Axial - UCLA #1
Analysis of exciting UCLA life sciences inventors and their inventions
From Seaborg and Merrifield in the past to Heck and Hsiao now, UCLA has been home to incredible inventors. As well as some incredible college basketball dynasties. On the edge of the world and all of western civilization, UCLA has built exciting companies from these inventions from Agensys (led by Arie Belldegrun, a legend who has transformed oncology treatment) to Bloom Sciences. The best is yet to come. In the backdrop of Hollywood, the aerospace industry, Amgen and maybe Xencor, and junk bonds, UCLA and Los Angeles in general has the potential to help build enduring life sciences businesses.
Finding the connections between the gut and the brain.
Elaine Hsiao has done incredibly elegant work that amazed me when I first read her work that is mapping out the connection between the microbiome and the brain. With the Hsiao Lab driving the creation of a new field, the group is positioned to make new discoveries and bring new treatments to patients. Forming the basis of Bloom Science, the Hsaio Lab recently characterized the connection between the gut microbiota with the ketogenic diet, which is used to treat refractory epilepsy - https://www.sciencedirect.com/science/article/pii/S0092867418305208 - discovering the mechanism-of-action acts through the bacterial species, Akkermansia and Parabacteroide :
A useful overview of on the impact of the microbiome on behavior - https://science.sciencemag.org/content/365/6460/1405.abstract
A definitive paper linking gut microbes with neurodevelopmental disorders - https://hsiao.science/static/pdf/EYHCell.pdf - showing that Bacteroides fragilis maintains gut permeability and modulates the metabolite, 4EPS, that is sufficient to induce anxiety in mice.
From the Cell paper, doing a fantastic overview on the role microbial dysbiosis in autism spectrum disorder- https://hsiao.science/static/pdf/VUONG2016.pdf
Engineering biology at the quantum limit.
Bioproduction is incredibly important whether for design of chassis or the hardware itself, but the potential to transform industrial biotechnology and therapeutics is massive. The Di Carlo Lab recently invented a new method for adherent cell culture and processing with minimal perturbation of cells. Using a hydrogel microcarrier, the method creates a “shelter” for cells against shear stress during flow processing - https://www.nature.com/articles/s41378-018-0020-7
What enabled the previous piece of work, was the lab development of scalable hydrogel manufacturing - https://onlinelibrary.wiley.com/doi/10.1002/adfm.201900071
Creating an integrated device that relies on vortex trapping and microfluidics to capture and concentrate rare cell types - https://www.pnas.org/content/115/40/9986 - the proof-of-concept focused on circulating tumor cells (applications for liquid biopsies); capturing the cells in ~15 minutes and concentrating them 100,000x from 1 mL to 10Ks of 2 nL droplets:
In the past, that built up the CTC paper in PNAS, invented a microfluidic device using vortex capture for rare cell capture - https://pubs.rsc.org/en/Content/ArticleLanding/2017/LC/C7LC00355B#!divAbstract
Studying natural product synthesis and catalysis.
The Tang Lab is one of the world’s leader in studying natural products. With his work supporting Hexagon Bio, the lab recently designed a clever approach to discover a new natural product herbicide - https://www.nature.com/articles/s41586-018-0319-4 - for a given target (DHAD) with no known natural product for it, the lab studied clusters with variants of DHAD in other organisms with the premise that natural products encoded in these bioactive clusters can bind DHAD but not the variants, which would have resistance:
After scanning the genomes of various microbes, in Penicillium variabile, the lab discovered a cluster expressing the natural product, Varicidin A that inhibits Diels–Alderases that create decalins (pericyclase) - https://pubs.acs.org/doi/abs/10.1021/jacs.8b12010 - showing the power of bioactive clusters for drug discovery and a new ability to modulate Diels–Alder reactions, an important part of chemistry to form rings.
Similarly, the lab discovered a pericyclase that catalyzes the inverse Diels–Alder reaction - https://pubs.acs.org/doi/abs/10.1021/jacs.9b02204 - for the production of the natural product, Ilicicolin H.
A fantastic overview of the toolkit to discover natural products in yeast, Saccharomyces cerevisiae - https://www.sciencedirect.com/science/article/abs/pii/S0958166916300556
Creating new models for cancer and innate immunity.
