Biotech. Interests: oncology, transcription factors, RNA, biomolecular condensates, RNA-binding proteins, neurodegeneration, aggregation, disordered proteins
Boston
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Now that vaults are having another twitter moment, huge shoutout to Nancy Kedersha who co-discovered vaults and stress granules and did cool shit for a long time, all without having an independent laboratory.
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This is a must read.
>be cell biology postdoc at UCLA, 1986
>job: purify vesicles from rat liver
>ez
>purify the vesicles
>something else in the tube
>weird little barrels, way bigger than a ribosome
>fkisdis
>purify the barrels instead
>mostly protein, tiny bit of RNA
>not related to vesicles at all
>new organelle just dropped?
>lab holds a naming contest
>"vaults" "sure, "great name" "
>write it up, publish
>conclusion section: "function: unknown"
>surely we'll figure it out in a couple years
>reviewers: "are you sure this isn't just a virus"
>prove it isn't a virus
>apply for grants to study it
>first question on every call: "what does it do"
>"we're working on it"
>be early 90s
>vaults hang around the nucleus
>"they must plug the nuclear pores"
>they do not
>be different scientist, Netherlands, 1995
>chasing LRP, mystery protein that shows up in chemo-resistant tumors
>clone it
>~88% identical to rat vault protein
>it was vaults the whole time
>whole cancer field piles on
>a decade of papers on vaults and drug resistance
>nobody ever proves vaults cause it
>back at UCLA
>one of the vault proteins binds telomerase
>"guys what if this is the fountain of youth"
>knock it out in mice
>telomeres fine, aging fine, mice fine
>2002
>knock out the main vault protein
>mice: perfectly healthy
>knock out all three vault proteins
>completely vaultless mice
>mice: basically fine, some subtle immune stuff
>mfw something in every cell since the dawn of eukaryotes does nothing obvious
>"just test it in yeast"
>yeast don't have vaults
>"worms then"
>no vaults
>"fruit flies"
>no vaults
>mfw every easy model organism dropped them
>try making recombinant vaults in insect cells
>expecting to get some loose protein at best
>get fully assembled vaults
>can't find a single free copy of the protein anywhere
>turns out ribosomes 3D-print the barrel straight off the mRNA
>lolwut
>still no function
>be structural biologists
>spend years modeling it as 96 proteins with 8-fold symmetry
>2009 X-ray structure
>it's 78 proteins, 39-fold
>caps still blurry
>2025: caps are closed, 13-fold, tiny hole in the middle
>still no function
>NIH funds vault research for 15 years
>NIH: "so what does it do"
>"...we're working on it"
>NIH stops returning calls
>if we can't figure out what it does, we'll make it do something
>stuff a cancer-fighting chemokine inside the barrel
>inject into mouse lung tumors
>immune cells swarm in, tumors shrink
>2011: "human trials within three years"
>2024: "human trials next year"
>2025 database: preclinical
>start a YouTube channel explaining vaults to anyone who'll listen
>be different scientist, Broad Institute
>want to record what genes a cell turned on over time
>try tethering mRNA to a bacterial protein
>doesn't work
>stumble onto a YouTube channel about some obscure barrel organelle
>engineer vaults to grab mRNA
>RNA half-life goes from ~17 hours to ~132 hours
>publish in Science, 2026
>use it to catch drug-resistance genes in lung cancer cells before the drug even hits
>the vault guy is thrilled
>still nobody knows what vaults are for
>be epigeneticists
>screen the whole genome for methylation set at random in the early embryo
>separately study kids conceived in different seasons in rural Gambia
>both screens independently point at the same gene
>it's the goddam vault RNA gene
>its methylation depends on conditions around conception, locked in for life
>linked to cancer outcomes, blood sugar, cleft palate
>mfw the mystery barrel has a mystery RNA that remembers when you were conceived
>40 years later
>one of the most abundant structures in your cells
>still not in a single textbook cell diagram
>we use it anyway because yolo
>function: unknown
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Bede Portz retweeted
New in @NatStructMolBio! 🧬 We screened 730 RNA-binding proteins and found 281 that control circular RNAs, from how they’re made to how much protein they produce. Thanks to our collaborators at MSK, Columbia, and UCSD, and to my amazing lab, led by Tao Yu nature.com/articles/s41594-0…
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Bede Portz retweeted
What do vault particles do? Scientists have been asking this for 40 years. Our biology team at Anthropic set out to tackle this long-standing open question in cell biology, working with Claude.
We haven't uncovered their biological function yet, but we've found something new: vault proteins in prokaryotes that assemble into complexes that are larger than human vaults. And we show that we can engineer their shapes to produce even larger nanocapsules!
The mystery of vaults goes deeper than anyone knew...
Read the blog and technical report to learn more!
Blog: anthropic.com/research/inves…
Technical report: www-cdn.anthropic.com/76e55f…
Very grateful to have such fantastic coauthors who made this research project possible, including Januka Athukoralage, @ntperry13, @PeterHYoon, @ekabrams, and @amirshanehsaz. A big thank you to Dr. Leonard Rome, who discovered vaults in 1986, for providing feedback on the technical report. Thank you to @FutureHouseSF for supporting me as a research fellow when I first started learning about vaults. And, of course, grateful to my many @AnthropicAI teammates that work tirelessly to make Claude the best model for biology!
