A New Phase in Brain Research: Creating a Detailed Map of Human Brain Cells

A collaborative effort led by the Salk Institute, as part of the BRAIN Initiative under the National Institutes of Health (NIH), has culminated in the creation of an extensive atlas of human brain cells. This endeavor involved analyzing over 500,000 cells from three human brains. This groundbreaking study signifies a transformative moment in understanding the variety and roles of brain cells.

This research, integral to the NIH BRAIN Initiative, is instrumental in advancing strategies for the treatment, prevention, and cure of brain disorders.

Researchers from Salk, collaborating with global research teams, meticulously examined over half a million brain cells from three individuals, resulting in a detailed categorization of various human brain cell types.

Published in the Science journal’s special issue on October 13, 2023, this research marks the first application of mouse-brain cell subtype identification techniques to human brains.

Professor Joseph Ecker of Salk’s Genomic Analysis Laboratory, and a Howard Hughes Medical Institute investigator, expresses excitement over the successful adaptation of these methods to human brain samples, indicating the dawn of a new era in brain science. This advancement will enhance our understanding of brain development, aging, and disease impact.

The BRAIN Initiative and Brain Cell Diversity

This research is a part of the NIH’s Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative, launched in 2014. The initiative aims to comprehensively categorize cells in mammalian brains using various techniques. Salk is among the three institutions awarded grants as key contributors to the NIH BRAIN Initiative Cell Census Network (BICCN).

An innovative visual representation of brain cell diversity showcases individual nuclei in vivid colors typical of t-SNE plots in epigenomic analysis. This helps differentiate brain cell types, with background layers indicating environmental factors influencing cell function in each brain region. (Credit: Michael Nunn)

Every brain cell shares the same DNA sequence, but distinct cell types activate different genes, transcribing them into RNA for protein synthesis. This variation in protein presence across cells accounts for the diversity and complexity of brain cells. Understanding these genetic mechanisms is crucial for comprehending brain functionality and addressing brain disorders.

Margarita Behrens, a research professor at Salk’s Computational Neurobiology Laboratory and a co-principal investigator, anticipates addressing previously unexplored questions by scaling up these techniques.

From Mice to Humans: Technique Adaptation

In 2020, Ecker and Behrens led a Salk team in profiling 161 cell types in the mouse brain, focusing on methylation markers along DNA that regulate gene activity. This study applied similar methods to human brains, analyzing methylation patterns in over 500,000 cells from 46 brain regions of three healthy male donors. The human brain, more complex and varied than the mouse brain, posed significant technical challenges that the team successfully navigated.

Pioneering Methods and Collective Efforts

The team also utilized a second method, analyzing the three-dimensional DNA structure in cells for additional insights into active DNA sequences. Jingtian Zhou, a co-first author and postdoctoral researcher in Ecker’s lab, highlights this as a novel approach to understanding genome dynamics in brain cell types.

Parallel research efforts, such as those led by Bing Ren at UC San Diego, used cells from the same three brains for independent profiling methods. Ren’s team established connections between specific brain cell types and neuropsychiatric disorders, using AI deep learning models for risk prediction.

A diagram showcases the use of “barCodes” (or “scMCodes”) for brain cell type identification and classification. It includes an anatomical brain cross-section with colored circles representing brain regions and a barcode illustrating the scientists’ technique. (Credit: Salk Institute)

Other groups in the collaboration concentrated on RNA level measurements, categorizing cells into subtypes. These studies revealed a strong correlation in each brain region between activated genes identified by Ecker and Behrens’ DNA studies and those transcribed into RNA.

Future Prospects: Awaiting Further Discoveries

Although the Salk study serves as a preliminary investigation, it opens the possibility of identifying unique human brain cell types not present in mice. Co-first author Wei Tian, a staff scientist in Ecker’s lab, emphasizes the ongoing nature of this research.

In 2022, the NIH Brain Initiative launched the BRAIN Initiative Cell Atlas Network (BICAN) to extend the BICCN efforts. Salk’s new Center for Multiomic Human Brain Cell Atlas, funded through BICAN, aims to study cells from over a dozen human brains to explore changes across development, lifespan, and disease. Ecker envisions this comprehensive understanding of the brain across various stages as a pathway to identifying and potentially rectifying detrimental changes associated with disease.

Reference: “Single-cell DNA methylation and 3D genome architecture in the human brain” by Wei Tian, Jingtian Zhou, and a team of researchers, published on October 13, 2023, in Science.
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More about Brain Cell Atlas

• Salk Institute Brain Cell Atlas Study
• NIH BRAIN Initiative Overview
• Brain Cell Diversity and Function
• Techniques in Brain Cell Research
• Brain Disorders and Genetic Analysis
• Brain Cell Atlas and Neuroscience Research
• DNA Methylation in Brain Cells
• 3D Genome Architecture Analysis
• Human Brain Cell Types and Disorders
• Future of Brain Research and Treatment Developments