Researchers have measured electrical activities in miniature brains in the laboratory that resemble the brain waves of preterm babies. The miniature brains are about one million times smaller than a human brain, but from about four months of age, they show rhythmic network activities.

The researchers who work with Alysson Muotri at the University of California in San Diego (California, USA) regard such organoids as models that can be used, for example, to investigate pathological brain abnormalities or the effect of drugs. The study was published in the journal “Cell Stem Cell”.

“The level of neuronal activity that we are seeing is unprecedented in vitro,” Alysson Muotri is quoted in a media release of the journal. Alysson Muotri and his colleagues are one step closer to having a model that can actually generate the early stages of a sophisticated neural network. Networks are created when nerve cells form connections with each other.

The researchers cultivated many of these three-dimensional organoids from special stem cells and allowed them to grow in the laboratory for ten months. They recreated the environmental parameters as they are necessary for the development of the cerebral cortex of a human brain.

From progenitor cells to brain cells

Using genetic markers, the researchers investigated what type of cells are found in different stages of the organoid. After one month, 70 percent of the cell systems consisted of progenitor cells. After three and six months, specialized brain cells, such as glial cells and nerve cells, were most frequently observed. The researchers also discovered nerve cells with what are known as GABA receptors, which had not previously been produced in the laboratory.

The pea-sized mini-brains grew on a dishes equipped with multi-electrode arrays. Alysson Muotri’s team was able to determine the electrical activity of the developing neuronal network over and over again. They compared these measurements with measurements performed by other researchers on premature babies. They trained an artificial intelligence system using the data from the premature babies and the program was able to approximate the developmental stage of the organoids.

Alysson Muotri and his colleagues are aware that their research also raises social and ethical questions. They stress that organoids are different from the human brain in many ways. “Organoids are still a very rudimentary model – we have no other brain parts and structures," says Alysson Muotri. For example, blood vessels are missing and there is no division into two brain halves.

In particular, he highlights the opportunities: “I can help people with neurological diseases by providing them with better therapies and a better quality of life.” Alysson Muotri also has a stake in a company that, among other things, aims to use brain organoids to advance the treatment of certain neurological diseases.

Not really comparable to a real brain

Oliver Brüstle from the Bonn University Hospital also sees great opportunities in research on brain organoids. He attests that the group working with Alysson Muotri is doing a good, serious job that is technically sound. However, he is disturbed by the interpretation that the neuronal activities are comparable to those of humans: “One should be very careful with such a statement.” For example, inhibitory neurons are difficult to create in organoids because they are formed elsewhere in the brain and then migrate into the cerebral cortex.

Jürgen Knoblich from the Institute of Molecular Biotechnology in Vienna also considers the comparison with the brain activities of premature babies to be inappropriate: “This interpretation goes too far and can raise false hopes.” In the scientific community, there are also doubts as to whether the flat electrode dishes can actually be used to measure the activities of the entire organoid. However, the organoid is a very good research model, much better than the mouse model often used so far.