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These 3D model brains with cells from several people are first of their kind

A chimeroid seen in blue, purple, pink and green colours

After one month of growth, a brain organoid comprised of cells from multiple human donors is just over one millimetre wide.Credit: N. Antón-Bolaños et al./Nature

For the first time, researchers have grown 3D models of the brain that include a wide variety of cell types from several people1. These ‘village in a dish’ organoids could help to reveal why the brain’s response to drugs differs from person to person.

Other teams have made 2D sheets of brain cells sourced from more than one human donor2, but this work reports 3D systems that are robust enough for research.

“It’s a really powerful technology, and a powerful approach,” says Tomasz Nowakowski, a biologist at the University of California, San Francisco, who was not involved in the study. Many groups are likely to embrace this method, he adds. “It’s a technical tour de force.”

These chimeric cultures, which the authors call Chimeroids, combine cells from as many as five donors. But future iterations could host cells from hundreds of people. “What if one day we could use Chimeroids as avatars to predict individual responses to new therapeutics before testing these in a trial? I like to imagine that future,” says Paola Arlotta, a stem-cell biologist at Harvard University in Cambridge, Massachusetts, and senior author of the study, which was published today in Nature.

It takes a village

Model systems called organoids mimic the cellular make-up of organs, such as the gut and the lungs. Researchers make them by bathing stem cells from a human donor in a precisely formulated cocktail of chemicals, which encourages the stem cells to mature into all the cell types that are typically present in a given organ. The culture conditions also encourage the cells to gather into a complex 3D shape.

Brain organoids are particularly slow-growing and finicky to use, and researchers have been on the hunt for better ways to make them. One approach has been to combine cells from several donors into a single organoid. Multi-donor clumps of cells might be easier to work with, and would capture a broad diversity of human genetics in a single model. However, because the starting stem cells grow at different paces, fast-growing lines inevitably take over.

Out of many, one

The trick, Arlotta and her colleagues now report, is to first make a set of single-donor organoids. As these mature, the cells in all the organoids take on similar growth rates. By then homogenizing these structures and pooling the cells together, it is possible to grow a composite organoid. The authors’ Chimeroids expanded to about 3–5 millimetres after three months and contain the same cell types that are present in fetal cortical tissue.

“This is a really good advance,” says Robert Vries, chief executive of organoid-research firm HUB Organoids in Utrecht, the Netherlands. The community that studies the central nervous system “really needs more organoid systems”.

Chimeroids should enable researchers to work out whether drugs will have distinct effects on different people. As a test case, the team treated the multi-donor organoids with neurotoxic drugs. Ethanol, which causes fetal alcohol syndrome, reduced the number of cells from just one donor’s cell line. Cells from that donor grew faster when combined with valproic acid, an anti-epileptic drug linked to an increased risk of autism spectrum disorder in children who’d been exposed to it in utero.

Growing pains

But careful follow-on work will be needed to ensure that any effects seen in the chimeric models come from the genetics of a given cell line, rather than from an interaction between closely packed cells, cautions Vries.

Chimeroids are also labour-intensive to grow, adds Nowakowski, who is experimenting with the model in his laboratory. But automated cell-culture systems should ease the workload and make these models viable for more-efficient experiments into diseases of the brain.