Human brain disorders have always presented researchers with a daunting challenge. They’re hard to study in laboratory mice because they affect the very organ that separates us from animals. And they’re difficult to study in humans because patient safety depends on noninvasive techniques.

Enter the brain organoid. Advances in stem cell biology and a new appreciation of the self-organizing powers of developing brain tissue have allowed researchers to create 3-D clusters of living brain that open a new window onto brain development and disease.

“I think that these brain organoids hold incredible potential for modeling human neurological disease in completely new ways,” said Paola Arlotta, the Golub Family Professor of Stem Cell and Regenerative Biology and chair of Harvard’s Department of Stem Cell and Regenerative Biology. “I like to imagine a future scenario where we will be able to ask very precise questions about what goes wrong in the context of psychiatric illness, for example.”

Arlotta has devoted her career to understanding brain development and what goes wrong in disease. She twice has stood accepted wisdom on its head. In 2013, challenging the theory that neurons cannot change, she used lab mice to show that one type of neuron can be transformed into another. A year later, she demonstrated that the insulating sheath of nerve cells, thought to be distributed identically along the axons of all neurons, instead displays distinct patterns in different cells. That led to the reinterpretation of some theories regarding the role of that insulation, called myelin, and how neurons use it in complex behaviors.

In recent years, Arlotta has become a pioneer in brain organoids, which she believes may one day shed light on little-understood conditions such as autism, schizophrenia, and bipolar disorder.

Arlotta collaborator Jeff Lichtman, the Jeremy R. Knowles Professor of Molecular and Cellular Biology, has held a front row seat to all this mystery. Through his “Connectome” project, he is working to build a map of neural connections by taking high-resolution images of thin brain slices.

“If getting to a full understanding of the brain is a mile, we have walked at least six inches,” Lichtman said. “You look at the actual structure of the brain or even an organoid and it’s just extraordinarily complicated. It’s much more complicated than anything humans have ever built. This is a little humbling.”

One consequence of that lack of understanding, Arlotta said, is that theories can stagnate.

“It is rather daunting,” Arlotta said. “How are we going to develop new treatments if we do not know what cell types, among the thousands present in the brain, are involved in psychiatric illness? How are we going to find molecular targets for new drugs if we cannot study the very organ that is affected? This is particularly problematic when diseases that start in the womb, during brain formation, manifest later in life.”

Arlotta said that creating organoids from people afflicted with brain disorders is akin to going back in time to watch how development plays out.

“What if we could somehow go back, so to speak?” she said. “What if we could take a sample of blood from a child with autism, make his or her own stem cells and turn those into a model of their brain? Could we then begin to watch in some small part how the brain had formed? And in so doing, will we have the unprecedented opportunity to shed light on what abnormalities have occurred?

“I think that if, in the next decade, we will have built on the use of brain organoids to understand what the neurobiological substrate of psychiatric illness may be, then we would look very proudly at the work that we are doing today.”