When developmental neurobiologist Arnold Kriegstein talks about his work, it sounds for all the world like he is talking about the brains of teenagers.
They are stressed. Their identity is mixed up. But putting them in a good environment is helpful to their development.
Kriegstein, though, who is the John Bowes Distinguished Professor in Stem Cell and Tissue Biology and the founding director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at the University of California at San Francisco, was describing brain organoids.
In the Jan. 29, 2020, issue of Nature, he and his colleagues reported that cells from more than three dozen individual organoids, generated from four different starting cell lines by any of three different protocols, universally showed gene expression patterns indicative of cellular stress.
Furthermore, although organoids did develop into multiple cell types, there were “important differences” to normal brain development, Kriegstein said.
In general, the organoids failed to develop the full repertoire of cell subtypes that is a defining feature of the brain.
Individual cell identities were also less well-defined, with many cells co-expressing markers of both progenitor cells and differentiated cells, or of different brain cell subtypes.
Finally, excitatory neurons in the normally developing forebrain will have distinct gene expression signatures depending on their location within the cortex. In organoids, the researchers did see signatures that would be location-specific in the brain – but cells expressing the signatures of distant locations could frequently be found right next to each other.
All of those are challenges for studying brain diseases, which are often highly cell type-specific.
In summary, Kriegstein told BioWorld, “we see that [organoid brain cells] have an identity crisis, we see that they are stressed, and those two features are related.”
On the plus side, “the data suggest that this is a tractable problem,” he said. “You can solve the identity problem as well as the stress problem.”
In their paper, Kriegstein and his colleagues did so by transplanting the organoids into mouse brains, providing them with a richer, more naturalistic environment.
After transplantation, the stress-related signature disappeared, and “cell identity becomes crisper,” he said.
Kriegstein’s laboratory studies the developing human brain, and diseases of the developing human brain.
A powerful advantage of using organoids to do so is that organoids can be generated from cells of patients who carry genetic diseases. “So that brings us to the question of how good are these organoids at modeling normal development, and modeling disease,” he said.
Organoids are being used by many research groups to model multiple aspects of brain development, from cell migration in brain tumors to epigenetic contributions to developmental processes.
On the same day that Kriegstein and his team published their findings, a team from the University of Trento reported on using brain organoids to understand genetic alterations in medulloblastomas and the effects of those alterations on drug sensitivity.
His own take, based on the paper, is that organoids remain valuable tools in many instances, but in some cases, the features that he and his team have identified may provide more of a challenge.
In particular, he advocated for skepticism where organoid studies “claim to have found mechanisms of diseases that we know are related to metabolic stress – and that includes many neurodegenerative diseases.”
The work now published in Nature shows that “the cells themselves are enormously stressed.” And that makes it much more difficult to tease out stress-related disease mechanisms.