First ‘trip’ inside an embryo in one of the central stages of its development
The embryonic development exceeds a biological line at 14 days. From that moment on, one of the most important stages of the embryo’s formation begins, which ensures its biological individualization. Until then, the embryos can divide in two or merge.
After 14 days, one of the most important stages of embryo formation begins, ensuring its biological individualization.
This process is known as gastrulation and runs until the 21st. During that week there is a explosion diversity in cells aimed at specializing. In fact, this process lays the foundation for the formation of the various types of cells in the body.
The embryo takes the form of a simple flattened disc, giving rise to three germ layers with progenitor cells that will become the various tissues and organs that characterize the human being. It is at this stage that many abortions and congenital anomalies.
For decades it has been considered that this third week after fertilization, which precedes the formation of organs, is the moment in which an individual becomes a being and the first signs of development of the nervous system are marked.
However, due to the rarity of such early embryonic samples, this phase could not be studied directly and was only known from experimental models. Now a new study, published today in the journal Nature, offers for the first time a unique vision of the naturally formed embryo in the uterus until this crucial stage of human development.
“Our study represents a missing link, so to speak, in our knowledge of the progression from the fertilized ovum to the more mature cell types of the body ”, the lead author, from the University of Oxford (UK), comments to SINC, Shankar Srinivas.
An embryo of 16 to 19 days
Scientists from the University of Oxford (UK), the Helmholtz Center in Munich-German Research Center for Environmental Health in Germany and the Cambridge Institute for Epigenetics and Stem Cells analyzed a single embryo between 16 and 19 days after fertilization in the uterus, donated ethically through the Human Developmental Biology Resource (HDBR) to investigation after voluntary termination of pregnancy.
It is important to know this process to understand how we came to exist
At that time of embryonic development, most pregnant women do not know that they are pregnant, but “in this case, the person knew it and decided to interrupt the pregnancy and gave their consent for the sample to be used in research, all in time to that we could get it early, ”explains Srinivas.
At this stage, the embryos are very small (just over a millimeter long) and very difficult to collect. “This is the only sample from such an early stage of development in the more than five years that we have been receiving HDBR samples,” says the researcher.
Description of cell types and gene expression
Thanks to the single cell RNA sequencing, the work has provided a detailed description of the types of cells present that develop and diversify at different rates. But the activity of the genes that they express and how they change over time during the gastrulation process, making comparisons with experimental models in vitro which gave similar results. “It is important to know this process to understand how we came into being,” Srinivas emphasizes.
“The new study provides a Rosetta stone for developmental biologists. By analyzing an exceptionally rare human embryo at a very early stage of development, the results allow researchers to translate their results from other experimental systems into a common language, ”he says. Peter Rugg-Gunn, group leader of the epigenetics research program of the Babraham Institute who has not participated in this work.
This information provides new clues to understand why these processes sometimes go wrong during pregnancy, which can lead to developmental defects in some babies.
The study provides important new insights into how the first lineages are formed and positioned in the developing embryo. “This information provides new clues to understand why these processes sometimes go wrong during pregnancy, which can lead to developmental defects in some babies,” adds Rugg-Gunn.
Developing blood cells
After verifying that this particular embryo was correct and morphologically intact, the authors detected primordial germ cells (precursor cells which give rise to eggs or sperm) –although they did not know where to specify–. The work also shows that at this early stage the human embryo has several types of blood cells, including primitive red blood cells.
“It was a surprise to see red blood cells so soon; they form earlier in humans than we might have thought based on mouse studies. Another interesting aspect is that we already see many different types of blood cells, both red and white. This points to the fact that blood is diversifying very soon ”, Srinivas tells SINC, who compared these results with mouse models, which reinforces the role of this animal in the research.
Furthermore, using RNA sequencing, the scientists found that all the blood cells detected were male, like the embryo itself, and did not come from the mother.
Although they could only analyze an embryo, “the process was very similar to that of mice, which gave us a lot of security,” he explains. Antonio Scialdone, co-author of the work and researcher at the German center.
In addition, they discovered that cellular specification of the nervous system It had not yet started at this stage of development, when there were already signs of it in the mouse. “We do not see any neurons in this phase, which indicates that the embryo does not yet have the necessary apparatus to receive sensations or other inputs,” says Srinivas, “something to keep in mind when we review the ’14-day rule’ in relation to with the culture of human embryos ”.
The authors discovered that the cellular specification of the nervous system had not yet begun at this stage of development.
“In this research the scientists did not observe the neuronal specification of cells during the period of time studied, which suggests that it occurs at a slightly later stage of development compared to other model organisms ”, points out Darren Griffin, Professor of Genetics at the University of Kent (UK) and independent researcher.
Thus, the work allows to know more in depth what happens in the embryo at this stage. “Since there is a lot of interest in using stem cells to generate other useful cell types, we can learn from nature and try to recreate those conditions in the laboratory or clinic,” Srinivas emphasizes.
For Robin Lovell-Badge, from The Francis Crick Institute and also an independent scientist, the relevance of this study lies in the fact that it is “a very important period to study, not only to understand our beginnings, but also to help develop methods that help embryos to develop normally ”.
A limit of 14 for cultured embryos
In 1979 it was established the 14 day limit for human embryo culture by the Ethics Advisory Council of the US Department of Health, Education and Welfare, followed in 1984 by the UK Warnock Committee. The Human Embryo Research Panel of the US National Institutes of Health did so in 1994. Now, that standard is extended to at least 12 countries, including Spain.
However, before the requests of many groups of researchers, are restrictions were softened last May in the last revision of the guidelines of the International Society for Stem Cell Research (ISSCR). Thus, the cultivation in vitro intact human embryos went from being a prohibited research category to a permitted one, always with rigorous supervision and approval in accordance with the law, insisting that no other method could provide the same information.
“The updated guidelines of the ISSCR will still have to reach the legislation of several countries. In addition, they recommended a public consultation, so it may still take some time for publicly funded research to go beyond 14 days, ”Srinivas emphasizes.
Their study could provide important data to improve the 14-day rule, especially regarding the information it provides on the development of the nervous system.
Richard C.V. Tyser “Single-cell transcriptomic characterization of a gastrulating human embryo” Nature, 2021.