Columbia-led team wins $9.1 million research grant to create fundamentally new maps that will plot cellular diversity in human brains.
Researchers from Colombia University and the Icahn School of Medicine are collaborating on a project to create atlases of whole human brains, including all 180 billion cells and their counts. This type of data can help uncover how the structure and organization of the brain drive behavior, emotion and cognition, in disease and in health.
Until now, the cellular-level brain atlas has been limited to much smaller animals or smaller sections of the human brain due to the enormous amount of time and technical complexity required to map the whole of the human brain.
“Throughout the history of science, new tools have driven some of the most dramatic advances,” said Elizabeth Hillman, PhD, Herbert and Florence Irving Professor at the Zuckerman Institute at Columbia and project leader. “We are developing technologies that should make high-speed, large-scale imaging of tens or even hundreds of human brains a feasible prospect within the next five years. The unprecedented troves of data we hope to produce should pave the way to previously unattainable insights into the human brain.
To enable Dr. Hillman and his collaborators to undertake this ambitious project, the National Institutes of Health BRAIN Initiative recently awarded them a $9.1 million grant. Funding will be shared between Columbia University, Icahn School of Medicine at Mount Sinai, and Carnegie Mellon University. Since 2014, the BRAIN initiative has invested more than $2.4 billion in research funding to improve our understanding of brain function. The new project falls under the auspices of the BRAIN Initiative Cell Census Network, which was established in 2017 to encourage researchers to find ways to generate comprehensive atlases of brain cells.
“If successful, our microscope should be able to image an entire human brain in cellular detail within days,” said Dr. Hillman, who is also a professor of biomedical engineering and radiology at Columbia. “These data will be like Google Earth for the brain, allowing the analysis of patterns and distributions of different types of human brain cells on vastly different length scales. To get a sense of the challenge, keep in mind that it there are only eight billion people on earth, but more than 180 billion cells in the brain.
The team is not just interested in cell counting. Developing a map of the brain tracing the diversity of the many cell types that make up the brain is a top priority.
“We know the brain contains billions of neurons, but there are many different subtypes of neurons,” says 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 is not just made of neurons. Its mesh includes other cell types, including a range of glial cells and cells that make up the cerebrovascular system. All of these cell types are essential for normal brain function and could hold important clues to what is wrong with disease.
“To make these datasets really useful, we need to find a way to capture as much information as possible when we scan the whole brain,” said Dr Hillman, who has a reputation for inventing new techniques of powerful and fast microscopes.
“If successful, our microscope should be able to image an entire human brain in cellular detail within days.”
For this brain atlas project, she is developing another new microscope technique. This is called HOLiS (Human Brain Optimized Light Sheet) microscopy. The team chose this name to emphasize the importance of holistic imaging and analysis of each individual’s whole human brain.
The first step in the imaging process is to carefully slice the brain into 5 millimeter thick sections and process them to make them completely transparent. This near-magical feat is the specialty of the project’s co-principal investigator, Zhuhao Wu, PhD, an assistant professor at Mount Sinai’s Laboratory of Neural Systems, Structures, and Genetics. Dr. Wu has optimized a method for cleaning the human brain, which includes a step that can infuse each section of the brain with an array of fluorescent tags that identify individual cells and their various properties based on their different colors .
Next is the HOLiS microscope, which works at lightning speed to generate massive 3D technicolor images of each section. The technique works by shooting laser light into the fabric to create a sheet of light that illuminates a very thin inclined plane, while a fast camera captures an image of the same plane. By moving the brain section at constant speed, successive images from each plane can be stacked to form a long 3D block. The fabric is then scanned back and forth to cover its entire volume before moving on to the next section.
“Trying to image an entire human brain with existing conventional instruments would take years,” Hillman said. “We expect our HOLiS system to be able to image a whole brain in about a week.”
That kind of speed, Hillman added, will take whole-brain imaging from a single proof-of-concept to a technology capable of imaging hundreds of brains. “We suspect that every 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 diseases and disorders.”
Another challenge remains, however. The team expects each brain atlas run to generate around two petabytes of data, a huge amount. Collaborators at Carnegie Mellon’s Pittsburgh Supercomputing Center will help the team convert these torrents of data into more manageable, searchable and user-friendly databases that can be analyzed and compared. Carl Vondrick, PhD, and Cynthia Rush, PhD, of Columbia’s Data Science Institute, as well as Luke Hammond, director of the Zuckerman Institute’s Cellular Imaging Core.
Dr. Wu’s colleagues at the Icahn School of Medicine, including John F. Crary, MD, PhD, director of the school’s Neuropathology Brain Bank and an expert in human brain preservation and neuropathology, are joining the effort. . Alan Seifert, PhD, an assistant professor at Mount Sinai’s Institute of Biomedical Engineering and Imaging, will acquire detailed magnetic resonance images of the entire brain before it is cut. This will allow all data collected with HOLiS to be recorded in current brain atlases and analyzed to compare HOLIS data at the cellular level to the properties of the MRI signal. The Icahn team also includes Bradley Delman, MD, Professor of Radiology, and Patrick Hof, MD, Professor of Neuroscience, who will bring their particular expertise in neuroradiology and neuroanatomical reading of human brain data.
Adding to the project’s talent mix is Pavel Osten, MD, PhD, a pioneer in the field of whole-brain cell imaging and now president, founder and chief scientific officer of a new startup. Dr. Osten has been instrumental in planning the project and will provide advice and guidance on the best ways to quickly analyze HOLiS images to find all cells and map information from HOLiS scans to established anatomical atlases of the human brain.
“If we can streamline the process, we can build a foundational database that enables analysis of the human brain like never before,” Dr. Hillman said. “Having this data should accelerate our efforts to understand what so often goes right in the human brain and what goes wrong in developmental, neurological and psychiatric disorders.
The prize details are as follows:
“Cell Type Atlas of Whole Human Brains Using HOLiS: An Optimized Pipeline for Staining, Clearing, Imaging, and Analysis” (1RF1MH128969-01)
Total price: $9,121,879 over three years.