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A study published in Nature provides the first detailed cellular and molecular examination of a human embryo in the process of gastrulation.
This Roundup accompanied an SMC Briefing.
Dr Adam Stevens, Lecturer in Child Health and Growth at the University of Manchester, said:
“The work by Tyser et al is an important advance. The data presented provides deep knowledge of a period of human development not previously visualised. This work uses a state-of-the-art assessment of the rate of change of mRNA (RNA velocity) to understand developmental trajectories. Despite morphological differences between human and mouse gastrulation a fundamental transcriptomic similarity is revealed providing insight to mammalian evolution. A major potential significance of this work is that a “map” of the transcriptomic trajectories in human gastrulation can now be used as a basis for further investigation into neural tube defects that occur downstream, such as spina bifida.”
Dr Harry Leitch, Stem cell biologist and group leader at the MRC London Institute of Medical Sciences, and Academic Clinical Lecturer in Clinical Genetics, Imperial College London, said:
“This is a fascinating study offering a unique insight into a very early stage of human development. This was made possible by the Human Developmental Biology Resource, a very important UK-based research initiative that consents women having a termination of pregnancy to allow access to the post-mortem tissue. This provides an invaluable resource to researchers to study the earliest stages of human development – which will increase our understanding of human developmental biology, and facilitate further advances in stem cell biology and regenerative medicine. The Srinivas and Scialdone laboratories studied a sample at an unusually early stage of development using single cell RNA sequencing – and have produced a unique catalogue of cells which can be used by the whole research community.”
Prof Darren Griffin, Professor of Genetics, University of Kent, said:
“It is a landmark paper, upon which many will base their future findings. Gastrulation is such a fundamental process and marks the point that an organism first shows signs of any sort of nervous system. Interestingly in this research – the first time they’ve been able to study this in detail in a human embryo – they did not see neural specification of cells during the time frame studied, suggesting it happens at a slightly later point in development compared to other model organisms.
“The paper is detailed and comprehensive and it is refreshing to see the data so freely and readily available.
“The authors rightly point out that the major limitation is that this is a single embryo and we have no way of knowing how representative this is. One thing is certain however, that we are about to find out.”
Dr Peter Rugg-Gunn, Group Leader in Epigenetic research Programme, Babraham Institute, said:
“The new study provides a Rosetta Stone for developmental biologists. By analysing an exceptionally rare human embryo at a very early stage of development, the findings allow researchers to translate their results from other experimental systems into a common language. Although further validation of the findings will be required, this work will lead to more accurate and useful experimental models. The new study is already yielding important new insights into how the early cell lineages are formed and positioned in the developing embryo. This information provides new leads to understand why these processes sometimes go wrong during pregnancy, which can result in developmental defects in some babies.”
Prof Robin Lovell-Badge FRS FMedSci, Group Leader, The Francis Crick Institute, said:
“It is remarkable that so much high-quality data has been obtained from a single human embryo at this stage (16-19 days post fertilization; Carnegie stage 7; mid-gastrula with a clear node at the anterior end of the primitive streak). This reveals the power of single cell RNA sequencing methods – especially when they are applied so carefully as in this case. Moreover, it is very rare to obtain such an early embryo – many women don’t know they are pregnant at this stage and the embryos are very small and probably difficult to collect. This also shows the importance of the Human Developmental Biology Resource (HDBR) – it provides ethically sourced samples that are invaluable for learning about the biology of human embryos and fetuses.
“The authors highlight several important and novel findings. There were a few primordial germ cells present (the cells that will ultimately go on to make either eggs or sperm) already at this stage. They can’t say precisely where they were located – other methods would be needed to do this – but that they are generated early in gastrulation is important to know. There was also perhaps more complexity to endoderm and mesoderm tissues than might have been expected. And there were two surprises. One that cells of the blood system (that will make both the vessels and red and white blood cells) were present at a stage earlier than seen in the mouse, and that the nervous system had not yet started to develop*, when there would already have been signs of this in the mouse. That there are differences between human and mouse is now very evident, but this again highlights the importance of directly studying human embryos.
“At the moment, only rather tenuous conclusions can be reached, because the work involved just a single embryo and the authors only suggest what they might have through comparisons with some historical fixed and sectioned human embryos (the ‘Carnegie collection’ of staged human embryos), from animal embryos and from (unvalidated) stem cell-based embryo models. Additional samples at the same and different stages will be required to build up a convincing picture of how normal human embryo development proceeds, using the same RNA sequencing methods and other methods to allow spatial resolution. These samples could be obtained in a similar way, from early terminations, or perhaps by culturing intact human embryos until they reach relevant stages of development. The latter would have to go beyond 14 days, which is currently not permitted in the UK. The so-called 14-day rule was established in UK law in 1990, with the passing of the Human Fertilisation and Embryology Act. Similar legal restrictions are present in some other jurisdictions, but not all – however, scientists everywhere have followed it until now**. Nevertheless, it is permitted to obtain embryos beyond 14 days after terminations, as in this case.
