Save the date! 🧪The EMBO Workshop on Chemical Biology returns to EMBL Heidelberg on 8–11 Sep 2026.
Co-organisers: Bryan Dickinson (UChicago), Maja Köhn (Bonn), Edward Lemke (IMB), Xiao Wang (MIT).
#ChemicalBiology #EMBOChemBio #EMBO #EMBL #SaveTheDate #Biotech #Science
www.embl.org/about/info/c...
My lab’s next paper is out in JACS! Congrats to Taemin and Ching who discovered that Brønsted acids unlock mild interfacial catalytic halogen atom transfer at Ag electrodes!
pubs.acs.org/doi/10.1021/...
Grateful to iDefine for supporting a new project aimed ultimately at helping these patients.
www.idefine.org
Check out our new review on binder discovery! In a fast-moving world, here are some thoughts we have in the moment.
Congrats @jzy2799.bsky.social and Eddy!!
www.sciencedirect.com/science/arti...
Huge congrats to rockstar grad student Riley - who led all aspects of this work, from design, to engineering, to deployment and in vivo testing. This is a tour de force in preclinical development.
This work validates translational activation as a therapeutic strategy for haploinsufficiency. With ~3000 dosage-sensitive genes and limited tools to address underexpression, CIRTS-4GT3 opens new possibilities for precision gene expression control.
This is the first demonstration that targeted translational activation can rescue a haploinsufficiency phenotype in vivo. The approach offers unique advantages: no permanent DNA changes, mRNA-level specificity, and protein increases matched to cellular context.
Beyond SCN1a: CIRTS-4GT3 also increased protein expression from CHD2 (epilepsy/developmental delay) and ARID1B (intellectual disability/autism) by 50-100%. The platform is programmable—just change the guide RNA to target new transcripts.
The results were striking: Female SCN1a+/− mice showed 50% mortality by P50. With CIRTS-4GT3 treatment? Only 13% mortality. We also saw significantly higher seizure thresholds in treated mice—key functional improvements.
We tested this in Dravet syndrome—a severe epilepsy caused by SCN1a haploinsufficiency affecting 1:15,000 people. AAV9 delivery of CIRTS-4GT3 targeting SCN1a to neonatal mice increased NaV1.1 protein ~25% in cortex and hippocampus.
Key advantages of CIRTS-4GT3: (1) Flexible gRNA design targeting 5' or 3' UTRs, (2) fits in single AAV vectors, (3) made entirely from human proteins (reduced immunogenicity), (4) protein boost scales with endogenous mRNA levels—no overexpression toxicity.
We screened 11 translational effector domains and optimized eIF4GI truncations to create CIRTS-4GT3—a compact 601 amino acid activator that doubles target protein expression. It works by recruiting eIF3 and the translation machinery to guide RNA-targeted mRNAs.
Our approach: Use CIRTS (CRISPR-inspired RNA-targeting system) to programmably increase translation from endogenous mRNAs. Unlike gene therapy, this boosts protein only in cells that already express the target mRNA—built-in cell-type specificity.
www.cell.com/cell/fulltex...
The challenge: ~3000 "dosage-sensitive" genes cause disease through haploinsufficiency (loss of one copy = ~50% protein). Brain genes are especially sensitive. We have great tools to knock genes DOWN, but few to boost them UP—especially in neurons.
Excited to share our new work in @narjournal.bsky.social ! We engineered a human-based translational activator that rescued phenotypes in a Dravet syndrome mouse model by boosting protein expression from haploinsufficient genes. A thread on targeting translation 🧵
academic.oup.com/nar/article/...
The final version of our new paper is out now - and open access @acs.org Central Science!!
Such a fun collaboration!
pubs.acs.org/doi/10.1021/...
A true Christmas story well worth a read 👇
14/ Huge congrats to Jingzhou Yang and our team whole team. This was an “all hands-on deck” collaboration to get the selections done in 26 days and is a testament to team science. Also, our @uchicagomedicine.bsky.social collaborators were essential to success.
13/ Also, if selectivity is your jam – check out our other recent paper on isoform/epitope selectivity in PANCS-binders:
www.biorxiv.org/content/10.1...
bsky.app/profile/chem...
14/ On the other hand, we recently showed that our PANCS-binder data can improve ML-based PPI prediction. So while computation is not perfect yet, our high-quality data can keep moving things forward:
www.biorxiv.org/content/10.1...
bsky.app/profile/chem...
13/ Think of it like this – in those 26 days we comprehensively tested all pairwise combinations (experimentally) of 6 target proteins against 40,000,000,000 protein variants. Maybe someone can do the math of how much electricity and time this would take by the state-of-the-art MD/ML/AI methods…
12/ I think there is a bias that computational methods – despite their inherent limitations - are ultimately faster and cheaper than experiments. We challenge that assumption. Experiments can be high fidelity while also being faster AND cheaper than computation.
11/ We also tested computational design (BindCraft) retrospectively. 0/4 designs showed detectable binding. Not a knock on computation—but a reminder that experimental validation remains essential (we are not in the “one design-one binder” era).
www.nature.com/articles/s41...
10/ The bigger picture: This isn't just about one degrader. It's a workflow—from gene name → binder → functional tool → therapeutic hypothesis → to new biology. No protein purification. No massive compute. Just phage, E. coli, and ~$0.60 in water bottles.
9/ Then we went hunting. We profiled NSD3 degradation across ovarian cancer models and found something unexpected: some lines (ES-2) were exquisitely sensitive while others (CAOV-3) were completely resistant—independent of NSD3 expression levels. New biology to explore.
8/ We swapped RNF8's substrate-recognition domain for our NSD3 binder → a mini-protein degrader that potently depleted endogenous NSD3 in colorectal cancer cells and completely blocked proliferation in NSD3-dependent lines.
7/ But binders are just the beginning. We next asked: can we turn these into degraders? We screened 9 E3 ligases and found RNF8—previously unexplored for TPD—was the most potent, driving 90% target depletion.
6/ Key outcome: The binders are all selective and worked in mammalian cells, not just E. coli. We could use them to relocalize proteins in live mammalian cells.
5/ The timeline: Day 1: design constructs. Day 8: genes arrive. Day 17: start selections. Day 20: all 6 selections showed high titers (!). Day 26: sequence-verified, function-validated binders for ALL THREE targets. Affinities ranged from 58 nM to 1.8 µM.
4/ The targets: NSD3 (histone methyltransferase), NMNAT2 (NAD+ biosynthesis), and CSF1R (macrophage receptor)—structurally diverse, clinically relevant, and with few existing targeting tools. A real test.