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Inventors #7
A set of ideas and observations on inventions and discoveries in life sciences.
Immunology
The immune system and everything in it.
Bone Morphogenic Proteins Are Immunoregulatory Cytokines Controlling FOXP3+ Treg Cells - https://www.cell.com/cell-reports/fulltext/S2211-1247(20)31208-0?sf238554703=1 - out of the Kraj Lab from Old Dominion University, they define the role of bone morphogenic proteins (BMP) in Treg (essentially brakes for T-cells) development. Their role for CD4+ T-cells and Th17 cells has been defined. The authors used the observation that deleting BMPR1α promoted CD4+ cell differentiation in Th17 cells to think that BMPs play a similar role for Tregs. They found that BMPR1α controls expression of FOXP3, a master regulator of Treg development and function:
Decreased levels of BMPR1α activates a demethylase, KDM6B, which may lead to chromatin modifications modifying gene expression in CD4+ and Treg cells. This is an avenue for further exploration.
Deleting BMPR1α in Tregs leads to the accumulation of senescent Tregs
Put this all together: BMPs are necessary for the maturation and activity of peripheral Tregs
Biochemistry and structural biology
The granddaddy of them all.
Interhelical interactions within the STIM1 CC1 domain modulate CRAC channel activation - https://www.nature.com/articles/s41589-020-00672-8 - work from the Muller Lab at Johannes Kepler University Linz uses NMR to identify 2 interhelical sites that control the activation of STIM1, a endoplasmic reticulum (ER) calcium sensor originally discovered in an RNAi screen in Drosophila. The ER is essential for protein production in the cell and calcium (Ca2+) in the ER is important for protein folding. The process of calcium being stored and released from the ER comes in 3 steps:
Pumping against the electrochemical gradient to transport Ca2+ from the cytosol to the ER lumen. STIM1 activates this process.
Calcium binding proteins in the lumen store it
Activation of Ca2+ channels from the ER lumen to the cytosol along the electrochemical gradient
STIM1 senses Ca2+ concentration in the lumen and activates at low concentrations to lead to calcium influx into the ER. Upon activation, the C-terminus of STIM1 goes from a tight/inactive form to an extended/active form. Using nuclear magnetic resonance (NMR) combined with mutational scanning, the group discovers two sites (CC1α1/2) are key to control the tight and extended forms of STIM1.
Neuroscience
Roughly 20 years behind but set up to transform the concept of human.
Microglial Phagocytosis: A Disease-Associated Process Emerging from Alzheimer’s Disease Genetics - https://www.cell.com/trends/neurosciences/fulltext/S0166-2236(20)30222-8 - the Goate Lab at Mount Sinai put out a useful review combining Alzheimer’s (AD) genetics and myeloid cell lineage biology to focus on the role of phagocytosis in AD:
From genome-wide association studies (GWAS) and other genetic analyses, microglia-related genes and in particular myeloid-specific enhancers are significantly associated with AD - https://www.sciencedirect.com/science/article/abs/pii/S1474442219304351
The enhancers associated with AD control the expression of phagocytosis and endolysosomal genes (in particular early endosomes)
Outstanding questions is to understand the function of these genes/variants in AD? This would be a place for new targets in drug development (i.e. Alector).
The authors focus on the need of human based models (i.e. iPSCs, organoids, grafts of human cells in mice brains) to translate functional variants to humans. System1 has some cool technology here. Maybe they should just partner with Biogen?
In organoids derived from AD patients actually show errors in the endolysosomal process - https://www.nature.com/articles/s41380-018-0229-8
New targets for AD suggested by the authors are: TREM2, CR1, SORL1, PTK2B, CD2AP, RIN3, SPPL2a, DAM genes, ABCA7
Cell biology
Cell structure and function.
Tracking cells in epithelial acini by light sheet microscopy reveals proximity effects in breast cancer initiation - https://elifesciences.org/articles/54066 - the Jechlinger Lab from EMBL combined light-sheet microscopy with cancer organoids (where oncogenes are inducible by a Tet promoter) to study the behavior of single-cells (over ~4 days) in a breast cancer model:
The premise is to activate tumorigenesis in single cells with healthy cells surrounding them and then temporally studies to monitor the fate of these cancer cells
They found that activated cells did not divide at the same rate and that this is dependent on how many cancer cells are clustered together. Likely, healthy tissues can suppress single cancer cells but larger clusters can inhibit anti-cancer signalling of healthy cells. Understanding this signalling will likely sow the seeds for new medicines in oncology and resistance.
There are two main models for cancer evolution: hierarchical where a tumor is derived from a cancer stem cell and stochastic where each cell within the tumor is equally likely to have initiated the tumor. This type of imaging study tracking individual cells and populations will begin to bridge the gap between the two models.
Genetics, genomics, and developmental biology
Heredity and variation.
PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4 - https://www.cell.com/cell-reports/fulltext/S2211-1247(20)31213-4 - from the Susan Lindquist (a legend) lab at MIT posthumously, discovered that APOE4 (the gene with the strongest association with Alzheimer’s (AD) onset) disrupt clathrin-mediated endocytosis:
Using a yeast model and iPSC-derived astrocytes, the group discovered that APOE4 drives defects in early endocytosis. On a side point, endocytosis might be one of the most understudied important problems in molecular biology. If someone doesn’t do it, when I get the capital, I am going to set up a grant program to fund fundamental research here. Discoveries here will lay the groundwork for next-generation therapies that cure disease.
In yeast, they found that expressing Yap1802 alleviates disruption of endocytosis in APOE4 expressing cells
The human homolog of Yap1802, PICAML was then found to reverse endocytic defects in astrocyte models expressing APOE4
The work establishes a link between APOE4 and PICALM (another genetic risk factor for AD) in controlling endocytosis suggesting a new MoA to treat AD. A protective mutation for AD is APOE2 and the next steps is to see if this variant has an effect on endocytosis as well.
Moreover, this study shows the power of the interplay between yeast and human models to identify disease targets and map out mechanisms. This is the premise of Susan Lindquist-founded Yumanity Therapeutics.