TOP STORIES The mysterious dance of cricket embryos

The mysterious dance of cricket embryos

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In June, 100 fruit fly scientists gathered on the Greek island of Crete for a biennial meeting. Among them was Cassandra Extavour, a Canadian geneticist at Harvard University. Her lab works with fruit flies to study evolution and development – “evo devo”. Most often, such scientists choose as their “model organism” the species Drosophila melanogaster, a winged workhorse that served as an insect collaborator on at least several Nobel Prizes in physiology and medicine.

But Dr. Extavour is also known for cultivating alternative species as model organisms. She has a particular fondness for crickets, especially Gryllus bimaculatus, the two-spotted field cricket, although it does not yet enjoy anything near the fruit fly. (Approximately 250 principal investigators applied to attend the meeting in Crete.)

“This is crazy,” she said during a video interview from her hotel room, waving away the bug. “If we tried to have a meeting with all the heads of laboratories working on this kind of cricket, there could be five or 10 of us.”

crickets have already participated in research on the circadian clock, limb regeneration, learning, memory; they served as disease models and pharmaceutical factories. Real scholars, crickets! They are also becoming more and more popular as food, in chocolate or not. From an evolutionary perspective, crickets provide more ways to learn about the last common ancestor of insects; they share more traits with other insects than fruit flies. (Remarkably, insects make up over 85 percent of animal species.)

Dr. Extavour’s research aims to explore the basics: how do embryos work? And what does this tell us about how the first animal appeared? Each animal embryo follows a similar path: one cell becomes many, then they layer on the surface of the egg, providing an early blueprint for all parts of the adult body. But how do the cells of an embryo — cells with the same genome but not all of them doing the same thing with that information — know where to go and what to do?

“It’s a mystery to me,” said Dr. Extavour. “This is always the place I want to go.”

Seth Donough, a biologist and data scientist at the University of Chicago and a graduate of Dr. Extavour’s laboratory, described embryology as the study of how a developing animal creates “the right parts in the right place at the right time.” In one new study showing an amazing video of a cricket embryo showing certain “correct parts” (cell nuclei) moving in three dimensions, Dr. Extavour, Dr. Donow and their colleagues found that the good old geometry plays a major role.

Humans, frogs, and many other widely studied animals start out as a single cell that immediately divides again and again into individual cells. In crickets and most other insects, only the cell nucleus first divides, forming many nuclei that travel through the common cytoplasm and only later form their own cell membranes.

In 2019, Stefano Di Thalia, development quantifier at Duke University, studied the movement of fruit fly nuclei. and showed that they are carried in pulsating currents in the cytoplasm, a bit like leaves moving along the whirlwinds of a slowly moving stream.

But in the embryonic cricket, some other mechanism was at work. Researchers spent hours watching and analyzing the microscopic dance of the nuclei: the luminous clumps divided and moved in a mysterious pattern, not quite ordered, not quite random, with different directions and speeds, and neighboring nuclei were more synchronized than those farther away. The performance was a choreography that went beyond mere physics or chemistry.

“The geometry the nuclei take on is the result of their ability to sense and respond to the density of other nuclei near them,” said Dr. Extavour. Dr. Di Thalia was not involved in the new study, but found it interesting. “This is an excellent study of a beautiful system of great biological significance,” he said.

Cricket researchers initially took a classic approach: look carefully and pay attention. “We just watched it,” Dr. Extavour said.

They filmed a video using a laser-powered microscope: the pictures captured the dance of nuclei every 90 seconds during the first eight hours of embryonic development, during which time about 500 nuclei accumulated in the cytoplasm. (Crickets hatch in about two weeks.)

As a rule, biological material is transparent and difficult to see even with the most sophisticated microscope. But Taro Nakamura, then a postdoctoral fellow in Dr. Extavour’s laboratory and now a developmental biologist at the National Institute for Basic Biology in Okazaki, Japan, developed a special breed of crickets with nuclei that glowing fluorescent green. As Dr. Nakamura said, when he recorded the development of the embryo, the results were “amazing”.

According to Dr. Donough, this was the “starting point” for the research process. He paraphrased a remark sometimes attributed to the science fiction writer and biochemistry professor Isaac Asimov: “Often you don’t say ‘Eureka!’ when you discover something, you say, “Yeah. This is strange.'”

Initially, the biologists watched the video in a loop, projecting it onto a conference room screen — the cricket equivalent of an IMAX, given that embryos are about one-third the size of a grain of (long-grain) rice. They tried to spot patterns, but the datasets were overwhelming. They needed more quantitative savvy.

