Researchers at UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research have developed brain organoids – 3D brain-like structures grown from human stem cells – that exhibit organized waves of activity similar to those found in living human brains.
Then, while examining organoids grown from stem cells from patients with Rett neurological syndrome, the scientists were able to observe patterns of electrical activity that resemble seizures, a hallmark of the disease.
The study, published today in the journal Nature Neuroscience, expands the list of brain diseases that can be studied in organoids and illustrates the value of these human cell-based models in studying the underlying causes of disease and testing potential therapies.
“This work demonstrates that we can make organoids that resemble real human brain tissue and can be used to accurately model certain features of human brain function and disease,” said Bennett Novitch, a member of the Broad Stem Cell Research Center and senior author of the learning .
Over the past decade, researchers have discovered how to take cells such as skin or blood cells from a person’s body, coax them into induced pluripotent stem cells or iPS cells in the laboratory, and then train those cells to make any type of cell in the body found – including neurons. Scientists can now even stimulate iPS cells to aggregate into three-dimensional shapes, creating organoids that look more like small human organs than cells in a shallow bowl.
This advance has allowed scientists to study how a person’s cells might differ from the norm and conduct experiments that are impossible in living people – manipulating the genetics of kidney cells or using lung organoids to study how COVID-19 becomes infected and damages the lungs, for example.
However, when it comes to the human brain, it is especially difficult to create an organoid that mimics the organ’s structural complexity. Getting the cells to organize like in a human brain is only part of the battle.
The cells also need to connect to each other and function like neurons in a human brain. Healthy human brain cells not only send electrical signals through the brain in response to stimuli, but they also have coordinated waves of activity called neural vibrations or brain waves. Pronounced patterns of brain waves are associated with certain activities – such as studying or sleeping – and abnormalities in these patterns can be indicative of an illness.
“Many neurological diseases can have terrible symptoms, but the brain is physically good-looking,” said Dr. Ranmal Samarasinghe, member of the Broad Stem Cell Research Center and lead author of the study. “In order to find answers to questions about these diseases, it is very important that we can use organoids to model not only the structure of the brain, but also its function.”
After Novitch, Samarasinghe, and colleagues at the UCLA Intellectual and Developmental Disabilities Research Center made a batch of brain organoids from the skin cells of healthy people, they used two different approaches to study the patterns of electrical activity within them – one was to use a probe in each organoid measures the brain activity, the other observes the brain cells in action under a microscope.
Some of the information gathered was in line with the data scientists who would normally be found in brain scans called electroencephalograms, or EEGs. The analysis showed several types of neural vibrations.
“I didn’t expect the range of vibrational patterns we would see with,” said Novitch, who is also Ethel Scheibel’s professor of neuroscience at UCLA. “By learning to control which vibrational patterns an organoid exhibits, we may be able to model different brain states.”
Next, the team developed brain organoids using cells from people with Rett syndrome, a genetic disorder associated with learning delays, repetitive movements, and seizures. While the organoids appeared normal in structure and organization, their neural oscillations were abnormal: they lacked the variety of oscillations demonstrated in the non-Rett organoids. Instead, the Rett organoids had rapid, disorganized activity, as clinicians see in EEGs from people with Rett syndrome and related disorders.
When Novitch and Samarasinghe treated the Rett organoids with an experimental drug called pifithrin-alpha, the seizure-related activity patterns disappeared and the organoids’ neural activity became more normal.
The use of organoids to study brain disease will remain limited because organoids do not replicate every aspect of a human brain – they lack blood vessels, for example – and they are more like brains in early development than adult brains. However, the UCLA study suggests that they could still be used to test a wide variety of brain functions, disorders, and drugs that could not be examined with brain cells in a petri dish.
“This is one of the first tangible examples of drug testing in a brain organoid,” said Samarasinghe, who is also an assistant professor of neurology. “We hope it will serve as a stepping stone to a better understanding of human brain biology and brain diseases.”
Reference: Samarasinghe RA, Miranda OA, Buth JE et al. Identification of neural oscillations and epileptiform changes in organoids of the human brain. Nat Neurosci. 2021: 1-13. do: 10.1038 / s41593-021-00906-5
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