In the heart of the Massachusetts Institute of Technology’s Computer Science and Artificial Intelligence Laboratory (MIT CSAIL) lies some of the most intriguing innovations and research studies, creating seismic shifts in our understanding of the human brain and its diseases. Professor Manolis Kellis, a stalwart of MIT CSAIL who has long been known for his pioneering efforts in computational biology, is now delving deep into a new research effort: a comprehensive molecular atlas of the human brain’s vascular cells, with an intimate look at its implications for Alzheimer’s Disease (AD).
Gary Drenik: Professor Kellis, congratulations on your team’s breakthrough in unveiling a systematic molecular atlas of human brain vasculature. To begin with, can you elaborate on the significance of this discovery?
Professor Manolis Kellis:: Thank you. Our work is instrumental in understanding the intricate changes in the vascular cells of the brain in Alzheimer’s Disease (AD) across different regions at single-cell resolution. The molecular atlas we have created provides a comprehensive look at these changes, paving the way for understanding Alzheimer’s disease progression and creating new therapies.
Drenik: Your study revealed striking differences in gene expression between Alzheimer’s patients and healthy individuals. Could you tell us more about these findings?
Professor Kellis:: Indeed, we found significant changes in gene expression between individuals afflicted with AD and those without. The most extensive changes were found in capillary endothelial cells, which play a crucial role in waste removal, immune surveillance, and blood-brain transport of nutrients and more. These changes were highly pronounced in the genes clearing amyloid beta protein, one of the defining hallmarks of AD thought to ultimately lead to neuronal death, so understanding how they change in AD can be very important in guiding therapeutic interventions.
Drenik: You mentioned that vascular cells differ between brain regions. How does this factor into Alzheimer’s disease?
Professor Kellis:: Our research showed that the abundance of vascular cell types varied between brain regions. For instance, neo-cortical regions, characteristic of higher human cognition, displayed more capillary endothelial cells and fewer fibroblasts than subcortical regions, highlighting the regional heterogeneity of the blood-brain barrier (BBB). This heterogeneity has important implications for understanding how AD impacts different areas of the brain that play different roles, and can help understand cognitive decline and memory loss associated with AD.
Drenik: Your team utilized single-nucleus RNA sequencing in your research. How does this technique enhance our understanding of Alzheimer’s disease?
Professor Kellis: Our brain is made up of highly distinct cells with very specific functions. Traditional methods have studied RNA expression at the tissue level, not knowing which cell type each RNA molecule came from. With single-cell RNA sequencing, we can distinguish changes in each cell type, across dozens of cell types, and also in each cell, across thousands of cells and millions of RNA molecules. This level of detail was inconceivable just a few years ago and can be transformative to enable precision medicine targeting individual proteins in specific cell types.
Drenik: Your study also mentioned “master controllers”. What are they, and how are they important in the progression of Alzheimer’s Disease?
Professor Kellis: “Master controllers” are gene-regulatory proteins that control the activity of other genes and orchestrate distinct cellular functions and responses. When things go wrong, like in AD, they might be responsible for the downturn, but also potentially critical in restoring healthy cellular states. The master controllers we discovered provide potential intervention points for drug targets against AD.
Drenik: Finally, how does your research inform the development of potential new treatments for Alzheimer’s disease?
Professor Kellis: Our findings offer multiple candidate target points for intervention. Targeting the discovered dysregulated genes, or their upstream regulators, might help slow down AD progression, or even reverse AD phenotypes. Moreover, the cell-cell communication pathways that we predict mediate the impact of genetic variants in AD suggest the possibility of manipulating the brain vasculature to spread beneficiary signals to the rest of the brain, even without crossing the blood-brain barrier directly. Despite remarkable advancements in collecting intricate health data—evidenced by a recent Prosper Insights & Analytics survey showing that half of adults currently use electronic devices to monitor their health—the definitive diagnosis of Alzheimer’s Disease (AD) remains reliant on post-mortem brain tissue examination. As it stands, no singular blood test, imaging scan, or wearable device can conclusively determine the presence of the disease. Therefore, the logical progression of our research efforts involves translating these preliminary findings into effective treatments. This crucial endeavor will necessitate comprehensive preclinical and clinical trials, as well as a collaborative partnership spanning both academia and industry.
Drenik: Professor Kellis, your insights today have provided an invaluable look into the meticulous work and timely findings of your research team. By unveiling a systematic molecular atlas of human brain vasculature, you’ve shed new light on the complexities and intricacies of Alzheimer’s Disease and have given the global community enhanced understanding of how we can better disentangle this debilitating condition. I’m personally inspired by the depth and scope of your team’s discoveries, from the differences in gene expression to the powerful “master controllers” and their potential for therapeutic intervention. On behalf of our audience and all those touched by Alzheimer’s, I want to thank you for your time and for dedicating your expertise to such a paramount cause. We eagerly anticipate the next steps and developments that will arise from your monumental work.
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