Tiny clusters of lab-grown cells are a new window into the human brain

"The biggest challenge in psychiatry today is that most disorders are still defined behaviorally," says Sergiu Pasca, a neurobiologist at Stanford University. "We don’t have molecular markers. We are very far behind in finding therapeutics."

• "For the human brain, we cannot access it at will at the molecular and cellular level. The need for creating these models comes from this frustration."

How it works: Far from being full brains, neural organoids are three-dimensional clumps of cells, typically a few millimeters in diameter, that begin in the lab as stem cells that are then chemically coaxed into becoming neurons.

• They're both a closer proxy for the human brain than the animal models researchers have traditionally used and an alternative to studying tissue from humans that can raise ethical challenges.

Brain organoids are typically grown for weeks or a few months and model the earliest stages of brain development.

• Pasca and his colleagues reported this week that organoids can be maintained for nearly two years and, after about nine months, the tissues undergo changes in gene expression that are similar to some of those in the brain after birth.
• The researchers then looked at when genes associated with brain-related disorders — like autism, epilepsy and neurodegenerative diseases — turn on and off in the organoids, which could help them to tune these models to capture the biology they are interested in studying, says Pasca.
• "It opens the door to look at aspects of development that happen after birth and hopefully disorders that affect brain after birth," says Madeline Lancaster, a developmental biologist at the Medical Research Council's Laboratory of Molecular Biology in Cambridge, U.K., who pioneered brain organoid techniques.

The big picture: A recent burst of studies illustrates how scientists are honing and applying brain organoid research to probe an expanding list of questions.

Humans' evolutionary history: Brain organoids can be grown from the cells of any species, including apes, making it possible to compare the brain development of humans and our closest relatives, says Lancaster.

• In a recent study, researchers grew organoids containing a genetic variant found in Neanderthals and Denisovans for a gene involved in forming synapses between neurons. The resulting tissues were smaller and had a different texture and the neurons fired faster compared to those of modern humans, they reported earlier this month.
• It's difficult to draw many conclusions about the brains of Neanderthals from the study, Lancaster and other experts say, but it demonstrates the breadth of studies researchers can now consider.

How disease affects the brain: Researchers are also using the lab-grown tissues to understand how SARS-CoV-2 may infect brain cells.

The basic biology of the brain and its development: Organoids are helping researchers better understand what cells and signals direct the brain's development.

• "It allows you to almost re-create embryology," says Debra Silver, a developmental neurobiologist at Duke University who uses brain organoids to study microcephaly and other conditions.
• What's new: Pasca and other researchers are taking organoids made from brain cells that give rise to different parts of the brain and putting them together in a dish to make "assembloids." These models help them to see how cells migrate to other regions of the brain during development and how different regions connect with one another.

Yes, but: Brain organoids aren't brains.

• They lack the organization of the brain and can't communicate with other brain regions.
• They lack the inputs from eyes, ears, skin and other sensory organs — in other words, a body — that shape the brain's function.
• And they don't contain the brain's other cells, including immune cells, or blood vessels.

What to watch: As brain organoids become more complex, some bioethicists say the potential ethical and legal challenges will grow.

• One question — sparked by brain organoids demonstrating coordinated electrical activity among the neurons — is whether these brain models could eventually become conscious, Sara Reardon writes in Nature News.
• But philosophers and scientists don't agree on a definition of consciousness, and today's organoids are far from a fully formed brain, says Jeantine Lunshof, a bioethicist at Harvard University who leads the Brainstorm Project, an NIH-funded project that brings ethicists and scientists together to discuss brain organoid research and ethical issues emerging from it.
• "Assuming you could make such a model, you still don’t know what you are looking for," she says.