In the year 1899, a Spanish physician named Santiago Ramón y Cajal published a book titled “Comparative Study of the Sensory Areas of the Human Cortex.” In it, he makes some of the first detailed characterizations of cells that would go on to be deeply studied by neuroscientists—most notably pyramidal cells—noting how their architecture changes throughout the brain.
Cajal walked so modern neuroscience could run: In three studies slated to publish Oct. 13 in Science, scientists from the University of California, San Diego (UCSD), the Salk Institute, the University of Washington Allen Institute for Brain Science and Sweden’s Karolinska Institute presented the first draft of the human cell brain atlas, an extensive chart of all the cell types in the brain commissioned by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies, or BRAIN, Initiative.
Nineteen additional articles, which will also run in Science or in its sister publications Science Advances and Science Translational Medicine by researchers at Mount Sinai School of Medicine, Arizona State University and others—all part of the BRAIN Initiative Cell Census Network, or BICCN—add more details and use the data to answer questions about how brains change with development, across species and between individuals.
“[These studies] are the very first to systematically survey the entire human brain from front to end, from inside to out, including the midbrain, hindbrain, frontal cortex and so on,” Bing Ren, Ph.D., a neuroscientist at UCSD who led one of the three core studies, told Fierce Biotech Research in an interview. “All of these were surveyed in a coordinated manner, and that would really represent a first-of-its-kind brain atlas.”
Using a combination of techniques to analyze the RNA levels, DNA methylation patterns and chromatin access in millions of cells from across the brains of multiple deceased donors, researchers from Ren’s lab at UCSD, the University of Washington Allen Institute for Brain Science, Sweden’s Karolinska Institute and the Salk Institute showed that the brain has 3,000 unique cell types in total. Just how much the cellular landscape changes from one section to the next came as a surprise.
“[Cajal’s] work already gave us some idea that the neuron diversity is likely very high,” Ren said. “And yet, we saw that different brain regions are characterized by a different set of neurons—in one part of the brain, neurons would adopt a very different identity than in other brain regions, so this is a very large degree of diversity.”
How long a section of the brain had been around also influenced the types of cells found there. Evolutionarily older parts of the brain, such as the brainstem, had greater complexity. This has implications for scientists’ understanding of the kinds of diseases that arise there, Trygve Bakken, M.D., Ph.D., a researcher at the Allen Institute, told Fierce Biotech Research in an email.
“Some cell types in the brainstem are known to be vulnerable in brain diseases, such as dopaminergic neurons in Parkinson’s disease,” he said. “It will be important to study this complex region in more detail to see how other cell types contribute to normal brain function and disease.”
Among the map’s many uses is figuring out how to best study mental illnesses in animals—and where it isn’t possible. Animal models are powerful tools to help scientists gain insight into how drugs can reverse or modify gene defects, Ren explained, but they aren’t good representatives of psychiatric disease.
“The problem with applying animal models to neuropsychiatric disease has been that much of what we see in the clinic is that there is a lack of animal model or reliable animal model that could capture the characteristics of these conditions,” he said. “So having a deeper understanding of the cell types in the brain and how they are conserved and not conserved [between animal models and humans] will be essential for us to assess what aspects of a condition are suitable for examination in animal models, such as rodents or primates, and which parts are not.”
The data are already helping establish connections between cell types and disease. As part of its contribution to the atlas, Ren’s team identified 107 different cell types and showed how their molecular biology is linked to schizophrenia, bipolar disorder, Alzheimer’s disease and depression. This allowed them to create algorithms that predict how sequence variations in DNA can alter gene regulation and lead to disease, even across species.
“We trained this model on the human brain and tested whether it made fair predictions in the mouse genome, and, indeed, we managed to show that this type of model actually can make predictions from sequences between different species,” Ren said.
The brain cartography will feed into the Human Cell Atlas, a larger effort to map all the cells in the human body. Though the initial phase of the mapping project has ended, work will continue with the help of a joint effort by Ren’s lab at UCSD, the Salk Institute team and other scientists. Called the Center for Multiomic Human Brain Atlas, it will examine individual cells from 1,500 brain samples to understand their expression patterns and see how they change over the life span and with disease.