Stacks of little plastic dishes in a laboratory incubator, each one holding a free-floating blob of human brain might sound like the stuff of science fiction. But this is no futuristic flight of the imagination: these strange creations, known as brain organoids, are already being cultivated in labs all over the world, and researchers believe they could unlock some of the deepest secrets of how our brains grow and what happens when they go wrong.
“I don’t think that any of us set out to try and grow a brain in a dish,” says Madeline Lancaster, a neurobiologist at the MRC Laboratory of Molecular Biology in Cambridge. “If you’d asked me even just a few months before I started working on it, I would have said it was completely nuts – but in my case, it was an accident!”
Lancaster’s accidental experiments with organoids started when she was a postdoctoral researcher working in Vienna with molecular biologist Jürgen Knoblich, investigating how the brain forms during development in the womb. She started by growing brain stem cells in flat layers in a dish, but soon realised they lacked many of the key characteristics of nerve cells in a real brain. In search of a better method she tried a new technique for growing neural ‘rosettes’ – flat, flower-like circles of cells that were more realistic, albeit still two-dimensional.
“When I put the cells in the culture dish, there was something wrong with the reagents that I was using,” she says. “Rather than forming these nice flat rosettes, mine were forming these weird, floating balls. I thought they looked interesting, so I continued growing them.”
Speaking to other researchers in the field, she discovered that some of them had also seen these strange blobs, but had thrown them away because they looked wrong. But while these brain balls looked curious from the outside, what Lancaster found inside was fascinating. Each was made from bulging layers of cells connected by cavities, just like the fluid-filled ventricles that connect the hemispheres of the cerebral cortex in a real brain. Even the layers of cells mimicked the arrangement in normal brain tissue, with stem cells lining the ventricles and layers upon layers of more specialised cells and neurons built up towards the outside.
Building a brain
Despite their ‘mini-brain’ nickname, these organoids are a long way from being full-size human organs. They’re around half a centimetre in diameter – roughly the shape and size of the eraser on the end of a pencil – and they lack key structures such as blood vessels, which limits how big they can grow. Organoids are also remarkably hardy, as long as they’re grown in a scrupulously clean environment, and can stay alive for more than a year.
Lancaster’s mini-brains are enabling her to prise open the ‘black box’ of human brain development. Because they reflect the cell types and organisation of a growing human brain, organoids are opening a window into time of life that has previously been inaccessible to science.
“People have done MRI…