Prof. Lin Lu: China Brain Project: from bench to bedside

      The complexity of the brain has attracted scientists from all over the world. Much effort has been paid to explore the mechanisms from genetics to molecules, from cells to circuits, and from Caenorhabditis elegans to humans. Brain research contributes to the development of new technologies, especially artificial intelligence (AI). According to the International Data Corporation, the global revenue of the AI market is expected to exceed $500 billion by 2023 and $900 billion by 2026, highlighting the great importance of brain research for social progress. Treatments for brain disorders also get optimized, reducing disease burden and economic loss. Take dementia, for example: according to data from the World Health Organization, in 2019 the global cost for treatment in this field was estimated at $1.3 trillion, and this amount is expected to rise to $1.7 trillion by 2030. Despite its importance for health, economy, and society, a systematic understanding of the brain is still lacking, possibly due to the fragmentation of research strategies. Therefore, many countries have carried out brain projects, following a unified research strategy supported by national governments. In contrast to studies that are conducted by individual researchers and groups, brain projects are characterized by systematic research directions, large funding, and across-the-aboard participation. The expectation is that brain projects will achieve major breakthroughs in a short period of time.

  Various brain projects have been launched worldwide (Table S1 online). In Europe, the Blue Brain Project and the Human Brain Project have been established. The former focuses on digital reconstruction and simulation of the brain of rodent animals, and the latter aims to construct a research infrastructure to advance knowledge of human brain structure and function. The United States launched the “Brain Research Through Advancing Innovative Neurotechnologies” (BRAIN) Initiative, aiming to develop novel technologies for a better understanding of the brain. Based on that, BRAIN 2.0 was announced in 2022, rolling out three new programs, including a cell atlas of the human brain, a whole microconnectivity map of the mammalian brain, and developing tools for modulating neural circuits. The Australian Brain Initiative (ABI) was initiated in 2016. Its main research directions include exploring brain function throughout life and developing novel neural interfaces and brain-inspired computing. Japan launched the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) and Brain/MINDS Beyond with the goal of developing a marmoset model for neuroscience. The Republic of Korea also started the Korea Brain Initiative, focusing on the mechanisms of decision-making and developing new technologies for integrated brain mapping.

  These large-scale brain projects share three research priorities in which they achieved important progress: brain mapping, developing novel technologies, and brain disorders. (1) Brain mapping. Building brain maps benefits understanding of the structure and function of the brain. A digital reconstruction of the rodent brain was built by the Blue Brain Project , and Brain/MINDS also presented a systematic mesoscale connectivity map of the marmoset in 2019 . The multimodal cell atlas of the human primary motor cortex released by BRAIN, and the NIH Human Connectome Project of high-quality neuroimaging data are excellent examples of scientific progress achieved by brain projects . The Julich-Brain atlas (a 3D atlas including cytoarchitectonic maps of the human brain) and BigBrain model (an ultrahigh-resolution 3D human brain model) developed by researchers from the Human Brain Project further provide publicly available tools for deciphering the human brain structure . The resulting increase in the precision of brain mapping not only promotes technological progress for neuroscience research, but also provides insight into the development of new AI. (2) Developing novel technologies. Several novel technologies have been developed by brain projects. These include optimizing and creating new techniques to investigate the brain more precisely and accurately. Another advance is the development of next-generation AI, for example in neurorobotics and brain-inspired intelligence. (3) Brain disorders. Research on brain disorders led to a better understanding of the pathogenesis of several neurological and psychiatric disorders, exploring promising biomarkers for prediction and diagnosis, and developing innovative treatments such as brain-computer interface and personalized medicine .

  The China Brain Project (CBP), also named “Brain Science and Brain-Like Intelligence Technology”, was launched in September 2021 after six years of preparation. The main objective of this project is to explore the neural mechanism of cognitive function, aimed at promoting the development of brain-inspired intelligence technologies and the diagnosis and treatment of brain disorders. This framework has been referred to as “one body two wings” . At present, the first phase of 59 projects has been launched with a budget of about RMB 3.2 billion. These projects include five research directions: analysis of the principles of cognitive function, disorders related to cognitive impairment, brain development of children and adolescents, brain-inspired computing and brain-computer intelligence, and construction of technology platforms.

