Scientists grow functioning human brain cells in mice

Stanford researchers have created mice with millions of functioning human brain cells integrated into their own brains, a development they say could help scientists study neurological and psychiatric disorders that cannot be fully modeled in ordinary lab animals.

The work, published in Nature, involved genetically engineering mice so they developed almost none of their cerebral cortex, the outer layer of the brain involved in reasoning, memory, senses and consciousness. Researchers then implanted lab-grown human brain tissue into the vacant space, allowing human neurons to expand, connect with the animals’ nervous systems and help restore some lost functions.

The scientists stressed that the animals are not “mice that think like humans” and that the experiment was conducted with independent ethical scrutiny.

“Here we have a new model that allows us to actually capture aspects of human brain function in a way that has not been possible before,” said Prof. Sergiu Pașca of Stanford University, the study’s senior author.

The goal, researchers said, is to build better models for conditions that are difficult or impossible to study in mice because they occur in humans in ways rodents do not naturally reproduce. Pașca said psychiatry has “one of the lowest success rates for clinical trials,” adding that even drugs that appear promising in animal models often “fail dramatically in clinic.”

The team began with skin cells taken from humans and reprogrammed them into organoids, small collections of connected living brain-like cells rather than whole brains. Those organoids were implanted into the brains of mice that had been engineered to lack much of their own cortex.

Earlier attempts to place human neurons in mice were limited because human brain cells develop at least 20 times more slowly than mouse cells, Pașca told NPR. By the time human cells began extending connections, mouse cells had already built much of the brain circuitry. In the new study, the researchers created space first.

“We thought we could provide the human cells more opportunities to connect by removing parts of the nervous system of the mouse in a very precise, very clean way,” Pașca said.

According to NPR, the researchers removed about 14 million mouse neurons and added around 4 million lab-grown human cortical neurons. Within days, the implanted cells began dividing. Over weeks and months, they expanded, became vascularized and connected with the mouse brain and spinal cord.

The resulting cortex was not normal. A typical cortex forms organized layers, while the implanted cells did not align that way. Pașca said the cells “don’t know where up and down really is,” and neuroscientist Dr. Ilary Allodi of St Andrews University, who was not involved in the work, told the BBC that scans looked “a bit messy.”

After several months, however, the human cells began to resemble and function like the outer layer of a mouse brain. Pașca said the altered mice performed “largely as [the normal] mice did” in basic behavioral tests and showed “no enhancement.” NPR reported that mice with the human cells did better than cortex-depleted mice at memory tasks and interacting with other mice.

The altered mice also reacted differently from ordinary mice when deprived of oxygen, developing walking problems. Pașca said that could make them useful for studying conditions linked to low oxygen, including cerebral palsy, intellectual disability and epileptic encephalopathies. Stanford researchers also said the model could be important for studying complex conditions such as epilepsy, autism and cerebral palsy.

Outside scientists called the work technically significant while emphasizing ethical questions. “There’s no indication that what’s being created here are mice that can think like humans, or a human brain in a mouse body,” Dr. Sarah Chan, a bioethicist at the University of Edinburgh, told the BBC. But she said the study raises questions about “what it might mean when we start changing animal cognition.”

Nita Farahany of Duke Law, who served unpaid on an external ethics board for the project, told NPR the team stopped the experiments before human cells reached a developmental point associated with a marker of consciousness. She said the work enters “new gray areas for which there are not clear ethical guidelines or norms.”

Hongkui Zeng of the Allen Institute said the technology is powerful for studying human neurons in a more natural environment than a dish, but future use in larger, longer-lived animals could raise bigger ethical concerns.