Axial - Inventors #4
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.
Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis - https://immunology.sciencemag.org/content/5/52/eaba0759/tab-pdf - the Bluestone Lab at UCSF developed a mouse model to prove out that mechanism that adding a second checkpoint inhibitor in combination with an anti-PD1 antibody can help overcome resistance for patients with liver cancer metastasis. The Bluestone is legendary for doing work that led to the development of Abatacept for RA and Belatacept for kidney transplant along with contributing to the body of work that helped develop Yervoy (anti-CTLA-4). This Science paper does a great job to develop a mouse model where cancer cells (of the same type) are injected into two sites to mimic metastasis. A model as simple as this (but pretty hard to execute; bench work is art work) combined with flow cytometry enabled the group to discover that the presence of tumor antigen in the liver led to systemic suppression of activity against that antigen throughout the mouse. They then discovered that Tregs and intratumor CD11b+ monocytes were upregulated. With this observation, the group figured that depleting Tregs with an anti-CTLA-4 antibody could make the model responsive to an anti-PD-1 antibody.
Biochemistry and structural biology
The granddaddy of them all.
Selective inhibition of human translation termination by a drug-like compound - https://www.nature.com/articles/s41467-020-18765-2 - out of the Cate Lab at UC Berkeley with a peer who lived on the opposite room from me in Straus during college on the paper, the group uses cryo-EM beautifully to show that a compound, PF846, known to inhibit the synthesis of specific proteins do so by stalling the nascent chain that comes out of the ribosome during protein synthesis. PF846 was already known to prevent elongation by disrupting peptidyl-tRNA binding. But this paper adds to the mechanism by showing the compound also binds to the ribosome exit tunnel. Combined with the Cate Lab’s previous discovery that PF846 inhibit protein synthesis in a sequence-dependent manner - https://pubmed.ncbi.nlm.nih.gov/31160784/, the group uses cryo-EM and in vitro assays to validate that the compound first inhibits elongation then termination ultimately locking the nascent chain within the ribosome.
Roughly 20 years behind but set up to transform the concept of human.
Autophagy Pathways in CNS Myeloid Cell Immune Functions - https://www.cell.com/trends/neurosciences/fulltext/S0166-2236(20)30197-1 - out of the Lünemann Lab at University of Münster, the group wrote up a nice review on autophagy’s role in the central nervous system (CNS). In particular, autophagy regulates the activity of immune cells from the myeloid lineage within the nervous system, which are essential for inflammatory response in the brain. Neuroimmunology is likely the next frontier to bear new medicines in the field. Autophagy in the brain seems to act through different pathways than other organs and generate structures called autophagosomes to regulate myeloid-immune cell activity and their corresponding signals.
Cell structure and function.
Pluripotent Stem Cell-Based Cell Therapy—Promise and Challenges - https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30460-4 - Shinya Yamanaka, the co-winner of the Nobel Prize for his work on stem cells out of Kyoto University recently published a great overview on the roadmap for stem cell medicines. Stem cells come in two major types: induced pluripotent stem cells (iPSC) for which Yamanaka is known for and embryonic stem cells (ESC). The former were first discovered with 4 legendary factors: Oct3/4, Sox2, Klf4, and cMyc, which were able to induce pluripotency in mouse fibroblasts. Yamanaka lays out 3 key problems to solve in order to realize the potential of regenerative medicine:
Tumorigenicity - the proliferative capacity of stem cells can lead to tumors
Immunogenicity - stem cells from one patient to another could lead to immune rejection and even autologous rejection has been surprisingly observed
Heterogeneity - each line of stem cells from the same class have different morphologies, gene expression profiles, division rates, and more that make them hard to develop into medicines. More precise sorting tools are needed.
Genetics, genomics, and developmental biology
Heredity and variation.
Somatic mutation distributions in cancer genomes vary with three-dimensional chromatin structure - https://www.nature.com/articles/s41588-020-0708-0 - from the Futreal Lab at MD Anderson, the group studied the role of the 3D genome in cancer. They first annotated 5 different human cancer cell lines for known topologically associating domains (TAD). The TADs and corresponding markers are from a larger dataset of 125 human cell lines. They group was able to discover:
Boundaries between TADs is a way to measure cancer mutational load. TADs ~ variation rate in somatic cancer mutations
Somatic mutations in cancer seems like not show selectively for active and inactive TADs
This makes sense from a mechanistic perspective because TADs and the 3D organization of the genome is directly coupled to transcription and genome replication rates. So mutations in cancer that alter the genome to increase these rates will lead to higher proliferation.
Consequently, the connection between the 3D genome and cancer is an emerging target class for companies to pursue.