LW - Fun With CellxGene by sarahconstantin

The Nonlinear Library

Welcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: Fun With CellxGene, published by sarahconstantin on September 9, 2024 on LessWrong. For this week's post, I thought I'd mess around a bit with the CellXGene tool provided by the Chan Zuckerberg Institute. It's based on a big dataset of individual cells, classified by tissue, cell type, and disease state, and their gene expression profiles (single-cell RNA counts). You can automatically compare how gene expression looks different between sick and healthy individuals, for a variety of diseases, and drill down into which cells/tissues are different and how. It's a fascinating toy and a great way to generate hypotheses. Here, I'll do it for Alzheimer's, comparing 138,438 Alzheimer's brain cells to 9,203,998 normal/healthy brain cells to see what the most "differentially expressed" genes are, and what that might tell us about how the disease works. Top Hits LINC01609 1.6x overexpressed in Alzheimer's, d =4.203 This is a non-protein coding RNA. Typically most expressed in the testis. In CellxGene's healthy brain cells, it's expressed only in activated microglia and astrocytes; but in the Alzheimer's brain, it's expressed in roughly half of all types of cells. Like many long non-coding RNAs, its function is unknown. SLC26A3 10.6x overexpressed in Alzheimer's, d = 3.310 This is a chloride anion exchanger, a membrane protein that transports chloride ions across the cell membrane. It's most heavily expressed in the colon, where it controls the resorption of fluid from the intestines. Defects in this gene are associated with congenital diarrhea, as the body is unable to maintain the right osmotic concentration and loses water in the stool. But we're interested in SLC26A3 in the brain, not in the intestine. In the healthy brain, once again, it's only expressed in activated astrocytes and microglia; in the Alzheimer's brain it's expressed in large numbers of all cell types. CellxGene classifies it as one of the top "markers" for mature astrocytes and mature microglial cells, with a specificity of 1.00. Other researchers have observed the upregulation of SLC26A3 in Alzheimer's, e.g. as part of a pattern of "gliovascular" alteration around the clusters of astrocytes and endothelial cells that control the blood-brain barrier.1 A gliovascular unit is the place a blood vessel meets the brain. The vessel is surrounded by astrocytes and microglia, which control what goes in and out of the bloodstream, clearing excess glutamate and misfolded proteins. Under prolonged stress, these astrocytes in gliovascular units become reactive, and ultimately the blood-brain barrier breaks down. In Alzheimer's disease, the blood vessels get narrower, fragment, and break.2 Activated astrocytes no longer connect as tightly to the surface of the vessels with their "endfeet", compromising the BBB, while activated microglia engulf the endfeet, exacerbating the effect.3 What actually happens if you have more chloride anion exchange in the cells of a gliovascular unit? Is it causal for any Alzheimer's pathology? That, I don't think we know. RASGEF1B 5.5x overexpressed in Alzheimer's, d=3.267 This is a widely expressed cytoplasmic protein that allows the protein Ras to be "switched on", sending intracellular signals that lead to cell growth, differentiation, and survival. 4 Once again, in the healthy brain it is only expressed in activated astrocytes and microglia, while in the Alzheimer's brain it's expressed everywhere. CellxGene classifies it as the top "marker" for mature astrocytes and mature microglial cells, with a specificity of 1.00. In normal circumstances, astrocytes and microglia can grow and proliferate, but most neurons do not. Ras activity increases in conditions of neural stress or injury, as part of the body's attempt to promote cell survival and neurite regeneration. So it makes sense that we...