An adult fruit fly brain has been mapped—human brains could follow
For now, it is the most sophisticated connectome ever made
Oct 2nd 2024
FRUIT FLIES are smart. For a start—the clue is in the name—they can fly. They can also flirt; fight; form complex, long-term memories of their surroundings; and even warn one another about the presence of unseen dangers, such as parasitic wasps.
They do each of these things on the basis of sophisticated processing of sound, smell, touch and vision, organised and run by a brain composed of about 140,000 neurons—more than the 300 or so found in a nematode worm, but far fewer than the 86bn of a human brain, or even the 70m in a mouse. This tractable but non-trivial level of complexity has made fruit flies an attractive target for those who would like to build a “connectome” of an animal brain—a three-dimensional map of all its neurons and the connections between them. That attraction is enhanced by fruit flies already being among the most studied and best understood animals on Earth.
For many years the race to assemble an adult fly connectome seemed likely to be won by the FlyEM project at the Howard Hughes Medical Institute’s Janelia Research Campus, in Virginia. In 2020 FlyEM’s researchers, led by Gerry Rubin, a veteran fly biologist, published a connectome of an adult fruit-fly “hemibrain”, a set of 27,000 neurons in the middle of the organ. This was followed in 2023 by a connectome of the 3,016 neurons of a first-instar fly larva—the tiny grub that emerges from an egg. But Janelia has been pipped at the post to create a connectome of a complete brain by a group called FlyWire, based at Princeton University. Ironically, Flywire has used data collected by Janelia but abandoned in 2018 for being too difficult to analyse with the artificial-intelligence (AI) software available at the time.
Mala Murthy and Sebastian Seung, FlyWire’s creators, however, had different AI software. They started the project in 2018 with the backing of the BRAIN Initiative (an attempt by America’s government to do for neuroscience what the Human Genome Project did for genetics) to analyse Janelia’s now-abandoned data. The outcome, published this week in Nature, is a model which paints a detailed picture of a female fly’s brain with 139,255 neurons, and locates some 54.5m synaptic connections between them.
Creating a connectome means taking things apart and putting them back together. The taking apart uses an electron microscope to record the brain as a series of slices. The putting back together uses AI software to trace the neurons’ multiple projections across slices, recognising and recording connections as it does so.
Janelia’s researchers had developed two ways of doing these things. The FlyEM team used a beam of gallium atoms to blast away nanometres of tissue from a brain sample and then record an image of each newly exposed surface with a scanning electron microscope (which fires a beam of electrons at a surface and detects any radiation subsequently emitted). Their own fruit-fly connectome, of a male, should be ready within a year.
Janelia’s second method involved shaving layers from a sample with a diamond knife and recording them using a transmission electron microscope (which sends its beam through the target rather than scanning its surface). This is the data used by FlyWire. With Janelia’s library of 21m images made in this way, Dr Murthy and Dr Seung, ably assisted by 622 researchers from 146 laboratories around the world (as well as 15 enthusiastic “citizen scientist” video-gamers, who helped proofread and annotate the results), bet their software-writing credibility on being able to stitch the images together into a connectome. Which they did.
Besides the numbers of neurons and synapses in the fly brain, FlyWire’s researchers have also counted the number of types of neurons (8,577) and calculated the combined length (149.2 metres) of the message-carrying axons that connect cells. More important still, they have enabled the elucidation not only of a neuron’s links with its nearest neighbours, but also the links those neurons have with those farther afield. Neural circuitry can thus be studied in its entirety. The project’s researchers have more than doubled the number of known cell types in the fly’s all-important optic lobes, and shown how the new cell types connect in circuits that deal with different elements of vision, including motion, objects and colours.
This sort of thing is scientifically interesting. But to justify the dollars spent on them, projects such as FlyEM and FlyWire should also serve two practical goals. One is to improve the technology of connectome construction, so that it can be used on larger and larger targets—eventually, perhaps, including the brains of Homo sapiens. The other is to discover to what extent non-human brains can act as models for human ones (in particular, models that can be experimented on in ways that will be approved by ethics committees).
Here, evolutionary biology gets involved. Fruit flies and humans are on opposite sides of a 670m-year-old division splitting bilaterally symmetrical animals into two groups: protostomes and deuterostomes. This separation almost certainly predates the evolution of brains, meaning the brains of insects (which are protostomes) and those of vertebrates (deuterostomes) have separate origins. Drawing conclusions about the one from the other is thus a risky business.
This should not matter for long. Several groups are currently working on mouse connectomes, bits of which have already been put together. Though Janelia has no plans to go in this direction, Dr Rubin (who is, along with several other researchers from Janelia, a co-author of part of the package of nine Nature papers) reckons a complete mouse connectome could be created in a decade if someone were willing to stump up $1bn to pay for it. By analogy with the Human Genome Project, where the technology became steadily cheaper as things scaled up, this would also bring down the cost to a point where smaller connectomes, like those of flies, could be mass-produced.
The deuterostome-protostome division, together with more recent evolutionary shifts, also offers the possibility of a new science of comparative connectomology. In some cases it is already clear that giving natural selection multiple bites at the cherry has resulted in more than one solution to the same problem. The overarching organisation of the neurons in fly brains and vertebrate brains, for example, is completely different. In other instances, though, both brains seem to work in the same way, suggesting that might be the optimal way of doing things.
