Scientists grow tiny brain ‘organoids’ for study

Using stem cells, scientists have grown human "brain organoids" that demonstrate development of a number of brain regions. In this cross-section of an entire organoid, neural stem cells are red and neurons are green.
(Madeline A. Lancaster)

Scientists have figured out how to grow human stem cells into “cerebral organoids” — blobs of tissue that mimic the anatomy of the developing brain.

The advance, reported online Wednesday by the journal Nature, won’t allow scientists to grow disembodied brains in laboratory vats, said study leader Juergen Knoblich, a stem cell researcher at the Institute of Molecular Biotechnology of the Austrian Academy of Science in Vienna.


But it does offer researchers an unprecedented view of human brain anatomy, he said. Having the ability to probe a 3-D model of a 9-week-old embryo’s brain could help scientists better understand conditions that have been linked to problems in brain development, including autism and schizophrenia.

In a first, Knoblich’s research team has already grown brain organoids using stem cells from a patient with microcephaly, a rare genetic disorder that stunts brain growth.

“This allows us to study the disease in a human context” and not just in mice, Knoblich said.

The Austrian team’s work follows a number of efforts to use stem cells — either from embryos or from mature cells that have been reprogrammed to a more flexible state — to grow three-dimensional brain tissues for researchers to study.

Scientists had been able to use such cells to make neurons, gut tissue, pituitary glands, livers and even rudimentary human eyes, Knoblich said. But they’ve never grown a proto-brain complex enough for its different regions to interact the way they would during early brain development.

The key was to seed the cells in a gel-based scaffold to support them as they grew into neural tissue and to bathe them in nutrients with a spinning device called a bioreactor. Following this recipe, the organoids grew to 3 or 4 millimeters in diameter — a relatively large size, in embryonic biology terms.

The organoid structure became apparent about 20 to 30 days after the start of the procedure, said Madeline Lancaster, the postdoctoral researcher in Knoblich’s lab who came up with the method. The process seemed to work most effectively when the tissues were allowed to self-assemble without too much guidance, she added.

The hundreds of organoids the team made didn’t look like 9-week-old embryo brains, exactly, but they shared many of their key characteristics. By evaluating gene expression in the tissues of 35 of the organoids, the scientists confirmed that all incorporated cells that would become the dorsal cortex, where neurons are generated.

Over two-thirds had a choroid plexus, which makes cerebral spinal fluid. A few developed retinal tissue or a hippocampus.

The regions weren’t spatially organized as they would be in a developing embryo. But their presence in the organoid was enough to allow the team to study how neurons form in and migrate through the early brain.

“I often compare this to a car — you have the engine, you have the wheels, but the engine is on the roof,” Knoblich said. “The car would never drive, but you could take that car and analyze how an engine works.”

In the past, scientists studying early human brain development had to work with mouse brains or human neurons in a dish, said Dr. Anthony Wynshaw-Boris, a medical geneticist at Case Western Reserve University in Cleveland who wasn’t involved in Knoblich’s work. That limited their ability to study diseases that don’t behave the same way in mice as they do in people, or that involved interactions between differentiated brain structures.

Microcephaly is a case in point. Knoblich and his team decided to study the rare disorder because they knew that it stemmed from a problem with cell division in the embryonic dorsal cortex.

They started with a skin cell from a microcephaly patient and followed their usual method. But the resulting organoid was not the same as those made with skin cells from healthy patients. The microcephaly organoids had progenitor cells that divided strangely and generated neurons too early. The result was fewer neural progenitor cells, which could explain the smaller brain sizes seen in people with the condition, Lancaster said.

Yoshiki Sasai of the RIKEN Center for Developmental Biology in Kobe, Japan, a leader in the field who was not involved in the study, called the work with the microcephaly cells an “important advancement” that showed why self-organizing cultures are preferable to traditional, two-dimensional cells in a dish.

Organoids could also be used to test drugs that might mitigate symptoms of microcephaly and other diseases, Wynshaw-Boris said.

Wynshaw-Boris said he would like to use organoids in his own research, which seeks to unravel the mechanisms behind autism and lissencephaly, a developmental disorder in which the surface of the brain never develops its characteristic folds and grooves. It is caused when neurons don’t migrate far enough through the layers of the cortex, though scientists aren’t sure exactly why they remain deeper in the brain than normal.

Knoblich and Lancaster said they hoped to figure out ways to improve the layering in the dorsal cortex tissues in their organoids to make a more realistic model.

The group has no plans to try to generate a functional brain. That would be extremely difficult because the organoids don’t have vascular systems to deliver nutrients to the cells, or circuitry to transmit any sensory information, among other practical barriers.

He also said he thought such a pursuit would be unethical.