Gray platter: Stanford team grows brain in a dish

STANFORD, Calif. – Stanford scientists have grown and assembled parts of a human brain in a dish.

Here’s what’s even more remarkable: Their mini-brain forms mental circuitry – and cells converse with each other.

“There is cross-talk,” said lead researcher Dr. Sergiu Pasca, assistant professor of psychiatry and behavioral sciences at Stanford University School of Medicine, whose study was just published in the journal Nature.

Researchers did not build an entire brain, the stuff of sci-fi fantasy. It doesn’t think; it’s not self-aware. That’s a far more complex and most likely unattainable goal.

Instead, they made a tiny but powerful model of the cerebral cortex for the study of such devastating human conditions as schizophrenia, epilepsy and autism – impairments not easily studied in people.

This mini-brain reveals how networks of our mind can grow, behave and communicate, giving scientists an unprecedented view of our most mysterious organ.

Researchers hope to learn what goes wrong with the mental circuitry of people with disease or disorders.

Their brain also can be used to test potential drugs, essential for improving the pharmaceuticals used by psychiatrists.

“It’s the first example of assembling, in a 3D culture, this brain region,” Pasca said. “Essentially, we get a small cerebral cortex in a dish.”

Understanding the neurobiology of the brain remains one of the great challenges of modern medicine. That’s because we haven’t had direct views of the brain’s cellular behavior. While we can watch mental function through tools like Magnetic Resonance Imaging, that doesn’t show us what’s happening at the most basic level.

And we haven’t been able to watch brain development in the lab because it happens during the second and third trimester of pregnancy.

Researching other diseases, like cancer, don’t have this problem. That’s because doctors can sample tumor cells and look at them under a microscope. The sampling and study of brain cells is much harder.

Re-creating this important stage in brain development shows “the technique’s promise for discovery – and even for testing potential interventions,” said Dr. Joshua Gordon, director of the National Institute of Mental Health, which made a video to explain the research. “It moves us closer to realizing the goal of precision medicine for brain disorders.”

Stanford researchers started with longstanding tried-and-true techniques. They took skin cells and turned them into stem cells. Then they used chemical prods to turn them into two different types of brain cells.

In one dish, they grew cells called glutamatergic neurons, because they secrete the chemical glutamate, responsible for sending excitatory messages in the brain. Too much cellular excitement is thought to underlie disorders like epileptic seizures.

In a second dish, they grew cells that secrete a different chemical, called GABA, which sends inhibitory messages in the brain. Their job is to apply the brakes.

These aren’t just flat garden-variety layers of cells. Rather, they’re brainballs. Each ball measures about 1/16 of an inch in diameter and consists of over 1 million cells each, living for up to two years. They don’t adhere to the dish – they float, like little bobbing pearls.

Then they were introduced to each other.

And here’s the magic: Within three days, the two cell types fused into one big sphere – and then started organizing.

The cells that make GABA cells migrated over to the cells that make glutamate – and began forming the circuitry that is responsible for the brain’s most advanced cognitive activities, the team found.

“They start moving, and keep moving, for months,” making small hops in one direction, said Pasca. “They move to the other side and make connections.”

They grew long appendages called axons. They also grew little knobby spines that stick out like branches to receive chemical messages from other cells’ axons. It is this signaling that enables us to think and learn.

Using small electrodes, the team listened in on the fused cells and heard communication. The GABA-making and glutamatergic cells were successfully forming circuits and signaling to each other.

To be sure, their brainball is an incomplete model. It lacks complexity and is missing other cells that are part of the cerebral cortex. There aren’t blood vessels. It will never grow large.

But it’s already taught them about a rare developmental disease called Timothy syndrome, which includes symptoms of autism and epilepsy. Growing brainballs from skin cells donated by three patients, they found that these cells don’t migrate normally – their hopping movements are too quick, and too small. Over time, they got left behind.

The same gene that causes Timothy syndrome is linked to schizophrenia, different types of autism and bipolar disorder. Pasca suspects these conditions may also have flaws in the fusing and communication of cells.

“The exquisite timing and placement of these different neuron cell types is critical for establishing a balance between excitation and inhibition within brain circuits. This balance is thought to be disrupted in brain disorders,” Dr. David Panchision, chief of NIMH’s Developmental Neurobiology Program, said in a statement.

“Re-playing these developmental processes with a patient’s own cells can allow us to determine what distinguishes these different disorders,” Panchision said.

In the future, the Stanford team hopes to study the cells of individual patients to see if they can detect problems with their ability to move, migrate and communicate.

“It is a powerful platform for asking how the human brain develops,” Pasca said. “Can we find abnormalities that are associated with disease? If we do, can we test drugs? That is its potential.”