Lundbeck Foundation Fellowship to uncover the art of silencing in the human brain
With roughly 86 billion neurons, the human brain is nature's most complex structure, and yet how it builds itself remains surprisingly poorly understood. How does a single stem cell give rise to billions of specialised neurons, each finding their place in an intricate web of circuits? Answering these fundamental questions could one day change how we treat brain diseases.
Supported by the Lundbeck Foundation Fellowship, Anna Malkowska, a Postdoc in the Żylicz group at reNEW Copenhagen, will investigate how gene silencing is regulated during the complex, stepwise process of neural stem cell differentiation in the developing human brain.
Decoding neural differentiation
As the brain develops, neural stem cells give rise to cells that differentiate into many different types of neurons. At each step of this process, certain genes are activated while others are repressed. Malkowska is particularly interested in how that repression initiated by histone deacetylases (HDACs), proteins that remove certain chemical tags and switch genes off.
Much of what we know about this process comes from research in mice. The human brain is far more complex, with many more cell types, making it difficult to directly translate findings to human biology. Organoids, 3D models grown from human stem cells that closely mimic the developing human brain, now make it possible to study these processes directly in human cells.
During this project, she will collaborate with Associate Professor Silvia Velasco from reNEW Melbourne, a leading expert in the generation and study of brain organoids.
‘‘I am really excited about the collaboration with the Velasco lab. I hope that their expertise on these 3D models can give us more insight into human specific neurodevelopmental processes. This grant gives me the opportunity to bring this knowledge together and start this collaboration. It is all about bringing people together who are good at different things,’’ she said.
A foundation for the future
Using these 3D models alongside innovative single-cell sequencing technology, Malkowska will map which HDACs silence specific genes at each stage of development and uncover which proteins are essential for neural development.
HDACs are important drug targets for neurological disorders, including epilepsy, but their role in brain development is yet to be fully uncovered. ‘‘With these 3D models, we can really ask questions about how different cell types develop and how the human brain achieves its complexity,’’ she added.
By unravelling how these proteins function in human cells, this research could lay the foundation for determining how HDAC-targeting drugs affect brain development and how different cell types are born. In the future, these insights could open doors to safer and more targeted treatments for neurological disorders, including the potential generation of specific brain cell types.