Researchers at Stanford University have created mice whose brains are about half human tissue by volume, using lab-grown human brain cells to study disorders including schizophrenia, epilepsy, cerebral palsy, intellectual disability and rare dementias.
The mice were genetically engineered to lack a cerebral cortex and hippocampus, leaving room for human brain organoids to grow. The transplanted tissue connected to the animals’ blood supply and formed some links with mouse brain cells and the spinal cord, although it remained immature and was not wired like a human brain.
How the xenocortical mice were made
The team first reprogrammed donated skin cells to create human brain organoids. Newborn mice then received several injections of the organoids into the spaces where their own cortex and hippocampus were missing. The approach followed earlier work in which human neurons were transplanted into rat brains, but the rat skulls provided too little room for substantial growth. Related coverage: IUCN red list highlights species with remarkable survival skills endangered by human impact.
The engineered mice survived because other parts of their brains took on functions normally associated with the missing regions. They appeared normal but had a shaky gait, were more cautious on their feet and showed cognitive problems. The transplants did not enhance the animals, although some of those problems improved slightly.
Key figures
- About 100,000 human brain cells were delivered in each injection into newborn mice.
- The mice lacked about 14 million mouse brain cells and developed about 4 million human ones.
- After three months, the human tissue had almost entirely filled the space left in the brain.
- The transplanted tissue was equivalent to human brain tissue about halfway through pregnancy.
What the model revealed about disease
To test whether the mice could model human disorders, researchers exposed some of them to five hours of low oxygen. The experiment showed the vulnerability of the human nerve cells to oxygen deprivation, a process that can contribute to cerebral palsy during pregnancy or birth.
The human tissue also contained von Economo neurons, rare cells previously seen in postmortem examinations. These cells are among the first to die in frontotemporal dementia, and Sergiu Pașca, the Stanford psychiatry professor who led the research, hopes to use the mice to study that disease.
Why the research remains ethically sensitive
Neural organoids can reproduce some features of real brains, but their use in animals raises questions about animal welfare and whether brain-like tissue could become conscious or feel pain. Pașca said the work had received extensive ethical oversight from the outset.
Emily Jackson of the London School of Economics said the animals would need close monitoring to assess the impact on them. Madeline Lancaster of the MRC Laboratory of Molecular Biology said the approach was most useful when studying disorders or treatments that require a whole animal, while noting that it is artificial and does not show how a human brain develops naturally. Researchers continue to pursue fully laboratory-based models that could reduce the need for animals. Read the context: Researchers create viable viruses with artificial intelligence.
What happens next
Pașca plans to use the xenocortical mice to investigate frontotemporal dementia, while experts say continued close monitoring and ethical oversight will be necessary.
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