Development of 3D MICrobrains for drug testing

At the Department of Psychiatry of Erasmus MC, researchers, including neurologist Femke de Vrij, have been working on the development of brain organoids for some time. For them, the challenge from ZonMw, with the challenge to develop practically applicable human brain models, was just right. With the subsidy they can now start working on the development of 3D MICrobrans.

Brain organoids have the potential to become a reliable and more predictive alternative to animal research for new drugs for neurological and psychiatric diseases. The value of so-called mini brains, in those cases made of skin cells, for brain research was also recently demonstrated in three publications by neurobiologist Nael Nadif Kasri from Radboudumc.

Development 3D MICrobrains

De Vrij took up the challenge and contacted Core Life Analytics, one of the initiators of the challenge. They develop software to analyze so-called high content imaging images.

“We were already able to reprogram human skin, blood and other cells into pluripotent stem cells, and grow them into all kinds of brain cells in 3D structures. We are now going to make 3D MICrobrains from that. MICro stands for 3D Myelination and Inflammation Cortical Network. They are 3D models, made of clumps of cells that grow on the bottom of a cell culture tray of 3 by 3 millimeters, making them easy to view under a microscope,” says Femke de Vrij

The software and technology that private partner Core Life Analytics is developing are used in the research to assess how the 3D MICrobrains behave when certain substances are added to them. “An automated microscope then makes a lot of images from a plate with 384 of those 3D MICrobrains and then we use special software and Artificial Intelligence to investigate in those images what differences arise when you add those substances,” says De Vrij.

Functioning as a human brain

The 3D MICrobrains are intended to function in the same way as the human brain, but in a micro format. Its size is about one millionth of the normal brain volume. Within the model, all cells – neurons, astrocytes, white matter cells and microglia – lie in the same organized structure as in early development of the frontal cortex.

The researchers will test whether the 3D MICrobrains respond to medicines and nutrients in the same way as a real human brain. “A mouse is not a human being, but a brain organoid is not an ordinary brain either. So we will carry out tests with existing substances. We know about certain substances that cause the microglia to go crazy. Do the microglia in the 3D MICrobrains react the same when we add those substances to them?”, explains De Vrij.

Ultimately, the researchers hope that in the 3D MICcrobrains it will be possible to study the white matter cells (oligodendrocytes) and the microglia in particular. “Oligododendrocytes are important for making white matter, which acts as a kind of insulating layer around the extensions of the neurons. And microglia are the cells involved in the immune system in the brain. We would like to study white matter and inflammatory mechanisms so that we can gain more insight into psychiatric disorders. For these studies, we need brain structures with a human-specific biology. Laboratory animals are not suitable for this,” says De Vrij.