The mysterious dance of cricket fetuses

In June, 100 fruit fly scientists gathered on the Greek island of Crete for their biennial meeting. Among them was Cassandra Extafor, a Canadian geneticist at Harvard University. Her lab works with fruit flies to study evolution and evolution – ‘evo devo’. Most often, these scientists choose Drosophila melanogaster as their “model organism” – a winged work horse that has served as an insect collaborator for at least a few Nobel Prizes in Physiology and Medicine.

But Dr. Extavor is also known for cultivating alternate species as model organisms. It is particularly keen on cricket, especially Gryllus bimaculatus, the two-pointed field cricket, although it does not enjoy anything near Drosophila. (About 250 principal investigators came to the meeting in Crete.)

“It’s crazy,” she said during a video interview from her hotel room, as she walked away from a beetle. “If we try to have a meeting with all the heads of the labs that work on these kinds of cricket, there might be five of us, or 10 people.”

Cockroaches have already been included in studies of circadian clocks, limb regeneration, learning, and memory; They served as disease models and drug factories. Real multiplayer, crickets of the night! It is also increasingly popular as a food, covered in chocolate or not. From an evolutionary perspective, crickets provide more opportunities to learn about the last common ancestor of insects; They have more in common with other insects than fruit flies. (It is worth noting that insects make up more than 85 percent of animal species.)

Research aims to d. Extafor to Basics: How do embryos work? And what can reveal how the first animal appeared? Each animal embryo follows a similar journey: one cell becomes numerous, and then arranges itself in a layer on the surface of the egg, providing an early outline of all parts of the adult body. But how do embryonic cells–cells that have the same genome but don’t do the same with that information–know where to go and what to do?

“That’s the mystery to me,” Dr. Extavor said. “This is where I always want to go.”

Seth Donoghue, a biologist and data scientist at the University of Chicago and a graduate of Dr. Extavor’s lab, described embryology as the study of how a developing animal makes “the right parts in the right place at the right time.” In some new research that includes a fascinating video of a cricket embryo – showing some of the “correct parts” (cell nuclei) moving in three dimensions – Dr. Extavour, Dr. Donoghue and their colleagues have found that good old geometry plays a role.

Humans, frogs, and many other widely studied animals begin as a single cell that immediately divides over and over into separate cells. In cockroaches and most other insects, the cell nucleus divides only at first, forming numerous nuclei that travel through the common cytoplasm and later form their own cell membranes.

In 2019, Stefano Di Talia, a quantitative evolutionary biologist at Duke University, studied the movement of nuclei in Drosophila and showed that it is carried by pulsating flows in the cytoplasm — somewhat like leaves traveling on slow vortices. Stream move.

But there was another mechanism at work in the cricket embryo. Researchers have spent hours watching and analyzing microscopic nuclei: Glowing nuclei split and move in a bewildering pattern, not quite orderly, not completely random, in different directions and speeds, neighboring nuclei more in sync than distant ones. The performance lied to a choreography that goes beyond just physics or chemistry.

“The geometry that the nuclei postulate is a consequence of their ability to sense and respond to the density of other nuclei nearby,” said Dr. Extavor. Dr. did not participate. De Thalia is in the new study, but he found it impressive. “It’s a beautiful study of a beautiful system with great biological relevance,” he said.

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

They filmed videos with a laser-light sheet microscope: the footage captured the dance of the nuclei every 90 seconds during eight hours of embryo development, at which time 500 or so nuclei had coalesced into the cytoplasm. (Cockroaches hatch after about two weeks.)

Biological material is usually transparent and difficult to see even with the most powerful microscope. But Taro Nakamura, then a postdoctoral researcher in Dr. Extavour’s lab and now a developmental biologist at the National Institute of Basic Biology in Okazaki, Japan, designed a special strain of cockroaches with nuclei that glow a fluorescent green. As Dr. Nakamura recounted, when he recorded the development of the fetus the results were “amazing.”

Dr Donoghue said that was the “starting point” for the expedition. He paraphrased a remark sometimes attributed to science fiction author and biochemistry professor Isaac Asimov: “Often, you don’t say ‘Eureka! When you spot something, you say, ‘Huh. It’s weird.'”

At first, the biologists watched the videos on a loop, projected onto a conference room screen – the equivalent of an IMAX cricket, considering the embryos to be about a third the size of a grain of (long-grain) rice. They have tried to spot patterns, but the data sets have been overwhelming. They needed more quantum intelligence.

