Human mind organoids flourish in emptied mouse cortex
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he researchers successfully transplanted the human organoids into 25 out of 29 newborn engineered mice. The human-derived tissue proliferated, taking over the space and growing 4.7-fold between two and three months after transplantation. The grafts integrated into the mouse nervous system, and the mice performed similarly to wildtype controls on motor, learning and social tests.
“Replacing a substantial portion of an animal brain with human neural tissue represents an impressive technical advance,” In-Hyun Park, associate professor of genetics and neuroscience at Yale School of Medicine, wrote in an email to The Transmitter. Park was not involved in the study.
The grafts contained a diverse range of human cortical cell types, including rare von Economo neurons. VENs, which appear in large-brained, social animals, are implicated in some neuropsychiatric conditions and have been challenging to produce in cell culture, the paper says.
Replacing a substantial portion of an animal brain with human neural tissue represents an impressive technical advance.
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In-Hyun Park
The researchers then tracked the calcium dynamics in graft-derived neurons. Large, synchronous bursts occurred every few minutes, correlating with mouth and facial movements. Electrophysiologic signals also matched the bursts and were detected across the electrode, suggesting that the graft forms into a functional neural network, the researchers wrote.
To test if the mice could be used to study disease, the researchers modeled hypoxic injury, which affects humans more severely than mice. The team exposed xenocortical, cortex-less and control mice to low oxygen for five hours. The xenocortical mice were uniquely impacted, showing trouble maintaining their balance and sustaining a steady gait.
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he grafted organoids have their own set of limitations, Pașca says. The human-derived neurons still develop at their same, slower pace than the mouse cells. The tool so far applies only to the earliest stages of human development and is limited by the lifespan of the mice.
The neurons also aren’t organized in layers, and the organoids lack inhibitory neurons. Variability in how the organoids grow and integrate might make it difficult to answer some questions, says Joseph Gleeson, professor of neuroscience at the University of California, San Diego, who was not involved with the work.
“It doesn’t build a new cortex. What it does is it gives a lot of room for these organoids, or the cells in the organoids, to divide and grow and take up residence,” he says. “It’s the single biggest finding and also the single biggest limitation.”
“This was about the best you can do at this point,” he adds. “I’m really interested to see where the field goes.”
The team also published details on the experiment’s ethical oversight, describing how they consulted with bioethicists and other neuroscientists throughout the project. In addition, Stanford convened a group of legal scholars, patient advocates, ethicists and scientists to oversee and provide feedback on the experiments, as neuroscientists continue to grapple with the ethics of creating increasingly sophisticated human brain organoids.
Meanwhile, the model could help investigate both environmental injuries and genetic conditions. “Every time you have somebody with a genetic mutation, you can either induce it in control cells, or you can take that patient’s cells and transplant them,” Pașca says.
The approach is also apt to answer basic questions about how human circuits form, he adds. “What makes human circuits unique? Or primate circuits so unique?” he says. “How are they processing information very early in development?”
