Axial - Yale #1

Analysis of exciting Yale life sciences inventors and their inventions

Yale is a burgeoning source of great life sciences companies. With growing support from the university and the surrounding area, inventors from Yale are in a position to create exciting, new businesses from Arvinas to Simcha.

Crews Lab

Using chemical biology to understand cell biology.

Recent

• Defining the rules of proteolysis targeting chimeras (PROTAC) design - https://www.sciencedirect.com/science/article/abs/pii/S1367593118301522?via%3Dihub

• Viewpoint on the power of studying regenerative organisms - https://www.nature.com/articles/d41586-017-09008-4

Past

• Review on the power of small molecules to control intracellular protein levels - https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201307761- important as a research tool, but even more important to pursued undrugged targets

• Inventing PROTACs that are coupled to kinase activity - https://www.pnas.org/content/110/22/8942.long- where the PROTAC is activated upon phosphorylation activating specific pathways:

  

Steitz Lab

Studying and engineering RNA machinery.

Recent

• Review from the world-expert on how coral noncoding RNAs affect the host - https://www.annualreviews.org/doi/abs/10.1146/annurev-virology-092818-015811

Past

• Overview of computational methods to discover and characterize noncoding RNAs in viruses - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684774/- important to begin to make this class an attractive clinical target.

Campbell Lab

Computational and experimental analysis of heart disease.

Recent

• Review of methods to use human induced pluripotent stem cells (iPSCs) - https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP276753- to establish genotype/phenotype relationships for cardiomyopathy:

• Review of work done to model cardiomyopathy - https://www.jmmc-online.com/article/S0022-2828(18)30975-1/fulltext

Past

• Review of computational methods to predict familial hypertrophic cardiomyopathy from biophysical/genomic data - https://royalsocietypublishing.org/doi/pdf/10.1098/rsif.2011.0184

• Using computational models of ventricular myocytes to discover to mechanisms driving excitation–contraction coupling in the heart -   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2556206/- important proof-of-concept to show the value of computational analysis to clinically manage cardiomyopathy.

• Integrating genetics and biophysical data to predict how myofilaments affect cardiomyopathy - https://www.frontiersin.org/articles/10.3389/fphys.2016.00473/full

Isaacs Lab

High-throughput genome engineering.

Recent

• Designing a genetically encoded method to incorporate an unnatural amino acid into polypeptides for selective reactions with drugs - https://isaacslab.yale.edu/sites/default/files/costa_2019_acs.nanolett.8b03837.pdf- important to create drug delivery systems with precise control. Valitor is doing great work to pursue a similar problem:

• Overview of new methods to expand genetic codes - https://isaacslab.yale.edu/sites/default/files/arranz-gibert_cocb2018.pdf

Past

• An iconic paper to establish the method to genetically recode an organism - http://isaacslab.yale.edu/sites/default/files/lajoie_isaacs_science13_0.pdf- forming the basis of GRO Biosciences and 64-X:

• With the Jewett lab, another great inventor, engineering translation to improve multiplep-azido-phenylalanine (non-canonical amino acid) incorporation - https://isaacslab.yale.edu/sites/default/files/gan_et_al-2017-biotechnology_and_bioengineering.pdf

Rinehart Lab

Decoding the human phosphoproteome.

Recent

• Recoding E. coliusing technology pioneered by the Isaacs lab to mimic the human serine phosphoproteome - https://isaacslab.yale.edu/sites/default/files/barber_nbt_2018.pdf- important to discover molecules that interact with phosphorylated serines to drug. Also, very valuable to create post-translational modification (PTM) libraries with physiological relevance:

• Invented SERIOHL-KILR to profile and identify kinase substrates -https://pubs.acs.org/doi/10.1021/acs.biochem.8b00410- using E. coli-derived human peptides (with serines) and liquid chromatography and tandem mass spectrometry(LC-MS/MS) to measure in vitrokinase activity against the peptides:

  

Ring Lab

Engineer immune receptors using combinatorial biology.

Past

• Evolving interleukin-2, a T- and NK-cell growth factor, to be specific toward IL-2Rβ independent of CD25 to imbue specificity to create super-2, an IL-2 superkine - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338870/- promising approach to engineer interleukins for immunotherapies (Simcha, Neoleukin), but competition from other modalities could be an issue given proleukin revenue is in the $10Ms.

