As three-dimensional brain-like tissues made from human stem cells, cerebral organoids have been lauded for their potential to reveal how the complex structure and function of the brain develops. However, new research by the University of California, San Francisco (UCSF) shows that organoids are unable to replicate the most basic features of human brain development and organisation.
'Some people have branded organoids as 'brains in a dish' but our data suggest this is a huge exaggeration at this point,' said lead author of the study, Professor Arnold Kriegstein, of UCSF. 'We find that organoids do not develop the distinctive cell subtypes or regional circuit organisation that characterise 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 study is the result of efforts by Professor Kriegstein's group to map the expression of genes that control brain development using human tissue. To assess their genetic makeup, more than 235,000 cells were extracted from 37 different organoids (made using three different methods and four different stem cell lines). Gene expression patterns of the organoids were compared to those of 189,000 cells from different brain areas and developmental time points in normal human brains.
The analysis revealed that instead of differentiating normally into the brain's distinctive cell types, organoids express a mixture of genes normally found in different kinds of cells. Single-cell gene expression data from organoids made by other research groups also showed a lack of normal development. Subsequently, researchers found the organoids expressed abnormally high levels of cellular 'stress' genes. They hypothesised that this could be caused by methods used to grow organoids, preventing organoids from developing normal cell types and regional organisation.
'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 Dr Madeline Andrews, a postdoctoral researcher in the Kriegstein group.
'Before we can use organoids to study these diseases and search for potential cures, we need to ensure they are actually modelling the brain circuits that are affected,' fellow postdoctoral researcher Dr Aparna Bhaduri added.
However, organoids can still be useful tools for research applications that do not aim to model specific brain circuits in either health or disease, according to the authors of the study.