In June, 100 fruit fly scientists gathered on the Greek island of Crete for his or her biennial meeting. Amongst them was Cassandra Extavour, a Canadian geneticist at Harvard University. Her lab works with fruit flies to check evolution and development — “evo devo.” Most frequently, such scientists select as their “model organism” the species Drosophila melanogaster — a winged workhorse that has served as an insect collaborator on at the very least just a few Nobel Prizes in physiology and medicine.
But Dr. Extavour can be known for cultivating alternative species as model organisms. She is very keen on the cricket, particularly Gryllus bimaculatus, the two-spotted field cricket, although it doesn’t yet enjoy anything near the fruit fly’s following. (Some 250 principal investigators had applied to attend the meeting in Crete.)
“It’s crazy,” she said during a video interview from her hotel room, as she swatted away a beetle. “If we tried to have a gathering with all of the heads of labs working on that cricket species, there is perhaps five of us, or 10.”
Crickets have already been enlisted in studies on circadian clocks, limb regeneration, learning, memory; they’ve served as disease models and pharmaceutical factories. Veritable polymaths, crickets! Also they are increasingly popular as food, chocolate-covered or not. From an evolutionary perspective, crickets offer more opportunities to learn in regards to the last common insect ancestor; they hold more traits in common with other insects than fruit flies do. (Notably, insects make up greater than 85 percent of animal species).
Dr. Extavour’s research goals at the basics: How do embryos work? And what might that reveal about how the primary animal got here to be? Every animal embryo follows the same journey: One cell becomes many, then they arrange themselves in a layer on the egg’s surface, providing an early blueprint for all adult body parts. But how do embryo cells — cells which have the identical genome but aren’t all doing the identical thing with that information — know where to go and what to do?
“That’s the mystery for me,” Dr. Extavour said. “That’s at all times where I need to go.”
Seth Donoughe, a biologist and data scientist on the University of Chicago and an alumnus of Dr. Extavour’s lab, described embryology because the study of how a developing animal makes “the best parts at the best place at the best time.” In some recent research featuring wondrous video of the cricket embryo — showing certain “right parts” (the cell nuclei) moving in three dimensions — Dr. Extavour, Dr. Donoughe and their colleagues found that good old-fashioned geometry plays a starring role.
Humans, frogs and lots of other widely studied animals start as a single cell that immediately divides many times into separate cells. In crickets and most other insects, initially just the cell nucleus divides, forming many nuclei that travel throughout the shared cytoplasm and only later form cellular membranes of their very own.
In 2019, Stefano Di Talia, a quantitative developmental biologist at Duke University, studied the movement of the nuclei within the fruit fly and showed that they’re carried along by pulsing flows within the cytoplasm — a bit like leaves traveling on the eddies of a slow-moving stream.
But another mechanism was at work within the cricket embryo. The researchers spent hours watching and analyzing the microscopic dance of nuclei: glowing nubs dividing and moving in a puzzling pattern, not altogether orderly, not quite random, at various directions and speeds, neighboring nuclei more in sync than those farther away. The performance belied a choreography beyond mere physics or chemistry.
“The geometries that the nuclei come to assume are the results of their ability to sense and reply to the density of other nuclei near to them,” Dr. Extavour said. Dr. Di Talia was not involved in the brand new study but found it moving. “It’s a ravishing study of a ravishing system of great biological relevance,” he said.
Journey of the nuclei
The cricket researchers at first took a classic approach: Look closely and listen. “We just watched it,” Dr. Extavour said.
They shot videos using a laser-light sheet microscope: Snapshots captured the dance of the nuclei every 90 seconds in the course of the embryo’s initial eight hours of development, during which time 500 or so nuclei had amassed within the cytoplasm. (Crickets hatch after about two weeks.)
Typically, biological material is translucent and difficult to see even with essentially the most souped-up microscope. But Taro Nakamura, then a postdoc in Dr. Extavour’s lab, now a developmental biologist on the National Institute for Basic Biology in Okazaki, Japan, had engineered a special strain of crickets with nuclei that glowed fluorescent green. As Dr. Nakamura recounted, when he recorded the embryo’s development the outcomes were “astounding.”
That was “the jumping-off point” for the exploratory process, Dr. Donoughe said. He paraphrased a remark sometimes attributed to the science fiction creator and biochemistry professor Isaac Asimov: “Often, you’re not saying ‘Eureka!’ whenever you discover something, you’re saying, ‘Huh. That’s weird.’”
Initially the biologists watched the videos on loop, projected onto a conference-room screen — the cricket-equivalent of IMAX, considering that the embryos are about one-third the scale of a grain of (long-grain) rice. They tried to detect patterns, but the information sets were overwhelming. They needed more quantitative savvy.
Dr. Donoughe contacted Christopher Rycroft, an applied mathematician now on the University of Wisconsin-Madison, and showed him the dancing nuclei. ‘Wow!’ Dr. Rycroft said. He had never seen anything prefer it, but he recognized the potential for a data-powered collaboration; he and Jordan Hoffmann, then a doctoral student in Dr. Rycroft’s lab, joined the study.
