Researchers halted experiments before implanted cells formed consciousness markers
Researchers at Stanford University have published a method for installing millions of lab-grown human brain cells into mice, producing animals with brains partly composed of human neurons that the team says will improve models for studying neurodegenerative and developmental conditions.
The study, published in the journal Nature, was led by Sergiu Pașca, a professor of psychiatry and behavioral sciences at Stanford and the paper’s senior author. It describes mice bred without most of their cerebral cortex — the outermost layer of the brain involved in reasoning, memory and consciousness — that then received implants of lab-grown human cortical neurons to fill the vacant space. While it is not the first time human brain cells have been installed in mice, Pașca’s effort manages to connect significantly more human cells than previous attempts.
“For the past two decades, there’s been a quest to try to build models of the human brain outside of the human body,” Pașca said. “This is not going to replace all the models we had before, but it’s going to provide us access to other aspects of human brain function that would be very difficult to study otherwise.”
The approach addresses a stubborn obstacle in earlier chimera experiments. Human brain cells develop at least 20 times more slowly than those of mice, which meant that in standard mouse hosts, mouse neurons formed networks before the implanted human cells could compete. Pașca’s team removed key parts of each mouse’s cortex to give the slower-developing human cells room to integrate.
“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.
The depleted mice proved more capable than the researchers expected. “They actually have quite good locomotion,” Pașca said, noting that they performed poorly on memory tasks. “You wouldn’t be able to tell when you look at these animals that they’re lacking half of the volume of their brain.” Keng, a researcher at the Allen Institute who was not involved in the study, called the result evidence of “the remarkable adaptability of developing brains.” “Surprisingly, the animal can adapt,” Keng said. “It’s incredible to see that.”
After the human neurons were implanted, the mice recovered some of the functions they had lost. “We gently place them, through a very quick, simple procedure, right into that vacant space in the nervous system of the mouse,” Pașca said. “Within a few days, the cell starts to divide and expand. Within a few weeks to months, they will essentially grow, become vascularized, and largely take up the space that was present.” The mice with filled-out brains were better at memory tasks and interacting with other mice. “Many of the deficits that were present in the [depleted] mice are now not present in this animal,” Pașca said, suggesting the human cortical cells appear to contribute to “restoring some of these lost functions.”
The mice also exhibited a more human-like vulnerability to oxygen deprivation. Mice with human brain cells had problems walking properly after their brains were deprived of oxygen, a problem regular mice do not show because they are resilient to low-oxygen conditions, Pașca said. The more human-like reaction suggests the altered mice may be better models for studying brain conditions linked to low oxygen, such as cerebral palsy, intellectual disability and epileptic encephalopathies.
“Hopefully, it will be incredibly powerful for tackling questions of disease and developing therapeutics,” Pașca said.
The researchers emphasize that this is not a full brain transplant; in the experiment, they removed some 14 million mouse neurons and added around 4 million lab-grown human cortical neurons. The resulting mice still lack other important types of brain cells, which the researchers deliberately did not add, and their human neurons do not form a typical outer brain. “The cortex is usually beautifully organized into layers. But here, when we put the cells in, they don’t know where up and down really is,” Pașca said. “They fail to organize on a larger scale.” The model is best suited for certain diseases that begin in early human development, Pașca added, because the timing of human-paced growth is preserved even in a faster-developing animal.
Hongkui Zeng, executive vice president and director of brain science at the Allen Institute in Seattle, Washington, called the work “a powerful technology to study human neurons and how human brain circuits can form in a more natural environment” than a petri dish. She added that “going forward, there will be some considerations, if not concerns” — particularly if the technique is deployed in larger, longer-living animals.
That ethical dimension was a focus of the external review. Nita Farahany, a professor of law and philosophy at Duke Law, served as an unpaid member of the ethics board that advised the team. She said the researchers stopped experiments when the implanted human cells reached roughly six months of development, before they could form a connection considered by human development researchers to be a hallmark of consciousness.
“They’re trying to stop the study before the markers of consciousness, or the fact of consciousness, might emerge,” Farahany said. “But that line itself is a line that you might start to wonder about.”
Farahany suggested that implanted mice may warrant greater ethical care than standard laboratory mice. “Do you stop a study before an animal develops consciousness, if it has the potential or is on its way to develop consciousness? Does it have different interests or rights that we would assign to it?” she asked. “Do we treat it with greater ethical care than we treat traditional mice? I think probably so.” Her instinct, she added, was “to err on the side of caution with research like this rather than to be more permissive.”
She described the team’s conduct as “incredibly thoughtful,” while adding that “this brings us into new gray areas for which there are not clear ethical guidelines or norms.”
Future applications could include larger animals. Zeng said pigs and non-human primates live long enough for implanted human neurons to survive longer and form more functionally meaningful circuits — and that the ethical issues also become “a lot bigger, more serious as well.”
The paper’s release places a new research capability before the wider scientific community and the public. Farahany said the publication marks “a next step in this model. Now, it’s society’s turn to weigh in.”