These natural experiments, the circuit-diagrams of which connectomes will make available, might even help human computer scientists. Brains are, after all, pretty successful information processors, so reproducing them in silicon could be a good idea. As it is AI models which have made connectomics possible, it would be poetic if connectomics could, in turn, help develop better AI models.
https://www.economist.com/science-and-technology/2024/10/02/an-adult-fruit-fly-brain-has-been-mapped-human-brains-could-follow
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Scientists mapped the fruit fly brain’s more than 50 million connections, a step in aiding future human brain research
By Mark Johnson
October 3, 2024 at 6:00 a.m. EDT
Hundreds of scientists and citizen scientists from around the world have mapped out more than 50 million connections in the tiny fruit fly brain, a step toward one day producing an intricate map of the human brain that will aid in understanding and potentially treating numerous health conditions such as Parkinson’s, binge eating, depression and substance abuse.
The scientific milestone, the most detailed survey of an adult animal brain to date, helps to show the mechanisms involved as a fruit fly assembles, then acts on the impressions of the world that come through sight, smell and other senses.
Humble as fruit flies may seem, they have been evolving over tens of millions of years and engage in a host of complex behaviors using a tiny brain about the size of a poppy seed, explained John Ngai, who directs the National Institutes of Health’s BRAIN Initiative, responsible for the new map described this week in nine papers published in the journal Nature.
“They eat. They navigate toward . They show very sophisticated behaviors like mating behaviors, behaviors of aggression and other social behaviors,” Ngai said. “They do all these things and they can fly.” Fruit flies can also see ultraviolet light, which the human eye cannot.
The BRAIN project, which began a decade ago and represents an investment of more than $3.5 billion, works toward the practical goal of boosting knowledge of the nervous system and speeding the discovery of cures for the disorders that plague it. More than 40 percent of all humans suffer from some kind of nervous system disorder, according to a recent study.
Fruit flies are one of the most popular model organisms, along with zebra fish, roundworms and mice, used to understand some of the fundamental systems that drive life on the planet. As different as these organisms are, they share many of the same genes. Almost 75 percent of the genes involved in human diseases are also found in fruit flies. Mice share about 97.5 percent of their working DNA with humans.
Though there are vast differences between the number of nerve cells, or neurons, different species possess, the logic or “source code” at work when neurons communicate and interact with one another is similar, Ngai said.
Fruit flies see, sing, hear and court
Sebastian Seung, a professor of computational neuroscience at Princeton University, said the new map probably will be consulted by scientists trying to answer virtually any question about the workings and architecture of the fruit fly brain. Researchers will be able to probe brain differences between fruit flies that are male and female, adult and juvenile, healthy and diseased.
“People trying to understand how flies see, how they hear, how they sing ― they actually sing ― how they fly,” Seung said, citing examples of the map’s applications. “And then people are also studying complex behaviors courtship. They court each other, they navigate, and they store memories. All of that research is informed by the connectome.” Seung said the map will also help scientists delve into the questions of how genes are related to brain function and how they influence the wiring of the brain during development.
The connectome is the term given to the map of more than 50 million brain connections in the fruit fly, a task that presented a daunting technical challenge.
“I confess that in recent years, I verged on what I call neuro-nihilism, like we’re never going to understand it,” said Davi Bock, co-senior author of one of the Nature papers and associate professor at the University of Vermont’s Larner College of Medicine.
The fruit fly brain contains roughly 150 meters of wiring inside a space of about three-quarters of a millimeter by one-quarter of millimeter, “just fantastically compact,” Bock said. “And the wires coming out of these neurons are commonly 50 to 100 nanometers in diameter, and they’re tangled together, like in a bowl of spaghetti.” A human hair is about 80,000 to 100,000 nanometers wide.
It was indeed possible to untangle the spaghetti, and — somewhat to Bock’s surprise — it was also possible to begin understanding the wiring diagram. Scientists did so by painstakingly removing the fly brain and using several processes to turn the brain into a hard block. Using diamond knives, they then cut the brain into more than 7,000 ultrathin sections.
The scientists viewed the sections under a high-speed electron microscope and took 21 million images. Each pixel in an image represented a section of brain tissue about 4 by 4 by 40 nanometers.
“If you think about it, that’s, like, ridiculous resolution,” Bock said, “but you need it to trace these wires.”
Bock and his colleagues then determined the specific cell types for the neurons that form the wiring diagram. Fruit flies have thousands of different types of neurons.
Another group of scientists worked to convert the images produced by Bock’s team, using state-of-the-art segmentation algorithms, into a form that allowed them to pull out chunks of neurons. All of the chunks were proofread by volunteer scientists, and the proofread pieces were then assembled into the map.
The BRAIN Initiative is funded by 10 of the 27 institutes and centers in the National Institutes of Health, and by money approved by Congress as part of the 21st Century Cure Act, signed into law in December 2016.
https://www.washingtonpost.com/science/2024/10/03/fruit-fly-brain-mapped/?