Mini Brains That Throw Seizures

What happens when you grow a patient’s disease inside a lab-grown brain and then try to cure it?

What happens when you grow a patient’s disease inside a lab-grown brain and then try to cure it?  A UCLA research team grew tiny blobs of human brain tissue, infected them with Rett syndrome - a rare disorder that robs young girls of speech and movement and watched them develop epilepsy.

Brain organoids function as laboratory-developed neuron groups that use a patient's skin cells to create neuron clusters which contain the patient's DNA along with all disease-related genetic alterations. Early organoids exhibited normal physical appearance but showed complete electrical silence because they lacked any brain activity and their network connections did not function. The critical defect occurred because Rett syndrome causes brain function impairment while leaving physical structures intact. The missing ingredient was inhibitory neurons -the brain's braking system. Standard organoids only produced excitatory neurons. The solution required researchers to create two separate organoid units which would later be combined into one structure. Inhibitory neurons travelled through the organoid system just as they would during foetal brain development which allowed the organoid to create actual brainwave patterns

The team then swapped in cells from real Rett patients. The organoids displayed normal structural characteristics. The system showed electrical disturbances because it produced synchronized aggressive electrical discharges which eliminated stable gamma rhythms while generating high-frequency seizure signals that mirrored the signals used by neurosurgeons to identify epileptic brain areas in patients.

The results from the clever swap experiment showed that the inhibitory neurons had to be replaced with mutant versions to show the experiment's intended outcome. The researchers evaluated two different medications. The standard epilepsy medication Valproate led to spike reduction but it did not fix the disrupted network. Pifithrin-α works as a cancer-biology drug which prevents the activity of a protein named p53. This study proves organoids can model not just brain structure, but brain dysfunction - the broken rhythms underlying epilepsy, autism, and Rett syndrome. They're also powerful enough for real drug discovery, surfacing a lead that animal models missed entirely. The disease isn't in the cells. It's in how they talk to each other.

References:

Samarasinghe, R. A., Miranda, O. A., Butnaru, J. E., Mitchell, S., Ferando, I., Watanabe, M., Allison, T. F., Kurdian, A., Fotion, N. N., Gandal, M. J., Golshani, P., Plath, K., Lowry, W. E., Parent, J. M., Mody, I., & Novitch, B. G. (2021). Identification of neural oscillations and epileptiform changes in human brain organoids. Nature Neuroscience, 24(10), 1488–1500.