“The period between 14 and about 21 days is when the process of gastrulation occurs, which is critical to transform a simple disc of cells into an early embryo with several layers that are patterned and comprised of various progenitor cell types that will go on to develop into the various tissues and organs that characterise us. Many miscarriages and congenital abnormalities are likely to be due to problems arising during this period, which makes it a very important period to study, not only to understand our beginnings but also to help develop methods to help embryos develop normally.
“Studying intact embryos obtained after terminations or after culture beyond 14 days will help validate embryonic stem cell- or induced pluripotent stem cell-based embryo models. If these models do turn out to closely resemble normal embryos, in whole or in part, then this will reduce the need to use normal human embryos. But until this is shown, studies like the present one will be important.
Some additional points:
*One reason to propose a limit to embryo culture of 14 days is that this was assumed to mark the earliest signs of nervous system development, i.e. it would be before there was any possibility that the embryo could feel pain or be sentient (although we know that neither occur until many months later). But if the nervous system is not developing until several days later, then this again shows how arbitrary the limit was.
**The 2021 revised version of the ISSCR Guidelines has moved the culture of intact human embryos from a prohibited category of research to one that is permitted with rigorous review and oversight, and with public approval, that would have to be gained within the relevant jurisdiction (one where it is not illegal). The review would have to insist that no other methods could give the same information.
Dr Teresa Rayon, Postdoctoral Training Fellow, The Francis Crick Institute, said:
“Gastrulation comprises the most unknown stages of human pregnancy – between weeks 2 and 4, where women wouldn’t normally know if they are pregnant. The scarcity of availability of human samples makes the analysis of an embryo of ~ 19 days of development an important step towards our understanding of human development. The information of cell types in a single embryo through single cell transcriptomics provides insight into the distinct anatomical regions in the human embryo and serves as ground-truth for comparisons of human in vitro models as well as animal models.”
Prof Andrew Sharrocks, Professor of Molecular Biology, University of Manchester, said:
“The press release is a decent summary of the work.
“This is high quality, albeit fairly limited work based on a single RNAseq experiment on a single dissected embryo. They use the latest computational analysis techniques on the data to draw reasonable conclusions.
“This is a key stage in development that precedes organ formation and when all the basic cell layers become established. We know little about this in humans due to the scarcity of material. Recent advances in single cell RNA sequencing also make this timely and feasible whereas previously this would not have been possibly without this technology.
“The findings seem to fit well with what is known from other in vitro and animal systems, although there appear to be human-specific differences.
“While this is only work done on one embryo, one is always better than none and the authors have done reasonable quality control to suggest that this was a typical normally developing embryo. However, having more is obviously better, particularly several closely spaced embryos in developmental time, so that one could infer developmental trajectories and how cells change phenotype over time. Mechanistic insights could then be inferred from this.
“This is a well reasoned paper with reasonable conclusions. This is another piece in the puzzle for understanding human development and how this proceeds but as indicated above, ideally a lot more embryos would be needed to fully understand the developmental pathways in play.”
‘Single-cell transcriptomic characterization of a gastrulating human embryo’ by Richard C. V. Tyser et al. was published in Nature at 16:00 UK time on Wednesday 17th November.
DOI: https://doi.org/10.1038/s41586-021-04158-y
Declared interests
Dr Adam Stevens: “I have no conflict of interest with this work.”
Dr Harry Leitch: “None.”
Prof Darren Griffin: “No COI.”
Dr Peter Rugg-Gunn: “Peter Rugg-Gunn shares an affiliation at the Wellcome–MRC Cambridge Stem Cell Institute with two of the authors on the study (Shota Nakanoh and Ludovic Vallier).
“He is part of the Human Developmental Biology Initiative with one of the authors of the study (Shankar Srinivas).”
Prof Robin Lovell-Badge: “Robin Lovell-Badge has no conflicts of interest to declare except he was chair of the ISSCR Task Force that revised their guidelines and he serves on an the HFEA’s Scientific and Clinical Advances Advisory Committee (SCAAC).”
Dr Teresa Rayon: “I have recently published a single-cell atlas of the human developing spinal cord (PMID: 34351410)”
Prof Andrew Sharrocks: “No interests to declare.”
None others received.