“We can gain insight into what goes wrong in the brains of patients with neurodevelopmental disorders”
Neuroscientists have grown ‘spheroids’ made of human cells. Dr Sergiu Pasca, who was involved in the research, explains how these 3D structures could be used to better understand the brain
Where do the cells come from?
The ability to transform skin cells into ‘induced pluripotent stem cells’ has been a revolutionary step and holds great promise for understanding psychiatric disorders. These stem cells can become anything. You can now take a simple skin biopsy and grow cells in a non-invasive way to become cell types of interest.
But there are limitations to what you can do with neurones derived through conventional methods, which involves growing a single layer of cells at the bottom of a Petri dish. One is that the cells don’t interact in the same way as they would in the brain. So we’ve been building three-dimensional spheroid cultures. People have been calling these cultures ‘mini-brains’, which isn’t accurate. It resembles parts, but not the entire human brain.
How do you make a ‘spheroid’?
We move stem cells to plates where they cannot attach, so they curl and start making balls. We call them ‘spheroids’ because they’re sphere-like structures. With minimal instructions you can guide the cells to become derivatives of the ectoderm [embryonic tissue that develops into skin and nervous system]. There are all the cell types that make the cerebral cortex, which is the outer layer of the brain that’s responsible for thinking and most higher brain functions.
Which cells have you studied?
The cerebral cortex has two types of neurones. It has neurones that release glutamate at a synapse (a connection with another neurone) – that excite the other neurone. About 80 per cent of neurones in the cortex are ‘excitatory’ or ‘glutamatergic’. We also have the 20 per cent of neurones we call ‘inhibitory’ or ‘GABAergic’ because they release GABA, another neurotransmitter, that puts a brake on the activity of cells. There’s a balance between the two types: if you have too much excitation, the consequence is epilepsy and seizures.
What have you found so far?
GABAergic cells aren’t made at the same time and in the same place as glutamatergic cells, but in deep structures, migrating over many months to reach the cerebral cortex. So in one dish we make the glutamatergic cells and in another we generate GABAergic cells. After two to three months of maturing, we put them in one tube, label the cells fluorescently and watch them. What happens is
really wonderful: the two spheres fuse. Within weeks they start making connections. We listened to electrical activity and showed they’re receiving input from cells around them. So we started recreating a complex neural network, a circuit-like structure that has both cell types, as in the cerebral cortex.
Why are spheroids useful?
We call this a modular system: you can make specific brain regions and put them together. This is ultimately a platform that would allow scientists to ask questions about how different brain cells talk to each other, both in isolation as well as when you assemble them in a dish. We can gain insight into what goes wrong, presumably, in the brains of patients with neurodevelopmental disorders such as autism, schizophrenia or epilepsy, which are still untreatable.