The mysterious dance of the Cricket Embryo

In June, 100 fruit fly scientists gathered on the Greek island of Crete for their biennial meeting. Among them is Cassandra Extavour, a Canadian geneticist at Harvard University. Her lab works with fruit flies to study evolution and development — “evo worm.” Usually, such scientists choose the species Drosophila melanogaster as their “model organism” – a winged stallion that has been an insect collaborator of at least some species. Nobel Prize in physiology and medicine.

But Dr. Extavour is also known for cultivating alternative species as model organisms. She is particularly interested in crickets, especially Gryllus bimaculatus, the two-spotted field cricket, although it has no interest in fruit flies yet. (About 250 principal investigators signed up for the meeting in Crete.)

“It’s crazy,” she said in a video interview from her hotel room, as she wiped out a beetle. “If we tried to hold a meeting with all the heads of the lab working on that cricket, there might be five of us, or 10.”

Cricket has been involved in research on biological clocks, limb regeneration, learning, memory; They were once disease models and pharmaceutical factories. The crickets, the crickets! They are also growing in popularity as dish, covered with chocolate or not. From an evolutionary point of view, crickets offer more opportunities to learn about the last common insect ancestor; they have more in common with other insects than fruit flies. (Notably, insects make up more than 85 percent of animal species.)

Dr. Extavour’s research focuses on fundamentals: How does an embryo work? And what could that reveal about how the first animal was born? All animal embryos follow the same journey: One cell becomes many cells, which then arrange themselves in a layer on the surface of the egg, providing the initial blueprint for all the body parts. adult body. But how do embryonic cells – cells that share the same genome but not all behave the same with that information – know where to go and what to do?

“It was a mystery to me,” Dr. Extavour said. “It’s always been where I wanted to go.”

Seth Donoughe, a biologist and data scientist at the University of Chicago and an alumnus of Dr. Extavour’s lab, describes embryology as the study of how a developing animal makes “internal organs.” the right part in the right place at the right time”. In some new studies featuring a magical video of cricket embryos – showing some of the “right parts” (cell nucleus) moving in three dimensions – Dr Extavour, Dr Donoughe and their colleagues found out that’s very classic. geometry main character.

Humans, frogs, and many other widely studied animals begin as a single cell that immediately divides again and again into separate cells. In crickets and most other insects, it is initially just the nucleus that divides, forming multiple nuclei that travel throughout the cytoplasm and only later form their own cell membranes.

In 2019, Stefano Di Talia, a quantitative developmental biologist at Duke University, study the movement of nuclei in fruit flies and showed that they are carried by pulsating currents in the cytoplasm – a bit like leaves moving on the eddies of a slow-moving stream.

But several other mechanisms were at work in cricket embryos. Researchers have spent hours watching and analyzing the microscopic jump of nuclei: glowing nuclei divide and move in a confusing fashion, not entirely ordered, not entirely random. , at different directions and speeds, neighboring nuclei are more in sync than more distant nuclei. The performance offers a choreography that’s more than just physics or chemistry.

Dr Extavour said: “The geometric shape that nuclei assume is a result of their ability to sense and respond to the density of other nuclei near them. Dr Di Talia was not involved in the new study but noticed it was moving. “It’s an amazing study of a beautiful system with amazing biological relevance,” he said.

Early cricketers adopted a classical approach: Look closely and pay attention. Dr Extavour said: “We just watched it.

They took video with a laser light plate microscope: Snapshots capture the nuclei jump every 90 seconds during the early eight hours of embryonic development, during which about 500 nuclei have been accumulated accumulate in the cytoplasm. (Crickets will hatch in about two weeks.)

Normally, biological materials are translucent and difficult to see even with the most difficult microscopes. But Taro Nakamura, then a postdoc in Dr. Extavour’s lab, now a developmental biologist at the National Institute of Basic Biology in Okazaki, Japan, designed the design. a special line of crickets with nuclear Fluorescent green glow. As Dr. Nakamura recounts, when he documented embryonic development, the results were “astonishing.”

That’s the “starting point” for discovery, says Dr. Donoughe. He paraphrased a comment sometimes attributed to science fiction author and biochemistry professor Isaac Asimov: “Usually you don’t say ‘Eureka!’ when you discover something, you say, ‘Huh. It’s strange.'”

Initially, biologists watched repeated videos, projected onto conference room screens – the IMAX equivalent of cricket, which assumed the embryos were a third the size of a grain of rice (the long grain). They tried to detect patterns, but the data sets were overloaded. They need more understanding of quantification.

