Researchers have made a major advance in the development of human brain “organoids” — miniature, 3D tissue cultures that model brains in a dish. The new method, published in Nature, consistently grows the same types of cells, in the same order, as the developing human cerebral cortex. The advance could change the way researchers study neuropsychiatric diseases and test the effectiveness of drugs.
The genetics behind human neurological disease are complex, with large spans of the genome contributing to disease onset and progression. Studying neurological diseases in other animals provides limited opportunities for relevant discovery, as human brains are quite distinctive.
Organoids — simplified, multicell replicas with some of the features of the organ they model, organoids allow scientists to see how cell types within a structure interact with one another — offer great promise for studying human disease directly. But so far, they have failed in one very important way: They’re inconsistent.
“We might all use our brains differently, but each of us has the same collection of cell types and basic connections,” said senior author Paola Arlotta, the Golub Family Professor of Stem Cell and Regenerative Biology at Harvard and a member of the Broad’s Stanley Center for Psychiatric Research. “That consistency is crucial and, with very few exceptions, it is reproduced every time the human brain forms in the womb. There are only the smallest differences between us in terms of the cell types and structures in our brains.”
So far, that has not been the case with organoids. While they do generate human brain cells, each one is unique. That means they cannot be used easily to compare differences between diseased and control brain tissues reliably.
“Organoids have dramatically advanced our ability to study the human developing brain,” said Arlotta. “But until now, each one has been its own snowflake, making its own special mix of cell types in a way that could not have been predicted at the outset. We solved that problem.”
Building on seminal work led by the late stem cell biologist Yoshiki Sasai, the team created organoids that are virtually indistinguishable from one another — even when grown for longer than six months in the laboratory.
Furthermore, under specific culture conditions the organoids were healthy and able to develop long enough to produce a broad spectrum of the cell types normally found in the human cerebral cortex.
These advances mean that brain organoids can now be used as viable experimental systems to study diseases in patient tissues directly, and to compare the effects of various drugs. “Human brain organoids create the opportunity to understand human brain development and provide a critical model, mediating between dispersed cell cultures and animals to study many devastating neurodevelopmental disorders,” said Steven Hyman, core institute member and director of the Stanley Center. “The utility of this model has been limited by its variability until now. The Arlotta lab has taken a giant step toward making brain organoids into much-needed models in which to study human brain disease.”