Axial - Inventors #11
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A set of ideas and observations on inventions and discoveries in life sciences.
The immune system and everything in it.
Affinity-Restricted Memory B Cells Dominate Recall Responses to Heterologous Flaviviruses - https://www.cell.com/immunity/fulltext/S1074-7613(20)30395-2 - the Bhattacharya Lab from the University of Arizona use flavivirus (has distinct serotypes that can escape serum antibodies) challenges to discover cross-reactive memory B-cells generated from the primary infection are sufficient for a secondary response:
After a virus infects an individual, long-lived plasma cells (LLPC) are terminally differentiated B-cells that still produce antibodies against the strain of the virus. Whereas, memory B-cells (MBC) are a quiescent immune cell surviving for decades that are available to respond to a similar viral infection.
This paper uses flavivirus infections to demonstrate the MBCs have a more diverse repertoire of antibodies versus LLPCs, which is sufficient enough, mainly because of cross-reactivity of MBCs, to respond to a diverse range of flavivirus infections from Zika to Dengue and West Nile
Biochemistry and structural biology
The granddaddy of them all.
MFSD12 mediates the import of cysteine into melanosomes and lysosomes - https://www.nature.com/articles/s41586-020-2937-x - from the Sabatini Lab at MIT, the group invented a tool, MelanoIP, to analyze melanosomes, organelles that produce melanin:
The group’s MelanoIP tool is an extension of a broader toolkit to isolate other organelles from mitochondria to lysosomes and peroxisomes. MelanoIP linked 3XHA epitope tags to GPR14314, a melanosomal marker. The epitope tags are immunoprecipitated (the IP in MelanoIP) along with the melanosome.
The group used the tool to purify melanosomes from melanoma mice and human cell lines and showed the ability to profile their metabolites
After validating the tool, the group studies a transmembrane protein, MFSD12, with unknown function but causes darker pigmentation when suppressed. They found that MFSD12 is necessary to import cysteine into melanosomes and mainly normal levels of cystine.
The paper is another example from the Sabatini Lab of combining clever tagging strategies to study specific organelles potentially opening up new classes of biology to develop new medicines
Roughly 20 years behind but set up to transform the concept of human.
Deterministic and Stochastic Rules of Branching Govern Dendrite Morphogenesis of Sensory Neurons - https://www.sciencedirect.com/science/article/pii/S0960982220315979 - the Lecuit Lab at Aix Marseille University study the branching of sensory neurons in Drosophila:
The paper used high-resolution live imaging to study class I vpda neurons in Drosophila melanogaster. The neurons are within the dendritic arborization (i.e. branching) class that are the first ventral neurons to project dorsally. They are part of Drosophila’s peripheral nervous system driving somatosensation.
The work found that primary branches of these neurons grow in a deterministic manner and secondary branches grow stochastically
With the observation the Dscam1 (adhesion gene) mutants drives cell identity for neurons in flies and lead to self-avoidance behaviors (implying defects in somatosensation), the group found that Dscam1 restricts the direction of secondary branch group to orthogonal to primary branches.
This paper use flies as a model to characterize how the geometrical structure of neurons provides feedback to itself to maintain stability and self-organize
Cell structure and function.
High-Spatial-Resolution Multi-Omics Sequencing via Deterministic Barcoding in Tissue - https://www.cell.com/cell/fulltext/S0092-8674(20)31390-8 - the Fan Lab at Yale invented a microfluidic device to barcode mRNAs and protein within a tissue, which they call deterministic barcoding in tissue for spatial omics sequencing (DBiT-seq):
The method delivers DNA barcodes to slides of mouse embryonic formaldehyde-fixed tissue after staining them with 22 target-specific antibodies tagged with DNA
Two sets of barcodes are used to generate A times B number of unique tags. Barcode A is flowed first to tag for mRNA and proteins (through the antibody). Barcode B is flow orthogonally to A to enable a spatial resolution up to 10 µm on the tissue sample.
Microscopy and next-generation sequencing are used to co-measure mRNAs with the 22 target proteins
DBiT-seq enables the spatial resolution of proteins and RNAs within tissues (without the need for lysis) to the single-cell level. The group also applied this tool to brain and eye lid tissue samples.
This is a foundational tool that can profile general microenvironments with particular value for tumor samples
The next steps are to scale the number of proteins measured, which is limited for the number of channels to deliver barcodes. Moreover, depending on the cell type, DBiT-seq might not be able to resolve to single-cells with the theoretical limit of 5 µm driven by tissue section thickness.
Genetics, genomics, and developmental biology
Heredity and variation.
Regulation of CEACAM5 and therapeutic efficacy of an anti-CEACAM5-SN38 antibody-drug conjugate in neuroendocrine prostate cancer - https://clincancerres.aacrjournals.org/content/early/2020/11/14/1078-0432.CCR-20-3396 - out of the Lee Lab at Fred Hutch, the group show an antibody-drug conjugate (ADC) against CEACAM5 as a promising target to treat neuroendocrine prostate cancer (NEPC):
From prior work discovering that CEACAM5 is a surface antigen for neuroendocrine prostate cancer cells (with minimal overlap with other prostate cancer markers like PSMA), the group used an ADC (labetuzumab govitecan) to target the protein and deliver the SN-38 cytotoxic agent to these cancer cells
NEPC represents ~20% of advanced treatment-resistant prostate cancers with a high unmet need; the incidence of the disease is actually increasing versus broader prostate cancer
Using preclinical xenograft models for NEPC, the group found the ADC led to significant tumor volume reductions as well as inducing DNA damage in CEACAM5-positive prostate cancer cell lines
The group is working with Immunomedics (bought by Gilead) to initiate a phase 1/2 trial for the ADC in NEPC patients