Mice with human brain cells created to study neurodegenerative disease

Researchers developed lab animals that lack nearly all of their cerebral cortexes, then filled those vacant areas with human brain cells instead. These living models are being used to study diseases that destroy nerve tissue, according to a report in Nature.

Researchers use genetic engineering to create mice missing most of their outer brain layer. They then implant clumps of lab-grown human neurons into those animals, linking far more human cells than earlier attempts managed. The outcome is a mouse carrying a humanized patch of cortex, and the field now wonders what comes next.

Making room for human neurons

The human brain cells take at least 20 times longer to develop than mouse cells do. Earlier efforts found that mouse neurons built a fast network while human cells fell behind, unable to keep pace. By the time the human cells finally reached a few millimeters, mouse cells had already formed most of their connections, and brain development was finished.

Pașca says the new method resolves the issue by eliminating particular regions from the mouse brain. “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,” The researchers discovered that the rodents remained surprisingly capable even after losing half of their brain volume. They moved well, though they had trouble with memory tests.

A more human-like lab mouse

A quick surgical procedure saw small clusters of human neurons inserted into the vacant mouse brains. The cells began dividing and expanding within a few days. Over a few weeks to months, they grew, became vascularized, and came to occupy the space that had been there.

The animals whose brains were swollen with human neurons did better on memory tests and social activities compared to the control group, which had been drained of their own neurons. Much of what was missing in the drained mice seemed to return in those carrying the human cortical cells, according to Pașca.

The humanized mice and regular ones showed clear differences when tested. When their brains were cut off from oxygen, the humanized mice struggled with walking. Normal mice can survive far better under low-oxygen conditions. According to Pașca, this human-like response points to the altered mice possibly serving as improved models for brain disorders tied to low oxygen, including cerebral palsy, intellectual disability, and epileptic encephalopathies.

What the model can’t do yet

The resulting mice still lack other important types of brain cells, which the researchers deliberately didn’t add. Their human neurons don’t 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 says. “They fail to organize on a larger scale.”

The model is best suited for certain diseases that begin in early human development, due to the human-paced growth of the implanted neurons. “It turns out the timing of development is well-conserved…even when we put them in an animal that is developing faster,” he says.

Ethicists ask: What’s next?

Npr’s study’s lead author says the work moved ahead with strict oversight and advances scientific knowledge. Independent experts concur that the technology is powerful, though they pose questions about its potential direction.

“It’s really a powerful technology to study human neurons and how human brain circuits can form in a more natural environment” than a petri dish, says Hongkui Zeng, executive vice president and director of brain science at the Allen Institute in Seattle, Washington, who was not affiliated with the study. She added that “going forward, there will be some considerations, if not concerns,” such as the implications of deploying this technique in larger and longer-living animals.

Nita Farahany, a professor of law and philosophy at Duke Law, worked as an advisor on the project. She says that some of the model’s limitations stem from deliberate ethical decisions taken by the researchers.

“Hopefully, it will be incredibly powerful for tackling questions of disease and developing therapeutics.”

The investigators make clear that this is not a complete brain transfer. They took out roughly 14 million mouse nerve cells and put in roughly 4 million lab-grown human surface-layer nerve cells. The human nerve cells do not develop into a standard outer brain, and the design is most suited to conditions that start during early human growth.

Rapid progress defines this field, and with each advance comes fresh inquiry. At present, the living models themselves serve as the demonstration: creatures that walk, remember, and respond to oxygen deprivation in ways that mirror human brain conditions.

ethics · human brain cells · medical research · mice · neuroscience