In the CPHMS human-relevant webinar series in the month of April, we had Dr Pavithra Chavali who spoke about how organoids are being used to understand neurodegenerative diseases. While various animal models, such as mouse or fruit flies have been used to study brain biology, Dr Chavali highlighted the vast differences in not just size but also structure between various animal and human brains. For example, mouse brain is “lissencephalic”, which literally means “smooth brain” or they lack the characteristic folding observed in human brains. She added that while organoids were much smaller, size is often not reflective of the complexity. For example, dolphin and elephant brains are bigger than human brain; however, “cognition as we understand” is not higher in elephants versus humans.
In 2003, Yoshiki Sasai, a Japanese stem cell biologist, became the first person to show that a specific cocktail of chemicals when given to embryonic stem cells could give rise to self-organised 3D spheroids. Subsequently, further protocols were developed by Dr Madeline Lancaster (a scientist at the Medical Research Council Laboratory, University of Cambridge, UK) leading to creation of brain organoids that had similar architecture and cellular layers compared to the human brain. Studies have subsequently shown that a 20-day old organoid resembles the brain of a 6-month old fetus (second trimester of pregnancy).
It is also possible to create organoids for specific regions of the brain, such as forebrain or a midbrain organoid. These organoids of different regions when cultured together can again self-assemble and organize.
Dr Chavali then highlighted how these brain organoids are being used to understand neurodevelopmental and neurodegenerative disorders, cancer, and infections in the brain. For example, a condition called microcephaly, a neurodevelopment disorder observed in infection by Zika virus, leads to thinner layer of neurons, leading to smaller cortex and cognitive deficiency in children. This small brain phenotype is associated with a particular mutation in a gene. Interestingly, introducing this mutation in mice does not produce a microcephalic effect, indicating that this was a very human-specific trait, requiring the need for a human biology-relevant model to study it. Indeed, when brain organoids were created using induced pluripotent cells reprogrammed using cells from a patient, they exhibited the small brain effect.
She also discussed examples how organoids were proving to be powerful windows into neurodevelopmental disorders, such as autism; brain evolution; and neural cancers.
Thus, these brain organoids can be used as very powerful tools for disease modelling, understanding basic brain biology, and drug discovery.
