With the help of brain organoids, IMBA scientists were able to determine that tuberous sclerosis, a rare neurodevelopmental genetic disorder, occurs developmentally rather than just genetically. With these patient-derived laboratory models of the human brain, they identified the origin of the disease in specific human progenitor cells. The results, now published in Sciencefurther show that the pathology of diseases affecting the human brain can only be well understood using models of human brain organoids.
The complexity of the human brain is largely due to its development involving processes unique to humans, many of which are still hidden in the darkest recesses of our current scientific knowledge. Tuberous sclerosis complex (TSC) is no exception in this respect, as it has long been described as a predominantly genetic disease based on data obtained from animal models. Now, groundbreaking research from the Knoblich lab at IMBA – Institute for Molecular Biotechnology of the Austrian Academy of Sciences – is using patient-derived brain organoid models to unlock the mysteries of this rare neurodevelopmental disease. “Our findings on the root cause of TSC led us to a type of progenitor cell specific to the human brain. This explains why the pathology of this disease could not be well established with other laboratory models,” explains the scientific director of the IMBA, Jürgen Knoblich, co-corresponding author on the publication.
In many affected patients, TSC manifests as severe epilepsy and psychiatric symptoms such as autism and learning difficulties. Morphologically, TSC is characterized by well-described signs often found in the brain of patients. These include benign tumors present in a defined area of the brain, as well as lesions of the cerebral cortex, or “cerebral mantle”, called “tubercles”. 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, mainly with regard to tubercles. “To study tuberous sclerosis, we developed brain organoid models of the disease: three-dimensional cell cultures that we use to model the brain and that we can derive from any patient,” says co-corresponding author Nina Corsini, research associate at the Knoblich Group at IMBA.
For the study led by Corsini and Knoblich, the team developed brain organoids from several affected patients, a method that makes it possible to study the molecular and cellular mechanisms that existed in patients’ brains at a given point in development. “With this approach, we found that, as in the brains of patients, the organoids developed tumors and had disorganized areas that resembled patient tubercles,” says Oliver Eichmüller, the first author of the study. However, summarizing the pathophysiology of a disease is only a first step towards identifying the culprit: “Digging deeper into the causes, we discovered that both of these abnormalities were triggered by the excessive proliferation of a specific cell type. to the human brain. says Eichmüller. These cells have been called Caudal Late Interneuron Progenitors, or CLIP cells. These are cells found during the developmental stage of the human brain, but not in animals like mice. “Our study shows that our brains are very complex – much more complex than the brains of most animals,” Corsini says.
Scientists draw parallels with other neurodevelopmental and neuropsychiatric diseases, but also with malignant diseases affecting the human brain, speculating that these could also be caused by human-specific developmental processes. “Our findings on human-specific principles in brain development and pathology could also apply to other known diseases for which no therapy currently exists,” says Knoblich.
After making headlines around the world in 2013 for establishing human brain organoids at IMBA, the Knoblich lab has already adapted this breakthrough technology to study the hidden processes of human brain development, as well as several diseases affecting the human brain. With their current findings, the team is now able to shed light on one of the darker slopes of neuroscience and medicine. “We are clearly not going to stop there! exclaims Knoblich. “As a next step, we aim to study other neuropsychiatric diseases by further adapting our technology. We are confident that this human-derived laboratory model will finally help us identify human-specific mechanisms that have been neglected for far too long!