Brain organoids, often called "minibrains," have changed the way scientists study human brain development and disorders like autism.
But the cells in these organoids differ from those in an actual brain in some important ways, scientists reported Wednesday in the journal Nature.
The finding suggests that scientists need to be cautious about extrapolating results found in organoids to people, says Dr. Arnold Kriegstein, a professor of neurology at the University of California, San Francisco.
"It's far too early to start using organoids as examples of normal brain development because we just don't know how well they really represent what's going on in utero," Kriegstein says.
But Dr. Guo-Li Ming, a professor of neuroscience at the University of Pennsylvania who is not connected to the study, says she is "not concerned too much" by the finding.
"If we are careful enough we can still learn from brain organoids," says Ming, who used the approach to help understand how Zika virus could affect the brains of babies in the womb.
Brain organoids are clusters of lab-grown brain cells that assemble themselves into structures that look a lot like human brain tissue. The process by which these cells become specialized and begin to communicate resembles the development of a human brain in the months before birth.
But Kriegstein's lab wondered just how accurate the model was.
"We wanted to see whether the organoids that we and others have been using to model normal brain development as well as disease actually represented the cell types faithfully," he says
So Kriegstein's team took a close look at 200,000 cells from organoids that mimic the brain's outer layer, the cortex. They used genetic tests to classify the cell types and then compared them with a database of cell types found in actual brain tissue.
"We were surprised to see that there were some dramatic differences that hadn't been reported before," Kriegstein says.
The organoids included the major cell types found in cortex. But the organoid cells were just a little off, says Aparna Bhaduri, a postdoctoral scholar in Kriegstein's lab.
"In the normal brain you have very clear and precise different types of cells," she says. "What we're seeing in the organoid is more of a confused identity."
The cells looked immature. It was as if they hadn't quite decided what kind of cells to be when they grew up.
The organoid cells also showed signs of metabolic stress, Bhaduri says, meaning they looked like cells that had been undernourished.
"Something about the artificial nature of the media or the conditions they're being grown in is actually resulting in this stress," says Madeline Andrews, another postdoc in Kriegstein's lab.
Two experiments backed that idea.
When the team transplanted normal brain cells into a growing organoid, those cells became stressed and "this confused identity begins to arise," Andrews says.
And when the team took cells from an organoid and transplanted them into a mouse brain, the stress and identity problems went away.
"It tells us that you can take away the stress from these cells, that they're not permanently stressed," Bhaduri says.
Ming's lab has also detected stress in organoid cells. But she's not convinced that stress is the reason organoid cells remain immature and fail to acquire clear identities. "That hasn't been established," she says.
Even so, Ming's lab is looking for ways to protect organoid cells from stress, and make them more like actual brain tissue.
Using "brain organoids is the best approach for allowing us to at least understand what's happening" to a human brain before birth, she says.
The new study doesn't invalidate current research using brain organoids, Kriegstein says. Instead it offers a roadmap to improve the model so that researchers can learn more about diseases and disorders including Parkinson's, Alzheimer's, autism, and schizophrenia.
"If you're going to model those diseases in a dish, you really want to make sure you're reproducing the same cells with the same cell type identities that they would normally have," Kriegstein says.
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