Dishing out new insights Alysson Renato Muotri

Can tiny brains grown in a dish reveal the secrets of sociability? Balls of brain tissue generated from stem cells are enabling us to understand the underlying differences between people who struggle to be sociable and those who have difficulty reining themselves in.

Alysson Muotri at the University of California, San Diego, and his team created the mini-brains by exposing stem cells taken from the pulp of children’s milk teeth to cocktails of growth factors that help them mature.

Eventually, they can develop as many as six layers of cerebral cortex – the outer surface of the brain. This region is much more sophisticated in humans than in other animals, and houses important circuitry governing our most complex thoughts and behaviours, including socialising with others.


Each mini-brain is approximately 5 millimetres across. “Though they’re not as well defined as they are in a real brain, they resemble what you find in an embryonic fetus,” says Muotri.

To understand how brain development affects sociability, the team used donated cells from children with autism and Rett syndrome, both of which are associated with impaired communication skills. They also used cells from children with Williams syndrome, a condition characterised by a hyper-sociable nature. People with Williams syndrome can be unable to restrain themselves from talking to complete strangers.

Altered connections

The team found that mini-brains grown using stem cells from children with autism form fewer neural connections, while those from Williams syndrome children have an abnormally high number. When cells from the teeth of children with none of these conditions were used, the resulting mini-brains were somewhere in between these two extremes.

“The differences are striking, and go in opposite directions,” says Muotri. “In Williams syndrome, one of the cortical layers makes large projections linking into many other layers, and these are important for sociality,” he says. “By comparison, autism-linked brains are more immature, with fewer synapses,” he says.

When Muotri’s team examined donated brains from deceased people with these disorders, they found similar patterns.

Research by other teams working with similar “organoids” suggests that the brains of people with autism also seem to have a higher number of inhibitory neurons, cells that act to damp down the signals transmitted through the brain.

Later this week, Muotri will discuss the results and outline the team’s future plans to probe sociability at a conference on stem cells in Olympic Valley, California. Ultimately, he wants to be able to understand how humans evolved to be so social, he says.

The team has begun comparing human mini-brains with ones made from chimpanzee and bonobo stem cells. “The most striking observation so far is that monkey brains mature way faster,” says Muotri.

Miniature eyes

Next, Muotri wants to try stimulating the mini-brains to see how they react. To do this, the team plans to develop eye-like tissue that can sense light, and hook this up to the mini-brains. “We hope to have projections from the retina going to the visual cortex in the mini-brain,” says Muotri. “We can then stimulate the eye and see what happens in the brain.”

As well as illuminating what makes us so sociable, the work may lead to treatments for conditions that affect sociability. Muotri has found that a growth factor called IGF1 can prompt mini-brains derived from cells from children with Rett syndrome to make extra neural connections. “Other people are now moving this into clinical trials in Rett syndrome,” he says.

Muotri’s work is a nice demonstration of the power of mini-brains to help understand the early, cellular features of neurological disorders, says Madeline Lancaster at the MRC Laboratory of Molecular Biology in Cambridge, UK, who developed the organoid-growing method Muotri used. But studying this tissue cannot reveal the features of such disorders that are more related to behaviour, she says.

“The human organoids are good for studying the very early stages of brain development, but may not reveal much about later, more mature stages on which things like sociality depend,” says John Mason at the University of Edinburgh, UK.