Scientists Create Genetically Engineered Mice with Half-Human Brains

Article By Frank Bergman

A group of leading American scientists has created genetically engineered mice with half-human brains in a disturbing new experiment that is raising serious ethical questions about how far researchers should go in manipulating animals with human brain cells.

Researchers at Stanford University genetically engineered mice to be born without key regions of their own brains before injecting the newborn animals with millions of lab-grown human brain cells.

The human tissue then grew inside the rodents’ skulls, connected to their blood supply, and even formed connections with the animals’ remaining brain cells and spinal cords.

Within three months, the transplanted human tissue had almost completely filled the deliberately created cavity.

The result was what researchers describe as “xenocortical” mice with approximately half of their brains, by volume, consisting of human tissue.

Scientists say the radical experiments could allow them to investigate schizophrenia, epilepsy, cerebral palsy, intellectual disabilities, and rare forms of dementia.

However, the rapidly advancing research is also fueling concerns about animal welfare and the possibility that increasingly sophisticated lab-grown human brain tissue could eventually develop properties associated with consciousness or pain.

Mice Engineered to Make Room for Human Brains

The experiments were led by Stanford University psychiatry professor Sergiu Pașca.

Pașca’s team published the findings in the journal Nature.

Researchers have struggled for years to study human neurological disorders because living human brains are largely inaccessible for direct experimentation.

“We’ve been trying really hard as a community to find therapeutic solutions for these conditions, but the reality is that in psychiatry and neurology we’ve been left behind [by] every single branch of medicine and we have fewer therapeutics than, again, every single branch of medicine,” Pașca said.

“That could be because the human brain is very complex, but it’s also because the human brain is inaccessible,” he continued.

“To a large extent, our goal has been to make aspects of human brain development and function accessible for investigation.”

The researchers turned to neural organoids, clumps of human brain cells grown in laboratories that can organize themselves into complex structures displaying some characteristics of actual brains.

Stanford researchers had previously implanted human neurons into rats.

Those cells survived and became integrated into the rats’ brain circuitry.

But there was a problem.

There wasn’t enough room inside the animals’ skulls for large quantities of human tissue to develop.

Researchers devised a radical solution.

They genetically engineered mice so that development of the cerebral cortex and hippocampus, two major areas of the brain, was severely stunted.

The resulting empty space could then be occupied by human brain tissue.

Millions of Human Cells Injected into Newborn Mice

The human brain organoids were produced by reprogramming donated human skin cells.

Newborn mice were then given several injections containing approximately 100,000 human brain cells each.

The genetically modified rodents were missing approximately 14 million mouse brain cells.

Researchers ultimately introduced around four million human cells.

Within three months, the human tissue had connected to the mice’s blood supply and expanded until it occupied roughly half of the animals’ brains by volume.

Some human neurons even established connections with mouse brain cells and the spinal cord.

The human tissue did not organize itself in the same manner as a normal human brain.

It also remained immature, with researchers comparing its developmental state to human brain tissue roughly halfway through pregnancy.

Nevertheless, the scale of human tissue successfully grown inside a living animal represents a dramatic expansion of previous organoid experiments.

The mice surprisingly survived despite being engineered without large portions of their normal brains.

Other regions apparently adapted to perform some of the missing functions.

The animals appeared outwardly normal but displayed an unsteady gait, cautious movement, and memory problems.

Researchers said the addition of human tissue did not make the mice more intelligent or otherwise enhance them.

However, their movement and cognitive problems improved slightly after the transplants.

Human Brain Tissue Used to Study Disease

Scientists believe the creatures could provide an entirely new way to study diseases affecting the human brain.

Researchers could take cells directly from a patient with a neurological disorder, reprogram them into brain tissue, and implant that tissue into mice.

They could then observe how the patient’s human cells behave inside a living organism and test potential treatments.

To demonstrate the technique, researchers subjected some of the mice to five hours of low oxygen.

The experiment allowed scientists to observe how human neurons responded to oxygen deprivation, which during pregnancy and birth can contribute to cerebral palsy.

Researchers also discovered rare human cells known as von Economo neurons growing inside the mice.

Until now, those cells had only been observed during postmortem examinations.

Von Economo neurons are among the first cells destroyed by frontotemporal dementia, a rare form of dementia.

Pașca now hopes the humanized mice can be used to investigate the disease.

Experiment Raises Ethical Questions

The breakthrough is intensifying an already contentious debate surrounding neural organoids.

Scientists can now grow increasingly sophisticated human brain tissue in laboratories and implant that tissue into living animals.

That has raised questions about what could eventually happen if the technology advances far enough.

Among the concerns is whether human brain organoids could someday develop the capacity for consciousness or pain.

There are also questions about the welfare of animals whose brains are extensively altered using human cells.

Pașca said the Stanford research has been subjected to extensive ethical oversight.

Emily Jackson, professor of law at the London School of Economics and chair of a recent Nuffield Council on Bioethics report examining neural organoids, said continued scrutiny will be essential.

“Animal welfare is a really important concern, and it will be necessary to closely monitor these animals in order to evaluate the impact on them,” Jackson said.

Prof. Madeline Lancaster, group leader at the MRC Laboratory of Molecular Biology in Cambridge, also warned that such experiments require strong justification.

“It’s obviously ethically sensitive, and there needs to be a very good reason to do this type of animal experimentation, which most scientific avenues do not require,” Lancaster said.

Lancaster noted that many scientists are attempting to develop brain organoids entirely in laboratory dishes rather than implanting them into animals.

“The field is still aiming for fully in vitro solutions, but this work can also inform on what may be needed to improve those in vitro models to reach more mature stages,” she said.

Lancaster also questioned how much the mice can reveal about normal human brain development.

“It’s less clear to me how this will inform our understanding of human brain development since it is rather artificial, and not at all like how the brain develops naturally,” she said.

Human Brain Experiments Push into New Territory

The Stanford experiments nevertheless demonstrate just how far human brain organoid technology has advanced.

Scientists have gone from growing small clusters of human neurons in laboratory dishes to placing millions of those cells inside living animals.

They have now deliberately engineered mice without major portions of their own brains so human tissue can take their place.

That tissue survives.

It receives blood from the animal.

It expands until it occupies approximately half the brain by volume.

And human neurons establish connections with the mouse’s own nervous system.

Researchers believe those extraordinary capabilities could eventually unlock treatments for devastating neurological and psychiatric disorders that medicine has struggled to address.

But the same breakthrough is pushing scientists into increasingly sensitive territory as the distinction between laboratory-grown human brain tissue and the brains of living experimental animals becomes increasingly blurred.

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