alex rubinsteyn

The thing I feel most about coding agents is tremendous gratitude. Every half-finished project that has haunted me for a decade gets to actually come to life

@kchonyc @owl_posting Curious what you think! Also tagging @BenjaminGVincen

half way in on this amazing episode on designing a cancer vaccine by @owl_posting with @iskander and ben vincent. link below

a few people have told me that this podcast sounds incredibly interesting, but that they don't have 3 hours to devote to it. i get it! life is busy. to help out, i have compiled together 19 minutes of the most interesting bits of the episode. hopefully more palatable, especially at 2x speed! timestamps: 0:00 — Why a cancer vaccine is theoretically the perfect drug 1:52 — How your immune system reads the inside of every cell 4:26 — Why cancer can't just hide from the immune system 5:35 — The one patient who proved a cancer vaccine can work 7:21 — Why flooding the immune system with tumor cells does nothing 10:04 — How cancer vaccines broke every rule of drug development 12:18 — Why not skip the vaccine and engineer the T cells directly? 14:03 — What we can — and can't — learn from a billionaire's cancer journey 16:48 — Why concierge oncology couldn't have worked until now

@wasserstein_rao @teortaxesTex Like, fine, you want to do it the slowest least algorithmic way possible. But….is there an API so my Python script can do it the normal way? (no)

@iskander @teortaxesTex they love it its crazy

might be quietly big news for accelerating biomedical research closer and closer to fully automated wet labs running at the speed of mitosis

@wasserstein_rao @teortaxesTex I asked a rep how to program combinations of peptides on a 96 well plate and she started dragging and dropping for a few minutes before I cut her off

@teortaxesTex Did you know that the most widespread and capable liquid handling robots on the market are almost exclusively programmed with drag and drop GUIs that only run on Windows? We are so early.

@DBashIdeas @ShabbosReads I mean their revolts though As soon as the Judeans were done, Samaritans had their own procession of rebellions

@iskander @ShabbosReads It def gives overview of the different populations living there and the different forms of Jewish life at the time.

I read this over Shabbos.

We're hiring a chemoproteomics / surfaceomics Senior Scientist at Deliverome to build a platform that profiles the internalization rate of proteins across the surfaceome. This person will lead from the bench and also explore new technologies for native surface profiling.

owlpod audience ridiculously high concentration of technical/scientific expertise

Listening to Anne of Green Gables on a drive through WV, have to explain Parthian archers bc kid lit from 100+ years ago is next level. Pull up to a Wendy’s where two kids are hanging out side by side on phones, swiperotting their brains on 10s TikTok clips the whole time we ate.

@alphabreacher Data leakage and problem underspecification breeds cargo cult cottage industries

@iskander any hypothesis like why this phenomenon is observed so often

Brutal

Source: "Assessing data size requirements for training generalizable sequence-based TCR specificity models via pan-allelic MHC-I point-mutation ligandome evaluation" (nature.com/articles/s4159…)

Ben and I had fun on owlpod Anyone else want to do one?

So much good stuff covered here by @owl_posting @BenjaminGVincen @iskander. Definitely recommend. Super long at 3 hours and I haven't finished, but it covers a large fraction of cancer immunology and immunotherapy. Certainly more than just cancer vaccines. I'm also really interested in Cancer-Testis Antigens (CTAs) and think why they're expressed in the testis and re-expressed in cancer is fascinating biology. Analogous to AIRE in the thymus driving widespread gene expression for central tolerance, the testis also transcribes a huge fraction of the genome to maintain sequence fidelity through transcription-coupled repair. Basically, the testes express a bunch of genes, checking for errors as they go, not necessarily for the function of sperm, but to make sure that your sperm aren't acquiring and passing on mutations to your children. See Xia et al. (@BoXia7 @ItaiYanai), ‘Widespread transcriptional scanning in the testis modulates gene evolution rates,' Cell (2020). More recent work suggests intergenic regions are transcribed as well. And there are at least 2 really interesting reasons why CTAs are expressed in cancer. First, many cancers are developmentally immature and stem-like, with more open chromatin (via DNA hypomethylation), and by virtue of their oncogenic programs, re-express a bunch of proteins important for stem cells and development. Second, many CTAs are useful to tumor cells in their own right. Some drive DNA damage tolerance and repair (e.g. MAGE-A4 stabilizing RAD18, MAGE-G1 in the SMC5/6 complex). Others block differentiation (e.g. PRAME repressing retinoic acid signaling). @pottslab has published some really interesting work on the function of MAGE-family genes for those interested. The name cancer-testis antigen predates the discovery of what a lot of CTAs actually do. And we now know many aren't restricted to cancer and the testis (as mentioned on the pod: ovary, placenta, and sometimes brain), but the name has persisted. My grad school mentor preferred "developmentally regulated antigens," or "cancer-germline antigens," which I think nicely encapsulate both CTAs and oncofetal antigens, get around the lack of true expression restriction to the testis, and reflect their developmental biology rather than a misleading tissue expression profile.

@Kyle_Dyson @owl_posting @BenjaminGVincen I think we all need to collaborate @BenjaminGVincen

Link: nature.com/articles/s4155… (Thanks @dshahh for sending it to me)

Synthetic RNA oligos instead of full length IVT mRNA for cancer vaccines... "Chemically synthesized, non-capped and non-polyadenylated peptide-coding RNA efficiently induces antigen-specific CD8+ T cells"

@anthonystaj Thanks! I feel like we’re in the golden era of hyper-niche deep dives: @owl_posting, @AcquiredFM, @approvedfm, @salonium / @JacobTref’s Hard Drugs, @corememory, @dwarkesh_sp, TWiV, &c

The best thing to come out of the podcasting era is stuff like this. Literally 3hours of hardcore nerd talk on cancer vaccines. I bet that this type of content will spawn more success in this field than the billion dollar AI x bio newcos. Keep planting seeds

@treypicou @owl_posting @BenjaminGVincen Ben too!

@owl_posting @iskander @BenjaminGVincen Alex is awesome!

How to design a cancer vaccine (and vastly improve them): Alex Rubinsteyn & Ben Vincent this is an interview with @iskander and @BenjaminGVincen, two UNC professors. it is three hours of incredibly detailed takes on cancer vaccines, personalized immunotherapy, and how both may be improved in the fullness of time. Alex and Ben are both wellsprings of knowledge and this was a very, very fun episode to film; i expect it could've gone on for an hour longer. enjoy! (other links in reply) youtu.be/EmbciAO9d-M