Video and sound made by Claude (with artistic direction from @ntperry13). Showing the new bacteriophage-derived vault structure that we solved.
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Bede Portz retweeted
Dave Ricks reveals Eli Lilly is building robotic wet labs that run 24/7, because drugs fail when companies think they understand the target and don’t
“The other side of the equation of course is target. And here I think we need our robotics effort to really kick in. Why do we have more targets, and why do we understand the targets we have better, which are probably structurally more complicated than we understand."
"And that’s one of the reasons drug development fails, is we think we have the target, but we don’t really understand it. And that’s because we need massively more amounts of experimental data on specific good targets. So I think here we’ll work with you on fleshing out."
"We already have one robotic lab running, wet lab, but we’ll build more. And we can have them running 24/7 experimenting around a target space to really fully profile that, and then couple that with those engineered drug design. So that’s a little bit harder problem. It’s more empirical, but I think machines are made to work day and night to solve this problem.”
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Bede Portz retweeted
Let's just run thru a few drug industry assumptions...
40% of new drug approvals in 2026 were first-in-class (FDA data)
Novel biology is generally riskier, so have to assume more than 40% of the INDs are first-in-class (well accepted)
1200 INDs from commercial sponsors last year (FDA data)
70%+ of initial clinical starts last year were from R&D stage biotechs, private and public (IQVIA data)
Implies at least ~500 were for first-in-class programs from biotech companies.
With preclinical failure rates, 500 INDs would require about 800 Development Candidates
800 DCs probably require 2000 new hit-finding discovery programs.
So you really think starting and funding 2000 discovery campaigns is only 1% of biotech invested capital?
The math just doesn't compute.
I suspect it's easily more like 20-30% of biotech invested capital today.
Since $25B has gone into biotech equity financings this year, that's at least $5-8B into first in class programs..
But we both agree that whatever it is, it should be an even larger proportion of industry activity!
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Bede Portz retweeted
New preprint.
We extend generative protein design to the disordered proteome…
A collaboration between the Lionnet, Holt, and Holehouse labs.
Link: biorxiv.org/content/10.64898…
@LiamHoltLab
@alexholehouse
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Bede Portz retweeted
This is an amazing thread on not only new exciting clinical data, but how a company with a platform and long term vision can invest and build a fly wheel of unfair advantages across the entire therapeutic generation value chain. More of this at the frontier - congrats, John!
Excited to share full data for BEAM-301 in GSD1a, covering the first two dose cohorts
** Importantly, 2/3 patients at the 2nd dose level achieved maximum fasting duration and no longer require corn starch supplementation after a single dose of BEAM-301
globenewswire.com/news-relea…
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Bede Portz retweeted
Delighted to share a landmark preprint from our lab, using genome language models and AI agents for biological discovery and genome mining!
The stretches of DNA between protein-coding genes are often called the genome’s “dark matter,” but they are far from empty. They encode RNA molecules that sense metabolites, regulate genes, and control some of molecular biology's most important tools (such as programmable genome editors e.g. CRISPR/bridge)
Much of this biology is unexplored. One reason is that RNAs can retain similar structures and functions even as their DNA sequences change dramatically, making their relationships difficult to recognize with conventional computational tools
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Bede Portz retweeted
Today in @NatureBiotech we introduce the "recordanelle", a synthetic organelle that enables transcriptome-wide single-cell RNA recording in human cells. Big thanks to team: @ReinkemeierCD, Marcos Manero-Carranza, et al. 🧵👇
@ETH_en @ETH_BSSE @BRC_CH
rdcu.be/5Pus7dyu63ta
Ever wondered what a cell has experienced in the past? This is in general hard to measure. Here we introduce the recordanelle, to equip cells with a tool that lets them record their own history.
nature.com/articles/s41587-0…
@NatureBiotech @ETH @randall_platt @ETH_BSSE
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Bede Portz retweeted
Transcription factor specificity isn’t encoded by DNA motifs alone. Live-cell single-molecule imaging shows that unstructured transcription factor interactions enable emergent specificity.
science.org/doi/10.1126/scie…
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Incredibly high value. Publishing target validation/invalidation work this thorough is a service.
Pleased to share my lab’s new manuscript integrating genomics, drug development, cell biology, and mouse modeling to comprehensively evaluate the cyclin-dependent kinase CDK11 as a drug target in cancer.
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Bede Portz retweeted
Me: What’s 2+2?
Old LLM: 5.
New LLM: The move isn’t to fixate on a number. It’s to ask what the number is doing. The real payoff comes from holding both twos in productive tension.
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Bede Portz retweeted
Transcriptomic reprogramming screen identifies SRSF1 as a regulator of aging: nature.com/articles/s43587-0…
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It’s possible to post your breakthrough on biorxiv while keeping it locked behind a paywall of a different sort. Dense, jargon-filled writing without general context. Some of the greats of biology, Sue Lindquist comes to mind, wrote disarmingly simple, accessible papers.
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