• Building on top of the superfine work, to create IL-2 variants that act as clamps - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560365/- enabling fine-tuning of the signal amplitude:

  

• Using yeast display to evolve a protein therapeutic (14 kDa, about 10x small than a monoclonal antibody) against PD-1 -https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4664306/- showing the ability to design non-antibody proteins against high-value targets where size of the drug could occlude target occupancy and reduce efficacy.

Joshi Lab

Investigate immune cell interactions within developing tumors.

Recent

• Inventing a mouse model (NINJA) to study tissue-specific peripheral toleranceimportant for T- and B-cells -https://www.jimmunol.org/content/200/1_Supplement/47.6

• Viewpoint on T-regulatory cells (Treg) plasticity and how it enables fine-tuned activity depending on a microenvironment - https://www.nature.com/articles/s41590-019-0389-y

Past

• With the legendary Tyler Jacks, overview of how tumors actually activate Tregs to suppress the immune system that would attack the tumor - https://science.sciencemag.org/content/339/6124/1160.long

• Important immunology paper to characterize tertiary lymphoid structures (TA-TLSs) - https://static1.squarespace.com/static/57e329372e69cffe309f906f/t/59c695b5cd39c354a175a7a0/1506186684556/1-s2.0-S1074761315003180-main-3.pdf- discovering that TA-TLSs recruit T-cells in particular Tregs for lung cancer in order to suppress anti-tumor activity.

Schatz Lab

Generating a diverse and effective repertoire of antibodies during an immune response.

Recent

• Evolution has been a great inventor; analysis of V(D)J recombination and RAG 1/2 evolution - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459667/- in order to understand the origins of how diversity is generated for antibodies (Ab) and T-cell receptors (TCR).

• Using cryo-electron microscopy (cryo-EM) of a relatives of the RAG proteins to understand how they evolved from acting as a transposase (moving across a genome) to a recombinase (recombining genes) and gaining specificity to generate Ab and TCR diversity - https://www.nature.com/articles/s41586-019-1093-7

Past

• Discovering that somatic hypermutation, which generates point mutations in B-cells to create diverse antibodies is influenced by antibody enhancers (activating genetic regions) to create a strong positive feedback loop to maximize Ab diversity - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972084/

Rothman Lab

Studying intracellular transport.

Recent

• Rothman along with Randy Schekman (UC Berkeley) and Thomas Südhof (Stanford) won the Nobel Prize in 2013 for Physiology or Medicine for discovering the “machinery regulating vesicle traffic, a major transport system in [cells].” Incredible work important for biologics manufacturing helping generate $100Bs in value. Nobel Lecture on the topic; an aside, reading these lectures in general are a great way to know what is important in life sciences - https://www.nobelprize.org/uploads/2018/06/rothman-lecture-1.pdf

• Offering a framework to become a great inventor - https://febs.onlinelibrary.wiley.com/doi/full/10.1002/1873-3468.12960

• Framing that software is helping biology make the transition from analog to digital instead of automating it (conventional but wrong wisdom) - https://febs.onlinelibrary.wiley.com/doi/full/10.1002/1873-3468.13308

• Using cryo‐electron tomography to discover the precise arrangement of the machinery required for exocytosis (active transport out of the cell) -https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353562/

Past

• Inventing single-stranded DNA conjugated with lipids to regulator specific SNAREs (important for membrane fusion) - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888371/- important as an orthogonal tool for research and bringing two selected membranes together.

• With Schekman, reviewing the field of protein folding - https://www.cell.com/cell/fulltext/S0092-8674(11)01011-7

Miller-Jensen Lab

Studying how cell signaling and cell-cell communication regulate immune cells.

Recent

• Overview of systems immunology - https://www.sciencedirect.com/science/article/abs/pii/S0958166918300119?via%3Dihub- to use multi-dimensional (many sources) and high-content (well characterized) to connect the state of the immune system to the state of the disease. Important work to use host-based reading to develop new medicines:

  

Past

• Mapping out the toolbox to characterize signaling pathway diversity at the single-cell level - https://www.cell.com/trends/biotechnology/fulltext/S0167-7799(16)00043-3

• Great work on analyzing single-cell cytokine secretion - https://stke.sciencemag.org/content/8/381/ra59- to discover that a decrease of IL-10 in a specific cell population, monocyte-derived macrophages, leading to a cascade of events and inhibition of inflammation. Important for showing the power of the method (single-cell, perturbation) to validate new targets.