MAPPING THE BRAIN LIKE NEVER BEFORE
At Harvard, a cubic mm of brain cells has been imaged and reconstructed as a “brain map” in excruciating detail. Most exciting is that it is open access
A cubic millimeter of brain tissue may not sound like much. But considering that that tiny square contains 57,000 cells, 230 millimeters of blood vessels, and 150 million synapses, all amounting to 1,400 terabytes of data, Harvard and Google researchers have just accomplished something stupendous.
Led by Jeff Lichtman, the Jeremy R. Knowles Professor of Molecular and Cellular Biology and newly appointed dean of science, an Harvard team helped create the largest 3D brain reconstruction to date, showing in vivid detail each cell and its web of connections in a piece of temporal cortex about half the size of a rice grain.
This mind-blowingly complex diagram is expected to help drive forward scientific research, from understanding human neural circuits to potential treatments for disorders.
Published in Science, the study is the latest development in a nearly 10-year collaboration with scientists at Google Research, combining Lichtman’s electron microscopy imaging with AI algorithms to color-code and reconstruct the extremely complex wiring of mammal brains. The paper’s three first co-authors are former Harvard postdoc Alexander Shapson-Coe, Michał Januszewski of Google Research, and Harvard postdoc Daniel Berger.
Why mapping the brain is so important
“If we map things at a very high resolution, see all the connections between different neurons, and analyze that at a large scale, we may be able to identify rules of wiring,” says Daniel Berger, one of the project’s lead researchers and a specialist in connectomics, which is the science of how individual neurons link to form functional networks. “From this, we may be able to make models that mechanistically explain how thinking works or memory is stored.”
How was the map created
In the lab lead by Jeff Lichtman, a professor in molecular and cellular biology at Harvard, researchers led by Alex Shapson-Coe, created the brain map by taking subcellular pictures of the tissue using electron microscopy. The tissue was the one from 45-year-old woman who, in 2014, was undergoing surgery for epilepsy. She had a tiny chunk of her cerebral cortex removed, a cubic millimiter.
The tissue was then embedded in resin so that it could be cut into really thin slices, just 34 nanometers thick (in comparison, the thickness of a typical piece of paper is around 100,000 nanometers). This was done to make the mapping easier, to transform a 3D problem into a 2D problem. After this, the team took electron microscope images of each 2D slice, which amounted to a mammoth 1.4 petabytes of data.
The brain was stained with heavy metals, which bind to lipid membranes in cells. This was done so that cells would be visible when viewed through an electron microscope, as heavy metals reflect electrons.
“One millimiter for the researchers, one giant leap for mankind”
“One millimiter for the researchers, one giant leap for mankind”, we could definitely say.This cubic millimeter of tissue has allowed Harvard and Google researchers to produce the most detailed wiring diagram of the human brain that the world has ever seen.
Once the Harvard researchers had these images, they did what many of us do when faced with a problem: They turned to Google.
A team at the tech giant led by Viren Jain aligned the 2D images using machine-learning algorithms to produce 3D reconstructions with automatic segmentation, which is where components within an image—for example, different cell types—are automatically differentiated and categorized. Some of the segmentation required what Lichtman called “ground-truth data,” which involved researchers (who worked closely with Google’s team) manually redrawing some of the tissue by hand to further inform the algorithms.
Digital technology enabled them to see all the cells in this tissue sample and color them differently depending on their size. Traditional methods of imaging neurons, such as coloring samples with a chemical known as the Golgi stain, which has been used for over a century, leave some elements of nervous tissue hidden
On top of identifying structures and connections, researchers have identified abnormal cells. Berger said he came across an unidentifiable egg-shaped “object” (much smaller than a cell body but part of a cell) when attempting to systematically categorize each cell in the dataset. Other ambiguous cells include those seemingly mirrored in shape and “tangled” cells that wrap around themselves; until further research is done, these cells remain mysteries. However, they may not remain so for long.
Open Access
The brain map has been made open access, which means that these images have opened up boundless possibilities for progress in neuroscience, particularly as this is the first publicly available wiring diagram of the human brain at subcellular level. Scientists involved emphasized that they did not go into the project with concrete aims of discovery but rather wanted to create the “possibility to observe,” and from this, they hope (and expect) that “further insights will come” from both the Lichtman lab and external researchers.
Future developments
Thanks to this advanced mapping. advancements could be made in understanding and treating mental conditions, such as schizophrenia. Potential future discoveries could also expand beyond the mind, as the functions of the biological brain may be used to improve deep-learning AI systems and their structures.
In terms of future projects, the Harvard Lichtman lab plans to continue its collaboration with Google to “factor this rendering up another scale of a thousand” by studying a whole mouse brain. The research lab is also working on more human brain samples, to expand research into other regions of the brain. This will enhance the already invaluable resource and its ability to inform and expand future discoveries.
You can read the full study, as published in Science, here: https://www.science.org/doi/10.1126/science.adk4858
souce: Wired UK I The original article appeared in the September/October 2024 issue of WIRED UK magazine.
cover image: Rocina Weermeijer via Unsplash
author: Barbara Marcotulli
