In June, 100 fruit fly scientists gathered on the Greek island of Crete for their biennial gathering. Among them was Cassandra Extavour, a Canadian geneticist at Harvard University. Her laboratory works with fruit flies to study evolution and development – ‘evo devo’. Usually, such scientists choose as their “model organism” the species Drosophila melanogaster – a winged workhorse that lives on at least some Nobel Prizes in physiology and medicine.
But dr. Extavour is also known for breeding alternative species as model organisms. She is particularly fond of the cricket, especially Gryllus bimaculatus, the two-spotted field cricket, even though it doesn’t enjoy anything close to the fruit fly’s following yet. (Some 250 principal investigators had signed up to attend the meeting in Crete.)
“It’s crazy,” she said during a video interview from her hotel room, as she smeared a beetle. “If we were to try to meet with all the heads of labs working on that species of cricket, there might be five or ten of us.”
crickets are already included in studies on circadian clocks, limb regeneration, learning, memory; they have served as disease models and pharmaceutical factories. True scholars, crickets! They are also becoming more and more popular as foodwhether or not covered with chocolate. From an evolutionary perspective, crickets offer more opportunities to learn about the last common ancestor of insects; they have more traits in common with other insects than fruit flies. (In particular, insects make up more than 85 percent of animal species).
The research of Dr. Extavour focuses on the fundamentals: How do embryos work? And what might that reveal about how the first animal came to be? Every animal embryo follows a similar journey: one cell becomes many, then they arrange themselves in a layer on the surface of the egg, forming an early blueprint for all adult body parts. But how do embryo cells — cells that have the same genome but don’t all do the same thing with that information — know where to go and what to do?
“That’s the mystery to me,” said Dr. ecstasy. “I always want to go there.”
Seth Donoughe, a biologist and data scientist at the University of Chicago and an alumnus of Dr. Extavour, described embryology as the study of how a developing animal makes “the right parts in the right place at the right time.” In a new study with amazing videos of the cricket embryo — showing certain “correct parts” (the cell nuclei) in three dimensions — Dr. Extavour, Dr. Donoughe and their colleagues that good old fashioned geometry plays a leading role.
Humans, frogs, and many other much-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 divides initially, forming many nuclei that travel through the shared cytoplasm and only later form their own cell membranes.
In 2019, Stefano Di Talia, a quantitative developmental biologist at Duke University, studied the movement of the nuclei in the fruit fly and showed that they are carried along by pulsating currents in the cytoplasm — a bit like leaves moving on the vortices of a slow-moving stream.
But there was another mechanism at work in the cricket embryo. The researchers spent hours observing and analyzing the microscopic dance of nuclei: glowing nuclei dividing and moving in an enigmatic pattern, not quite orderly, not quite randomly, in different directions and speeds, neighboring nuclei more in sync than those further away. . The performance belied a choreography that went beyond just physics or chemistry.
“The geometries that the nuclei are going to adopt are the result of their ability to sense and respond to the density of other nuclei nearby,” said Dr. ecstasy. dr. Di Talia was not involved in the new study, but found it moving. “It’s a wonderful study of a wonderful system of great biological relevance,” he said.
Journey of the Cores
The cricket researchers initially opted for a classic approach: look closely and pay attention. “We just checked it out,” said Dr. ecstasy.
They made videos using a laser light microscope: Snapshots every 90 seconds captured the dance of the nuclei during the first eight hours of the embryo’s development, during which time about 500 nuclei had accumulated in the cytoplasm. (Crickets hatch after about two weeks.)
Biological material is usually translucent and difficult to see even with the most tuned-up microscope. But Taro Nakamura, then a postdoc in Dr. Extavour and now a developmental biologist at the National Institute for Basic Biology in Okazaki, Japan, had a special kind of crickets with cores that glowed fluorescent green. Like dr. Nakamura said the results were “astonishing” when he recorded the development of the embryo.
That was “the starting point” for the exploration process, said Dr. donough. He paraphrased a comment sometimes attributed to science fiction author and biochemistry professor Isaac Asimov: “Often you don’t say ‘Eureka!’ when you discover something, you say, “Huh. That’s strange.'”
Initially, the biologists watched the videos on-loop, projected onto a screen in the conference room – the cricket equivalent of IMAX, as the embryos are about a third the size of a (long grain) grain of rice. They tried to spot patterns, but the data sets were overwhelming. They needed more quantitative insight.
dr. Donoughe contacted Christopher Rycroft, an applied mathematician now at the University of Wisconsin-Madison, and showed him the dancing cores. ‘Wow!’ said Dr. Rycroft. He had never seen anything like it, but he recognized the potential of a data-driven collaboration; he and Jordan Hoffmann, then a doctoral student in Dr. Rycroft, participated in the study.
