Geometry shapes life

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Embryo geometry has to be firm—without it, cells would be all over the map

Zebrafish. Humans and zebrafish are more alike than one might think, especially when it comes to embryonic development. In science, zebrafish (Danio rerio) often reveal principles that apply much more broadly, making them both practical and biologically relevant for understanding how early embryos develop. Image credit and copyright: ISTA

Life begins with a single fertilized cell that gradually transforms into a multicellular organism. This process requires precise coordination; otherwise, the embryo could develop serious complications. Scientists at the Institute of Science and Technology Austria (ISTA) have now demonstrated that the zebrafish eggs, in particular their curvature, might be the instruction manual that keeps cell division on schedule and activates the appropriate genes in a patterned manner to direct correct cell fate acquisition. These insights, published in Nature Physics, could help improve the accuracy of embryo assessments in IVF.

Nikhil Mishra opens a heavy door that leads into a unique room. Countless transparent boxes are stored on racks swarming with small striped fish. The water refracts through the containers, casting a bluish hue across the room. You could almost believe you were in the middle of the sea, and the gentle lapping of the water and the cozy warmth of 27 °C reinforce this feeling.

Mishra takes one of the boxes from the rack and points at a zebrafish.

“The zebrafish is an ideal organism for studying the earliest steps of development,” he explained passionately. “Their embryos are fertilized outside the mother, which means we can easily collect and study them—often hundreds at a time. They are also naturally transparent, so we can literally watch their cells divide, move, and change in real time.”

Research team. ISTA’s Carl-Philipp Heisenberg, Nikhil Mishra, and Yuting Irene Li (from left to right). Not pictured: Edouard Hannezo. Image credit and copyright: ISTA

From one cell to many
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Life begins with a single fertilized egg cell, called the zygote, which begins to divide repeatedly. First into two cells, then four, then eight, and so on. This process is very similar across most species, including in humans. “Initially, these divisions happen quickly and without the cells taking on special roles. But soon, patterns begin to emerge: some cells divide more slowly, some start activating different genes, and others move to new positions,” Mishra said.

These early differences mark the first steps of ‘symmetry-breaking,’ when the embryo stops being uniform and starts organizing itself. Over time, groups of cells specialize into the three major layers that will form all tissues and organs. “From what begins as a simple, seemingly identical cluster of cells, a structured and patterned embryo gradually takes shape—laying the foundation for the entire body plan.”

ISTA’s Aquatics Facility. Nikhil Mishra takes out a transparent box filled with zebrafish. Image credit and copyright: ISTA

A knowledge gap
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In its early stages, the zygote depends on information provided by the mother. Only after reaching a developmental milestone called the midblastula extension (MBT) does the embryo begin to develop independently. At that point, the embryo needs to activate the appropriate genes at the right times in the correct cells. But how does it determine when and where to activate its genes? This is a fundamental question and a major knowledge gap that Mishra and the Heisenberg group at ISTA are investigating. However, they are not the only ones exploring this mystery.

ISTA’s Hannezo group is also attempting to understand how the position and timing of individual cell behavior are coordinated. These two research teams have been collaborating for some time. In particular, Yuting Irene Li, a postdoc in the Hannezo group, has greatly aided Mishra’s research with valuable expertise in theoretical physics, mathematical modeling, and statistical approaches to complex biological systems.

Postdoc collaboration. ISTA’s Nikhil Mishra and Yuting Irene Li are looking for tiny striped zebrafish hiding behind seagrass. Image credit and copyright: ISTA

Geometry – the instruction manual
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This collaborative research tested a largely ignored hypothesis—that the embryo’s geometry drives its development. The ISTA scientists demonstrated that the embryo “reads” and correctly interprets the zygote’s geometry during the initial few minutes of its existence. When the researchers manipulated the early embryo geometry, it changed how cells developed later.

Peekaboo. Image credit and copyright: ISTA

Think of the zygote’s geometry as an instruction manual that the embryo must read and follow as it patterns itself. If there is an error in that manual or the embryo does not read it correctly, it could lead to major problems—imagine having an intestine where your head should be.

