Unlocking the mysteries of the brain - our most complex and powerful organ - remains one of science’s greatest challenges. Understanding how billions of diverse neurons form networks that enable perception, memory, and behavior is key to tackling brain diseases and advancing human knowledge.

BGI-Research stands at the forefront of this quest. As a key member of the Mesoscopic Brain Mapping Consortium, BGI recently co-led six landmark studies featured in a special article collection on the Consortium’s webpage in Cell - two of which were selected as cover stories in the latest issues of Cell and Neuron, respectively. These achievements underscore BGI’s global leadership in brain science.

Against this backdrop, we interviewed leading scientists at BGI-Research to explore their journey, innovations, and vision for the future of brain science.

Neurons, or nerve cells, are the fundamental units of the brain and nervous system. Brain mapping attempts to relate the brain's structure to its function or finding what parts give us certain abilities. (Credit: Shutterstock)

How Did BGI Become Involved in Brain Science? How Does It Achieve International Leadership Through Engineering Paradigms and Technologies?

Xu Xun (Chief Scientist of BGI Group):

We were initially introduced to the field of brain science by Professor Mu-Ming Poo. At that time, we had just developed the Spatial transcriptomics technology - Stereo-seq - which, though not yet officially published, had been pre-released on bioRxiv.

Two days before the 2021 Chinese New Year, Professor Poo visited BGI. Through our exchanges, we realized that this "nanoscale precision, centimeter-scale coverage" Stereo-seq technology was highly compatible with the requirements for constructing a brain atlas. From that Chinese New Year onward, our entire team dedicated itself wholeheartedly to this project, rapidly advancing the application of this technology in brain science.

Subsequently, we not only overcame technical challenges related to large-scale chip production but also saw Professor Poo lead the team at Institute of Neuroscience of the Chinese Academy of Sciences in establishing a large-scale data production team through an engineering approach.

One of the most unforgettable moments for me was during the completion of sequencing the last chip for the monkey brain project. The entire team worked tirelessly in relay-like shifts to complete the task. This process fully demonstrated that engineering, organizational, and systematic large-scale scientific paradigms can indeed drive major scientific breakthroughs, especially in a complex and cutting-edge field like brain science.

What Are the Key Technological Challenges in Brain Science, and How Can Technologies Like Genomics, Cell omics, and Spatiotemporal Omics Advance the Field?

Liu Longqi (Executive Dean and Researcher, BGI-Research):

Structure determines function. The brain, as the most complex organ, contains approximately 86 billion neurons. Analyzing the molecular characteristics, cell types, states, and neural connections of these neurons remains a significant challenge. The China Brain Mesoscopic Atlas Project is working to decode the mysteries of brain structure through large-scale scientific collaboration.

Rapid advancements in genomics, cell omics, and spatiotemporal omics technology, alongside engineering platforms, offer new hope. These advancements comprehensively support the analysis of genome elements and regulatory mechanisms related to brain function, cell classification and spatial distribution, as well as pathological features of diseases.

What Is the Significance and International Impact of the Recent Cell Special Issue? Which Breakthrough Excites You the Most?

Liu Shiping (Principal Scientist of Brain Science and Researcher, BGI-Research):

The recent Cell featured article collection on brain science is of great significance and has had a profound international impact. It covers multiple core and frontier areas of brain science - from fundamental reference cell atlases, disease mechanisms, developmental processes, and evolutionary trajectories to emerging key technologies. This represents a grand systematic project, made possible by the cross-disciplinary collaboration of top global teams, highlighting the power of large-scale scientific organizational models.

What excites me most is the breakthrough achieved through international collaboration based on BGI-developed technologies. We’ve seen research progress from the microscopic scale of single-cell and spatiotemporal omics to the more macroscopic "mesoscopic scale," such as projection technology. This means we can now analyze the fine structure and function of brain tissues at unprecedented multi-scale levels.

Scientifically, this marks a paradigm shift from molecular characterization of individual cells to more integrated explorations of tissue functions, developmental evolution, and other complex systems.

