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Inventors #2
A set of ideas and observations on inventions and discoveries in life sciences.
Immunology
The immune system and everything in it.
The science and medicine of human immunology - https://science.sciencemag.org/content/369/6511/eaay4014.full - legends in immunology, Mark Davis (discovered the first TCR) and Bali Pulendran wrote a very useful paper on the interplay between high-throughput data and human immunology. The key quote is from Sydney Brenner: “We don’t have to look for a model organism anymore. Because we are the model organisms.” The piece is more about overview instead of research, but some key points are:
- Vaccines are probes for immunologists to perturb immune systems to study infection, autoimmune diseases, and cancer
- Systems immunology combined with these probes (i.e. vaccines) can combine high-throughput data with mechanistic validation. Data alone to profile human immune systems does often generate insights by itself.
The Role of MicroRNAs in Development and Function of Regulatory T Cells – Lessons for a Better Understanding of MicroRNA Biology - https://www.frontiersin.org/articles/10.3389/fimmu.2020.02185/full - out of the Krueger Lab in Frankfurt, Germany, they wrote a great overview piece with specific case studies on the role of microRNAs (miRNA) in regulatory T-cell development (Treg). Tregs are immune cells important to make sure our immune system doesn’t attack our own cells. Dysfunction in Tregs contributed to autoimmunity, which is mainly driven by autoreactive B-cells that drive T-cells to attack self. If Tregs aren’t doing their job properly, the impact of autoreactivity is much more severe. In terms of medicines, engineering Tregs is a strategy to treat autoimmunity, but in the long-run complete and selective depletion of autoreactive B-cells will lead to cures. Dicer is a protein essential to generate mature miRNAs; when Dicer is knocked-out, Treg development is severely disrupted suggesting an essential role of miRNAs for Tregs. The overview paper does case studies on the function of 4 critical miRNAs. It’s not clear to me that these miRNAs are useful targets to treat autoimmunity miRagen Therapeutics took a good shot trying to develop an miRNA drug. However, the authors make an excellent point of using Tregs as a model to study the in vivo function of miRNAs, which could shed more light on the biology and make the target class more tractable in general.
Biochemistry and structural biology
The granddaddy of them all.
Bringing drug production home: how the US is rebuilding the drug supply chain after covid-19 - https://www.bmj.com/content/370/bmj.m3393 - a biomedical journalist wrote a compelling piece on the need/trend of on-shoring biomanufacturing to the United States. Over 90% of prescriptions in the US are generics where none of them are manufactured in the US. India exports $10B-$20B annually in generics alone. This shift happened over the last ~3 decades where the US among other developed countries made over 90% of all generics. Most generics are small molecules that have standard manufacturing methods. This phenomena probably doesn’t apply with more complex medicines like biologics. Also, what does a generic cell and gene therapy look like? Combined with COVID and various supply chain disruptions, on-shoring of biomanufacturing seems likely to form the basis of a new generation of businesses and institutions.
Merging C(sp3)–H activation with DNA-encoding - https://pubs.rsc.org/en/content/articlehtml/2020/sc/d0sc03935g - out of the Yu Lab at Scripps, the group developed a new reaction to increase the diversity/complexity of DNA-encoded libraries (DEL). DELs are very useful to screen for new drug hits cheaply; however, the library yield, diversity, and more limit the realization of their full potential in drug development. A big problem is the high molecular mass and lipophilicity of chemical matter in DELs. This is mainly a result of the limitations of the solvents for DELs; something like 20% at least has to be water to dissolve the DNA. So this limitation on solvents creates bottlenecks for the time of reactions that can occur mainly sp3 carbon:hydrogen (C-H) ones. I remember teaching orbitals as a TF in intro chemistry; I have a soft spot for all these premeds even though I wasn’t one and gave everyone As on their homework or helped them get there. I wasn’t asked to be a TF my senior year in college. To enable C-H sp3 reactions during DEL library creation, the Yu Lab developed a Pd-catalyzed arylation (i.e. adding an aryl group) relying on decoupling carboxylic acid and amides during each step. They got a pretty good yield: 69%. This is a very useful step forward to generate DELs with cool heterocycles and chemical matter with more sp3 chiral centers. Great work.
Molecular representations in AI-driven drug discovery: a review and practical guide - https://jcheminf.biomedcentral.com/articles/10.1186/s13321-020-00460-5 - a research out of AstraZeneca is Sweden, wrote a really interesting review on the use of abstract representation of molecules and proteins to feed into machine learning models. This is a good summary but the key to success is knowing when a protein, chemical, or something else in biology can be abstracted and why? Is there a lot of mechanistic data on the class? Strong connection between prediction and function historically? The trick is finding spots in bioinformatics and chemoinformatics to focus on.
Neuroscience
Roughly 20 years behind but set up to transform the concept of human.
Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies - https://www.cell.com/cell/fulltext/S0092-8674(20)31013-8?rss=yes - the Satpathy Lab at Stanford with Howard Chang involved did some exciting work to connect CAR-T neurotoxicity due to CD-19 recognition of pericytes, a cell type important to maintain the integrity of the blood-brain-barrier. The cool part of this paper is a demonstration of the power of single-cell sequencing in human immunology; mouse pericytes have low CD19 expression but some human ones have higher expression. Similar to the Davis review paper, making humans the model organism especially in immunology could help make better medicines, diagnostics, and products.
Cell biology
Cell structure and function.
Tissue-targeted R-spondin mimetics for liver regeneration - https://www.nature.com/articles/s41598-020-70912-3 - a research group a Surrozen (a company targeting the Wnt pathway to develop regenerative medicines), designed a bispecific mimetic molecule to activate the Wnt pathway while avoid interaction with intestinal targets to improve liver function in liver fibrosis mouse models.
Multi-scale 3D Cryo-Correlative Microscopy for Vitrified Cells - https://www.cell.com/structure/fulltext/S0969-2126(20)30281-1 - the Chiu Lab at Stanford combined cryo-fluorescence confocal microscopy, volume cryo-focused ion beam scanning electron microscopy, and transmission cryo-electron tomography to image the same sample at different scales. Really this is a tour de force type of paper with obvious applications to use cryo-EM for phenotypic screens.
Genetics, genomics, and developmental biology
Heredity and variation.
An interspecies translation model implicates integrin signaling in infliximab-resistant inflammatory bowel disease - https://stke.sciencemag.org/content/13/643/eaay3258 - the Lauffenburger Lab at MIT combined transcriptomics data from humans with IBD with proteomics data in mouse models to figure out what integrin singalling is important for resistance to anti-TNF therapies. Validation studies confirmed an integrin subunit negatively regulates anti-TNF therapies to suppress cytokine release. This is a good case study to combine data from humans and models to quickly identify new targets for medicines.
T cell subset-selective IL2RA enhancers shape autoimmune diabetes risk - https://www.biorxiv.org/content/10.1101/2020.07.22.216564v1.full.pdf - out of the Marson Lab at UCSF, one of my favorite groups, did a study some time ago to understand the role of enhancers in autoimmunity. The group used IL2RA (a regulator of T-cells and Tregs) as the model applying CRISPR activation tiling across the genetic locus. Using this method, the group identified elements (CaRE3/4) that help control IL2RA expression in Tregs and T-cells, respectively. The paper is a useful proof-of-concept to combine genomics and the CRISPR toolkit to study human immunology.