1/26/2020 Google's 3D Map of a Fly Brain Is Beautiful

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Google's 3D Map of a Fly Brain Is BeautifulIt looks like Silly String.

By Courtney Linder Jan 23, 2020

• Google and Janelia, a research campus at the Howard Hughes Medical Institute in Loudoun County, Virginia, have created "the mostcomplete map of the y brain ever created."

• Their research was published earlier this week in the biology pre-print journal bioRxiv.

• Connectomes, the maps illustrating connections in the brain, have been criticized by some scientists in the past because so far, theyhaven't led to any major breakthroughs.

Drosophila melanogaster, otherwise known as the fruit y, has a pretty impressive dome for being so small—as in,its brain contains over 100,000 neurons, or brain cells. For the rst time, we can see about 25,000 of those

SCREENSHOT/GOOGLE/FLYEM

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neurons, across 4,000 different kinds, and their millions and millions of connections in the brain.

Google and Janelia Research Campus, part of the Howard Hughes Medical Institute in Loudoun County, Virginia,have created what they claim to be the world's largest and most detailed map of a brain. Called a wiringdiagram, or a connectome, the map looks a bit like a 3D pile of Silly String, using neon colors to representvarious portions of the brain that scientists are interested in studying. The researchers can even pull apart themap and isolate brain regions dealing with a y's sense of smell, vision, or ability to navigate, drilling down intothe brain connections they'd like to see.

"This was a big bet on something people thought was almost impossible to do," Viren Jain, a research scientist atGoogle and former laboratory head at Janelia, said in a press statement. "This will be the rst time that we canreally have a nuanced look at the organization of a nervous system with 100,000 neurons on a synaptic scale."

Fly Hemibrain OverviewFly Hemibrain Overview

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The researchers nicknamed the lucky insect in question, a female fruit y, "hemibrain." Without high-poweredmicroscopes, data analysis and advances in imaging tech, and deep learning algorithms, this project could havetaken two decades, according to Gerry Rubin, vice president of Howard Hughes Medical Institute and executivedirector of Janelia.

Now the map can be used to study y behavior by analyzing certain portions of the brain under certainconditions. The only question is whether or not critics who say connectomes aren't really useful will ever comearound. In the past, these maps have faced pushback because they take so long to put together and haven't yetyielded any major breakthroughs.

A Brief History of Connectomes

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An axial view of rat brain connectivity. The corpus callosum, a thick band of nerve fibers that separates the left and right hemispheres, isshown, along with anterior commisures and connections into the gray matter. This image was taken at 300 microns.SHERBROOKE CONNECTIVITY IMAGING LAB (SCIL) / GETTY IMAGES

To date, only one animal has ever had its full connectome published: Caenorhabditis elegans, a transparentroundworm that's only about one millimeter long. In the 1970s, a biologist named Sydney Brenner beganpreserving parts of the worm, cutting up thin slices of its body and taking photos of it under an electronmicroscope. By 1986, a near-complete version of the connectome was published, showing off almost all of theworm's 302 neurons and 7,000 connections—called synapses—between them.

The crazy thing? This was all done by hand. Two decades later, Dmitri Chklovskii, then a group leader at Janelia,nished the work by publishing a more detailed version of the worm connectome. At the time, it was the largestmap of the brain to date.

Since then, scientists have done work to map out the brain of a rat, and of course, the fruit y. Sebastian Seung,a noted scientist from the Princeton Neuroscience Institute, is an outspoken proponent of the connectome, evengiving a TED Talk on the subject back in 2010.

Still, criticism remains. To create a connectome at the scale of the human brain—which contains about 86 billionneurons and 100 trillion synapses—would be a massive effort. In a 2012 debate with Seung, Anthony Movshon,

Sebastian Seung: I am my connectomeSebastian Seung: I am my connectome

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a neuroscientist at New York University, pointed out he doesn't believe the C. elegans connectome has led to anymajor new insights about the worm's behavior:

I think it's fair to say…that our understanding of the worm has not been materially enhanced by havingthat connectome available to us. We don't have a comprehensive model of how the worm's nervous systemactually produces the behaviors. What we have is a sort of a bed on which we can build experiments—andmany people have built many elegant experiments on that bed. But that connectome by itself has notexplained anything.

This appears to be one of those situations where the technology has somehow developed more quickly than thescience, so it's hard to say whether or not these connectomes will be central to nding the next big truths aboutthe brain.

Imaging the Fly Brain

The highlighted area shows the portion of the fly’s central brain that was imaged and reconstructed, superimposed on a grayscalerepresentation of the whole Drosophila brain.GOOGLE/JANEILA

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To begin the mapping process, the researchers used a ve-day-old female fruit y. Then, they wrote in theirpaper, they used a custom jig to microdissect the y's central nervous system, which they embedded in an epoxyresin called Epon. What resulted was a fully stained y brain with synapses dyed even darker, which made iteasier for a machine to detect those connections. The brain sections were then sliced into thin pieces at athickness of just 20 microns each.

Using eight microscopes that were originally meant to capture data over a period of minutes or hours, theresearchers congured them to run continuously for months or years. They used a technique called focused-ionbeam scanning electron microscopy to capture the intricacies of the tiny brain's connections—it's only about thesize of a poppy seed.

In this method, the microscope uses a focused beam of ions to gently blast away small pieces of brain tissuebefore it then shoots gallium ions at the tissue to polish it at the atomic level. This microscope takes an image ofthe tissue, polishes off another layer and then continues like that until the entire sample has been imaged. As thereal y brain is slowly shaved apart, a digital version forms.

GOOGLE/FLYEM

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M O R E F RO M

NEW TECHNOLOGY

To store all of those images, it would take about 100 terabytes of space, or about the same amount of space yourcomputer would need to keep 100 million photos. So researchers devised computer algorithms to stitch theimages together, automating the process that was once done by hand to map the worm's brain.

The trick was teaching a computer how to break up images into smaller pieces, labeling each part. This process,called image segmentation, has been a focus of Google's for some time, but teaching an algorithm to look forneurons within microscope images takes a huge amount of training data. It's further complicated by the fact thatneurons splay their tendrils across large portions of the brain, creating connections in many regions andultimately spanning many images.

MORE BRAIN CONNECTIONS

See These Incredible Maps of the Brain

Eventually, the scientists ended up using what's called a ood-lling network, which could follow the neurons'tendrils from one end to the other as it snaked its way through the images. Based on prior experience, thealgorithm can start making predictions about the shape of the tendrils and where they may lead.

The researchers estimated that Google's help in the computing sped up the process tenfold. Human proofreaderswere still required, though, because the algorithms aren't perfect. "There’s still a lot of manual effort required,"Ruchi Parekh, who leads a team of neuron tracers and proofreaders, said in a statement.

The researchers are now working on completing the full connectome while they continue to learn how to makesense of the images they've collected. Their goal? To learn something new about how the y brain functions inthe near future. Meanwhile, those heavy-duty microscopes are still hard at work, collecting images from a maley's brain. This time, the researchers want to capture its entire nervous system—not just what's in the brain. If itall goes to plan, the images should all be scanned by the end of this year.

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