Over quite a few screenings, the math-bio team contemplated many questions: What number of nuclei were there? When did they begin to divide? What directions were they getting in? Where did they find yourself? Why were some zipping around and others crawling?
Dr. Rycroft often works on the crossroads of the life and physical sciences. (Last yr, he published on the physics of paper crumpling.) “Math and physics have had loads of success in deriving general rules that apply broadly, and this approach might also assist in biology,” he said; Dr. Extavour has said the identical.
The team spent loads of time swirling ideas around at a white board, often drawing pictures. The issue reminded Dr. Rycroft of a Voronoi diagram, a geometric construction that divides an area into nonoverlapping subregions — polygons, or Voronoi cells, that every emanate from a seed point. It’s a flexible concept that applies to things as varied as galaxy clusters, wireless networks and the expansion pattern of forest canopies. (The tree trunks are the seed points and the crowns are the Voronoi cells, snuggling closely but not encroaching on each other, a phenomenon often called crown shyness.)
Within the cricket context, the researchers computed the Voronoi cell surrounding each nucleus and observed that the cell’s shape helped predict the direction the nucleus would move next. Principally, Dr. Donoughe said, “Nuclei tended to maneuver into nearby open space.”
Geometry, he noted, offers an abstracted way of enthusiastic about cellular mechanics. “For a lot 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 at play. But researchers could observe higher-order geometric patterns produced by these cellular dynamics. “So, enthusiastic about the spacing of cells, the sizes of cells, the shapes of cells — we all know they arrive from mechanical constraints at very superb scales,” Dr. Donoughe said.
To extract this kind of geometric information from the cricket videos, Dr. Donoughe and Dr. Hoffmann tracked the nuclei step-by-step, measuring location, speed and direction.
“This just isn’t a trivial process, and it finally ends up involving loads of types of computer vision and machine-learning,” Dr. Hoffmann, an applied mathematician now at DeepMind in London, said.
Additionally they verified the software’s results manually, clicking through 100,000 positions, linking the nuclei’s lineages through space and time. Dr. Hoffmann found it tedious; Dr. Donoughe considered it as playing a video game, “zooming in high-speed through the tiny universe inside a single embryo, stitching together the threads of every nucleus’s journey.”
Next they developed a computational model that tested and compared hypotheses which may explain the nuclei’s motions and positioning. All in all, they ruled out the cytoplasmic flows that Dr. Di Talia saw within the fruit fly. They disproved random motion and the notion that nuclei physically pushed one another apart.
As an alternative, they arrived at a plausible explanation by constructing on one other known mechanism in fruit fly and roundworm embryos: miniature molecular motors within the cytoplasm that reach clusters of microtubules from each nucleus, not unlike a forest cover.
The team proposed that the same variety of molecular force drew the cricket nuclei into unoccupied space. “The molecules might well be microtubules, but we don’t know that obviously,” Dr. Extavour said in an email. “We could have to do more experiments in the long run to search out out.”
The geometry of diversity
This cricket odyssey wouldn’t be complete without mention of Dr. Donoughe’s custom-made “embryo-constriction device,” which he built to check various hypotheses. It replicated an old-school technique but was motivated by previous work with Dr. Extavour and others on the evolution of egg configurations and dimensions.
This contraption allowed Dr. Donoughe to execute the finicky task of looping a human hair across the cricket egg — thereby forming two regions, one containing the unique nucleus, the opposite a partially pinched-off annex.
Then, the researchers again watched the nuclear choreography. In the unique region, the nuclei slowed down once they reached a crowded density. But when just a few nuclei sneaked through the tunnel on the constriction, they sped up again, letting loose like horses in open pasture.
This was the strongest evidence that the nuclei’s movement was governed by geometry, Dr. Donoughe said, and “not controlled by global chemical signals, or flows or just about all the opposite hypotheses on the market for what might plausibly coordinate an entire embryo’s behavior.”
By the top of the study, the team had gathered greater than 40 terabytes of information on 10 hard drives and had refined a computational, geometric model that added to the cricket’s tool kit.
“We have the desire to make cricket embryos more versatile to work with within the laboratory,” Dr. Extavour said — that’s, more useful within the study of much more points of biology.
The model can simulate any egg size and shape, making it useful as a “testing ground for other insect embryos,” Dr. Extavour said. She noted that this may make it possible to check diverse species and probe deeper into evolutionary history.
However the study’s biggest reward, all of the researchers agreed, was the collaborative spirit.
“There’s a spot and time for specialised knowledge,” Dr. Extavour said. “Equally as often in scientific discovery, we’d like to show ourselves to individuals who aren’t as invested as we’re in any particular final result.”
The questions posed by the mathematicians were “freed from all kinds of biases,” Dr. Extavour said. “Those are essentially the most exciting questions.”
