The extraordinarily diverse functions of the nervous system, from cognition to movement, are possible because neurons are assembled into precisely ordered networks that permit them to rapidly and accurately communicate with their synaptic targets. The Butler laboratory seeks to understand the mechanisms that establish these neuronal networks during development with the long-term goal of determining how this process may be co-opted to regenerate diseased or damaged circuits.
"The vast majority of stem cells that exist in the human cortex disappear prior to birth. Therefore, understanding how neurodevelopmental disorders emerge, responding to injury, and understanding how brain cancers emerge require the study of human brain development."
— Dr. Aparna Bhaduri
Dr. Bhaduri’s lab uses the concept of cell type to group cells based upon common features. This strategy enables them to find the genes or other properties of cells that define one population and distinguish it from others, enabling many comparisons between primary human brain samples, cortical organoids, and glioblastoma tumors.
Only recently has technology given us an opportunity to interrogate cells within the brain one at time, and to look at their transcriptome with a strategy called single-cell RNA sequencing. Dr. Bhaduri has led efforts as part of the BRAIN Initiative consortium to profile and identify the cell types that exist across the developing human brain from early stages of human brain development to the mid-stages where the peak of neuron birth occurs. This approach has highlighted similarities and differences across brain regions and across the different parts of the cerebral cortex, the top layer of the human brain that enables a variety of cognitive and perception functions. Now with a broad strokes understanding of the cell types that exist and how they change, Dr. Bhaduri is seeking to use cortical organoids to better understand the intrinsic and extrinsic cells that really instruct the various stem cell populations in the developing human brain to make the myriad cell types they give rise to.
Glioblastoma is unfortunately one of the most common and most aggressive adult brain tumors, with limited treatment options. In comparing single-cell RNA sequencing from glioblastoma to other datasets, Dr. Bhaduri noted an enrichment of the gene signature from outer radial glia, a developmental progenitor cell type that is expanded in primates and humans compared to rodents and that undergoes a very unique cell behavior called a mitotic somal translocation, or jump-and-divide. Using live imaging, she and her colleagues were able to show this cell behavior also existed in tumors, even though the outer radial glia cells ought to disappear from the developing human brain by birth. In addition to this progenitor cell type, she identified other cell types with similarities to development that may play a role in glioblastoma tumor progression and recurrence. Her laboratory is seeking to use a combination of single-cell genomics and experiments to figure where glioblastomas come from, which cell types are most important for tumor recurrence, and how to target these populations specifically to improve treatment options for patients.