is to develop these model embryos to mimic normal embryos, then they should be treated the same. "Currently in legislation they're not. People are worried about this."
Work Could Offer 'Valuable Insights into Genetic Disorders'
Commenting to the Science Media Centre (SMC), Dr Ildem Akerman PhD, associate professor in functional genomics at the University of Birmingham, said the work had "significant implications" that could offer "valuable insights into genetic disorders" and contribute to the advancement of in vitro fertilization (IVF) technologies.
"It's important to clarify that although the authors referred to them as 'synthetic' embryos, these cell clusters are not truly synthetic in the sense that they are created from scratch," she said. "Instead, they are derived from living stem cells that originate from an embryo. Essentially, what scientists do is cultivate a single stem cell and encourage its growth into an organized group of cells that, in theory, possesses the potential to develop into an implantable embryo."
While UK regulations do not permit culturing of human embryos beyond 14 days, the entities created from stem cells are considered 'integrated embryo models', and so can be cultured "for a minimum amount of time", but without a set time limit, she pointed out.
Development 'Potentially Broke' the Separation Between Embryos and Models
Until now an embryo (derived from IVF) and an 'integrated embryo model' (derived from stem cells) were two separate things, as the latter didn't possess the capability of growing further or implanting. Prof Żernicka-Goetz and her team's work "potentially broke this separation", Dr Akerman said. "Thus, it would be up to the individual ethical committee to decide whether the generated entity is an 'embryo' or an 'embryo model', and whether the entity would be allowed to grow past the 14-day limit."
She explained that the 14-day limit was intentionally chosen as a specific milestone in embryonic development, as on the 15th day the primitive streak begins to form and embryonic cells start to differentiate. It is also clearly ahead of day 22, when neurons start to form.
Roger Sturmey, professor of reproductive medicine at Hull York Medical School, told the SMC that the study built on "a steadily growing foundation of research" that demonstrates that under specialised lab conditions, stem cells can be persuaded to form a structure that resembles a blastocyst.
In normal development this is the time that the embryo begins the process of implantation and establishing pregnancy. "We know remarkably little about this step in human development, but it is a time where many pregnancies are lost, especially in an IVF setting," he said. "Models that can enable us to study this period are urgently needed to help to understand infertility and early pregnancy loss."
However, Professor Sturmey noted, while these 'synthetic embryos' share a number of features with blastocysts, "there is much work to be done to determine the similarities and differences between synthetic embryos and embryos that form from the union of an egg and a sperm". The research from Prof Zernicka-Goetz's lab offers "exciting prospects to answer these questions, and may provide an important tool to study early development while reducing the reliance on human embryos for such research."
Guidelines Needed for Responsible Research
He also noted that: "Given the nature of this work, UK lawyers, ethicists, and scientists are presently working to establish a set of voluntary guidelines to ensure that research on synthetic embryos is done responsibly."
Kathy Niakan, professor of reproductive physiology at the University of Cambridge, is principal investigator of the Governance of Stem Cell-Based Embryo Models (G-SCBEM) project, which is currently developing a framework for UK research involving SCBEMs. Also commenting to the SMC, she said the project was "working to address gaps, ambiguities, and differences of interpretation in the current regulation of human SCBEMs, particularly within the UK". The group has already submitted preliminary recommendations to the UK's Human Fertilisation and Embryology Authority.
Professor Niakan said: "We believe that greater clarity is required in this area, so that all concerned – including researchers, their funders and institutions, relevant regulators, and the general public – can be confident in their understanding of the types of research that are possible, permissible and legitimate."
Medicine Has Moved On But the Law Has Largely Stood Still
Asked to comment by Medscape News UK, a spokesperson for the Human Fertilisation and Embryology Association (HFEA) said: "The HFEA is responsible for the regulation of human embryo research; synthetic embryo-like entities are not human embryos as defined in the HFE Act and are, therefore, not regulated by the HFEA. The HFE Act does not allow the application of synthetic embryos in treatment.
"The HFEA recently consulted on the law that governs fertility treatment and human embryo research in the UK, which is over 30 years old. While medicine, science, and society have moved on, the law itself has largely stood still. As a result, the law is inflexible in responding to scientific innovation. We will continue to monitor developments of synthetic embryo like entities to understand these models' capabilities and to ensure new regulations can appropriately capture the evolution of these models."