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

Over the course of numerous viewings, a team of biological mathematicians pondered many questions: how many nuclei were there? When did they start sharing? In what directions did they go? Where did they end up? Why did some run and others crawl?

Dr. Rycroft often works at the intersection of the biological and physical sciences. (Last year he published a paper on the physics of paper crumpling.) “Mathematics and physics have made great strides in deriving general rules that are widely applied, and this approach can also help in biology,” he said; Dr. Extavour said the same thing.

The team spent a lot of time brainstorming ideas at the blackboard, often drawing pictures. The problem reminded Dr. Rycroft of a Voronoi diagram, geometric design which divides the space into non-intersecting subregions – polygons or Voronoi cells, each of which starts from the starting point. It’s a universal concept that applies to things as diverse as galaxy clusters, wireless networks, and forest canopy growth patterns. (Tree trunks are seed points, and crowns are Voronoi cells, closely pressed together but not invading each other—a phenomenon known as crown shyness.)

In the context of a cricket, the researchers calculated the Voronoi cell surrounding each nucleus and noticed that the shape of the cell helps predict the direction in which the nucleus will move next. In fact, as Dr. Donough said, “the nuclei tended to move into the nearest outer space.”

He noted that geometry offers an abstract view of cellular mechanics. “For most of the history of cell biology, we couldn’t directly measure or observe mechanical forces,” he said, although it was clear that “motors and pushes and pushes” were involved. But the researchers were able to observe the higher order geometric patterns produced by these cellular dynamics. “So when you think about the distance between cells, the size of the cells, the shape of the cells – we know that they arise from mechanical constraints on very small scales,” said Dr. Donough.

To extract this kind of geometric information from a cricket video, Dr. Donouch and Dr. Hoffmann tracked the nuclei step by step, measuring location, speed, and direction.

“It’s not a trivial process, and it ultimately involves many forms of computer vision and machine learning,” said Dr. Hoffmann, an applied mathematician now at DeepMind in London.

They also tested the results of the software manually by clicking on 100,000 positions, linking lines of nuclei across space and time. Dr. Hoffmann found this tiresome; Dr. Donough thought of it as playing a video game, “racing at high speed through a tiny universe inside a single embryo, sewing together the strands of each nucleus’ journey.”

They then developed a computational model that tested and compared hypotheses that explained the movement and position of the nuclei. Overall, they ruled out the cytoplasmic streams that Dr. Dee Thalia observed in the fruit fly. They disproved random motion and the notion that nuclei physically repel each other.

Instead, they came up with a plausible explanation based on another known mechanism in fruit fly and roundworm embryos: miniature molecular motors in the cytoplasm that pull clumps of microtubules from each nucleus, not unlike a forest canopy.

The team hypothesized that a similar type of molecular force was pulling the cricket nuclei into unoccupied space. “The molecules could very well be microtubules, but we don’t know that for sure,” Dr. Extavour said in an email. “We’ll have to do more experiments in the future to find out.”

This cricket odyssey would be incomplete without a mention of Dr. Donough’s custom-made “embryo constriction device” that he built to test various hypotheses. He reproduced old school method, but was motivated by previous work with Dr. Extavour and others on evolution egg size and shape.

This ingenious contraption allowed Dr. Donough to accomplish the painstaking task of wrapping a human hair around a cricket egg, thereby forming two regions, one containing the original nucleus and the other containing a partially plucked appendage.

The researchers then observed the nuclear choreography again. In the original region, the nuclei slowed down when they reached crowded density. But as a few cannonballs scrambled down the narrow tunnel, they accelerated again, taking off like horses in an open pasture.

This was the strongest evidence yet that the movement of the nuclei is determined by geometry, Dr. Donough said, and “is not controlled by global chemical signals, or currents, or nearly every other hypothesis that could plausibly coordinate the behavior of the entire embryo.”

By the end of the study, the team had accumulated more than 40 terabytes of data across 10 hard drives and had refined the computational geometry model to add to the cricket toolkit.

“We want to make cricket embryos more versatile in the laboratory,” said Dr. Extavour, “that is, to make them more useful for studying even more aspects of biology.”

The model can mimic eggs of any size and shape, making it useful as a “test bed for other insect embryos,” Dr. Extavour said. She noted that this will allow comparison of different species and deeper research into the history of evolution.

But the greatest reward of the study, according to all researchers, was the spirit of collaboration.

“There is a place and a time for specialized knowledge,” Dr. Extavour said. “Just as often as in scientific discovery, we need to open ourselves up to people who are not as interested in any particular outcome as we are.”

The questions asked by the mathematicians were “free of any kind of prejudice,” said Dr. Extavour. – These are the most exciting questions.

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