Dr. Donoughe contacted Christopher Rycroft, an applied mathematician now at the University of Wisconsin-Madison, and showed him the dancing nuclei. ‘OH!’ Dr. Rycroft said. He had never seen anything like it, but he recognized the potential for a data-driven collaboration; he and Jordan Hoffmann, then a PhD student in Dr. Rycroft’s lab, joined the study.

Through many experiments, the math-biology team pondered many questions: How many nuclei are there? When did they start dividing? Which direction did they go? Where did they end up? Why are some pulling around and others crawling?

Dr. Rycroft often works at the crossroads of the physical and life sciences. (Last year, he published on the physics of crumpled paper.) “Mathematics and physics have had great success in finding universally applicable rules, and this approach could also help biology,” he said; Dr. Extavour said the same thing.

The team spent a lot of time swirling ideas around the whiteboard, often drawing pictures. This problem reminds Dr. Rycroft of a Voronoi diagram, a geometry construction divide a space into non-overlapping subregions – polygons, or Voronoi cells, each of which arises from a particle point. It’s a versatile concept that applies to things as diverse as galaxy clusters, wireless networks, and forest canopy growth patterns. (The stalks are the granule points and the apex are the Voronoi cells, which hug each other but don’t overlap, a phenomenon known as shyness.)

In the context of cricket, the researchers calculated the Voronoi cell that surrounds each nucleus and observed that the shape of the cell helps predict which direction the nucleus will move next. Essentially, Dr. Donoughe said, “Nuoles tend to move into nearby open space.”

Geometry, he notes, provides an abstract way of thinking about cell mechanics. “For most of the history of cell biology, we were not able to directly measure or observe mechanical forces, although obviously ‘motors and hums and thrusts’,” he said. But the researchers were able to observe higher-order geometric patterns generated by these cellular dynamics. “So thinking about the spacing of the cells, the size of the cells, the shape of the cells – we know that they come from mechanical constraints on a very large scale,” said Dr. small.

To extract this kind of geometric information from cricket videos, Dr Donoughe and Dr Hoffmann tracked the nuclei step by step, measuring position, speed and direction.

Dr Hoffmann, an applied mathematician at DeepMind in London, said: “This is not a trivial process and it involves a lot of forms of computer vision and machine learning.

They also manually verified the software’s results, clicking through 100,000 locations, linking the nucleus’s lineages through space and time. Dr. Hoffmann found it tedious; Dr Donoughe thinks of it like playing a video game, “zooming at high speed through the tiny universe inside an embryo, connecting the threads of each nucleus’ journey together”.

Next, they developed a computational model that tested and compared hypotheses that could explain the motion and position of the nuclei. Overall, they ruled out the cytoplasmic lines that Dr. Di Talia had seen in fruit flies. They rejected random motion and the idea that nuclei repel each other.

Instead, they arrived at a plausible explanation by constructing another known mechanism in fruit fly and roundworm embryos: miniature molecular motors in the cytoplasm that elongate clusters of microtubules from each core, no different from the canopy of the forest.

The team proposes that a similar kind of molecular force attracts cricket nuclei into empty space. Dr Extavour said in an email: “The molecules could be microtubules, but we don’t know that for sure. “We’ll have to do more testing in the future to find out.”

This cricket adventure wouldn’t be complete without the mention of the “embryo contraction device” built by Dr Donoughe, which he built to test various theories. It copies a old school but motivated by previous work with Dr. Extavour and others on the development of egg size and shape.

This structure allows Dr. Donoughe to perform the odd task of wrapping a human hair around a cricket egg – thereby forming two regions, one containing the original nucleus, the other a partially compressed appendage. part.

The researchers then looked at nuclear choreography again. In the primordial region, the nuclei slow down as they reach dense density. But when a few nuclei snuck through the tunnel in the tight spot, they sped up again, galloping like horses in open pasture.

This is the strongest evidence yet that the motion of nuclei is governed by geometry, and is “not controlled by global chemical signals, currents or nearly all assumptions,” says Dr. Donoughe. other theories about what might reasonably coordinate the behavior of the entire embryo.”

By the end of the study, the team had accumulated more than 40 terabytes of data on 10 hard drives and had fine-tuned a computational, geometric model to add to the cricket toolkit.

“We want to make cricket embryos more flexible to work in the lab – that is, more useful in studying more aspects of biology,” says Dr.

The model can simulate any size and shape of eggs, making it “a testing ground for other insect embryos,” says Dr. This will make it possible to compare diverse species and probe deeper into evolutionary history, she notes.

But the biggest reward of the study, the researchers all agreed, was the spirit of collaboration.

Dr. Extavour said: “There is a place and time for expert knowledge. “As is often the case in scientific discovery, we need to be exposed to people who are not as invested as we are in any particular outcome.”

Dr Extavour said the questions posed by mathematicians were “without all prejudice”. “Those are the most interesting questions.”

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