This dual leap in technology and scientific frontiers is not only groundbreaking for brain science but will also profoundly inspire and propel advancements in the broader field of life sciences.

Can You Introduce the Study on the Claustrum, Often Referred to as the "Black Box of Consciousness"? What Significant Discoveries Were Made, and What Is the Importance of This Research?

Lei Ying (Principal Scientist of Brain Science and Researcher, BGI-Research):

Our research is the first to integrate single-nucleus RNA sequencing, BGI's proprietary spatial transcriptomics technology (Stereo-seq), and retrograde tracing-based whole-brain connectivity mapping to perform a multimodal analysis of the monkey claustrum. We systematically "mapped" the claustrum in terms of cell types, spatial distribution, and whole-brain connectivity.

The most surprising discovery was that excitatory neurons in the claustrum are not randomly distributed but instead exhibit highly ordered spatial organization along the medial-lateral and dorsal-ventral axes, potentially corresponding to different functional modules.

Additionally, through whole-brain connectivity mapping, we divided the claustrum into four “projection-selective zones” that specifically project to prefrontal, visual, memory, and motor related areas. Joint analysis of whole-brain connectivity and single-cell spatial transcriptome, we also identified the macaque-specific GNB4 neuron subtypes, which selectively projected to the entorhinal cortex-hippocampus or motor cortex, potentially playing a key role in advanced brain functions.

This research not only provides important neural foundations for understanding complex brain functions such as primate consciousness and attention but also establishes the first detailed map of the non-human primate claustrum, filling a critical gap in the field. Given the high similarity between the macaque and human brains, this study also serves as a critical bridge for exploring human cognitive mechanisms and lays a foundation for studying related brain diseases.

What Is the Potential of Blood Biomarkers Like CCK and PMP2 for Early Diagnosis of Alzheimer's Disease? What Are BGI's Future Research Directions in This Area?

Han Lei (Principal Scientist of Brain Science and Researcher, BGI-Research):

Alzheimer’s disease (AD), commonly known as dementia, is a devastating neurodegenerative disease. Our research primarily focuses on the hippocampus, a vital brain region related to memory formation. The early stages of AD often affect the function of hippocampus, making it crucial for understanding the disease's onset and development.

Using BGI's proprietary Stereo-seq technology, we identified a series of AD-associated genes across hippocampal subregions. By comparing these findings with brain-derived exosome data from the blood of AD patients, we found that proteins like CCK and PMP2 could serve as blood biomarkers for diagnosing AD. This could enable more precise blood-based screening for the biomarkers of AD, providing significant medical support for early diagnosis.

Looking ahead, we aim to explore the use of multiomics technologies to develop more accurate diagnostic reagents for early Alzheimer’s detection. Additionally, building on the current research data, we hope to uncover more drug targets related to Alzheimer’s, providing a foundation for the development of future therapeutic drugs.

What Was the Most Exciting Moment for You During the Project? How Do You Reflect on the Growth from Participating in Large-Scale International Collaboration Projects?

Chen Duoyuan (Project Leader of Brain Science and Associate Researcher, BGI-Research):

The most thrilling moment for me wasn’t the final publication of the paper but being entrusted with independently leading the entire brain evolution research module. In traditional academic systems, young researchers rarely have the opportunity to lead such large-scale international collaboration projects. BGI, however, dared to entrust this responsibility to a team with an average age of under 30. This trust in the younger generation is itself a form of innovation and breakthrough.

Through deep collaboration with top international brain science teams, I gained insights into cutting-edge research directions in brain atlas, evolution, diseases, and aging. With BGI’s support, I was able to apply the "Spatial-Temporal Dogma" to cross-species evolutionary research, developing new analytical methods and successfully uncovering evolutionary patterns of brain cells across reptiles, birds, and mammals.

This experience transformed me from a postdoctoral researcher into an independent project leader. It also taught me that many major scientific discoveries stem from providing young researchers with the freedom to innovate and take risks. Moving forward, I will continue this philosophy, leading my team to explore the frontiers of brain science while breaking down barriers of seniority, fueling continuous breakthroughs in BGI and global brain science research.