Cell Census Network (BICCN): Over 3,000 Cell Types Active in the Human Brain

Mammoth scientific project presents new brain atlas based on 21 studies

The human brain continues to pose a great mystery to researchers. Deciphering the genetic diversity of the roughly 86 billion neurons that form a human brain is therefore crucial to understanding the molecular foundations of our cognitive abilities and how they malfunction in neurological diseases. The secrets of the human brain are what a major research project aims to uncover once and for all, and it can now boast elementary progress.

Launched in 2017, the Cell Census Network (BICCN), an initiative of the National Institute of Health’s Brain Research through Advancing Innovative Neurotechnologies (BRAIN), aims to identify, map and understand cell types and their functions in the brains of humans, non-human primates and rodents.

To this end, several centers in the United States and Europe are studying the cellular composition of the adult and developing human brain at the transcriptional, epigenetic, and functional levels. A resulting new brain atlas will help provide a more in-depth understanding of the mechanisms of brain development and the genesis of neurological diseases. The new scientific papers also describe cells such as microglia, which are a form of immune cells in the brain, and the enigmatic and hitherto little-studied “splatter” neurons. The latter are a special type of neuron that resemble paint splatters in appearance.

The current findings have now been published in 24 separate articles in Science, Science Advances and Science Translational Medicine.

International collaboration: Activities for the brain cell atlas pooled in the BICCN project

For example, a research team led by Kimberly Siletti at the Karolinska Institute in Stockholm, Sweden, conducted an analysis on tissue samples from 14 human brains. They used an innovative method that made it possible to identify the specific RNA sequences in individual brain cells. RNA (ribonucleic acid) plays a central role in the process of protein biosynthesis by transmitting genetic information from DNA. Because of cellular functional diversity, RNA sequences vary from cell to cell. From these differences, the scientists were able to categorize exactly 3,313 different cell types. Overall, the study is based on an impressive data collection of more than three million brain cells.

In two other research projects, teams led by Yang Li of the University of California, USA, and Wei Tian of the Salk Institute for Biological Studies, USA, analyzed the epigenetic characteristics of individual brain cells. Epigenetic mechanisms regulate the frequency and manner in which certain genes are activated in a cell. They are not only determined by genetic factors, but are also influenced by environmental factors, nutritional habits and the aging process.

Every cell in the human brain contains the same DNA sequence, but in different cell types, different genes are copied onto RNA strands to be used as protein blueprints. This ultimate variation in which proteins are found in which cells-and in what amounts-allows for the enormous diversity in types of brain cells and the complexity of the brain.

Knowing which cells rely on which DNA sequences to function is critical not only to understanding how the brain works, but also how mutations in DNA can cause brain disorders and how those disorders can be treated.

Together, the findings from these three research approaches have produced a comprehensive brain cell atlas. This catalogs the different types of brain cells and assigns them to specific regions of the brain.

“Beginning of a new era in brain research.”

“We are really at the beginning of a new era in brain research that will give us deeper insights into brain development, aging and susceptibility to disease,” explains Joseph Ecker of the Salk Institute, who has been involved in several of these studies.

BICCN is opening up new opportunities to study the human brain, including how it compares to the brains of monkeys. For example, a team led by Nikolas Jorstad of the Allen Institute for Brain Science in Seattle studied tissue samples from a brain region associated with face recognition and reading in humans. They examined tissue samples from adults as well as chimpanzees, gorillas, rhesus monkeys and white-tufted monkeys.

“Only a small number of genes were found to have human-specific patterns, suggesting that differences in the structure of the cerebral cortex in adult humans are defined by comparatively few cellular and molecular changes,” Jorstad and his team said, summing up their research findings.

Alzheimer’s, schizophrenia, depression: Basic research for innovative therapeutic approaches

However, the scientists are also aiming for concrete applications in medicine: “By mapping the diverse cell types in the brain and understanding their interactions, we are creating the basis for developing innovative therapeutic approaches. These could be targeted to specific cell types that play a role in certain diseases,” explains Bing Ren of the University of California.

Ren is lead author of the study conducted by Li and his team. The researchers were able to establish molecular biological characteristics of 107 different subtypes of brain cells and link them to a wide range of neuropsychiatric disorders. These disorders include schizophrenia, bipolar disorder, Alzheimer’s disease and major depression.

Other research conducted by the team focused on the developmental stages of the human brain, beginning with the early embryonic stage. As part of this research, the team led by Sten Linnarsson of the Karolinska Institute in Sweden also gained new insights into glioblastoma, one of the most aggressive brain tumors known. The researchers found that the cells of this tumor resemble immature stem cells trying to form a brain – but in a completely chaotic and disorganized way.

Thanks to cutting-edge technologies: Creating a milestone in neuroscience

The research results presented by BICCN impressively demonstrate how the large-scale use of state-of-the-art technologies can help decipher the complex structures of the human brain, as well as the brains of our closest relatives in the animal kingdom.

The extensive data thus obtained will enable scientists around the world to address a wide range of research questions and already marks a milestone in the world of neuroscience. To understand what makes us human and what mechanisms cause neurological disorders, it is essential to gain a deep understanding of the human brain at the cellular level. It is precisely this knowledge that the BICCN’s comprehensive collection of papers seeks to achieve, according to an introduction to the studies in Science.

All 24 articles on the 21 individual studies, published Oct. 12-13, 2023, are open access.