A new study published last week on 21 August in the journal Nature may have shed some light on why studies on the mouse brain just don’t seem to translate to humans (1). For decades, scientists have believed that the cells and networks in mice and human brains to be similar. But an international team of scientists has now discovered fundamental differences between the brain cells of mice and humans. And perhaps, more importantly, huge variability in their gene activity, highlighting the importance of directly studying the human brain.
Mouse models are the dominant model organism used in research. But studies on brain diseases in mice seem to offer little to no indication of how humans will respond to the same drug or treatment. For example, many experimental drugs that cure mice of Alzheimer’s disease, schizophrenia, or glioblastoma have yet to successfully treat a single person. In fact, only one in every 100 neuropsychiatric drugs tested in clinical trials is approved.
To figure out why, an international team of researchers used something called single-nucleus RNA-sequencing to comprehensively study cell types of the human brain — more specifically, cells in the human cerebral cortex, which is the outermost layer of tissue surrounding the brain.
Importantly, they focused not just on the shapes and locations of cells, but on their gene activity. thus, making this study the most comprehensive classification of human brain cells — almost 16,000 cells comprised of 75 distinct cell types were analysed — to date.
Interestingly, they found huge species-specific differences that may help explain the poor drug development record for brain diseases. Nearly 20 per cent of the genes showed a 10-fold difference in expression between mice and humans. The biggest differences were observed for neurotransmitter receptors and proteins used to build neural circuits, suggesting major differences in the way neurons communicate in the mouse and human brain.
This was true for many key neurotransmitter receptors and molecules being targeted in drug development. These chemicals have become a target for treating many for neurodegenerative and neuropsychiatric disorders such as schizophrenia, depression, bipolar disorder, and autism.
Mouse models are based on the assumption that neurotransmitters receptors are located on the same neurons in mice and humans. But if this is not the case, neurotransmitters (chemical messengers that neurons use to communicate) like serotonin, dopamine, and other molecules that play key roles in brain function could have vastly different effects.
That’s not to say there aren’t similarities. Indeed, recognising both the similarities as well as the fundamental differences will help scientists make better use of existing mouse models. Or may even drive the development of valid in vitro models, such as human organoids or organ-on-a-chip approaches. And could allow at least some research to move away from animal models.
(1) Hodge, R.D. et al. Conserved cell types with divergent features in human versus mouse cortex. Nature (2019). DOI: 10.1038/s41586-019-1506-7