Axial - Inventors #12
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.
Amino Acids and Their Transporters in T Cell Immunity and Cancer Therapy - https://www.cell.com/molecular-cell/fulltext/S1097-2765(20)30614-6 - the Zou Lab at Michigan, a leader in oncology research, put out a useful review on the role of amino acid metabolism in cancer immunotherapy:
Amino acids are a key driver for cancer and T-cell metabolism so understanding how they get into these cells can reveal new drug targets to enhance immunotherapy
Amino acids are transported into cells by solute carrier (SLC) transport proteins
There are over 60 SLC classes - https://pubmed.ncbi.nlm.nih.gov/30177408/ with over 400 SLC proteins overall. SLCs can be sodium dependent or independent and are classified by their substrate: neutral, basic, and acidic classes.
Cells can use multiple SLCs to important the same amino acid, which makes selective targeting of one amino acids more difficult
When T-cells transition from a naive to effector state, their metabolic needs for amino acids increases dramatically. Enhancing this process could lead to better killing rates.
Cancer cells can overexpress SLCs to outcompete amino acids from normal cells leading to local nutrient depletion in the tumor microenvironment
One example of a target in amino acid metabolism is SLC7A2, which transports extracellular arginine causing T-cells to have insufficient levels of the amino acid and have impaired function
Biochemistry and structural biology
The granddaddy of them all.
Reactivity-Based Probe of the Iron(II)-Dependent Interactome Identifies New Cellular Modulators of Ferroptosis - https://pubs.acs.org/doi/10.1021/jacs.0c06709 - the Renslo Lab at UCSF invented a probe that induces ferroptosis (i.e. cell death dependent on iron) enabling proteomics studies on iron-dependent pathways:
Ferroptosis Inducing Peroxide for Chemoproteomics-1 (FIPC-1) developed is a reactivity-based probe that induces ferroptosis and labels cellular proteins that can be measured downstream by mass spectroscopy
Using this tool, the group discovered two genes, P4HB (disulfide isomerase) and NT5DC2 (dehalogenase), as modulators of ferroptosis
New lines of research are discovering the essential role of ferrous iron in cancer metabolism. As a result, developing new targets in these pathways as well as more selective, iron-dependent medicines are needed.
Roughly 20 years behind but set up to transform the concept of human.
Intracellular amyloid toxicity induces oxytosis/ferroptosis regulated cell death - https://www.nature.com/articles/s41419-020-03020-9 - the Currais Lab at the Salk discovered that Amyloid beta (Aβ) induces oxytosis (i.e. accumulation of reactive oxygen species) and ferroptosis in nerve cell models:
Aβ is a significant biomarker in Alzheimer’s disease (AD) and accumulates as plaques. However, the role of Aβ is still being determined as well as the mechanism by which neurons die.
The group combined RNA-seq, proteomics, and metabolomics and applied the toolkit to “MC65 nerve cells in the absence and presence of intracellular Aβ toxicity”
With the data generated, pathway analysis was used to find significant changes in genes related to oxytosis and ferroptosis in cells with Aβ toxicity. Specifically, decreases in glutathione and iron as well as increases in lipid peroxidation are key biomarkers.
Based on this observation, the group used glutamate and RSL3 to induce oxytosis/ferroptosis to find that nerve cells with Aβ toxicity are more sensitive than those without it
Excitedly, this paper opens up a lot of research avenues from mechanistic studies in AD to new drug targets and the role of mitochondria and protein transport in Aβ-induced oxytosis/ferroptosis
Cell structure and function.
Silencing of E-cadherin in induced human pluripotent stem cells promotes extraembryonic fates accompanying multilineage differentiation - https://www.biorxiv.org/content/10.1101/2020.11.01.363713v1 - the McDevitt Lab at UCSF uses hydrogels to modulate cell adhesions of human pluripotent stem cells driving differentiation and mimicking germ layers of an embryo:
Using alginate microbeads, the group encapsulated human induced pluripotent stem cells (iPSC) and were able to mimic embryonic differentiation
The group used this model to study the role of cell-cell adhesion during development: knocking down E-cadherin (CDH1), a cell adhesion protein, was found to initiate the emergence of trophoblast-like (i.e. outlier of early blastocyst) cells, which was verified by single-cell RNA-seq
This proof-of-concept study shows that physical microstructures are sufficient to mimic embryonic development and provide a platform to study the role of adhesion and other force-generating proteins during stem cell differentiation. An obvious application of the tool is IVF.
Genetics, genomics, and developmental biology
Heredity and variation.
Bacterial Retrons Function In Anti-Phage Defense - https://www.cell.com/cell/fulltext/S0092-8674(20)31306-4 - the Sorek Lab at Weizmann discovered the retrons, reverse transcriptase and non-coding RNA generate chimeric DNA/RNA molecules, are used by bacteria to defend against phages; this paper does a great job at uncovering an entirely new class of biology around retron immune defense:
The paper’s premise is based on discovering an intergenic region in an operon known to be involved in anti-phage activity
After sequencing the RNA of the region, the group discovered that it contained a retron, Ec48: a reverse transcriptase and a non-coding RNA that produces a chimeric nucleic acid that is coupled to an effector protein
The group studied phages the overcame Ec48-mediated phage defense and found that the phages contained mutation in proteins that inhibit RecBCD in bacteria, a protein important for phage DNA degradation
To confirm this mechanism, RecB inhibitors activated the Ec48 retron system leading to bacterial cell death. Ultimately, retrons may be a second-line defense for bacteria: if the phage breaks into the walls, retrons sense this and lead to cell death before the phage can replicate.