BBC Knowledge AUGUST 2017

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.

“We can gain insight into what goes

wrong in the brains of patients with

neurodevelopmental disorders”

NEUROSCIENCE

PHOTOS: ANCA PASCA LAB, REX/SHUTTERSTOCK

ILLUSTRATION: DAN BRIGHT

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

Transferred to

plates where they

cannot attach,

stem cells form

sphere- like

structures

Discoveries

science

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