Like a stadium wave
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Mishra explained that geometry sets off a series of highly consequential events causing cells to divide asymmetrically in an organized manner and thereby creating a gradient of cell size. These size differences create a gradient of cell cycle periods; smaller cells take longer to complete one cycle and divide into two cells.

Within the transparent embryo, this gradient is clearly visible under a microscope. Cells follow a repeating cycle, almost like a tiny internal clock, ticking through division and rest. “This repeating cycle, known as oscillation, varies slightly for each cell based on its size, which is determined by the fertilized egg’s geometry,” explains Li, an expert in oscillations. “Consequently, these varied ‘clocks’ align in a sweeping pattern across the embryo. What you see is a mitotic phase wave—a wave formed by different cells reaching the ‘division moment’ of their internal clocks one after another.”

Image credit and copyright: Nikhil Mishra/ISTA

Embryo representation. At the top is a normal embryo with a single lobe, which is a hemispherical cluster of cells (shown in different colors). The cells near the top of this lobe are usually the largest, and this is where the mitotic waves begin. Below is a bi-lobed embryo, which is the result of a mechanically manipulated zygote, resulting in two lobes and consequently two mitotic waves. When Mishra first observed this during his postdoctoral research, he considered it a groundbreaking moment. Image credit and copyright: Nikhil Mishra/ISTA

Improving IVF outcomes
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For the ISTA scientists, the next step is to determine how universal these principles are. If similar geometric rules are also found in mammals—and especially in humans—the implications could be very significant. This is relevant as more and more people turn to assisted reproductive technologies like IVF. Even for young, healthy individuals, fewer than half of IVF embryos reach the stage where they can be implanted and lead to viable pregnancies.

“Many embryos that fail during development show abnormalities in early division patterns or in how they activate their genes but we still don’t fully understand why. Our work suggests that the geometry of the early embryo—the physical shape and layout of its first cells—may play an important role in keeping development on track,” Mishra concluded.

In the long run, understanding these principles could help recognize early geometric “warning signs” in IVF embryos and perhaps design ways to correct or compensate for them. This could eventually contribute to more reliable embryo assessment and improved IVF outcomes.

Citations
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The study Geometry-driven asymmetric cell divisions pattern cell cycles and zygotic genome activation in the zebrafish embryo was published in Nature Physics Authors: Nikhil Mishra, Yuting Irene Li, Edouard Hannezo & Carl-Philipp Heisenberg

Acknowledgements
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We thank N. Petridou (EMBL) for sharing results before publication. N.M. was supported by funding from the European Union’s Horizon 2020 programme under the Marie Skłodowska-Curie COFUND Actions ISTplus grant agreement number 754411. Y.I.L. acknowledges funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement number 101034413. The research was supported by funding to C.-P.H. from the NOMIS Foundation, Project ID 1.844. We would like to thank past and present members of the Heisenberg and Hannezo groups for discussions, particularly S. Shamipour, V. Doddihal, M. Jovic, N. Hino, F. N. Arslan, R. Kobylinska and C. Camelo for feedback on the draft manuscript. This research was supported by the Scientific Service Units (SSU) of Institute of Science and Technology Austria through resources provided by the Aquatics Facility, Imaging & Optics Facility (IOF), Scientific Computing (SciComp) facility and Lab Support Facility (LSF).

Funding
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The study was supported by funding from the European Union’s Horizon 2020 programme under the Marie Skłodowska-Curie COFUND Actions ISTplus, Grant Agreement No. 754411 (NM); funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Grant Agreement No. 101034413 (YIL) & from the NOMIS Foundation, Project ID 506 1.844 (CPH).

Information on animal studies:
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To better understand fundamental processes, for example, in the fields of neuroscience, immunology, or genetics, the use of animals in research is indispensable. No other methods, such as in silico models, can serve as an alternative. The animals are raised, kept, and treated according to strict regulations.

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