Brain organoids reveal new causes of tuberous sclerosis

The complexity of human brain This is largely due to the fact that its development involves processes unique to the human being. THE tuberous sclerosis complex (TSC) – a rare inherited disease that causes non-cancerous tumors to form in many parts of the body – is no exception in this regard, having long been described as a disorder primarily genetic based on data obtained in animal models.

Now, groundbreaking research from the Knoblich’s Laboratory at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) used models of brain organoids – cell cultures that recreate parts of human organs, in this case, the brain – derived from patients to unravel the mysteries of this rare disease of the brain neurodevelopment. The results are published in the journal Science.

“Our work shows that processes that occur only in the human brain – and not in other brains, such as the mouse brain – can be crucial for the formation of human diseases, in this case tuberous sclerosis”, explains the scientific director to SINC of the IMBA, Jürgen Knoblichco-author of the publication.

Thanks to these laboratory models of the human brain derived from patients, it was possible to determine the origin of the disease in specific human progenitor cells.

In many patients, TSC manifests as severe epilepsy and psychiatric symptoms such as autism and learning difficulties, a heterogeneous group of disorders, manifested by significant difficulties in acquiring and using the ability to understand, speak, read, write and reason.

Morphologically, this disease is characterized by well-defined signs that are usually found in the patient’s brain. Among them are benign tumors present in an area of the brain, as well as lesions in the cerebral cortex called tubers.

For a long time, both morphological aberrations were attributed to a genetic cause. However, the results of the analysis of patient samples diverge from the prevailing theory, especially with regard to tubers.

“Before, it was thought that an error in the DNA, produced during development, gave rise to the disease. Now, on the other hand, our study has shown that there is a type of cell, which we only find in the human brain, that is responsible”, the author tells SINC.

Left: During mid-gestation, CLIP cells generate interneurons that migrate to the cortex. Right: In the Tuberous Sclerosis Complex (TSC), CLIP cells generate brain tumors and cortical tubercles. / Knoblich | IMBA

human brain development

As part of the study, the team grew brain organoids of several affected patients, a method that makes it possible to investigate the molecular and cellular mechanisms that existed in the patients’ brains at some point in their development. “With this method, we found that, just like in the patients’ brains, tumors grew in the organoids and there were disorganized areas that resembled the patient’s tubercles”, he explains. Oliver Eichmullerfirst author of the study.

However, recapping the pathophysiology of a disease is only the first step in identifying the culprit: “Deepening into the causes, we found that both abnormalities were triggered by the excessive proliferation of a specific type of human brain cell”, says the specialist.

The disease develops from the excessive proliferation of cells known as the caudal progenitors of late interneurons.

These cells were called caudal progenitors of late interneurons (or CLIP cells). This type of cell is found in the developmental stage of the human brain, but not in animals such as mice. “Our work shows that our brain is very complex, much more so than that of most animals,” he says. Nina Corsiniresearcher at IMBA and co-author of the study.

Scientists draw parallels with other neurodevelopmental and neuropsychiatric disorders, but also with malignancies that affect people’s brains, and speculate that they may also be caused by human-specific developmental processes. “Our findings about specific human principles of brain development and pathology may also apply to other known diseases for which there are currently no therapies,” adds Knoblich.

Our group was the first to use organoid models to understand brain diseases, and this study is an example of their successful use to understand these diseases and develop new therapies.

Jürgen Knoblich, Scientific Director at IMBA