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'Minibrains' In A Dish Shed A Little Light On Autism And Epilepsy

Apr 26, 2017
Originally published on April 28, 2017 2:31 pm

Tiny, 3-D clusters of human brain cells grown in a petri dish are providing hints about the origins of disorders like autism and epilepsy.

An experiment using these cell clusters — which are only about the size of the head of a pin — found that a genetic mutation associated with both autism and epilepsy kept developing cells from migrating normally from one cluster of brain cells to another, researchers report in the journal Nature.

"They were sort of left behind," says Dr. Sergiu Pasca, an assistant professor of psychiatry and behavioral sciences at Stanford. And that type of delay could be enough to disrupt the precise timing required for an actual brain to develop normally, he says.

The clusters — often called minibrains, organoids or spheroids — are created by transforming skin cells from a person into neural stem cells. These stem cells can then grow into structures like those found in the brain and even form networks of communicating cells.

Brain organoids cannot grow beyond a few millimeters in size or perform the functions of a complete brain. But they give scientists a way to study how parts of the brain develop during pregnancy.

"One can really understand both a process of normal human brain development, which we frankly don't understand very well, [and] also what goes wrong in the brain of patients affected by diseases," says Paola Arlotta, a professor of stem cell and regenerative biology at Harvard who was not involved in the cell migration study. Arlotta is an author of a second paper in Nature about creating a wide variety of brain cells in brain organoids.

Pasca's team began experimenting with organoids in an effort to learn more about brain disorders that begin long before birth. Animal brains are of limited use in this regard because they don't develop the way human brains do. And traditional brain cell cultures, which grow as a two-dimensional layer in a dish, don't develop the sort of networks and connections that are thought to go awry in disorders like autism, epilepsy and schizophrenia.

"So the question was really, can we capture in a dish more of these elaborate processes that are underlying brain development and brain function," Pasca says.

He was especially interested in a critical process that occurs when cells from deep in the brain migrate to areas nearer the surface. This usually happens during the second and third trimesters of pregnancy.

So Pasca's team set out to replicate this migration in a petri dish. They grew two types of clusters, representing both deep and surface areas of the forebrain. Then they placed deep clusters next to surface clusters to see whether cells would start migrating.

Pasca says the cells did migrate, in a surprising way. "They don't just simply crawl, but they actually jump," he says. "So they look for a few hours in the direction in which they want to move, they sort of decide on what they want to do, and then suddenly they make a jump."

Pasca suspected this migration process might be disrupted by a genetic disorder called Timothy syndrome, which can cause a form of autism and epilepsy. So he repeated the experiment, using stem cells derived from the skin cells of a person who had Timothy syndrome.

And sure enough, the cells carrying the genetic mutation didn't jump as far as healthy cells did. "They moved inefficiently," Pasca says.

Next Pasca wondered if there might be some way to fix the migration problem. He thought there might be, because Timothy syndrome causes cells to let in too much calcium. And he knew that several existing blood pressure drugs work by blocking calcium from entering cells.

So the team tried adding one of these calcium blockers to the petri dish containing clusters of brain cells that weren't migrating normally. And it worked. "If you do treat the cultures with this calcium blocker, you can actually restore the migration of cells in a dish," Pasca says.

Fixing the problem in a developing baby wouldn't be that simple, he says. But the experiment offers a powerful example of how brain organoids offer a way to not only see what's going wrong, but try drugs that might fix the problem.

Still, to realize their full potential, brain organoids need to get better, Arlotta says. This means finding ways to keep the cell clusters alive longer and allowing them to form more of the types of brain cells that are found in a mature brain.

Arlotta's team has developed techniques that allow brain cell clusters to continue growing and developing in a dish for many months. And what's remarkable, she says, is that over time the clusters automatically begin creating structures and networks like those in a developing brain.

"Using their own information from their genome, the cells can self-assemble and they can decide to become a variety of different cell types than you normally find," she says.

In one experiment, a brain organoid produced nearly all the cell types found in the mature retina, Arlotta says. And tests showed that some of these retinal cells even responded to light.

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RACHEL MARTIN, HOST:

Clusters of human brain cells are providing some hints about the origins of disorders like autism and epilepsy. These cell clusters grow in a petri dish. And as NPR's Jon Hamilton reports, they develop in some of the same ways that a baby's brain does during pregnancy.

JON HAMILTON, BYLINE: Brain disorders often begin long before birth, but there's been no good way to see what's going awry as the brain goes through its early development. Then a few years ago, scientists figured out how to get human brain cells to grow in a dish and form three-dimensional structures the size of a pinhead. They were often called minibrains or brain organoids. Sergiu Pasca of Stanford University says scientists realized these clusters offered a new way to search for the origins of disorders like autism and epilepsy.

SERGIU PASCA: So the question was really, can we capture in a dish more of this elaborate processes that underline brain development and brain function?

HAMILTON: One key process involves neurons generated deep in the brain. The cells slowly migrate to areas near the surface, where they form networks that allow us to do things like planning and problem solving. Pasca led a team that set out to replicate some of this process in a petri dish. The team grew two types of clusters, representing both deep and surface areas of the forebrain. Then they put a deep cluster next to a surface cluster to see whether cells would start moving. Pasca says they did, in a surprising way.

PASCA: They don't just simply crawl, but they actually jump. So they - you know, they look for a few hours in the direction in which they want to move. They sort of decide on what they want to do, and then suddenly, they make a jump.

HAMILTON: Pasca suspected this migration process might be disrupted by an extremely rare genetic disorder called Timothy syndrome. Symptoms often include both autism and epileptic seizures. So Pasca repeated the experiment using cells that carried the Timothy syndrome mutation. And he says sure enough, the affected cells didn't jump as far as healthy cells did.

PASCA: So they would move a shorter distance. And overall, they would be sort of left behind in their migration.

HAMILTON: Pasca says that could disrupt normal brain development. These minibrains can't grow into anything like an actual brain. But Paola Arlotta says they are proving to be hugely important to researchers.

PAOLA ARLOTTA: One can really understand both a process of normal human brain development, which we frankly don't understand very well, but also make us understand what goes wrong in the brain of the patients affected by these prominent diseases.

HAMILTON: The brain cell clusters also offer a new way to test potential treatments. In the Timothy syndrome experiment, Pasca was able to use a drug to allow the defective cells to move normally. Arlotta says the challenge now is to create brain cell clusters that can live longer and include many more of the cell types found in a mature brain.

So far, her team has been able to sustain brain organoids for more than nine months. And she says when brain cell clusters live long enough, they spontaneously begin making connections, forming networks and creating new types of cells.

ARLOTTA: Using their own information from their genome, the cells can self-assemble. And they can decide to become a variety of different cell types that you normally find.

HAMILTON: She says the clusters have even produced nerve cells like those found in the retina. And like actual retinal cells, she says, they respond to light. Both Arlotta and Pasca's research appears in the journal Nature. Jon Hamilton, NPR News. Transcript provided by NPR, Copyright NPR.