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Ten years ago, Dr. Jeff Lichtman – professor of molecular and cellular biology at Harvard University – a small brain sample in his laboratory.
Although tiny, the 1 cubic millimeter of tissue was large enough to hold 57,000 cells, 230 millimeters of blood vessels and 150 million synapses.
“It was smaller than a grain of rice, but we started cutting it and looking at it, and it was beautiful,” he said. “But as we were collecting the data, I realized we had way, way more than we could handle.”
Eventually, Lichtman and his team obtained 1,400 terabytes of data from the sample – roughly the content of over 1 billion books. Now, after ten years of the lab team’s close collaboration with scientists at Google, that data has been turned into the most detailed map of a human brain sample ever created.
300 million images
The brain sample came from a patient with severe epilepsy. It’s standard procedure, Lichtman said, to remove a small portion of the brain to stop the seizures, and then look at the tissue to make sure it’s normal. “But it was unknown, so I knew nothing about the patient, other than their age and gender,” he said.
To analyze the sample, Lichtman and his team first cut it into thin sections using a diamond-edged knife. The sections were then embedded in hard resin and sliced again, very thinly. “About 30 nanometers, or about 1,000th the thickness of a human hair. They were almost invisible, unless we stained them with heavy metals, which made them visible in electron imaging,” he said.
The team completed thousands of slices, selected with custom tape, creating a kind of film strip: “If you take a picture of each of those parts and align those pictures, you get a three-dimensional piece of a brain at the microscopic level.”
That’s when the researchers realized they needed help with the data, as the resulting images would take up a significant amount of storage.
Lichtman knew that Google was working on a digital map of the fruit fly brain, which was released in 2019, and that he had the right computer hardware for the job. He contacted Viren Jain, a senior staff research scientist at Google who was working on the fruit fly project.
“There were 300 million unique images (in the Harvard data),” Jain said. “The reason for so much data is that you’re imaging at very high resolution, the level of the individual synapse. And just in that small sample of brain tissue there were 150 million synapses.”
To make sense of the images, scientists at Google used AI-based processing and analysis, identifying what type of cells were in each picture and how they were connected. The result is an interactive 3D model of the brain tissue, and the largest data set ever made at this resolution of the human brain structure. Google made it available online as “Neuroglancer,” and a study was published in the journal Science at the same time, with Lichtman and Jain among the co-authors.
Understanding the brain
The collaboration between the Harvard and Google teams resulted in colored images that make the individual components more visible, but are otherwise a true representation of the tissue.
“The colors are completely arbitrary,” explained Jain, “but other than that, there’s not a lot of artistic license here. The whole point of this is that we’re not making it up – these are the real neurons, the real wires in this brain, and we’re just making it convenient and accessible for biologists to look at and study on them.”
There were some surprises in the data. For example, rather than forming a single connection, pairs of neurons have more than 50. What is going on there? Why are they so strongly associated? We don’t know the function or significance of this phenomenon yet, we will have to study it further,” he said.
Eventually, looking at the brain at this level of detail could help researchers make sense of unsolved medical conditions, according to Lichtman.
“What does it mean to understand our brain? The best we can do is to describe it, and we hope that these descriptions will lead to realizations, for example, of how normal branches differ from brains that are malformed. order, in adult psychiatric diseases or developmental disorders like the autism spectrum — that kind of comparison will be very valuable,” he said. “Ultimately, it will give us some insight into what is wrong, which, in most cases, is still in the dark.”
Lichtman also believes that the dataset could be filled with other amazing data that, because of its size, has not yet been discovered: “And that’s why we’re sharing it online, so anyone can look at it and finding things,” he said. added.
Next, the team behind the project aims to create a complete map of the mouse brain, which would require between 500 and 1,000 times the amount of data in the human brain sample.
“That would mean 1 exabyte, which is 1,000 petabytes,” Lichtman said. “A lot of people are thinking hard about how we’re going to do this, and we’re in the first year of a five-year proof of principle. I think that would be a watershed moment for neuroscience, to have a complete wiring diagram of the mammalian brain; he would answer many, many questions. And of course, it would reveal a lot of other problems, things we didn’t expect.”
What about mapping the entire human brain? That would be 1,000 times more, Lichtman explained, meaning the data would be equal to 1 zettabyte. In 2016, that was the amount of total internet traffic for the year, according to Cisco. At the moment, Lichtman said, not only would it be difficult to even store that much data, but there would be no ethically acceptable way to find a clean, well-preserved human brain.
New ground was broken
Researchers in the same field who were not involved in the work expressed their enthusiasm when approached by CNN for comment.
“This study is amazing, and there is so much to learn from data like this,” said Michael Bienkowski, assistant professor of physiology and neuroscience at the University of Southern California’s Keck School of Medicine.
“Much of what we think we understand about the human brain has been extrapolated from animals, but research like this is vital to uncovering what makes us human. Visualizing neurons and other brain cells is extremely challenging due to their sheer density and complexity, and the current data set does not capture the longer-range connections,” said Bienkowski.
“What other brain regions do these inputs come from, and where do the outputs go when they leave the area? But it’s amazing to see these different cell types and their interactions and you get a great sense of the masterpiece of the architectural world,” he said.
Andreas Tolias, professor of ophthalmology at Stanford University in California, agreed. “This is an amazing technical study that recreates the structure of the human cortex at high resolution,” he said. “I was particularly delighted when rare axons were discovered that could make up to 50 synapses. This finding is interesting and raises important questions about their computational roles.”
The brain mapping project opens the door for future investigations, according to neuroscientist Olaf Sporns.
“Each human brain is a vast network of billions of neurons,” said Sporns, distinguished professor of psychological and brain sciences at Indiana University. “This network allows cells to communicate, in very specific patterns that are fundamental to memory, thought and behaviour. Mapping this network, the human nexome, is essential to find out how the brain works,” he said, noting that the study opens new ground towards this important goal, and six exciting new opportunities for exploration and discovery.
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