A recently unveiled compendium of studies is giving science its deepest-ever look at the enigmatic organ. In a collection of 24 papers published across three journals, an international consortium of scientists just unveiled exceptionally detailed cell atlases for both the human and primate brains. This massive piece of work is part of a project with even more far-reaching aims, and could be the gateway to a new generation of treatments for psychiatric and neurological disorders. What is a cell atlas? Before we delve into the incredible level of detail in these new cell atlases, we need to understand what one actually is. A cell atlas is a map of all of the different types of cells within a tissue, organ, or an entire organism. The idea is similar to the inspiration behind huge genetic mapping initiatives like the Human Genome Project – in order to understand how organisms work, how things can go wrong, and how we can treat them when they do, we need a comprehensive understanding of what they’re made of. Since the very first human reference genome was unveiled in 2003, technology has come on in leaps and bounds. Just this year, we saw the release of the first ever pangenome, which seeks to incorporate the diversity of our entire species, as well as the long-awaited full sequence of the human Y chromosome. When it comes to cell atlases, these new releases are not the first. There’s an ongoing international effort to map the diversity of human cell types to create the Human Cell Atlas. In 2020, Chinese scientists detailed the cellular composition of all the major human organs, a big step forward in this work. Cell atlases for other organisms have also been created in research projects that have led to groundbreaking results, from a better understanding of how the human brain evolved, to the surprising similarity between squid and dogs. What were the aims of this project? The research that led to the suite of papers that have just been published was backed by a National Institutes of Health (NIH) project called the BRAIN Initiative®. Through this, the NIH awarded funding to a consortium called the BRAIN Initiative Cell Census Network (BICCN). The BICCN’s aims were to add to our knowledge of the many cell types within the brain and how they’re organized in 3D. To do this, they leveraged advanced techniques that have previously only really been used in animal models. You might think that we already have a pretty good idea of what’s going inside our heads, given the sophisticated brain imaging techniques that are now available, as well as cutting edge neurosurgical and neurological treatments. But the central nervous system continues to surprise us – it was only last month that a study reported on a whole new type of brain cell. “Mapping the brain’s cellular landscape is a critical step toward understanding how this vital organ works in health and disease,” said director of the National Institute of Mental Health, Dr Joshua A. Gordon, in a statement. “These new detailed cell atlases of the human brain and the nonhuman primate brain offer a foundation for designing new therapies that can target the specific brain cells and circuits involved in brain disorders.” What kinds of things are covered in the 24 papers? The scale of this work means that all of the different research findings from the many international teams involved have been divided into numerous scientific papers, published across three journals. In an introduction to the collection in the journal Science, Senior Editor Mattia Maroso explains how the research is divided into five broad themes: Single-cell atlases of the human brain – a deep look at the inner workings of all the cell types in the human brain, including all the RNA molecules they express and any epigenetic modifications. Single-cell atlases of the nonhuman primate brain – as above, but in marmosets and macaques. Comparative single-cell analyses – looking at similarities and differences between the human and primate brains. Single-cell analyses of brain development in both humans and primates. Characterizing the anatomy and function of each cell type in living human brain tissues, and contrasting this with rodent models. With such a plethora of new findings to explore, it’s difficult to know where to begin. This sentiment was echoed by Ed Lein, a senior investigator at the Allen Institute for Brain Science, whose organization was involved in the work behind eight of the papers. When asked to pick out a highlight in an interview with Technology Networks, Lein responded, “It’s really difficult to pick your favorite children!” Two of the major results came from teams at the Karolinska Institutet in Sweden, in conjunction with international collaborators. “We’ve created the most detailed cell atlases of the adult human brain and of brain development during the first months of pregnancy,” said Sten Linnarsson, professor of molecular system biology, in a statement. “You could say that we’ve taken a kind of brain-cell census.” Another of the studies, published in Science Advances and led by a team at Massachusetts General Hospital, produced a high-resolution map of Broca’s area, a region of the cerebral cortex that’s closely associated with speech. In a statement, the researchers explained how the techniques they developed could now be used to study any part of the brain in unprecedented detail. Meanwhile, researchers at the Salk Institute published their work, which used a technique that had never before been used in humans to create “barcodes” for cells based on their unique patterns of DNA methylation. “It’s a big jump from mice to humans and also introduces some technical challenges that we had to overcome,” said co-principal investigator Margarita Behrens in a statement. “But we were able to adapt things that we had figured out in mice and still get very high quality results with human brains. All this is but a tiny snapshot of the abundance of new information that has been generated in this project. In line with the original aims of the BICCN, much of the data contained within these papers will be made freely available to scientists across the world working on a whole range of questions. So, what types of advances might we see from this work in the future? What can the cell atlases be used for? As well as the results it has produced, the very process of performing all of this research has generated vital new knowledge for the scientific community. As we mentioned before, lots of the techniques developed during these studies had never been used in humans before, so this package of papers can also be thought of as a shiny new neuroscience toolbox. Gaining a better understanding of the brain’s cellular makeup will hopefully lead to new and better ways of treating diseases and disorders. The emergence of a cell atlas of the human brain has the potential to significantly change the way neuroscientists work. Dr Sandra Jurado (CSIC-UMH, Spain) Speaking about the high-resolution models created by the team at Massachusetts General Hospital, co-senior author Bruce Fischl said, “These advances will help us understand the mesoscopic structure of the human brain that we know little about. Structures that are too large and geometrically complicated to be analyzed by looking at 2D slices on the stage of a standard microscope, but too small to see routinely in living human brains.” “Currently we don’t have rigorous normative standards for brain structure at this spatial scale, making it difficult to quantify the effects of disorders that may impact it such as epilepsy, autism, and Alzheimer’s disease.” Similarly, Professor Joseph Ecker of the Salk Institute team noted: “We want to have a full understanding of the brain across the lifespan so that we can pinpoint exactly when, how, and in which cell types things go wrong with disease – and potentially prevent or reverse those harmful changes.” And the potential implications of this work are already being felt more widely, by researchers who were not directly involved in the studies. Neuroscientist Sandra Jurado told Technology Networks, “The emergence of a cell atlas of the human brain has the potential to significantly change the way neuroscientists work by providing them with a wealth of valuable information about the cellular and molecular composition of the brain.” This collection of papers, outstanding though the achievement may be, is really just the beginning. With this groundwork in place, work can truly get going on the generation of a complete reference atlas for the human brain across its lifespan. We’ve seen before with the Human Genome Project that since that first milestone was reached, greater advances have kept on coming. There’s no reason to think that things won’t be the same with the human brain cell atlas. And given the huge burden that disorders of the brain represent to global health systems, this impressive feat of scientific collaboration could not be more timely, nor more urgently needed. Source
