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 Lawrence Tabak, D.D.S., Ph.D.
“Location, location, location.” While most of us know this phrase as a real estate adage, location—specifically that of various cell types—is becoming a key area of investigation in studying human disease. New techniques are enabling scientists to understand where certain cells are with respect to one another and how changes in their activity may affect your overall health.
In one recent example of the power of this approach, NIH-funded researchers  used a sophisticated method to map immune cells within human skin to get a more detailed picture of psoriasis, a common, chronic disease in which the immune system becomes overactive leading to skin inflammation. People with psoriasis develop patches of itchy, red, and flaky lesions on their skin, which can be mild to severe. For reasons that aren’t entirely clear, they’re also at higher risk for developing a wide range of other health conditions, including a unique form of arthritis known as psoriatic arthritis, diabetes, mental health issues, heart problems, and more.
The hope is that these newly drawn, precise maps of cellular “neighborhoods” in human skin will help chart the precise course of this disease to understand better the differences between mild and more severe forms. They may also yield important clues as to why people with psoriasis develop other health problems more often than people without psoriasis.
In the new study, a team including Jose Scher and Shruti Naik, NYU Langone, New York, analyzed immune cells within 25 skin samples from 14 volunteers, including those with active psoriasis, those with psoriasis but no active lesions, and people with healthy skin who do not have psoriasis. The researchers relied on a sophisticated approach called spatial transcriptomics  to map out what happens at the single-cell level within the samples.
In earlier approaches to single-cell analysis, researchers first would separate cells from the tissue they came from. While they could measure gene activity within those cells at the individual level, they couldn’t put things back together to see how they all fit. With spatial transcriptomics, it’s now possible to molecularly profile single cells to measure their activity in a tissue sample while also mapping their locations with respect to other cells.
The new study led to some intriguing findings. For instance, certain immune cells, specifically B cells, moved to the upper layers of the skin during active disease. That’s notable because prior studies had been unable to capture B cells in the skin adequately, and these cells are thought to play an important role in the disease.
Interestingly, the spatial cellular maps revealed inflammatory regions in both actively inflamed skin and in skin that appeared healthy. This finding highlights the fact that the inflammation that goes with psoriasis can affect the skin, and likely other parts of the body, in ways that aren’t easily observed. In future studies, the researchers want to explore how the presence of psoriasis and its underlying changes in immune cell activity may influence other organs and tissues beneath the skin.
Their fine-scale maps also showed increased gene activity in dozens of molecular pathways that are tied to metabolism and the control of lipid levels. That’s especially interesting because these factors are known to go awry in diabetes and heart conditions, which happen more often in people with psoriasis compared to those without. They also could see in their maps that this altered activity sometimes occurred in clear skin distant from any apparent lesions.
Having discovered such signals with potential consequences for other parts of the body, the researchers report that they’re working to understand how inflammatory immune cells and processes in the skin may lead to more widespread disease processes that affect other parts of the body. They plan to conduct similar studies in larger groups of people with and without active psoriasis lesions and studies following individuals with psoriasis over time. They’ll also explore questions about why people respond differently to the same anti-inflammatory treatment regimens.
To speed the process of discovery, they’ve made their maps and associated data freely available as a resource for the scientific community. About 7.5 million adults in the U.S. and millions more worldwide have psoriasis and associated psoriatic conditions . The hope is that these maps will one day help to steer them toward a healthier future.
 Spatial transcriptomics stratifies psoriatic disease severity by emergent cellular ecosystems. Castillo RL, Sidhu I, Dolgalev I, Chu T, Prystupa A, Subudhi I, Yan D, Konieczny P, Hsieh B, Haberman RH, Selvaraj S, Shiomi T, Medina R, Girija PV, Heguy A, Loomis CA, Chiriboga L, Ritchlin C, Garcia-Hernandez ML, Carucci J, Meehan SA, Neimann AL, Gudjonsson JE, Scher JU, Naik S. Sci Immunol. 2023 Jun 8;8(84):eabq7991. doi: 10.1126/sciimmunol.abq7991.
 Method of the Year: spatially resolved transcriptomics. Marx V. Nat Methods. 2021 Jan;18(1):9-14. doi: 10.1038/s41592-020-01033-y.
 Psoriasis Prevalence in Adults in the United States. Armstrong AW, Mehta MD, Schupp CW, Gondo GC, Bell SJ, Griffiths CEM. JAMA Dermatol. 2021 Aug 1;157(8):940-946. doi: 10.1001/jamadermatol.2021.2007.
Psoriasis (National Institute of Arthritis and Musculoskeletal and Skin Diseases/NIH)
Jose Scher (NYU Langone Health, New York, NY)
Shruti Naik (NYU Langone Health, New York, NY)
NIH Support: National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Advancing Translational Sciences, National Institute of Allergy and Infectious Diseases