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Inventors #24
A set of ideas and observations on inventions and discoveries in life sciences.
Immunology
The immune system and everything in it.
CSF1R inhibition depletes tumor-associated macrophages and attenuates tumor progression in a mouse sonic Hedgehog-Medulloblastoma model - https://www.nature.com/articles/s41388-020-01536-0 - the Joyner Lab at MSKCC used longitudinal MRI to discover that tumor-associated macrophages (TAM) are significantly higher in around half of lethal tumors:
TAMs are a major driver for sonic hedgehog subgroup of medulloblastoma (SHH-MB), a tumor type of the central nervous system
However, TAMs have been found to have both promoting and inhibiting SHH-MB progression - https://pubmed.ncbi.nlm.nih.gov/31160587/ In humans, macrophage number is correlated with positive outcomes for patients. Other papers show conflicting results where TAMs are associated with mortality from SHH-MB.
This paper works to hone in on this phenomenon with implications for SHH-MB, which has a ~70% survival rate but awful side effects as well as tumor microenvironments in general
Colony-stimulating factor 1 receptor (CSF1R) is known to drive TAM growth. As a result, the group used PLX5622, an CSF1R inhibitor, to study the effects of TAM depletion on SHH-MB tumors and mouse survival.
Relying on a tamoxifen-induced Cre recombinase system, the group measured TAMs in an SHH-MB mouse (n=20) model across several weeks by MRI and RNA-seq
The study showed the TAMs were correlated with progressing tumors. Depletion of T-cells/Tregs had no effects on mortality in the model whereas depletion of TAMs increased mouse survival.
This studies adds to the observation that TAMs drive tumor progression in SHH-MB; however, nuances within the tumor microenvironment in the model as well as the initial T-cell populations are probably key drivers on dual nature of TAMs
Biochemistry and structural biology
The granddaddy of them all.
Ester modification at the 3′ end of anti-microRNA oligonucleotides increases potency of microRNA inhibition - https://www.sciencedirect.com/science/article/pii/S0968089620307240 - out of the Beal Lab at UC Davis, the group discovered an anti-microRNA (miRNA) oligonucleotide modification that increased potency by 5x-9x depending on the scaffold:
miRNAs are non-coding RNAs that regulate the expression of a wide range of genes through mRNA translation inhibition and degradation
Antisense oligonucleotides (ASO) can be used to inhibit miRNAs, and the current focus has been on modifying the ASO backbone to increase their binding affinity to miRNAs
The group took an alternative approach to modify the 3’-end of these ASOs with the premise that stabilizing this end can increase affinity since the 3’ part of the ASO interacts with the 5’-end of the miRNA
One hundred and nineteen ASOs with triazole-modified 3’-ends were screened virtually for their complementarity to miR21 (an abundant miRNA in HeLa cells) with 17 of them picked for follow up studies
Then luciferase (under the control of miR21) cell-based assays were used to assess the anti-miR21 ASOs potency in vitro versus an standard ASO with a 3’ adenosine. The screen found an ASO with an ester group on the triazole was the most potent with a 9x increase in an ability to inhibit miR21.
The group established a new strategy for ASO design with a proof-of-concept for anti-miRNAs.
Neuroscience
Roughly 20 years behind but set up to transform the concept of human.
Neuronal Primary Cilia: An Underappreciated Signaling and Sensory Organelle in the Brain - https://www.nature.com/articles/npp2013203 - a quick overview (from 2013) from the Mykytyn Lab at The Ohio State University lays out the open field to study primary cilium within neurons:
Defects in primary cilia, called ciliopathies, are involved in many neurological disorders - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098370/
However, the roles of primary cilia in neurons are still not well understood (even after 7-8 years). GPCR signaling is known to play a key role in transmitting signals from the extracellular environment through the cilium - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576980/
However, identifying which GPCRs and other components are enriched for primary clia is still unknown. Also, specialization of clia and what determines it is still an open question.
Excitedly, primary cilia have the potential to be a non-synaptic way for neurons to communicate and signal with each other
Cell biology
Cell structure and function.
CiBER-seq dissects genetic networks by quantitative CRISPRi profiling of expression phenotypes - https://science.sciencemag.org/content/370/6522/eabb9662 - the Ingolia Lab at UC Berkeley invented a method to measure genetic perturbations with barcoded reporters, called CiBER-seq:
The tool connects CRISPR interference (CRISPRi) with barcoded expression reporters to create “genome-wide phenotypic profiles. The group first applied CiBER-seq to yeast cells to study the stress response.
The method matches a guide RNA (gRNA) to the expression of a barcode RNA through a target gene. A phenotype is measured by the expression levels of the barcode before and after the gRNA is induced by a tetracyclineinducible promoter and all of this work can be pooled into one experiment.
In budding yeast, CiBER-seq was applied across ~60K guides across ~6K genes.The group found that elongator tRNA depletion initiated a specific stress response in yeast through GCN4 - https://www.nature.com/articles/s41467-017-00539-y
Long-term, a method like CiBER-seq can be applied to other cell types (i.e. mammalian) to connect a genetic perturbation to a phenotype in one pooled step. Setting up experiments to select for certain TCR affinities can be done here along with screening for new targets across a wide range of diseases.
Genetics, genomics, and developmental biology
Heredity and variation.
The N-glycome regulates the endothelial-tohematopoietic transition - https://science.sciencemag.org/content/370/6521/1186?rss=1 - out of the Nicoli Lab at Yale, the group established the role of microRNA-223 (miR-223) and the N-glycome in the endothelial-to-hematopoietic transition (EHT) in zebrafish:
Deletion of miR-223 in zebrafish leads to an increase of nascent hematopoietic stem and progenitor cells (HSPC); however, the mechanism of the miRNA’s role in EHT was still uncharacterized
To study miR-223, the group generated a zebrafish model with miR-223 labeled with two reporters: GFP and mCherry. This work established that miR-223 is expressed in hemogenic endothelial cells (EC).
The next step was to find the target of miR-223 that might play a role in EHT. Out of the top 8 candidates, 4 were genes that regulate N-glycosylation.
In wild type ECs, mannose is the predominant glycan versus miR-223 KOed ECs where sialic acid is overwhelming (~97%) the most abundant glycan along with identifying particular genes whose modifications changed significantly with and without miR-223
This work elegantly establishes the role of the N-glycome in EHT mediated through a particular microRNA switch
This creates a lot more questions than answers and opens a new field to study glycan engineering in HSPCs