Axial - Inventors #10
Surveying great inventors and businesses
Axial partners with great founders and inventors. We invest in early-stage life sciences companies such as Appia Bio, Seranova Bio, Delix Therapeutics, Simcha Therapeutics, among others often when they are no more than an idea. We are fanatical about helping the rare inventor who is compelled to build their own enduring business. If you or someone you know has a great idea or company in life sciences, Axial would be excited to get to know you and possibly invest in your vision and company . We are excited to be in business with you - email us at email@example.com
A set of ideas and observations on inventions and discoveries in life sciences.
The immune system and everything in it.
Two subsets of stem-like CD8+ memory T cell progenitors with distinct fate commitments in humans - https://www.nature.com/articles/s41590-020-0791-5 - the Lugli Lab at IRCCS in Milan used single-cell RNA-seq to discover two new CD8+ (i.e. killer) memory T-cell subsets:
The group’s premise was that memory T-cells bifurcate into functional and exhausted classes during viral infectious and similar events that lead to T-cell differentiation
To characterize this phenomena, the paper brough the power of single-cell RNA-seq to this population of immune cells
Naive T-cells develop into effector cells after leaving the thymus and becoming activated by dendritic cells, which present antigens that a TCR recognizes
Overtime effector T-cells undergo apoptosis after the immune response is complete; however, some portion of these T-cells persist and become memory T-cells to ensure pathogen response is robust if re-exposed. This phenomenon is also why vaccines work so well.
The group discovered that memory T-cells without PD-1 and TIGIT were functional (TSTEM) and those with the two receptors (TPEX) were within the exhausted lineage of cells. This adds a new set of targets to sort memory T-cells beyond existing ones like CCR7 and CD95.
The authors hypothesize that the TSTEM and TPEX lineages branch off when T-cells are first presented the initial antigen. This is an area for further study; but, the idea is that having a way to shift a proportion of memory T-cells into exhaustion early on is a risk mitigating tool to reduce immunopathology.
Overall, discovery two new subsets of immune cells especially in the CD8+ lineage is pretty important for checkpoint inhibitors, vaccines, and other medicines that modulate the human immune system
Biochemistry and structural biology
The granddaddy of them all.
Molecular mechanism for direct actin force-sensing by α-catenin - https://elifesciences.org/articles/62514 - the Alushin Lab at Rockefeller used optical trapping and cryo-EM to understand how force influences binding to actin filaments:
In the cell, the cytoskeleton is made up of actin filaments that experience various forces to generate movement within the cell
The group’s premise was the forces on actin can influence their binding affinity to various regulatory proteins
To validate this hypothesis, the group used the actin-binding adhesion proteins , α-catenin and vinculin, as a model. They discovered that piconewton forces applied to actin increases its binding affinity to α-catenin but does not affect the vinculin dynamics.
Using cryo-EM, the group discovered a region within the C-terminus of α-catenin that acts as a force detector - when removed from α-catenin, negates the proteins ability to bind actin more tightly with more force and confers the feature to vinculin when added. Pretty amazing to get the structure of two processes and do the biochemical experiment to validate the mechanism all in one paper.
This paper is does a great job to understand the interplay between forces on actin and protein binding setting up more work to understand how cells maintain sensitivity to mechanical force and the ability to cell-cell adhesion to change over time
Roughly 20 years behind but set up to transform the concept of human.
Neuropixels 2.0: A miniaturized high-density probe for stable, long-term brain recordings - https://www.biorxiv.org/content/10.1101/2020.10.27.358291v1 - the Harris Lab at Janelia invented new probes, called Neuropixels 2.0, to record neurons from ~10K sites in mice brains:
The group extended their Neuropixels probes to measure 10K sites simultaneously
The key design breakthroughs were miniaturization to get the device weight to a little over a gram and shrink the distance of each recorder from 20 µm to 15 µm while putting the recording sites aligned within two columns (each probe records 5K sites: 5K x 2 = 10K), which led to the 2.0 probe becoming ~3x smaller than the first version
Excitedly, the 2.0 probes worked for a little over 2 months in free-moving mice with 21/22 implants and 7/8 recoveries successful
The other breakthrough was around the analysis algorithms to stabilize the data retrieved “post-hoc.” I am not an expert on the algorithmic part but their recording data did look good.
Overall, this tool is a pretty important move forward to study the spiking of thousands of neurons during free movement over months. Great work.
Cell structure and function.
Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans - https://www.cell.com/molecular-cell/fulltext/S1097-2765(20)30719-X - out of the Patel Lab at the University of Cambridge, the group discovered two enzymes, ALDH2 (mitochondrial) and ADH5 that remove formaldehyde and if knocked out lead to hematopoietic disruption:
The group sought out to study the role of endogenous aldehydes in health
Their first step was to use single-cell RNA-seq to profile aldehyde-detoxifying enzymes across bone marrow cells in mice
They found that ALDH2 and ADH5 were widely expressed in this cell lineage
So the group created mice with duals knockouts for the genes discovered that the mice developed leukemia and had significantly shortened lifespans
After validating that formaldehyde is a substrate of both enzymes, the group linked the phenotype of the KO mice to toxic accumulation of formaldehyde that disrupts hematopoiesis
The Patel Lab characterized a new class of biology particularly around the stress response and health. Whereas, reactive oxygen species and aging/disease is pretty well studied, the role of endogenous aldehydes and their metabolites is the natural extension of this work.
Genetics, genomics, and developmental biology
Heredity and variation.
PD-1H (VISTA)–mediated suppression of autoimmunity in systemic and cutaneous lupus erythematosus - https://stm.sciencemag.org/content/11/522/eaax1159.short - the Chen Lab at Yale discovered the connection between a new target, VISTA, and lupus:
The group had previously discovered VISTA as an inhibitory receptor for T-cells and connected it to GvHD - https://pubmed.ncbi.nlm.nih.gov/21768399/
With the observations that VISTA is a brake for T-cells and that lupus patients have been found with autoantibodies with PD-1 (another brake) to increase T-cell activity and inflammation, led the group to study of effects of knocking out VISTA in a lupus mouse model and study patient-derived samples
Mice with VISTA knocked out developed “cutaneous and systemic autoimmune diseases resembling human lupus”
Immune cells from lupus patients (either with SLE or DLE) had increased expression of VISTA
The group also used cytometry to ID myeloid-derived neutrophils as upregulated in VISTA KO’ed mice
The next steps are to understand the mechanism by which VISTA regulates the immune response for lupus. The group alludes to type I interferon releasing dendritic cells. The group does good in vivo work to show VISTA as a promising target to activate to treat lupus. Lupus is a very large and underserved indication mainly due to its heterogeneity, which makes setting the right clinical endpoints difficult. Systemic lupus erythematosus (SLE) has had one new drug approval over the last 6 decades: an anti-BAFF antibody, and discoid lupus erythematosus (DLE) has no FDA-approved medicines. Work to discover new targets combined with better endpoints might lead to a resurgence in the development of new medicines for lupus patients.