InsideOut Bio
Every approved atopic dermatitis (AD) drug blocks the type-2 pathway from the outside: injectable antibodies against extracellular cytokines.
Core trick
Knockout signatures across about 34,000 perturbations are ranked by similarity to the STAT6 and GATA3 Th2-collapse signature, then checked in lesional skin.
Description
Every approved atopic dermatitis (AD) drug blocks the type-2 pathway from the outside: injectable antibodies against extracellular cytokines. The frontier is inside the cell, at the transcription factors that run the allergic program, because degrading a master node promises deeper, oral suppression. STAT6 is the proof of concept, but no one had systematically asked which other intracellular regulators would collapse the program if shut down.
I screened a genome-scale CD4⁺ T-cell Perturb-seq atlas (~34,000 knockout signatures), scoring every perturbation for how strongly it phenocopies the STAT6 and GATA3 "Th2-collapse" signature. The pipeline recovers both anchors at rank 1 which is a built-in positive control and surfaced an unexpected finding: in circulating cells, STAT6 and GATA3 knockouts anti-correlate, meaning GATA3 maintains the type-2 program STAT6-independently. This is corroborated three ways (cosine screen, an independent supervised classifier that ranks GATA3 #4/6,923 but STAT6 #4,809, and prior literature(Ouyang 2000, Yamashita 2004), and it reproduces in independent lesional-skin scRNA-seq (GSE147424). I then expanded to every AD immune axis a T cell can represent (JAK-STAT, Th22/AHR, Th1, activation-tone, AD-GWAS TFs), cross-referenced the known AD drug universe, and layered on degrader-tractability, human-genetics (allergic-disease GWAS), and literature-novelty annotation. Deliverables: a druggability-annotated multi-axis target map, a reusable Th2-collapse classifier, and a fully rerunnable pipeline others can build on.
Why it matters: it converts a single validated drug target (STAT6) into a ranked, evidence-annotated landscape of the next ones with IL4R, ORAI1, SMARCA4, SMAD4 and a TYK2-axis lead (IFNAR1/anifrolumab) surfacing as candidates, and it delivers a classifier that scores any new perturbation for Th2-collapse potential.
sayaneshome/atopic-dermatitis★ 00 forksJupyter NotebookNOASSERTIONCreated Jul 13, 2026 · last push Jul 13, 2026
README excerpt
# An intracellular master-regulator map of atopic dermatitis *A genome-scale CD4⁺ T-cell Perturb-seq phenocopy screen for druggable nodes beyond STAT6.* *Submitted to [Built with Claude — Life Sciences](https://cerebralvalley.ai/e/built-with-claude-life-sciences) (Cerebral Valley), a global hackathon of ~500 selected participants. Built end-to-end with Claude Science.* > **Researcher Track — Build From the Bench.** We started from a bench question — > *which intracellular regulators beyond STAT6 would collapse the allergic program if > degraded?* — found the dataset built to answer it (the Marson lab's genome-scale > CD4⁺ T-cell Perturb-seq atlas), and used Claude Science to turn it into a discrete, > reproducible finding plus a druggability-annotated target map. One command > re-derives the positive controls; every claim links to a figure or a primary paper. --- ## Summary (100–200 words) Every approved atopic dermatitis (AD) drug blocks the type-2 pathway from the **outside** — injectable antibodies against extracellular cytokines. The field is moving **inward**, to the intracellular transcription factors that run the allergic program, because degrading a master node promises deeper, oral suppression. STAT6 is the proof of concept. But no one had systematically asked which *other* intracellular regulators would collapse the program if shut down. We screened a genome-scale CD4⁺ T-cell Perturb-seq atlas (~34,000 knockout signatures), scoring every gene knockout for how