In a tour de force for neuroscience, teams of researchers have published a voluminous set of brain-cell atlases for humans and other primates.
The atlases are detailed in 21 research papers appearing in Science, Science Advances and Science Translational Medicine — and could point scientists toward new strategies for addressing mental conditions ranging from Alzheimer’s disease and schizophrenia to epilepsy and ADHD.
“We need to understand the specifics of the human brain if we hope to understand human diseases,” Ed Lein, a senior investigator at Seattle’s Allen Institute, said in comments provided via video.
“Most of disease research tries to create a replicate or a model of a human disease in a species that doesn’t get that disease,” Lein explained. “But if we want to understand why we get it, and what the consequences are, and how one should treat it, we need to have a deep understanding of the human brain itself.”
The studies in the package released today are part of the National Institutes of Health’s BRAIN Initiative Cell Census Network, or BICCN, a program that was launched in 2017. The Allen Institute for Brain Science has played a major role in sharing data produced by the program.
One study analyzed more than a million cells taken from 42 regions of the brain. Another study drew high-quality samples from more than 100 brain regions. Yet another study focused on samples from prenatal brain tissue. The collective efforts of the research teams characterized more than 3,000 human brain cell types.
The researchers didn’t just examine the brain cells themselves. They also ran them through DNA analysis to learn which genes appeared to be linked to the cells’ functions and dysfunctions.
A study led by Allen Institute scientist Nelson Johansen assessed variations in brain-cell types across 75 adult humans undergoing epilepsy and tumor surgeries. Johansen’s team saw wide variation among cells, but found that less than half of the differences could be explained by demographic indicators such as sex or ancestry.
“There is no single prototypical human; a spectrum of differences in genetic variation and environmental response exists both in healthy individuals and in disease states,” neuroscientists Alyssa Weninger and Paola Arlotta wrote in a commentary on the studies.
Some researchers focused on analyzing brain cells from four non-human primate species — chimpanzees, gorillas, rhesus macaques and marmosets — to learn more about neural similarities and differences with respect to humans.
“Only a few hundred genes showed human-specific expression patterns, and these were disproportionately near genomic regions with signs of evolutionary selection in humans,” Weninger and Arlotta noted. “These results suggest that the specific properties of the adult human cortex may derive from relatively few cellular and molecular changes.”
Jay Shendure, a genomics professor at the University of Washington and director of Seattle’s Brotman Baty Institute, was a senior author of the macaque study. “Our data, which we have made open and available to the scientific community and broader public, represent the largest and most comprehensive multimodal molecular atlas in a primate to date, and are crucial for exploring how the many cells of the brain come together to give rise to the behavioral complexity of primates including humans,” Shendure said in a news release.
The newly published findings are expected to provide a baseline for future research into how healthy brains work, and what to do when someone’s brain isn’t working the way it should.
Weninger and Arlotta said the genetic differences found between the brains of human and non-human primates “highlight the need to complement the use of animal model systems with human model systems” — for example, human brain organoids that are grown in the lab from stem cells.
“Understanding how to build organoids, and whether they replicate features and properties of the native tissue, requires comprehensive datasets of the human brain not only in the adult but also across development,” they wrote.
The hundreds of researchers listed as co-authors for the 21 papers published in Science, Science Advances and Science Translational Medicine include more than 100 researchers affiliated with institutions based in the Seattle area, including the Allen Institute, the University of Washington, the Brotman Baty Institute for Precision Medicine, Providence Health & Services, Seattle Children’s Research Institute and Sage Bionetworks.