A single egg cell is fertilised – it starts to divide continuously. The young embryo slowly assembles. The initially chaotic cluster of cells gradually develops into highly organised structures. An international research team, including scientists from the Institute of Science and Technology Austria (ISTA), has now gained new insights into this process. The results, which have been published in Science, emphasise the crucial role of chaos and order.

Klosterneuburg, October 10, 2024: Bernat Corominas-Murtra and Edouard Hannezo from the Institute of Science and Technology Austria (ISTA) have gone beyond the usual scientific work and taken a creative approach. Corominas-Murtra became aware of a data set during a poster session at a collaborative conference in Spain. This was followed by a lively discussion with fellow researchers at the Hubrecht Institute in Utrecht, Netherlands. The discussion eventually led to a publication in Science.

The international research team developed a comprehensive atlas of early mammalian morphogenesis – the process of the development of an organism’s form and structure. Using this atlas, the researchers analysed how the embryos of mice, rabbits and monkeys develop in space and time. They realised that individual events such as cell divisions and movements are very chaotic, but that the embryo as a whole always looks very similar in the end. With this data set, they propose a physical model that explains how a mammalian embryo builds structure out of apparent chaos.

From one to many

In animals, embryonic development begins with the fertilisation of an egg cell. This event triggers a series of successive cell divisions, also known as cleavages. In short, a single cell divides into two, two become four, four become eight and so on. Finally, the mass of cells forms into a very well organised structure, the blastocyst, from which all future organs and tissues develop. The entire process is known as morphogenesis.

‘The early steps of embryonic development are of crucial importance as they form the basis for all subsequent developmental processes,’ explains Edouard Hannezo. In C. elegans, a transparent nematode and the model organism most frequently studied by developmental biologists, for example, the divisions in the early embryo are extremely well regulated and oriented in the same way, resulting in organisms that all have the same number of cells. In mammals, however, divisions appear to be much more random, both in terms of timing and orientation. This raises the question of how reproducible embryonic development occurs in mammals despite this disorder.

A detailed embryo map

Takashi Hiiragi’s research group investigated precisely this question. To do so, they looked at many different embryos and analysed them quantitatively. Using a so-called ‘morphomap’, they analysed the similarities between the embryos of mice, rabbits and monkeys, both within and between these mammalian species. A morphomap is a map that can be used to visualise high-dimensional morphological data. ‘It’s an image analysis pipeline that shows exactly how embryos behave in time and space – a precise atlas of an embryo’s morphogenesis, so to speak,’ explains Hannezo.

The map enabled the researchers to quantitatively analyse the development process and answer questions such as the variability of development between individual embryos. This enabled them to define what ‘normal’ morphogenesis looks like.

It was precisely this morphomap that Fabrèges presented at the conference in Spain. The data showed that the first divisions after fertilisation in mice, rabbits and monkeys were not regulated. The cells divided randomly until they reached the 8-cell stage, a stage in which all embryos suddenly looked the same. ‘After looking very different in the first stages, the embryos seemed to converge at the end of the 8-cell stage,’ Hannezo continues. But how does that happen? What brings structure to this chaos?

An embryonic Rubik’s cube – cell cluster optimises its arrangement

The two theoretical physicists, Corominas-Murtra and Hannezo, were immediately fascinated by this data set and set out to understand this process from a theoretical point of view.

However, the shape of an embryo is very complex. It is therefore difficult to judge whether two embryos are similar or different. The scientists discovered that they could approximate the full complexity of an embryo’s structure simply by examining the arrangement of cell contacts. ‘We believe that we can deduce most of the important details about the morphology of an embryo by understanding the arrangements of cells or knowing which cells are physically connected to each other – similar to the connections in a social network. This approach greatly simplifies data analysis and comparison between different embryos,’ says Corominas-Murtra.

With this information, the scientists created a simple physical model of how embryos fuse into a reproducible form. The model shows that physical laws cause embryos to form a specific morphology common to all mammals.

This particular shape is achieved by physical cell interactions that unbalance most cell arrangements, except for a few that reduce the surface energy of the embryo. In other words, the cells tend to stick together more and more. This seemingly simple process actually drives the embryo towards the most optimal arrangement through successive rearrangements. It is as if embryos are solving their own Rubik’s cube.

No chaos, no order

The results provide a detailed insight into the development of mammalian embryos, which is determined by variability and robustness. Without chaos there is no order; one needs the other. Both are essential components of ‘normal’ development. ‘We now finally have tools to analyse the variability of morphogenesis, which is crucial for understanding the mechanisms of developmental robustness,’ summarises Hannezo. Chance appears to be a primary force in the emergence of complexity in nature.

The more researchers learn about what normal looks like, the more they learn about anomalies. This can be very helpful in areas such as disease research, regenerative medicine or fertility treatment. In the future, this knowledge may help to select the healthiest embryo for in vitro fertilisation (IVF) and thus improve the success rate of implantation.



Information on animal experiments

In order to better understand fundamental processes in areas such as neuroscience, immunology or genetics, the use of animals in research is essential. No other methods, such as in-silico models, can serve as an alternative. The animals are reared, kept and treated in accordance with the strict legal guidelines of the countries in which the research was conducted (the Netherlands).

About ISTA

The Institute of Science and Technology Austria (ISTA) is a research institute with its own right to award doctorates. It employs professors according to a tenure-track model, post-doctoral researchers and PhD students. ISTA’s Graduate School offers fully funded doctoral positions to highly qualified students with a Bachelor’s or Master’s degree in biology, mathematics, computer science, physics, chemistry and related fields. In addition to its commitment to the principle of basic research driven purely by scientific curiosity, ISTA is committed to transferring scientific knowledge to society through technological transfer and knowledge transfer. The President of the Institute is Martin Hetzer, renowned molecular biologist and former Senior Vice President at The Salk Institute for Biological Studies in California, USA.

Originalpublication:

D. Fabrèges, B. Corominas Murtra, P. Moghe, A. Kickuth, T. Ichikawa, C. Iwatani, T. Tsukiyama, N. Daniel, J. Gering, A. Stokkermans, A. Wolny, A. Kreshuk, V. Duranthon, V. Uhlmann, E. Hannezo, T. Hiiragi. 2024. Temporal variability and cell mechanics control robustness in mammalian embryogenesis. Science.
DOI: 10.1126/science.adh1145

Further Information:

(https://doi.org/10.1126/science.adh1145)

ImageSource: Gerd Altmann Pixabay