September 27, 2022


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New atlas technology will create ‘panoramic map’ of all 18 billion-plus cells in the human brain

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New atlas technology will create ‘panoramic map’ of all 18 billion-plus cells in the human brain


New atlas technology will create ‘panoramic map’ of all 18 billion-plus cells in the human brain.

A team led by Columbia University has won $9.1 million in research funding to create fundamentally new maps that map cellular diversity across the human brain.

Researchers at Columbia University and the Icahn School of Medicine are collaborating on a project to create an atlas of the entire human brain, including all 180 billion cells and counts.

Such data can help reveal how the structure and organization of the brain generates behavior, emotion and cognition in disease and health.


New atlas technology will create 'panoramic map' of all 18 billion-plus cells in the human brain



Until now, brain mapping at the cellular level has been limited to smaller animals or small parts of the human brain due to the enormous time and technical complexity required to map the entire human brain.


“Throughout the history of science, new tools have been behind some of the most dramatic advances,” said Elizabeth-Herbert and Florence-Irwin Professors at Columbia University’s Zuckerman Institute and the project’s leader. Dr Hillman said. “We are developing technologies that will enable high-speed, large-scale imaging of tens or even hundreds of human brains to be a viable prospect within the next five years.

The unprecedented amount of data we hope to generate should be available to people who were previously inaccessible Brain knowledge opens the way.


To enable Dr. Hillman and her collaborators to carry out this ambitious project, the NIH BRAIN program recently awarded them a $9.1 million grant.

The funding will be shared by Columbia University, the Icahn School of Medicine at Mount Sinai and Carnegie Mellon University.

Since 2014, the BRAIN program has invested more than $2.4 billion in research funding to advance understanding of how the brain works.

The new project falls under the umbrella of the BRAIN Initiative Cell Census Network, which was established in 2017 to encourage researchers to find ways to generate comprehensive brain cell maps.


“If successful, our microscope should be able to image cellular details throughout the human brain within days,” said Dr. Hillman, who is also a professor of biomedical engineering and radiology at Columbia University. “These data will be like Google Earth for the brain, enabling the analysis of the patterns and distribution of different types of human brain cells on huge length scales. Get a feel for it, there are only 8 billion people on Earth, but there are more than 180 billion cells in the brain. “


The team was not interested in just counting cells. Developing a brain map, mapping the diversity of the many different kinds of cells that make up the brain, is a priority.


“We know that the brain contains billions of neurons, but there are many different neuron subtypes,” explains Dr. Hillman. “How many there are, how they are organized, and how they vary between different brain regions and different people is largely unknown.”


But the brain isn’t just made up of neurons. Its meshwork includes other types of cells, including a series of glial cells and cells that make up blood vessels in the brain.

All of these cell types are essential for normal brain function and may hold important clues about what’s going wrong in disease.


“For these datasets to be really useful, we have to find a way to capture as much information as possible as we scan the entire brain,” said Dr. Hillman, who is in the field of inventing new, powerful and fast microscopy techniques Has a good track record. “If successful, our microscope should be able to image the entire human brain in cellular detail within a few days.”


For this “brain-opening” project, she is developing another new microscopy technique. It is called Human Brain Optimized Light Sheet (HOLiS) microscopy. The team chose the name to emphasize the importance of holistic imaging and analysis of each individual’s entire human brain.


The first step in the imaging process is to carefully cut the brain into 5 mm thick slices and process them to make them completely transparent.

This near-magical feat is the specialty of the project’s co-principal investigator, Wu Zhuhao, Ph.D., assistant professor in the Laboratory of Nervous System, Structural and Genetics at Mount Sinai.

Dr. Wu has optimized a method for human brain cleanup that includes a step that injects each brain slice with a series of fluorescent tags, making it possible to identify individual cells and their different properties based on their different colors .


Then there’s the HOLiS microscope, which operates at lightning speed, generating huge technically colored 3D images of each section.

The technology works by projecting laser light into the tissue, creating a light sheet that illuminates a very thin inclined plane, while a fast camera captures an image of the same plane. By moving parts of the brain at a constant speed, successive images of each plane can be stacked together to form a long, three-dimensional block.

The tissue is then scanned back and forth to cover its entire volume before moving on to the next section.


“Trying to image the entire human brain with existing conventional instruments would take years, and we hope that our HOLiS system will be able to image the entire brain in about a week,” Hillman said. “This speed will enable whole-brain imaging. From a one-off proof-of-concept to a technology capable of imaging hundreds of brains. We suspect that each brain will be very different, so we need to be able to image large numbers of brains to understand brain diversity across the lifespan , and ultimately be able to explore a wide range of diseases and disorders.”


Yet another challenge remains. The team expects each brain-tracking run to generate about 2 petabytes of data, a massive capacity. Collaborators at Carnegie Mellon University’s Pittsburgh Supercomputing Center will help the team transform this massive amount of data into a more manageable, searchable and user-friendly database for analysis and comparison.

Drs Carl Von Derek and Cynthia Rush of Columbia University’s Data Science Institute and Luke Hammond, director of the Cell Imaging Core at the Zuckerman Institute, are known for their research in computer science, machine vision, information theory and statistics. expertise in this area contributes to this critical aspect of the project.


Also participating in the work were Dr. Wu’s colleagues at the Icahn School of Medicine, including Dr. John F-Clary, director of the School’s Neuropathology Brain Bank and expert in human brain preservation and neuropathology.

Alan Seifert, Ph.D., assistant professor at the Mount Sinai Institute for Biomedical Engineering and Imaging, will obtain detailed magnetic resonance images of the entire brain before cutting.

This will enable all data collected using HOLiS to be registered on the current brain atlas and analyzed to compare cellular-level HOLIS data with MRI signal properties.

The Icahn team also includes Bradley Delman, PhD, professor of radiology, and Patrick Hof, PhD, professor of neuroscience, who will contribute their particular expertise in neuroradiology and neuroanatomical reading of human brain data.


Dr. Pavel-Osten, a pioneer in whole-brain cell imaging and now president, founder and chief scientific officer of a new company, adds to the program’s talent portfolio.

Dr. Osten was instrumental in planning the project and will provide guidance and advice on the best way to rapidly analyze HOLiS images to find all the cells and map the information from the HOLiS scans to an established atlas of human brain anatomy.


Dr Hillman said: “If we can simplify this process, we can build a foundational database that will make the analysis of the human brain unprecedented, and having this data should accelerate our understanding of what goes wrong in the human brain and how it develops. , neurological and psychiatric disorders.”


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