Article in brief
By reviewing data from at least a dozen studies funded by the National Institutes of Health’s federal BRAIN initiative, scientists created the first atlas of brain cells. The director of the National Institute of Mental Health says this work offers “a much richer picture of the complexity of the human brain and surprising themes that suggest we can make progress to ultimately better treat human diseases.”
New genetic and molecular approaches designed to study individual human brain cells have allowed scientists to create the first brain cell atlas comprising hundreds, if not thousands, of newly identified distinct brain cells.
The techniques that made this possible were developed over the past decade, largely through the National Institutes of Health’s federal BRAIN initiative. The NIH initiative brought together dozens of research teams from around the world to develop tools to understand gene expression at the level of an individual human cell. Many techniques were based on working with animals.
Results from a dozen studies funded by the BRAIN Initiative were published in the October 13 issue of Science.
“This is the beginning of a new era in brain science,” said Joseph Ecker, PhD, director of the Genomic Analysis Laboratory at the Salk Institute and an investigator at the Howard Hughes Medical Institute. Dr. Ecker had first studied plant genomics, then individual mouse brain cells, and looked to the human brain to see if their tools would work.
His lab is one of several grants awarded to generate data for the NIH BRAIN Initiative Cellular Census Network (BICCN). Founded in 2017, BICCN has grown into a collaboration of more than 250 scientists from nearly 50 institutions around the world. Their mission is to develop new technologies to identify and catalog brain cell types in mouse, monkey and human brains.
In three of the studies carried out in Science, researchers had access to the brain tissue of three men aged 20 to 50 who donated their brains to science. The researchers worked closely with Ed Lein, PhD, a principal investigator at the Allen Institute for Brain Science in Seattle. Now that they know the technology can identify, characterize and catalog cell types, teams of scientists are increasing the number of brains in all age groups, Dr. Ecker said.
Two years ago, he and his colleagues published 161 types of mouse brain cells. For the recent human studies, they used the same method of stringing methyl chemical markers along DNA to track methylation patterns in half a million brain cells in 46 brain regions in the three brain donors. healthy. They also used a second new way to examine which DNA structures are used to analyze the 3D structure of DNA molecules in each cell.
“Although every cell has the same DNA, you can distinguish cells by their phenotype (cell shape), epigenome, or gene expression,” Dr. Ecker said. Epigenetic regulation occurs through DNA methylation.
Jingtian Zhou, co-first author of the paper and a postdoctoral researcher in Dr. Ecker’s lab, added: “This is the first time we have examined these dynamic genome structures at a whole new level of cell type granularity. in the brain, and how these structures can regulate which genes are active in which cell types.
In another article in the special issue of ScienceBing Ren, PhD, professor of cellular and molecular medicine at the University of California, San Diego, worked on the same three human brains while studying another profiling technique.
Working with the Salk team, he and his colleagues identified a link between specific types of brain cells and neuropsychiatric disorders, including schizophrenia, bipolar disorder, Alzheimer’s disease and major depression. They also developed and tested deep learning artificial intelligence (AI) models that predicted the risk of these disorders. They created heat maps and were able to show that immune cells were enriched in Alzheimer’s disease and that there were significant enrichments of cell types in specific layers of the hippocampus in tissues from people with Alzheimer’s disease. bipolar illness and schizophrenia died.
“Examining epigenetic maps will help identify cells that scientists need to look at when trying to understand certain diseases and develop new treatments,” Dr. Ecker said.
(Scientists can now use gene enhancers identified by epigenetic mapping to regulate gene expression by introducing them into viruses and inserting them into brain regions to study how the expression of introduced genes affects cells. This will transform gene therapy studies allowing the expression of introduced genes more precisely in the brain.)
Another team of scientists from the Karolinska Institutet in Sweden studied gene expression by measuring RNA levels in 100 brain regions and was able to group cells into their subtypes. All of these studies of autopsied tissues have found information that has taken the entire cell atlas to a level never before seen in brain genomic research.
Postdoctoral student Kimberly Siletti, PhD, and colleagues used single-cell RNA sequencing to identify up to 3,000 groups of cells that may or may not correspond to cell types, but are different enough that they probably involves cell types. (Dr. Ecker’s group looked at fewer regions (46) compared to the Siletti group and found 161 cell types. Many of these overlap with Karolinska’s findings.)
The next step is to expand the studies with at least a dozen more brains from tissue taken from humans throughout their lives.
Other studies published in the special issue of Science compared the genomics of mice, marmosets and macaques to understand what DNA is conserved across species and identify similarities and differences. Others have studied cortical tissue extracted from epileptic patients undergoing surgery to remove the tissue causing their seizures. Dr. Ecker said the challenge going forward is to take all this information and build models of how circuits are built, and “that’s not going to be easy in humans.”
What the documents mean
“We’ve come a long way,” said Joshua A. Gordon, MD, PhD, director of the National Institute of Mental Health (NIMH). “We didn’t realize how much progress we could make so quickly once we understood the technology. Thanks to the BRAIN Initiative, we now have a comprehensive view of what the types are, where they are found, and how they differ across species, locations, and different times in development and lifespan.
“These papers give us a much richer picture of the complexity of the human brain and surprising themes that suggest we can make progress to ultimately better treat human diseases.” This is not just a cellular map, but (also) a road map for the future of neuroscience,” said Dr. Gordon, who noted that NIMH funded the work of the cellular atlas via BICCN.
“This is a fundamental set of data that will help many scientists understand the brain and doctors better diagnose diseases,” added Josh Huang, PhD, distinguished professor of neuroscience at the Duke School of Medicine and professor in biomedical engineering at the Duke Pratt School of Engineering. “This progress is directly fueled by recent technological advances. »
“At the gross anatomical level, the brain consists of many interacting regions (or parts), and each region contains a large number of different types of nerve cells that communicate with each other and with cells in other regions,” continued the Dr. Huang. “A major challenge for brain researchers is how to navigate this immense, complex matrix across microscopic and macroscopic levels without getting lost.”
“What we need, above all, is to establish a cellular resolution parts list – a brain cell atlas – as a first step towards creating a high-resolution brain cell map,” said Dr. Huang. “This will allow us to navigate the brain in a way analogous to the Google map, allowing us to zoom in and out seamlessly as we navigate the Earth.” Dr. Huang added: “Single-cell genomic approaches have this type of molecular resolution and scalability. The research published in this issue of Science represents a major step in the construction of an atlas of human brain cells.
He said many teams of neuroscientists funded by the US BRAIN initiative are working to create a catalog of parts of the human brain to elucidate the many types of cells and how they are related, connect and function. .
“Then we need a way to record and manipulate these cells so that we can really understand the complexity of brain diseases,” Dr. Huang said.
“This is a huge amount of work, and it’s really a big step,” said Joshua Sanes, PhD, professor of molecular and cellular biology at Harvard University. “This brings us closer to a conclusion.”
He compares the scientific journey to the human genome project, in which so many scientists sequenced fragments of the human genome until every gene was cataloged.
“It has become a resource used for many purposes,” Dr. Sanes said. “I think the same will be true for the human cell atlas.”
Dr. Sanes and his colleagues study visual processing and have created a cellular atlas of the mouse and human retina. They also used single-cell RNA sequencing to analyze the transcriptomes of approximately 85,000 cells from the fovea and peripheral retina in adult human donors. Together, they identified 85 cell types in the human retina. The ultimate goal is to better understand eye diseases and develop treatments to restore vision.
