Stanford Scientists Grow Functioning Human Brain Tissue Inside Mice

Scientists at Stanford University have grown large amounts of functioning human brain tissue inside genetically engineered mice, creating what researchers say could become a powerful new way to study neurological and psychiatric disorders.

In the study, published Sept. 16 in the journal Nature, researchers transplanted laboratory-grown human cortical organoids into newborn mice engineered to develop without most of their cerebral cortex and hippocampus. The human tissue subsequently expanded, connected with the animals’ nervous systems and produced organized electrical activity.

The researchers call the animals “xenocortical mice,” stressing that they are not mice with fully human brains. The animals retain a mouse nervous system, but parts of the space normally occupied by the mouse cortex are instead filled with human-derived neural tissue.

“This gives us a way to study human neural tissue across several levels,” Stanford neuroscientist Sergiu Pașca, the study’s senior author, told Reuters.

Human tissue takes over much of the cortical space

Researchers first genetically engineered mice so that most of the cells that would ordinarily form the cerebral cortex and hippocampus did not develop. Adult mice produced through the process retained only about two percent of the cortical and hippocampal tissue normally found in mice, according to Stanford Medicine.

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Shortly after birth, the mice received several human cortical organoids. Each contained roughly 100,000 cells and had been produced from human induced pluripotent stem cells.

The transplanted tissue survived and expanded rapidly. Three months after transplantation, more than 90 percent of the cortical tissue by volume in some of the animals was human-derived, Stanford reported.

Importantly, that does not mean more than 90 percent of the entire mouse brain was human. Other regions of the animals’ brains remained mouse tissue.

The human neurons also did more than simply grow inside the skull. According to the Nature study, they formed connections throughout the mouse nervous system, with some nerve fibers extending into the spinal cord. Researchers recorded spontaneous electrical activity in the grafts that resembled activity in developing neural circuits.

Pașca cautioned against descriptions such as “humanized mice” or “mice with human brains,” telling Reuters that such terminology is “not accurate.”

The animals generally continued to behave like mice. Researchers found some differences in fine motor coordination, memory and spontaneous behavior, but no evidence that the human tissue gave the animals dramatically enhanced abilities.

“Our findings suggest” other regions of the brain can compensate when cortical circuitry is lost very early in development, Pașca said in a Stanford Medicine report.

Rare human brain cells appear inside mice

One of the most unexpected findings involved an unusual type of human neuron known as a von Economo neuron, or VEN.

These large, distinctive cells are exceptionally rare and are found primarily in particular areas of the human brain associated with social awareness and decision-making. Similar neurons have also been identified in several other highly social, large-brained animals, including great apes, whales, dolphins and elephants.

Scientists have struggled to produce the cells in conventional laboratory cultures.

Yet cells resembling VENs appeared inside the human tissue growing in the xenocortical mice, according to the researchers.

The finding could be particularly important for studying frontotemporal dementia. VENs appear to be especially vulnerable in some forms of the disease, which can cause changes in behavior, personality and language.

“Yet here they were,” Pașca said of finding the cells inside the transplanted tissue, according to Stanford Medicine.

The researchers also demonstrated how the mice could be used to investigate brain injuries that are difficult to reproduce accurately in conventional animal models.

Some xenocortical mice were exposed to five hours of extremely low oxygen. The human cortical tissue showed substantial signs of injury, and the affected animals later developed problems with gait and motor coordination.

Ordinary mice and the cortex-deficient mice without human grafts were much less affected.

The difference could help scientists investigate why oxygen deprivation during pregnancy or childbirth can cause severe neurological damage in humans, including cerebral palsy.

Pașca said the model could potentially help researchers identify why human neural tissue is particularly vulnerable and provide a system for testing possible treatments.

Researchers believe the method could eventually be adapted to study conditions including schizophrenia, epilepsy, autism and some forms of dementia by creating organoids from cells donated by patients carrying disease-associated genetic changes.

Research raises ethical questions

The experiment also pushes neuroscience further into an area that has generated growing ethical debate: placing increasingly sophisticated human neural tissue inside living animals.

The Stanford researchers said the work underwent review by the university’s stem-cell and animal-research oversight committees, as well as consultation with an independent ethics committee. Donors whose cells were used to create the organoids had consented to their use in animal transplantation.

The study’s authors said they specifically considered whether the human tissue might produce “altered or improved capacities” in the mice and conducted behavioral and cognitive testing to look for such effects.

Outside researchers say continued scrutiny will be necessary as the technology advances.

“Animal welfare is a really important concern,” Emily Jackson, a professor of law at the London School of Economics, told The Guardian.

Madeline Lancaster, a researcher at the MRC Laboratory of Molecular Biology in Cambridge, said the technique is scientifically useful but “obviously ethically sensitive.”

Lancaster also cautioned that the model should not be treated as a perfect recreation of human brain development because human neural tissue is developing under highly artificial conditions inside another species.

The questions extend beyond animal welfare. As human neural organoids become larger and more complex, scientists and ethicists have begun debating whether such tissue could someday develop properties associated with sensation, pain or other forms of experience.

Earlier this month, a Stanford-led group called for an international framework to oversee neural-organoid research. Pașca said the scientific community should not resolve those questions alone.

“This research does raise important ethical questions,” he said in the Stanford ethics report.

For now, researchers reported no evidence that the transplanted human tissue made the mice human-like or produced extraordinary cognitive abilities.

But the experiment demonstrates that human cortical tissue can survive, mature, organize itself and become functionally incorporated into a living animal’s nervous system on a scale not previously achieved.