Building out a computational model of γ-chain cytokine receptors and their binding activity - https://www.biorxiv.org/content/10.1101/778894v1 - γ-chain cytokine receptors interact with large classes of interleukins and modulate their specific activity. The Meyer Lab mapped across the receptors activity across cell types to build out a new set of rules with the potential to design new immunotherapies and measure the immune response to existing therapies:
Recently composed an overview on the integration of various data sets to study cancer - https://www.sciencedirect.com/science/article/pii/S245231001930040X?via%3Dihub - using a systems approach to combine data across scales (i.e. single-cell, tissue) and type (PK, phenotype):
Contributed to a compendium on the use of systems biology in oncology - https://cancerres.aacrjournals.org/content/early/2016/11/18/0008-5472.CAN-16-1580
Using machine learning to predict complex phenotypes.
Developing convolution neural networks to analyze MRI data of acute stroke patients to identify affected tissues and guide clinician decision making for interventions - https://labs.dgsom.ucla.edu/arnold/files/papers/HoJMI2019.pdf?_ga=2.241404353.210413632.1571104432-924763074.1570926389 - in general image analysis tools in healthcare have the chance to follow a PathAI business model:
With 182 patients over the course of 3 months, inventing a machine learning model to use Fitbit (activity-tracking) data to match patient reported outcomes - https://labs.dgsom.ucla.edu/arnold/files/papers/MengJBHI2019.pdf?_ga=2.242067649.210413632.1571104432-924763074.1570926389 - the key breakthrough for the group was treating each week as a set of probabilities of the previous one instead of being completely independent.
Engineering cells and materials for regeneration.
Transplants are a powerful way to reset the immune system. The Li Lab used polymeric rods encapsulated with macrophages and myofibroblasts in combination with a bone marrow transplant to induce tissue repair for a chronic kidney disease rat model -https://www.sciencedirect.com/science/article/pii/S0142961218308421?via%3Dihub
A great overview on the potential of biomaterials to reprogram cells and modify their microenvironments - https://www.sciencedirect.com/science/article/pii/S2211339817300023
Systems biology for metabolic disorders.
Psoriasis is a debilitating autoimmune disease often triggered by an environmental insult. Various large-scale studies have been done in autoimmunity for target identification - the Yang Lab took various data sets (i.e. genome-wide association studies, tissue-specific information) to validate existing targets for psoriasis and discovering new ones, in particular catabolism branched chain amino acids - https://link.springer.com/epdf/10.1186/s12918-018-0671-x?author_access_token=LcImCsKIb0oH_HWA-kut3W_BpE1tBhCbnbw3BuzI2ROiU6VJn2NkeSJadaazyfS6D8YyRwUJ76DTnvdmI8Pupaju80NUiJWJtyogk7YJYWPNFgARInJmMpl2E0TaKavMcbq9vb1MiiJqEtm5DcYVZA%3D%3D
Using Drop-seq, identifying key cell populations that drive traumatic brain injury - https://www.nature.com/articles/s41467-018-06222-0 - in general, single-cell technologies are seeing more uptake in the clinic and have the power to transform drug discovery:
A tour de force type of paper, using early network analysis to match a set of genes to a cause, in this case abdominal fat - https://www.nature.com/articles/ng.325 - by combining variation across a genome, phenotype, and transcriptional data, Yang as the first author showed the validity of the model with 8 out of 9 genes IDed showing a causal effect on abdominal obesity in mouse models. This was an early paper, but the potential to analyze biological variation combining them with new data sets (i.e. single-cell, RNA-seq, protemomics) has the potential to drive the creation of new medicines:
Engineering biological circuits and proteins for new medicines.
From a good friend, the Chen Lab is a relatively young lab doing pioneering work in synthetic biology with a focus on CAR-T. Previously a Junior Fellow at Harvard (an incredibly prestigious position), Chen collaborates with the Parker Institute to translate her inventions into transformative drugs. Recently, designed a chimeric antigen receptor (CAR) that is sensitive to transforming growth factor beta (TGF‐β), a major signaling axis for cancer particularly solid tumors - https://aiche.onlinelibrary.wiley.com/doi/full/10.1002/btm2.10097 - with the potential to bring the power of CAR-T, which has had utility in liquid cancers to solid ones: