Posted on by Lawrence Tabak, D.D.S., Ph.D.
When NIH launched The BRAIN Initiative® a decade ago, one of many ambitious goals was to develop innovative technologies for profiling single cells to create an open-access reference atlas cataloguing the human brain’s many parts. The ultimate goal wasn’t to produce a single, static reference map, but rather to capture a dynamic view of how the brain’s many cells of varied types are wired to work together in the healthy brain and how this picture may shift in those with neurological and mental health disorders.
So I’m now thrilled to report the publication of an impressive collection of work from hundreds of scientists in the BRAIN Initiative Cell Census Network (BICCN), detailed in more than 20 papers in Science, Science Advances, and Science Translational Medicine.1 Among many revelations, this unprecedented, international effort has characterized more than 3,000 human brain cell types. To put this into some perspective, consider that the human lung contains 61 cell types.2 The work has also begun to uncover normal variation in the brains of individual people, some of the features that distinguish various disease states, and distinctions among key parts of the human brain and those of our closely related primate cousins.
Of course, it’s not possible to do justice to this remarkable body of work or its many implications in the space of a single blog post. But to give you an idea of what’s been accomplished, some of these studies detail the primary effort to produce a comprehensive brain atlas, including defining the brain’s many cell types along with their underlying gene activity and the chemical modifications that turn gene activity up or down.3,4,5
Other studies in this collection take a deep dive into more specific brain areas. For instance, to capture normal variations among people, a team including Nelson Johansen, University of California, Davis, profiled cells in the neocortex—the outermost portion of the brain that’s responsible for many complex human behaviors.6 Overall, the work revealed a highly consistent cellular makeup from one person to the next. But it also highlighted considerable variation in gene activity, some of which could be explained by differences in age, sex and health. However, much of the observed variation remains unexplained, opening the door to more investigations to understand the meaning behind such brain differences and their role in making each of us who we are.
Yang Li, now at Washington University in St. Louis, and his colleagues analyzed 1.1 million cells from 42 distinct brain areas in samples from three adults.4 They explored various cell types with potentially important roles in neuropsychiatric disorders and were able to pinpoint specific cell types, genes and genetic switches that may contribute to the development of certain traits and disorders, including bipolar disorder, depression and schizophrenia.
Yet another report by Nikolas Jorstad, Allen Institute, Seattle, and colleagues delves into essential questions about what makes us human as compared to other primates like chimpanzees.7 Their comparisons of gene activity at the single-cell level in a specific area of the brain show that humans and other primates have largely the same brain cell types, but genes are activated differently in specific cell types in humans as compared to other primates. Those differentially expressed genes in humans often were found in portions of the genome that show evidence of rapid change over evolutionary time, suggesting that they play important roles in human brain function in ways that have yet to be fully explained.
All the data represented in this work has been made publicly accessible online for further study. Meanwhile, the effort to build a more finely detailed picture of even more brain cell types and, with it, a more complete understanding of human brain circuitry and how it can go awry continues in the BRAIN Initiative Cell Atlas Network (BICAN). As impressive as this latest installment is—in our quest to understand the human brain, brain disorders, and their treatment—we have much to look forward to in the years ahead.
A list of all the papers part of the brain atlas research is available here: https://www.science.org/collections/brain-cell-census.
 M Maroso. A quest into the human brain. Science DOI: 10.1126/science.adl0913 (2023).
 L Sikkema, et al. An integrated cell atlas of the lung in health and disease. Nature Medicine DOI: 10.1038/s41591-023-02327-2 (2023).
 K Siletti, et al. Transcriptomic diversity of cell types across the adult human brain. Science DOI: 10.1126/science.add7046 (2023).
 Y Li, et al. A comparative atlas of single-cell chromatin accessibility in the human brain. Science DOI: 10.1126/science.adf7044 (2023).
 W Tian, et al. Single-cell DNA methylation and 3D genome architecture in the human brain. Science DOI: 10.1126/science.adf5357 (2023).
 N Johansen, et al. Interindividual variation in human cortical cell type abundance and expression. Science DOI: 10.1126/science.adf2359 (2023).
 NL Jorstad, et al. Comparative transcriptomics reveals human-specific cortical features. Science DOI: 10.1126/science.ade9516 (2023).
Posted on by Dr. Francis Collins
As a graduate student in the 1980s, Bruce Yankner wondered what if cancer-causing genes switched on in non-dividing neurons of the brain. Rather than form a tumor, would those genes cause neurons to degenerate? To explore such what-ifs, Yankner spent his days tinkering with neural cells, using viruses to insert various mutant genes and study their effects. In a stroke of luck, one of Yankner’s insertions encoded a precursor to a protein called amyloid. Those experiments and later ones from Yankner’s own lab showed definitively that high concentrations of amyloid, as found in the brains of people with Alzheimer’s disease, are toxic to neural cells .
The discovery set Yankner on a career path to study normal changes in the aging human brain and their connection to neurodegenerative diseases. At Harvard Medical School, Boston, Yankner and his colleague George Church are now recipients of an NIH Director’s 2016 Transformative Research Award to apply what they’ve learned about the aging brain to study changes in the brains of younger people with schizophrenia and bipolar disorder, two poorly understood psychiatric disorders.
Posted on by Dr. Francis Collins
We know that heredity, along with environment, plays an important role in many mental illnesses. For example, studies have revealed that if one identical twin has bipolar disorder, the chance of the other being affected is about 60%. There are similar observations for autism, schizophrenia, and major depression. But finding the genes that predispose to these conditions has proven very tricky.
Now, an NIH-funded team at Baylor College of Medicine has demonstrated for the first time that extra copies of a gene that codes for a protein called Shank3 can cause manic episodes similar to those seen in some types of bipolar disorder . The researchers initially tested their hypothesis in mice and then, building upon those findings, went on to find extra copies of the SHANK3 gene in two human patients—one with seizures and attention deficit hyperactivity disorder and another with seizures and bipolar disorder.