Dr. Donog called Christopher Rycroft, an applied mathematician at the University of Wisconsin-Madison, and showed him the dance core. ‘Fabulous!’ Dr. Rycroft said. He had never seen anything like this, but he realized the possibility of data-backed collaboration; He and Jordan Hoffman, a doctoral student in Dr. Rycroft’s lab, joined the study.

During several presentations, the Math and Biology team pondered several questions: How many cores are there? When did they start splitting? What directions were they going? Where did they end up? Why were some walking around and others crawling?

Dr. Rycroft often works at the crossroads of life and the physical sciences. (He published last year on the physics of paper curling.) “Mathematics and physics have been very successful in deriving general rules that are broadly applicable, and this approach may also help in biology,” he said. Dr.. Extavor said the same thing.

The team spent a lot of time moving ideas around a whiteboard, often drawing pictures. The problem reminded Dr. Rycroft of the Voronoi diagram, a geometric construct that divides space into non-overlapping subregions – polygons, or Voronoi cells, each of which emanates from its starting point. It’s a versatile concept that applies to things as diverse as galaxy clusters, wireless networks, and the growth pattern of forest canopies. (Trunks are seed points and crowns are Voronoi cells, incubating closely but not encroaching on each other, a phenomenon known as crown shyness.)

In the course of cricket, the researchers counted a Voronoi cell surrounding each nucleus and noted that the cell’s shape helped predict which direction the nucleus would move next. Essentially, Dr. Donoghue said, “the cores tend to move into a nearby open space.”

He noted that geometry offers an abstract way of thinking about cellular mechanics. “For most of the history of cell biology,” he said, “we have not been able to directly measure or monitor mechanical forces,” although it was clear that “motors, pressure, and pressure” play a role. But researchers can observe higher-order geometric patterns produced by cellular dynamics. “So, thinking about cell spacing, cell sizes, cell shapes – we know they come from mechanical constraints at very precise scales,” said Dr. Donog.

To extract this kind of engineering information from cricket videos, Dr Donoghue and Dr Hoffman traced cores step by step, measuring position, speed and direction.

“This is not a trivial process, and it ends up involving a lot of forms of computer vision and machine learning,” said Dr. Hoffman, an applied mathematician now at Deep Mind in London.

They also checked the results of the program manually, clicking on 100,000 loci, and correlating strains of cores across space and time. Dr. Hoffman found it boring. Dr. Donoghue considered it to be playing a video game, “zooming at high speed through the tiny universe within a single embryo, tying the threads of each nucleus’s journey together.”

Next, they developed a computational model that tests and compares hypotheses that might explain the motions and position of the nucleus. In general, they excluded the cytoplasmic fluxes that Dr. de Thalia saw in Drosophila. They disproved random motion and the idea that nuclei are physically spaced from one another.

Instead, they came up with a plausible explanation by building on another mechanism known in fruit fly and roundworm embryos: miniature molecular motors in the cytoplasm that extend clusters of microtubules from each nucleus, unlike in the forest canopy.

The team suggested that a similar type of molecular force led to the cockroach cores being drawn into unoccupied space. “The particles may be microtubules, but we don’t know that for sure,” Dr. Extavor said in an email. “We’ll have to do more experiments in the future to find out.”

This cricket trip would not be complete without mentioning a specially made ‘fetal contraction device’ which Dr Donoghue made to test different hypotheses. He replicated an old but motivated approach to previous work with Dr. Extavor and others on the evolution of egg sizes and shapes.

This strange tool allowed Dr. Donoghue to carry out the difficult task of wrapping a human hair around a cricket’s egg – thus creating two regions, one containing the original nucleus and the other a partially pinched appendix.

Then the researchers monitored the nuclear choreography again. In the original region, the cores slowed down once they reached a crowded density. But when a few cores crept through the tunnel at the constriction, they accelerated again, leaving like horses on open pastures.

Dr. Donoghue said this was the strongest evidence that nucleus motion was governed by geometry, and “not controlled by global chemical signals, fluxes or pretty much all the other hypotheses out there for what might reasonably coordinate the behavior of an entire embryo.”

By the end of the study, the team had collected more than 40 terabytes of data on 10 hard drives and refined a computational engineering model that added to the cricket’s toolkit.

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

Dr. Extavor said the model can simulate any size and shape of an egg, making it useful as a “testing ground for other insect embryos”. She noted that this would make it possible to compare diverse species and research more deeply into their evolutionary history.

But all the researchers agreed that the study’s biggest reward was the collaborative spirit.

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

Dr. Extavour said the questions asked by the mathematicians were “free of all kinds of bias”. “These are the most exciting questions.”

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