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Pattern formation: How undifferentiated cell clusters develop orderly structures

Dr. Patrick Müller explores cellular signalling pathways that turn undifferentiated cell clusters into orderly structures as embryos develop. Supported by an ERC grant, the Max Planck researcher from Tübingen uses a broad range of methods from the fields of genetics, biophysics, mathematics and the computer sciences for his investigations. Regenerative medicine is one field that particularly stands to benefit from Müller’s findings.

Dr. Patrick Müller studies the signalling pathways involved in embryonic development and the formation of biological patterns in general and hopes to come up with new findings for use in regenerative medicine approaches involving stem cells. © MPG

Dr. Patrick Müller has received around 1.5 million euros from the EU to study the signalling pathways involved in embryonic development and the formation of biological patterns in general. The prestigious European Research Council (ERC) Starting Grant is not the first award Müller has received. The former Harvard researcher has previously been awarded the Max Planck Society's Otto Hahn Medal and Emmy Noether funding from the German Research Foundation (DFG). Since 2014, Müller has been the head of a group of researchers at the Friedrich Miescher Laboratory, which is the smallest institute on the Max Planck Campus in Tübingen, and is specifically focused on zebrafish embryos and embryonic mouse stem cells.

Genetic research on zebrafish and research into biological pattern formation have an equally strong tradition in Tübingen. Müller says: "It was here on the Max Planck Campus in the 1990s that the team of Nobel Laureate Christiane Nüsslein-Volhard established the world's first zebrafish laboratory focussing specifically on mutation research. It was also in Tübingen in the 1970s that Hans Meinhardt and Alfred Gierer formulated their theory on biological pattern formation." Meinhardt's and Gierer's research into sea shells and snail shells revealed a central organising principle which had previously been observed by the English mathematician Alan Turing. In 1952, Turing, whose life inspired the 2014 film "The Imitation Game", devised a theory on biological pattern formation.

Müller combines the broad know-how of the scientists from Tübingen with his own experience and has already successfully carried out simulations in complex geometries. "The ERC Grant will give me a stable platform and a lot of freedom to study the general principles of self-organising development," says the researcher.

Signalling – studying the interplay of activation and inhibition

Whether it is the sometimes spectacular patterns on the shells of tropical sea molluscs or the patterns that form during cell divisions in embryonic development – these biological processes have one thing in common: they are controlled by the interplay of activating and inhibitory signals. Müller aims to study in detail this interplay in fish embryos both experimentally and theoretically using computer simulations. He is specifically interested in the quantitative aspects of signal transduction events. In which time scales are signalling molecules active and how are molecule quantities and processes regulated? Müller realises that interdisciplinary collaborations are needed to be able to answer such complex questions. His team already includes developmental and systems biologists, computer scientists and mathematicians and he will use the ERC Grant to bring on board international experts from other fields.

The signalling pathways involved in the embryonic development of vertebrates are already well known, which makes Müller's work easier. "We are working with the first patterns that develop after fertilisation and lead to the three germ layers of an organism. It's a relatively simple system with only three cell types. The few signalling pathways involved have been known for quite some time from classical mutagenesis experiments. We know the receptors and the molecules that mediate the signals," says Müller. The so-called Nodal signalling pathway and the Nodal proteins induce the development of endoderm and mesoderm. The so-called Lefty proteins (left-right determination factors, i.e. factors that determine the orientation of cells along the left-right axis of an organism) are the antagonists in these events. Although this signalling pathway has been studied in great detail, little is yet known about its kinetics. Müller therefore plans to simulate its temporal course on the computer.

"We have already done some measurements and found out that Nodal proteins move slowly and Lefty proteins move relatively quickly through the embryo. In general, the system consists of short-range activators that are self-reinforcing and are inhibited by long-range antagonists," says Müller. He takes sand dunes as an example to explain how short- and long-range signals interact. "The sand grains are the activators of sand dunes. While the sand is fairly homogeneously distributed at first, the wind piles it into small hills and ridges. The creation of dunes is a self-reinforcing, short-range process, as piles of sand usually accumulate in the "wind shadow" of existing ones which slow down the wind. At the same time, the formation of sand piles also leads to long-range inhibition because they prevent the formation of new piles in their immediate vicinity; new piles only form at a greater distance from existing ones." Müller and his team hope that the computer simulations will provide them with information on the behaviour of cells in developing embryos. It is not unlikely that some time in the future the findings will be used for regenerative medicine approaches involving stem cells. The researchers hope that detailed knowledge of the self-organisation of cells will provide them with ideas on how to specifically control tissue and organ formation.

Three circles with different degrees of filling (homogeneously purple, circle on the left; circle with white filling in the middle, and a circle with a dark purple order on the right) showing how different patterns are formed.
Example of a simple pattern formation mechanism: a homogeneous field is developing into a pattern with two different tissues. © MPG

The secrets of biological self-organisation – relevant for regenerative medicine

Unfortunately, one particular aspect of biological pattern formation is a hard nut to crack: the natural polarity of embryos. In fertilised egg cells that have undergone the first cell divisions, an embryonic area that differentiates into the actual embryo develops at one pole, and a non-embryonic area that nourishes the embryo during the first few days develops at the other. In order to study the natural polarity of embryos in detail, Müller also uses embryonic stem cells from mice. "We are able to control the conditions precisely. We have a completely self-organising system with no outside influence; and this system gives us an idea of how the germinal layers develop," says Müller. The researchers are using both systems in the hope of speeding up the knowledge-finding process, which is in no small measure facilitated by modern imaging methods. Müller and his team have a state-of-the-art light sheet microscope that enables them to study a single embryo in around 300 different planes. Only one plane at a time is excited with light. This protects the object, i.e. the living embryo, when it is being studied under the microscope. With this technology, it is also possible to record different time series from four angles. "We can create long observation series with high temporal and spatial resolution; this gives us unique access to the kinetics during the early developmental process," says Müller. All this means that Müller is in an excellent position to advance the investigation of pattern formation during the five-year ERC funding period.

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/pattern-formation-how-undifferentiated-cell-clusters-develop-orderly-structures