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Inventors #19
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 established the role of tumor-associated macrophages (TAM) in sonic hedgehog subgroup of medulloblastoma (SHH-MB), in mice:
Macrophages are the predominant immune cell found in SHH-MB tumors, and an important topic in the field is understanding if they have pro- or anti-tumor effects?
This paper doesn’t definitely answer the question, but established a correlation between TAMs and survival. SHH-MD serves as a broader case study on the impact of cancers with distinct mutations creating unique microenvironments (TME) - every solid tumor not only is different based on mutational burden but also their TME.
Relying on a mouse model for SHH-MD where the human oncogene, SmoM2, is fused to a YFP reporter and selectively expressed in granule cell progenitors, the group used manganese-enhanced magnetic resonance imaging to discover that TAMs are significantly higher in around half of tumors that lead to death in a mouse
This elegant experiment is pretty significant to show the correlation. The paper also shows that this phenomenon is dependent on colony-stimulating factor 1 receptor (CSF1R).
Biochemistry and structural biology
The granddaddy of them all.
Fluorescence Anisotropy-Based Tethering for Discovery of Protein−Protein Interaction Stabilizers - https://pubs.acs.org/doi/10.1021/acschembio.0c00646#.X7Ps9_sRGT8 - out of the Ottmann Lab at the Eindhoven University of Technology, the group developed a new method to augment protein-protein interactions (PPI):
An important step to develop new protein degraders and other probes is discovering stabilizers of PPIs
The group combines sulfide trapping and fluorescence anisotropy (FA) to find molecules that stabilize the interaction between 14-3-3 and Estrogen Receptor α
The method relies on labeling a Estrogen Related Receptor gamma (ERRγ) phosphopeptide with a fluorescent probe. ERRγ’s interaction with 14-3-3 is monitored by FA. Then fragments are screened that form disulfide bonds with ERRγ to stabilize the PPI.
The paper ended up finding a molecule that stabilized the complex by ~5x
This functional assay creates a less expensive and hopefully faster way to screen for both PPI stabilizers and inhibitors
Neuroscience
Roughly 20 years behind but set up to transform the concept of human.
Engineering Brain Parasites for Intracellular Delivery of Therapeutic Proteins - https://www.biorxiv.org/content/10.1101/481192v1 - the Rechavi Lab at Tel Aviv University invented (2018) a new way to deliver proteins to the central nervous system (CNS) relying on engineering the Toxoplasma gondii parasite:
About a third of the human population is thought to be chronically infected by T. gondii. The parasite actively moves into the CNS through 3 mechanisms: (1) crossing the blood-brain barrier (BBB) through immune cells, (2) passing through BBB tight junctions, and (3) directly infect endothelial cells on the BBB.
This specificity and ability to cross the BBB, made the parasite an attractive vehicle to deliver cargo to cells in the CNS
The method relies on generating fusion genes between a therapeutic protein and a secretion protein (2 MoAs: rhoptries, secreted before invasion, or dense granules, secreted continuously). After selecting 7 proteins to deliver, the group showed the ability to deliver across a mouse BBB. Excitedly, the paper showed an ability to deliver a fusion MeCP2 gene selectively to neurons.
A lot of work is left to do, but the research has the potential to deliver a diverse range of cargo, from enzymes to antibodies, to selective cells in the brain. Plus I think the hypothesis is pretty clever - hijacking a parasite for our own purposes. Really flipping the table.
Cell biology
Cell structure and function.
Identification of highly selective covalent inhibitors by phage display - https://www.nature.com/articles/s41587-020-0733-7 - the Bogyo Lab at Stanford used phage display for a new application discovering covalent inhibitors:
The group expresses a library of peptides (with 2 cysteines) on a phage coat protein (pIII)
The peptides are conjugated to a “warhead” molecule that reacts with a nucleophile found on the target
Focusing on a cysteine protease and serine hydrolase, the group discovered a set of covalent inhibitors, combination of the peptide and warhead.
This type of approach is pretty useful to find a covalent inhibitor without a good lead. Phage display allows on to discover a hit and iteratively improve its binding affinity to a target.
This type of method has the potential to discover covalent inhibitors for new targets for drug discovery, imaging probes, and profiling tools for global studies of amino acid reactivities
Genetics, genomics, and developmental biology
Heredity and variation.
The Ongoing Quest to Crack the Genetic Code for Protein Production - https://www.cell.com/molecular-cell/fulltext/S1097-2765(20)30644-4 - out of the Classens Lab at Wageningen University, a review on the principles of gene expression established new opportunities in mRNA and protein engineering:
Which coding and non-coding regions influence “protein production by modulating transcription, mRNA decay, and translation?”
To enable the design of synthetic genes with predictable behaviors, better tools and models are needed to detect “weak signals” from sequence that determine expression?
How to better tune and optimize several synthetic genes at once? Better codon optimization methods are needed. Mapping out untranslated regions (UTR) and open-reading frames (ORF) globally would help - machine learning definitely helps here.
Building large libraries of a single gene’s variants can explore to what extent individual codons influence expression. In particular, doing this work beyond model proteins like GFP.
All of this work has the potential to make cell design more predictable. Things like antibody expression become easier. New cell therapies could emerge. Biosensors for oil wells or food.