When scientists try to model human brain diseases using other organisms, whether they are truly pinpointing the cellular roots of these diseases in humans is always a question. Now, in a package of 21 research studies across Science, Science Advances and Science Translational Medicine, researchers present a resource that can help – an atlas of the human and non-human primate brain at the cell-type level, in unprecedented detail. The researchers' collective efforts characterized more than 3,000 human brain cell types, revealing features that distinguish us from other primates in some. Understanding the human brain at such resolution will not only help scientists pin down which cell types are most affected by specific mutations, leading to neurological diseases – it will also offer new understanding of who we are as a species.
The studies in this package are part of the National Institutes of Health's BRAIN Initiative Cell Census Network (BICCN), a program launched in 2017. As part of this effort, hundreds of scientists collaborated on a range of studies, leveraging the most advanced technologies of molecular biology. "These techniques have traditionally been mostly used in preclinical studies involving rodents and other experimental models," writes Science Senior Editor Mattia Maroso. "The work presented here showcases how human research might have now caught up with preclinical work."
The core work to build the atlas is represented by three studies in the package (Kimberly Siletti et al., Yang Li et al., and Wei Tian et al.). Together, these groups' insights created the first draft of the human brain cell map, including underlying gene expression and gene regulatory architecture. A study led by Nelson Johansen – which involved assessing brain cell type variation across 75 adult humans undergoing epilepsy and tumor surgeries – shows how brain cells vary across individuals. This provides a baseline for cell typing in health and disease. "There is no single prototypical human," say Alyssa Weninger and Paola Arlotta in a related Perspective. "[A] spectrum of differences in genetic variation and environmental response exists both in healthy individuals and in disease states." A study led by Nikolas Jorstad (adf6812) further explores how variation in cell types is influenced by brain region.
Understanding which features of brain cell organization are specific to humans, versus nonhuman primates, was a key goal of the project. A study led by Nikolas Jorstad (ade9516) used comparative single nucleus transcriptomics in adult humans, chimpanzees, gorillas, rhesus macaques, and common marmosets to explore this. Among other findings, the team showed that chimpanzee neurons are more like gorilla neurons than human neurons, even though chimpanzees and humans share a more recent common ancestor.
Studies exploring how the complex arrangement of cells in our brains is first established, in our earliest days, include work by Emelie Braun and colleagues. The team uncovered cell states in human brains during the first trimester. Nicola Micali and colleagues performed similar analyses in different areas of the prenatal macaque brain.
Other studies in the Science package are led by Brian Lee, Thomas Chartrand, Dmitry Velmeshev, and Chang Kim, respectively.
Among eight papers in the package from Science Advances, work led by René Wilbers explores how fast-spiking interneurons in humans maintain fast synchronization frequencies despite larger neuron-to-neuron distances than their rat counterparts. A Focus by Science Advances Deputy Editor Takaki Komiyama highlights the importance of cutting-edge single cell profiling techniques used in this and other work in the package.
A Science Translational Medicine study by Seth Ament and colleagues zeroes in on inflammation early in life – a clinically established risk factor for several neurological disorders. The impact of inflammation on human brain development is poorly understood. Focusing on the cerebellum, a brain area particularly vulnerable to postnatal perturbations, the team's analyses reveal that inflammation is associated with changes primarily in two subtypes of inhibitory neurons: Purkinje neurons and Golgi neurons.
"The data collected by the BICCN will now allow researchers to tackle fundamental scientific questions about the human brain," writes Maroso. "The era of cellular human brain research is knocking at our door!"
