Researchers can study physiological function by growing cells in culture, but these cells have traditionally been raised in a single layer in a dish or in liquid suspension. Cells that make up tissues in the human body, however, form three-dimensional structures. In an effort to improve cell culture as a research model, scientists developed organoids, which have been touted as three-dimensional balls of cells that can mimic an organ in miniature. Studies have shown that cell types that make up an organ can be grown together in ways that allow them to create simplified mini-organs. But new research has suggested that brain organoids are not the miniature brains that they have been made out to be.
Reporting in Nature, the University of California San Francisco (UCSF) researchers have shown that commonly used organoid models are not replicating the basic characteristics of brain organization or development, and are nowhere near mimicking the complex circuitry that would be necessary to create a model of cognition.
“Some people have branded organoids as ‘brains in a dish’ but our data suggest this is a huge exaggeration at this point,” said Arnold Kriegstein, M.D., Ph.D., an organoid expert who is a professor of Neurology, among other appointments. “We find that organoids do not develop the distinctive cell subtypes or regional circuit organization that characterize normal human brain circuits. Since most human brain diseases are highly specific to particular cell types and circuits in the brain, this presents a grave challenge to efforts to use organoids to accurately model these complex conditions.”
The Kriegstein lab wants to create an atlas of the gene activity that accompanies brain development using human brain tissue. This map could help reveal what goes wrong in developmental disorders that impact the brain. But when data obtained from organoids was compared to the gene atlas, it became clear that the gene expression patterns seen during development were disrupted in the organoids.
Gene expression data from 235,000 cells that composed 37 organoids was obtained and compared to data from 189,000 human brain cells over various timepoints and brain regions. The cells making up the organoids were not differentiating into the specialized cells of the brain; they were expressing a bunch of genes that would usually be active in different types of cells. The organoid cells were also expressing high levels of cell stress genes.
“We were able to identify the major broad categories of cell types, but the normal diversity of subtypes – which play a key role in the proper function of neural circuits – was lacking,” Kriegstein said.
“The brain’s ability to wire together different cell types into highly structured and regionally distinctive circuits is central not only to normal brain function and cognition, but it is also these highly specific circuits that go awry in different ways in brain diseases such as autism, schizophrenia, and other psychiatric and neurological disorders,” said postdoctoral researcher, Madeline Andrews, Ph.D.
“Before we can use organoids to study these diseases and search for potential cures, we need to ensure they are actually modeling the brain circuits that are affected,” added postdoctoral researcher Aparna Bhaduri, Ph.D.
The scientists suggested that it may be possible to rethink brain organoid techniques so that cell stress can be reduced, and the cells replicate the brain more closely. They also noted that organoids are still useful for other research that does not need to mimic the circuitry of the brain.