Small cultures of human neuronal cells developing in a dish are not quite “brains in a petri dish” as they are sometimes described. But these cerebral organoids give scientists unprecedented options for studying and understanding the early embryonic stages of human brain development. Two recent papers published in Nature show just how powerful these neuroscience research tools are. The first paper characterizes these neural developments more fully, while the second uses organoids as a tool to show how a neurodevelopmental disorder known as Timothy Syndrome develops.
Making a brain-like thing
The first paper focused on fully understanding brain organoids, which start out as a cluster of neural stem cells. The authors of the paper describe them as cell systems that build themselves up with their own internal growth program. After a month of growth in the dish, these organoids started to show brain regionalization, with different clusters of cells appearing to differentiate into the forebrain, midbrain, hindbrain, and retina, according to the gene markers for each of these regions.
After six months of growth, brain organoids developed 10 distinct cell classes, each of which mapped to neuron populations in the developing human brain, like astrocytes, retina cells, and cortex cells. Different brain organoids showed different distributions of these 10 neuron cell populations, and these differences were linked to the growth environment that the organoids were in. So, even though the brain organoids weren’t receiving growth signals from a human body, the culture environment could still direct their growth.
Overall, the paper showed that the cells in mature brain organoids have the same structural traits as mature neurons, including dense dendritic spines. By eight months, the brain organoids were spontaneously generating active neurons and neuronal networks. They also contained cells that were responsive to light, which suggests it may be possible to study how sensory inputs affect brain organoids.
The characterization of these cells shows that brain organoids present a unique opportunity to study developmental processes, including synaptic pruning, that have previously proven almost impossible to study in culture and would be unethical to study in humans. Many of these processes have been implicated in developmental disorders.
Studying a disease
In the second paper on brain organoids, the authors describe how they treated their cultured brain cells with growth factors that stimulated the development of organoids that resembled the forebrain. These organoids contained cells that relied on one of two different signal transmission molecules (GABA or glutamine). Using these organoids, the authors were able to model the role these cells play in the development of the fetal brain.
The authors focused on Timothy Syndrome, a neurodevelopmental disorder that is caused by mutations in a gene that encodes a protein that lets calcium transit across cell membranes. They were able to grow organoids from cells that carried these Timothy Syndrome mutations. Neurons in these organoids showed odd patterns in their activity while they were migrating through the culture. After migration, however, these Timothy Syndrome cells were able to integrate with the other neurons in the brain organoid, forming complete neural circuits.
This type of study, the authors suggest, could also allow for the examination of various other neurological diseases that couldn’t previously be modeled in a cell culture dish. Previously, researchers were limited to studying mutations in animals that lack the complexity of the human nervous system or working with cells in culture that didn’t form complicated networks. So the continued development of these brain organoids holds a lot of promise for the future of neuroscience.
Listing image by Allan Ajifo