  The CBP extends the three research priorities discussed above. To build a comprehensive brain map for exploring the neural mechanism of cognitive function, diverse animal models have been involved in ongoing projects, such as the mouse, tree skunk, and macaque. The aim is to construct neural cell atlases and microcircuitry maps deciphering the cellular properties and the ways they transmit information. In addition, several projects in the first phase relate to different scales of human brain mapping. These include gene and protein expression profiling of the human brain at the single-cell level, and characterizing the brain development in infants and children. These plans benefit from the important preparation work in China. For expression profiling, a high-definition fluorescent micro-optical sectioning tomography (HD-fMOST) method was developed in 2021, enabling a high-precision brain-wide 3D cell counting in real time, providing support for precise brain mapping at mesoscale. For the brain development project, the first human brainnetome atlas with 210 cortical and 36 subcortical subregions was developed. Additional datasets that provide important resources for brain research include the Chinese Color Nest Project (aiming at establishing protocols on the Chinese normative brain development trajectories across the lifespan), the Chinese Imaging Genetics study (aiming at analyzing genetic and environmental factors and their interactions that are correlated with neuroimaging and behavioral phenotypes), and the Chinese Human Connectome Project (aiming at providing multimodal neuroimaging, behavioral, and genetic data on the Chinese population). Furthermore, the CBP is establishing an analytical center providing support by developing novel methods for brain mapping at multiple scales.

  CBP is emphasizing the development of brain-inspired intelligence, such as developing cognitive computational models and brain-inspired chips [8]. AI technique will be used as a tool for translation from basic research to clinical application, for example for biomarker development.

  Since in China, as in other countries, mental disorders are a significant disease burden, CBP places great emphasis on reducing the incidence of neurological and mental disorders by building a platform for human brain health. This brain health platform is covering disorders related to cognitive impairment and mental illness across the lifespan, such as autism in childhood, depression/anxiety and addictions in adulthood, and dementia in the older population. More than 100,000 participants will be recruited, including healthy individuals and patients with neuropsychiatric disorders. The recruitment of such a large number of participants requires collaboration of clinical and community-based acquisition programs, as well as data processing systems. An integrated data management and storage system have been developed for the brain health platform to collect information from different data modalities, including electronic data capture (EDC) system (for collecting demographic information and clinical characteristics), electroencephalogram (EEG) analyzing system (for signal preprocessing and denoising, time–frequency extraction, functional network analyzing, and event-related potentials (ERP) component analyzing), and imaging data system (including three dimensional T1 weighted imaging (3D-T1), functional magnetic resonance imaging (fMRI), and diffusion tensor imaging (DTI)). In areas where the internet cannot be accessed, this system also supports data batch uploading. In addition to the online database, the brain health platform also includes a biobank collecting and storing blood, urine, feces, and cerebrospinal fluid. A team for multi-omics analysis will be responsible for quality control and preprocessing of genome-wide association studies (GWAS), whole exome sequencing/whole genome sequencing (WES/WGS), transcriptome sequencing, metabolomics analyses, etc. Data access will be provided to national and international researchers following an application procedure, and in the future, the international application will also be taken into consideration.

  Initial plans for analysis strategies for brain health platform data involve the building of a comprehensive knowledge map of brain disorders through data description methods, developing specialized biomarkers for single disease or shared biomarkers for multiple brain disorders, and establishing AI-assisted prediction or diagnosis models via machine learning. The expertise in databasing and management has been gathered in previous large-scale projects, such as the National Population Health Data Center (NPHDC), launched in 2004, which currently contains over 1 PB of data from studies on diabetes and prostate cancer .

  The “one body and two wings” of the CBP is in an ideal situation, but there are still many difficulties and challenges in the actual implementation. The individual differences increase the translation difficulty from bench to bedside. Then, a large number of datasets from different species, different levels, and different modes will be generated in the various investigations of the CBP. How to realize the interoperation among these data is also a technical challenge. Otherwise, it is hard to organize and manage such a large project. While 59 programs in the first stage have been announced by the Ministry of Science and Technology of the People’s Republic of China, how to plan and determine the priority of future programs is a still question. Furthermore, the implementation of CBP is not immune to some of the common problems of large projects, such as how to deploy such a large financial investment and manpower, and the barriers between different disciplines.

  Large-scale projects, such as the CBP, facilitate the development of new research paradigms such as population neuroscience which aims at revealing the brain-behavior associations by combined analyses of genetics, epidemiology, and environmental factors . The CBP should collect advice nationally about the research direction of projects and management, and the plans of management and investigations should also be announced to the public in a timely manner. The CBP has developed several training and capacity-building programs for young researchers. Meanwhile, providing more channels for collaboration merits more attention, such as forming interdisciplinary development teams and setting up specific fundings for interdisciplinary groups. In addition, bringing together the needs and suggestions of researchers from basic investigations to practical application through organizing the communication meetings, not just contributes to completing one certain task, but more importantly translating the research outcomes into the real world, especially the clinical use.

  In conclusion, the solid foundations in basic research, cutting-edge technologies in brain-inspired intelligence, and large database platforms of human brain health empower the progress of CBP . Although there will be many challenges in the future, we look forward to breakthroughs in China Brain Project and its contributions to global brain research.


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