Scientists have made mice with a remarkable amount of room for human brain tissue to grow.
By genetically engineering animals lacking part of their brain, researchers created a living model in which pea-sized clumps of human neurons could expand, mature and wire into a developing nervous system, ultimately coming to dominate the mouse cortex, the brain’s outer layer.
The model offers a new way to study human neural circuits and brain disease, researchers report September 16 in Nature.
“Our goal has been to make aspects of human brain development and function accessible for investigation, so we can develop therapeutics,” says Sergiu Pașca, a neuroscientist at Stanford University.
The idea of growing miniature brain structures in a lab dish emerged in the early 2010s, when researchers in Austria showed that stem cells could self-organize into 3-D tissue resembling aspects of the developing human brain. But these tiny clusters of human nerve cells, called organoids, lacked the connections and sensory inputs of a living brain.
In 2022, Pașca and his colleagues developed a way to transplant human organoids into newborn rats, eventually getting the human cells to make up about one-third of one side of the rat’s cortex. But rat neurons mature faster than their human counterparts, capping how much the human tissue could develop in this rodent model.
Pașca and his colleagues bred mice genetically engineered to develop without most of their cortex and the neighboring hippocampus — two structures involved in movement, learning and memory that together account for about half of the brain’s total volume. Although the resulting animals showed some behavioral defects, they were “surprisingly functional,” Pașca says.
The cavernous space created by the missing tissue could then accommodate human brain organoids grown from healthy donor stem cells — a transplantation that successfully took hold in 25 of 29 attempts.
Over the next three months, the human tissue expanded nearly fivefold in volume in these mice, ultimately filling more than 90 percent of the cortex. The tissue developed into a range of cell types, including rare neurons that have proved nearly impossible to generate in a dish. The tissue lacked some features of a mature cortex, including its characteristic layers, yet still wired extensively into the mouse nervous system, providing a platform for studying human neural circuits gone awry.
The researchers used the mice to model cerebral palsy, a disability caused by damage to the developing brain. They subjected the grafted animals to oxygen deprivation. Afterward, the human tissue showed cellular signs of injury, and the mice developed problems with gait and limb coordination — features of the disability in people, too.
“This could be used down the line to test many therapeutics that are being considered for cerebral palsy,” Pașca says. He plans to study [frontotemporal] dementia and genetic forms of autism with the mice, using organoids made from patient-derived cells affected by those conditions.
The technique “is certainly bold,” says H. Isaac Chen, a neurosurgeon at the University of Pennsylvania who studies brain organoids but was not involved in the research. The extent of humanization raises questions about the ethical boundaries of such experiments, Chen notes, but Pașca has gone to unusual lengths to grapple with those concerns. “He has done a lot more than others in terms of not just holding these discussions but actually driving them,” Chen says.
Pașca, for example, consulted an outside panel of experts, led by Insoo Hyun, a bioethicist at the National University of Singapore Yong Loo Lin School of Medicine. Hyun acknowledges that this new mouse model raises legitimate questions about where to draw the ethical line, but says there is little evidence that these mice have crossed it.
What matters, he says, is not how much human tissue an animal contains, but what that tissue enables it to do. On tests of fine motor control and memory, the grafted mice’s performances fell somewhere between that of the mice with intact brains and those lacking a cortex. “From a secular ethical point of view,” Hyun says, “it boils down to cognitive capacity” — and so far, these mice don’t seem to have gained any obvious extra brainpower.
That may be a relief to anyone picturing the lab mice from Animaniacs, the genetically enhanced rodents who spend each night plotting to take over the world. In Pașca’s lab, there’s little evidence of any plans for world domination. His mice, despite their mostly human-derived cortex, remain far more Pinky than Brain.
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