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Inventors #17
A set of ideas and observations on inventions and discoveries in life sciences.
Immunology
The immune system and everything in it.
Lymph nodes are innervated by a unique population of sensory neurons with immunomodulatory potential - https://www.cell.com/cell/fulltext/S0092-8674(20)31564-6#%20 - out of the von Andrian Lab at Harvard, the group uses a wide array of tools to discover sensory neurons that interact with distinct cells within lymph nodes:
Nociceptors, are sensory neurons, that have been previously observed to interact with the immune system to regulate pain, inflammation, among other things
Past work has established the role of nociceptors in barrier tissues - https://www.sciencedirect.com/science/article/pii/S0092867412000888 and the spleen - https://pubmed.ncbi.nlm.nih.gov/7193506/
Combined with the observation that nociceptor ablation changes immune responses in lymph nodes (LN) - https://www.nature.com/articles/nature12479/figures/5 This work sought to study the role of these neurons in LNs
The group combined single-cell sequencing, imaging, and optogenetics to study neurons within lymph nodes: (1) labeling sensory neurons with tdTomato to visualize the 3D morphology of nerve fibers within LNs (2) to define this population, single-cell sequencing (scSeq) revealed that LN-localized neurons were from 4 peptidergic subtypes as well as inferring potential interactions with specific immune cells (3) combined scSeq with optogenetics to test the interactions between LN cells and innervating sensory neurons in vivo; sensory neurons were selectively activated by 3 hours of pulsed blue light and both cell types were sequenced discovering upregulated genes in immune cells (i.e. Tnc, Agrn, Nrxn2) and downregulated (i.e. Nrp2, Robo1).
This work does great work to establish a neuroimmune axis in lymph nodes. Do specific immune responses with distinct LN-innervating neurons?
Biochemistry and structural biology
The granddaddy of them all.
Ultra-high sensitivity mass spectrometry quantifies singlecell proteome changes upon perturbation - https://www.biorxiv.org/content/10.1101/2020.12.22.423933v1.full.pdf - the Mann Lab at Max Planck developed a new proteomics method for single-cell measurement:
The paper established a proof-of-concept for the idea of single-cell proteomics. Right now, ensembles of cells are needed by mass spec machines to measure proteins with enough sensitivity.
To increase mass spec sensitivity, a device with a brighter ion source along with other optimizations was developed
Chromatography flow rates were reduced from 1 microliter/minute to 100 nanoliter/minute to enable the lowest loss rate during sample prep
A microliter prep and sorting, relying on FACs, method was established as well
This method was applied to study the cell cycle in HeLa cells arrested at various stages - a few hundred proteins per single cell were measured across 4 stages defining the effects of drug perturbation on single-cell proteomes
Moreover, the data was matched with single-cell transcriptomics and 6-cell proteomics to established a core proteome that had not be measured
Next steps are to bring post-translational modification (PTM) measurements on board as well as multiplexing the method
Neuroscience
Roughly 20 years behind but set up to transform the concept of human.
Context-Specific Striatal Astrocyte Molecular Responses Are Phenotypically Exploitable - https://www.cell.com/neuron/fulltext/S0896-6273(20)30745-5 - the Khakh Lab at UCLA find a new connection (in mouse models), through GPCR signalling, between astrocytes and Huntington’s disease (HD):
The role of astrocytes, the most abundant cell type in the CNS (20%-40%) important for the maintenance of the blood-brain barrier, in disease is an important outstanding question
Using 14 different perturbations in vivo, such as LPS and MPTP and ablation of specific neurons, the group measured the gene expression of various cell types in the mouse brain
This worked found overlapping changes in astrocyte genes involved in both Huntington’s disease (HD) G protein-coupled receptor (GPCR) signalling
Stimulation of this GPCR (Gi) led to rescue of several HD phenotypes in mice
This paper make 2 important contributions to the CNS field: the first observation of astrocytes responding to multiple different perturbations in vivo and the role of the cell type in HD
Cell biology
Cell structure and function.
RNA-Centric Methods: Toward the Interactome of Specific RNA Transcripts - https://www.cell.com/trends/biotechnology/fulltext/S0167-7799(20)30306-1 - out of the Vermeulen Lab at the Radboud Institute for Molecular Life Sciences, the research team published a nice overview on methods for measuring RNA-protein interactions:
Recent advances in proteomics has uncovered the catalog of RNA-binding proteins
The next step in the field is identifying what proteins bind specific transcripts and how?
The 4 main approaches to work on this problem set are: Global measurements through proteomics, RNA capture relying on hybridization or aptamers, RNA purifications from lyates, and dCas13-based methods
In particular, using dCas13 is uniquely suited to study specific RNA transcripts and mapping which proteins bind them
The study on RNA interactions, RNA-protein, RNA-RNA, RNA-DNA, and RNA-chromatin, is likely to reveal new therapeutic targets and set up the possibility to engineer these interactions for selective editing and degradation
Genetics, genomics, and developmental biology
Heredity and variation.
In situ genome sequencing resolves DNA sequence and structure in intact biological samples - https://science.sciencemag.org/content/early/2020/12/29/science.aay3446 - the Chen Lab at Harvard invented a way to match genetic sequence with structure with in situ genome sequencing (IGS):
An important problem in biology is matching structure with function
IGS relies on cell fixation then DNA barcodes, that map out spatial relationships, are inserted into the cell’s genome and amplified/imaged. The sample is sequenced with the 3D structure of the genome reconstructed.
The tool was applied to human fibroblasts and mouse embryos to map and sequence 1000s of genes discovering new chromatin domains in the former and chromosome positioning in the latter
This invention has the potential to understand how the 3D genome affects gene expression