“Fake” brains to better understand early aging

In the box kept at 37°C, there are six cavities filled with an orange liquid in which small white balls float, like cotton. Miria Ricchetti’s laboratory at the Institut Pasteur in Paris works on progeroid genetic diseases. Rare, these disorders cause accelerated aging in children and a very short life expectancy, like progeria. Each white ball in the box is actually a cerebral organoid, a kind of “baby brain”. The room contains nearly 400.

Let’s be clear: these organoids are not complete brains and cannot become one. After two or three months, they cease their development, for lack of vascularization. For them to develop, they would have to be implanted in an animal, which would result in a chimera, a technique authorized by the latest bioethics law.

A way to test theories

In this case, the researchers do not go that far, and maintain them as they are, by renewing the culture medium. These cells are still very much alive, and we even record electrical activity, almost as we would for “real” brains. ” It’s quite spectacular, and I think we still don’t understand all the implications of these organoids.», recognizes Miria Ricchetti.

For her, who is not a specialist in this organ, these cultures represent above all a tool, a means of testing theories. “Animal models do not reproduce the Cockayne syndrome we are working on”, she justifies. The brain of mice or even that of primates proves to be too distant to be useful, and it is out of the question to work directly with the children affected, very weakened by the premature aging of their organism. It was therefore necessary to invent another approach to analyze the neurodegenerative problems linked to this syndrome.

In vitro structures to test future treatments

The team starts from the skin cells of sick children, which have been removed to confirm the diagnosis. These cells are treated to become induced pluripotent stem cells (iPSCs). These are then cultured to produce neurons. There, various techniques make it possible to create not just a simple layer of cells, but a veritable “organoid” in three dimensions. “Unguided, these iPSCs give cells of the whole brain, guided, they can recreate particular areas, explains the research director. They are not brains, but they have the composition closest to the human brain. »

These organoids from sick patients are then compared to other organoids from healthy people, to better understand the neurodegenerative mechanisms of accelerated aging diseases. The millimetric structures in the boxes are also used to test possible treatments.

With, eventually, an application to other more common diseases? “These organoids have more limitations for Alzheimer’s and Parkinson’s,” warns Miria Ricchetti. Blocked at a very early stage of their development, they could prove to be of little use for these disorders linked to a mature brain. But here again, research is moving quickly, very quickly.

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