Over countless screenings, the math bio team pondered many questions: How many cores were there? When did they start sharing? Which direction did they go? Where did they end up? Why did some run around and others crawl?
dr. Rycroft often works at the intersection of the life and natural sciences. (Last year he published on the physics of crumpled paper.) “Mathematics and physics have had great success in deriving general rules that apply widely, and this approach can help in biology as well,” he said; dr. Extavour has said the same.
The team spent a lot of time spinning ideas on a white board, often with drawings. The problem made Dr. Rycroft think of a Voronoi diagram, and geometric construction that divides a space into non-overlapping subregions – polygons, or Voronoi cells, each of which arises from a starting point. It is a multifaceted concept that applies to things as diverse as galaxy clusters, wireless networks and the growth pattern of forest canopies. (The trunks are the seed tips, and the crowns are the Voronoi cells, which are close together but do not interact, a phenomenon known as crown shyness.)
In the cricket context, the researchers calculated the Voronoi cell that surrounds each nucleus and noted that the shape of the cell helped predict which direction the nucleus would move. In fact, said Dr. Donoughe: “Warheads tended to move to the nearby open space.”
Geometry, he noted, offers an abstracted way of thinking about cellular mechanics. “For most of the history of cell biology, we couldn’t directly measure or observe the mechanical forces,” he said, although it was clear that “motors and squishes and pushes” were involved. But researchers were able to observe higher-order geometric patterns produced by these cellular dynamics. “So when we think about the distance between cells, the size of cells, the shapes of cells — we know they come from mechanical constraints on very fine scales,” said Dr. donough.
To extract this kind of geometric information from the cricket videos, Dr. Donoughe and Dr. Hoffmann the nuclei step by step, measuring location, speed and direction.
“This is not a trivial process, and ultimately involves many forms of computer vision and machine learning,” said Dr. Hoffmann, an applied mathematician now at DeepMind in London.
They also manually verified the results of the software, clicking 100,000 positions and connecting the nuclei’ lineages through space and time. dr. Hoffmann found it annoying; dr. Donoughe saw it as playing a video game, “zooming in at high speed through the tiny universe in a single embryo, stitching together the threads of each core’s journey.”
They then developed a computational model that tested and compared hypotheses that could explain the movements and positioning of the nuclei. All in all, they ruled out the cytoplasmic currents that Dr. Di Talia in the fruit fly saw. They disproved random movements and the idea that nuclei physically pushed each other apart.
Instead, they arrived at a plausible explanation by building on another well-known mechanism in fruit fly and roundworm embryos: miniature molecular motors in the cytoplasm that expand clusters of microtubules from each nucleus, not unlike a forest canopy.
The team proposed that a similar type of molecular force pulled the cricket nuclei into unoccupied space. “The molecules could very well be microtubules, but we don’t know for sure,” said Dr. Extavour in an email. “We’ll have to do more experiments in the future to find out.”
The geometry of diversity
This cricket odyssey would not be complete without the mention of Dr. Donoughe’s custom “embryo-constriction device,” which he built to test several hypotheses. It replicated a old-fashioned technique, but was motivated by previous work with Dr. Extavour and others on the evolution of egg sizes and shapes.
This device enabled Dr. Donoughe is able to do the finicky job of braiding a human hair around the cricket egg – thus forming two regions, one containing the original core, the other a partially pinched attachment.
Then the researchers looked at the nuclear choreography again. In the original region, the cores slowed down once they reached a busy density. But as a few cores crept through the tunnel at the narrowing, they accelerated again and let loose like horses in the open pasture.
This was the strongest evidence that the motion of the nuclei was determined by geometry, said Dr. Donoughe, and “not controlled by global chemical signals, or currents, or virtually any other hypotheses out there for what could plausibly 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 an arithmetic, geometric model that was added to the cricket’s toolbox.
“We want to make cricket embryos more versatile to work with in the lab,” said Dr. Extavour – that is, more useful in the study of even more aspects of biology.
The model can simulate any size and shape of eggs, making it useful as “a testing ground for other insect embryos,” said Dr. ecstasy. She noted that this will make it possible to compare different species and delve deeper into evolutionary history.
But the study’s greatest reward, all researchers agreed, was the collaborative spirit.
“There is a place and time for specialized knowledge,” said Dr. ecstasy. “Just as often with scientific discoveries, we have to expose ourselves to people who are not as invested in a particular outcome as we are.”
The mathematicians’ questions were “free of all sorts of bias,” said Dr. ecstasy. “Those are the most exciting questions.”