‘Alien-cortical’ mice: Can human brain cells grow inside animals?

In a laboratory in California, in the United States, mice are scurrying around their cages, as mice do. But inside their brains are millions of working human neurons.

Researchers at Stanford University have implanted lab-grown human cells into mice genetically engineered to lack parts of their brains, including the cerebral cortex, the outer region that plays a major role in perception, movement, decision-making and attention.

According to a study published in Nature, these so-called “alien-cortical mice” may offer a new way to study neural circuits and brain disorders such as schizophrenia, cerebral palsy and dementia.

Putting human brain tissue inside an animal sounds like something out of Mary Shelley’s Frankenstein, but how “human” are these mice, really? And what have the researchers found?

Here is what we know.

How did the experiment work?

Researchers genetically modified the mice so they were born and grew without most of the cerebral cortex and the neighbouring hippocampus, which are needed for movement, learning and memory.

When the animals were two days old, researchers injected human “organoids” into the empty spaces. Organoids are miniature masses of cells grown in a laboratory from stem cells or tumour tissue which mimic real human organs. Each was grown from healthy donors’ stem cells and holds about 100,000 human cells.

Overall, researchers removed about 14 million mouse neurons and added about 4 million human ones.

This is not the same thing as a brain transplant, and the animals are not “mice that think like humans”, the researchers emphasised.

They tried the transplants on 29 mice, and it worked on 25 of them.

What happened to the mice?

Within three months, the human tissue had grown about five times larger inside the mice’s brains, connected to their blood supply and filled more than 90 percent of the cavities.

The “alien cortex” mice walked and vocalised mostly normally, even though human tissue made up about half their brain volume.

In a maze test, mice without the implanted human tissue kept getting lost, however, while those with human cells did better, suggesting the human tissue contributed to cognition.

Unexpectedly, some of the tissue developed into von Economo neurons, which are long, rare cells normally absent in mice and almost impossible to make in a lab. They are found in highly social animals such as humans, apes, whales and elephants.

The experiment might also help explain cerebral palsy.

While human infants can suffer from oxygen deprivation as a result of more frequent complications during much longer and trickier childbirth, mice infants rarely do, which has made the condition hard to study in rodents.

When the modified mice in this case were exposed to low oxygen, they showed brain damage, an altered gait and poor limb coordination.

Why put human neurons in a mouse?

Human brain diseases are among the hardest conditions to study. The brain contains about 86 billion nerve cells linked by trillions of connections. Ethical and safety barriers, along with the brain’s high biological complexity, limit access to living human brain tissue.

Scientists have spent years growing “organoids” instead: Small clusters of human nerve cells grown in a lab. But they are not brains in a dish. They lack the connections, inputs and environment of a living brain.

Sergiu Pasca, senior author of the research paper and a professor of psychiatry and behavioural sciences at Stanford University, said this has the potential to give researchers unprecedented insight into the human brain.

“For the past two decades, there’s been a quest to try to build models of the human brain outside of the human body,” he 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.”

What are the ethical concerns?

As research into brain organoids advances, so too do calls for clear regulations and oversight, given the sensitive ethical questions raised by these technologies.

These questions centre on the possibility that cell clusters and brains grown outside the bodies of their owners possess the capacity for sensation or consciousness, and whether this can be scientifically verified.

The researchers stopped the experiments when the human nerve cells implanted in the brains of mice were six months old, before they could form more neural connections with the animals’ brains, and before any signs of consciousness appeared.

John Evans, a sociology professor at the University of California, San Diego, who was not involved in the study, said this experiment does not in itself raise major ethical issues, but it provides evidence that other animals could be created that might raise more serious ethical concerns.

Setting clear boundaries for this research remains a challenge.

According to Evans, the problem lies in the lack of clear stopping points on the gradual path that research could take from mice to non-human primates.

Accordingly, he suggested that researchers should not go beyond rodents for the time being, in order to avoid creating neurohybrid organisms that combine human and animal characteristics and could provoke an ethical controversy.