Why the human brain is more vulnerable to disease

Date:
January 27, 2022
Source:
IMBA- Institute of Molecular Biotechnology of the Austrian Academy
of Sciences
Summary:
With the help of cerebral organoids, scientists were able to
ascertain that tuberous sclerosis, a rare neurodevelopmental genetic
disorder, arises developmentally rather than only genetically. With
these patient- derived laboratory models of the human brain,
they pinpointed the origin of the disease to progenitor cells
specific to humans. The findings further show that the pathology
of diseases affecting the human brain could only be well understood
using human-derived brain organoid models.



FULL STORY ==========================================================================
With the help of cerebral organoids, IMBA scientists were able to
ascertain that Tuberous Sclerosis, a rare neurodevelopmental genetic
disorder, arises developmentally rather than only genetically. With these patient-derived laboratory models of the human brain, they pinpointed
the origin of the disease to progenitor cells specific to humans. The
findings, now published in Science, further show that the pathology of
diseases affecting the human brain could only be well understood using human-derived brain organoid models.


==========================================================================
The complexity of the human brain is largely due to its development
involving processes unique to humans, many of which are still lurking
in the darkest corners of our current scientific knowledge. Tuberous
Sclerosis Complex (TSC) is no exception in this respect, as it has long
been described as a chiefly genetic disorder based on data obtained from
animal models. Now, breakthrough research from the Knoblich lab at IMBA -- Institute of Molecular Biotechnology of the Austrian Academy of Sciences
-- uses patient-derived cerebral organoid models to pierce the mysteries
of this rare neurodevelopmental disease. "Our findings on the root cause
of TSC led us to a progenitor cell type specific to the human brain. This explains why the pathology of this disease could not be well established
with other laboratory models," explains IMBA Scientific Director Ju"rgen Knoblich, co-corresponding author on the publication.

In many affected patients, TSC manifests in the form of severe
epilepsy and psychiatric symptoms like autism and learning
difficulties. Morphologically, TSC is characterized by well-described
signs often found in the brains of patients. Among those are benign
tumors present in a defined area of the brain, as well as lesions in
the brain cortex, or "cerebral mantle," called "tubers." For a long
time, both morphological aberrations have been attributed to a genetic
cause. However, results from the analysis of patient samples diverged from
the prevalent theory, mainly with regards to tubers. "To study Tuberous Sclerosis, we developed cerebral organoid models of the disease: three- dimensional cell cultures that we use to model the brain and that we can
derive from any patient," explains co-corresponding author Nina Corsini, Research Associate in the Knoblich Group at IMBA.

For the study led by Corsini and Knoblich, the team grew brain organoids
from several affected patients, a method that allows to investigate
molecular and cellular mechanisms that existed in the patients' brains at
some point during development. "With this approach, we found that, like
in the patients' brains, the organoids grew tumors and had disorganized
areas that resembled patient tubers," explains Oliver Eichmu"ller, the
first author on the study. However, recapitulating the pathophysiology
of a disease is only the first step towards designating the culprit: "By digging further into the causes, we found that both of these abnormalities
were triggered by the excessive proliferation of a cell type specific
to the human brain," states Eichmu"ller. These cells were termed Caudal
Late Interneuron Progenitors, or CLIP cells. They are cells found during
the developmental stage of human brains but not in animals like mice.

"Our study shows that our brain is very complex -- much more complex
than the brains of most animals.," says Corsini.

The scientists draw parallels to other neurodevelopmental and
neuropsychiatric diseases, but also to malignant diseases affecting human brains, 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 therapies exist to this date," states Knoblich.

Having made headlines worldwide in 2013 for establishing human brain
organoids at IMBA, the Knoblich lab already adapted this revolutionary technology to studying 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 shady slopes
of neuroscience and medicine.

"We will clearly not stop here!," exclaims Knoblich. "As a next
step, we aim to investigate further neuropsychiatric diseases
by adapting our technology further. We are confident that this
human-derived laboratory model will finally help us identify
human-specific mechanisms that have been overlooked for far too long!"
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Austrian_Academy_of_Sciences. Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Oliver L. Eichmu"ller, Nina S. Corsini, A'bel Ve'rtesy, Ilaria
Morassut,
Theresa Scholl, Victoria-Elisabeth Gruber, Angela M. Peer,
Julia Chu, Maria Novatchkova, Johannes A. Hainfellner, Mercedes
F. Paredes, Martha Feucht, Ju"rgen A. Knoblich. Amplification of
human interneuron progenitors promotes brain tumors and neurological
defects. Science, 2022; 375 (6579) DOI: 10.1126/science.abf5546 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220127141611.htm

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