Researchers Grow Human 'Mini Brains' 09-01

Researchers Grow Human 'Mini Brains'

Researchers have used stem cells to grow pea-sized structures that resemble the developing human brain, an advance that offers a way to model brain maladies that are otherwise hard to study.

The human brain is one of the most elaborate natural structures known to science. These new lab-grown "mini brains" are imperfect, and a long way off from matching the real thing.

Still, the structures, which are about four millimeters in diameter, share some of the crucial three-dimensional architecture of a developing human brain. The different brain parts interact in a normal manner, though they aren't necessarily in the proper places.

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Credit: Madeline A. Lancaster

A cross-section showing development of different brain regions.

"It would be like a car with the engine on the roof, the gear box in the trunk and an exhaust pipe that points to the front," said Jürgen Knoblich at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences and leader of the research team. "You can still use such a car to study how an engine works."

The experiment was reported Wednesday in the journal Nature.

The advance is expected to allow researchers to investigate human brain disease in a lab—something that currently is a big challenge. Brain disorders such as Alzheimer's typically are studied in rats, mice and other animals, but these are inadequate proxies mainly because the human brain is much more complex.

By contrast, the new approach should enable scientists to study neurological disorders by examining brain tissue derived from actual patients.

Jürgen Knoblich created versions of developing brains in the lab.

In the Nature paper, Dr. Knoblich and his colleagues described how they used their technique to study brain tissue created from a patient suffering from microcephaly, a genetic disorder that leads to a smaller brain. His team's research builds on several experiments published by other researchers since 2008, which showed how stem cells could be manipulated to create not just nerve cells, but more elaborate neuron-based structures as well.

At a lab in Austria, Dr. Knoblich did experiments with human embryonic stem cells, which are derived from an embryo. He experimented with stem cells that were obtained by reprogramming mature tissue, such a person's skin cells, into an embryonic-like state. Both types of stem cells are "pluripotent"—they can be changed into all other cell types in the body.

The researchers added chemicals known as growth factors to the stem cells, which created tissues that would go on to form the central nervous system. The tissues were put in a gel-like substance resembling the environment of a developing human embryo.

That mix was then put into a spinning bioreactor, a vessel that helps cells develop and grow. After 20 to 30 days, the neural cells organized themselves into tiny structures, called cerebral organoids.

These structures had defined brain regions, including a dorsal cortex—which makes up the largest part of our brain—and the choroid plexus, where cerebrospinal fluid is produced. The neurons were active and fired.

"That was the big surprise—it was self-organizing," said Dr. Knoblich, who added that his team made hundreds of the "mini brains."

But within the structures, the various bits were in a jumble and the shape and overall spatial organization didn't fully match that of a real brain. Plus, key pieces—such as the cerebellum, an area involved in motor control—were missing.

After the organoids achieved a size of four millimeters in diameter, they stopped growing, probably because they lacked a circulatory system, the researchers said. At that stage, they resembled the developing brain of a nine-week-old human embryo.

"Despite these compelling data, the realization of a 'brain in a dish' remains out of reach," wrote Oliver Brustle of the University of Bonn, in an article that accompanied the study. Dr. Brustle, who wasn't involved in the study, added: Although parts of the organoids' exteriors "clearly bear a resemblance to the developing cerebral cortex, it remains unclear whether they can advance to the complex six-tiered architecture of their natural counterpart."

Nonetheless, even imperfect brain tissue has uses, such as the work by Dr. Knoblich's team to study a patient suffering from microcephaly, the malady that leads to a small brain size and which has been difficult to model in mice.

The researchers first reprogrammed the patient's skin cells into stem cells, then grew those into mini brains. As expected, the mini brains grew to a lesser-than-normal size.

By examining the mini brains in the lab, Dr. Knoblich's team was able to pinpoint some ways in which the disease develops. In such patients, it seems, stem cells get transformed into neurons prematurely—at the expense of a proper buildup of stem cells. That is why the brains of such patients end up being smaller than normal, the scientists theorized.

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