The Allen Institute for Brain Science has been working on just such a “periodic table” of human brain cell types and recently released the first data on 300 human neurons, complete with 3D reconstructions of 100 brain cells and detailed information about each neuron’s unique electrical signature. The data was collected from living human brain tissue that was raced to a lab after surgeries at nearby hospitals.
The 300 neurons became the first human brain cells added to the Allen Brain Atlas, an online database that went public in 2015 with interactive data about the physical and electrical properties of mouse brain cells. Even though mouse and human neurons share a lot of similar functionalities, they’re different enough that a drug treatment that may slow the spread of Alzheimer’s in a mouse will likely fail in human trials.
“The devil is really in the details,” Jonathan Ting, an assistant investigator at the Allen Institute for Brain Science, told Seeker. “And those are the details that are really going to matter when it comes to designing more effective strategies for treating human brain disorders.”
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The Allen Institute for Brain Science is part of the larger Allen Institute, a medical research nonprofit in Seattle, Wash. launched by billionaire Microsoft co-founder Paul Allen in 2003. The institute has partnered with four Seattle-area neurosurgeons to gain access to excised, living brain tissue delivered fresh from the operating room.
Most tissue samples are the size of a sugar cube, removed from the outer cortex when surgeons need to tunnel down to access deeper parts of the brain. Others are five times larger, such as the section removed during a temporal lobectomy to treat severe epilepsy. In the lab, the living tissue samples are sliced into discs the thickness of a business card and then examined under high-powered microscopes to locate individual neurons.
One by one, each neuron is suctioned into place by an ultra-fine-tipped glass tube. The cell membrane is then ruptured to probe the neuron’s electrical properties using a technique called patch clamp electrophysiology.
“Electrical activity is the currency that’s used by brain cell types to transmit information from point A to point B,” Ting said. “It’s very important to probe their electrical properties on a fine time scale with very high temporal resolutions to really understand the signatures of the individual cell types.”
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While the neuron is being probed, technicians also pump the cell full of dye. The dye allows special scanners to create a 3D rendering of the neuron in all of its gangly glory. Once the 3D models are uploaded to the database, any researcher with an internet connection can view each cell’s distinct morphology and compare them to the mouse neurons already in the system.
Ting said that one of the most surprising discoveries from the lab work was how robust human brain cells are compared to living mouse tissue. Brain slices from mouse brains can only survive in the lab six hours before they start to degrade, but the living human cells recovered from surgeries lasted up to three days on the countertop with some extra oxygenation.
Data from the 300 live neurons was only part of the new release. Researchers also pulled samples of dead brain tissue from their specimen bank to study gene expression in human neurons. They analyzed RNA data from the nuclei of 16,000 neurons to map each brain cell’s unique “transcriptome,” a complete list of all of the genes that are expressed at a single moment in time in a given brain cell.
By cataloging the similarities and differences in each brain cell’s transcriptome — which contains roughly 10,000 genes — the researchers felt confident in making an initial classification of 70 discrete cell types that exist in the human temporal cortex. The hard part is aligning those 70 gene-based cell types taken from dead tissue with the morphological and electrical data from the smaller sample of living cells.
“You can’t understand the true diversity of cell types until you’ve measured all of these different cell features: gene expression, electrical signatures, and morphology,” said Ting. “The only way to really connect the dots, to say that this gene expression signature corresponds to this morphological type or this electrical signature, is to obtain that data all at the same time from individual cells.”
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Recent advances in lab technology will soon allow Allen Institute researchers to do just that, Ting said, to scan living neurons for RNA data at the same time that they record electrical signatures and capture 3D cell models. The work will still have to be done one cell at a time, but thanks to new partnerships with more Seattle-area hospitals, Ting said that fresh tissue samples will likely be coming in every day.
Neuron by neuron, a comprehensive periodic chart of the human brain is being built for all the research world to share.
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