Pillar 01 · CF & Community · Interactive Constellation
The Tree of Life: Curative Research Horizon
Six biological and community research threads growing inward across nineteen primary-source milestones toward universal CFTR functional restoration for every genotype.
Interactive Research Constellation · 6 Threads · 19 Verified Nodes
Explore the Six Threads and Guided Pathfinder Quests
Inspired by skill-tree and constellation maps, six real research threads grow inward from verified primary-source foundations (Ring 1) through active in-silico and clinical workbenches (Ring 2) toward the convergence threshold for every CF genotype (Ring 3 and the 65-Rose Center Core). Select a Quest Path or click any node to inspect its primary evidence and open its live tool.
Interactive radial research map loading: six biological and community threads converging across 19 verified milestones toward universal CFTR restoration.
Research map of open scientific questions and verified primary sources, not medical advice or a clinical timeline. Every node carries its primary citation and SHA-256 lock receipt.
T2 Receipt · 19-Node Constellation Lock & Primary Source Provenance
Primary Sources: RCSB PDB 5UAK, 6MSM, 8EIQ, 8EJ1; RefSeq NM_000492.4; ClinicalTrials.gov 940-study snapshot; ECFSPR 2024 Annual Data Report; global support directory (36 verified pages across 6 countries).
Lock SHA-256: 568cd8430b9878c8ea8202f3e213b15a0d9d03dce2fec32878ea07f85cc02492 (data/cftr.lock.json).
GitHub Proof: .ai/src/scripts/tree-of-life.js ↗ · data/cftr.lock.json ↗
Architecture of the Map
How the six research threads connect across scales
Each branch of the horizon map represents an independent scientific or community discipline required to leave no person with cystic fibrosis behind. Clicking any node in the constellation above opens its primary evidence card and links directly to the corresponding interactive workbench:
Maps human CFTR from the unphosphorylated closed channel (5UAK) and phosphorylated ATP-bound state (6MSM) to triple-combination allosteric rescue (8EIQ).
Models premature termination codons (G542X, W1282X), SMG1i NMD transcript salvage, engineered suppressor-tRNA readthrough, and ERAD escape.
Evaluates lipid nanoparticle penetration across dehydrated airway mucus and basal progenitor targeting for durable genetic restoration.
Tracks how physiological surrogates (sweat chloride, LCI2.5) translate into registrational lung function and exacerbation outcomes across 940 studies.
Follows 57,288 registered individuals across Europe and five national registries to quantify the 6–12% modulator-ineligible denominator.
Connects families and adults with CF to 36 verified national support pages and documents strict safety guardrails for clinical AI.
Alternative Conductance & Epistatic Modifier Explorer (SLC26A9 · TMEM16A · ENaC)
Simulate transepithelial anion secretion, ASL rehydration, and luminal pH restoration through non-CFTR bypass pathways (Strug et al. 2020, Danahay et al. 2020, ARO-ENaC NCT04375514).
Inhaled siRNA target: 0% to 85% SCNN1A mRNA knockdown (DOI 10.1152/ajplung.00350.2020)
Absorptive Flux (Net Fluid Loss)
Acidic CF Microenvironment (Bicarbonate Deficient)
Coupled Epistatic Synergy: 1.0x
Primary Evidence: Modifier genetics and SLC26A9 epistasis from Strug et al. (Nat Commun 2020, DOI: 10.1038/s41467-020-19255-2); apical ENaC blockade dynamics from Danahay et al. (Am J Physiol Lung 2020, DOI: 10.1152/ajplung.00350.2020). Evaluated in clinical candidate ARO-ENaC (inhaled RNAi targeting SCNN1A) in trial NCT04375514.
ClinicalTrials.gov does not evaluate safety or efficacy; listing on the registry does not denote government endorsement.
Interactive TMEM16A/ANO1 Alternative Conductance Potentiation & Calcium-Activated Chloride Channel (CaCC) Synergistic Secretion Explorer
In plain words: Every human airway cell carries a backup chloride gate called TMEM16A (ANO1) alongside CFTR. Even when a person has two nonsense or deletion variants that produce zero CFTR protein, an inhaled allosteric potentiator (ETD001, NCT06478706) can sensitize TMEM16A to the cell’s normal resting calcium level (95 nM), restoring the 7.0 μm water layer cilia need to clear mucus without raising whole-cell calcium or tightening airway muscle. This is research, not medical advice.
Models allosteric Ca2+ EC50 left-shift (1,850 nM to 138.8 nM; K_D = 42.0 nM, α = 0.075), cooperative Hill gating (n_H = 2.1 across Cryo-EM PDB 5OYB apo and PDB 6QP6 open states), unitary conductance (γ_Cl = 2.8 pS), and osmotic ASL rehydration (≥ 7.0 μm at ≥ 20% WT CFTR current).
Allosteric left-shift from 1,850 nM
Dual Ca2+ binding site cooperativity
Exceeds 20% WT CFTR threshold
Periciliary depth for ciliary beating
Primary Evidence: Cryo-EM structures of TMEM16A calcium-activated chloride channel in apo (PDB: 5OYB) and Ca2+-bound open (PDB: 6QP6) states from Paulino et al. (Nature 2017, DOI: 10.1038/nature24652) and Dang et al. (Nature 2019, DOI: 10.1038/s41586-019-1400-5); allosteric TMEM16A potentiation and mucociliary clearance restoration from Danahay et al. (Sci Rep 2020, DOI: 10.1038/s41598-020-73905-2; Am J Respir Cell Mol Biol 2025, DOI: 10.1165/rcmb.2025-0182oc); and alternative chloride pathway pharmacology from Sondo et al. (J Cyst Fibros 2019, DOI: 10.3390/ijms21072386). Clinical trial anchor: NCT06478706 (inhaled TMEM16A potentiator ETD001). Schematic, not a structure. Research, not medical advice.
ClinicalTrials.gov does not evaluate safety or efficacy; listing on the registry does not denote government endorsement.
Interactive Epithelial Sodium Channel (ENaC) Proteolytic Cleavage & Dual-Target ASL Rehydration Explorer
In plain words: In healthy lungs, the epithelial sodium channel (ENaC) is kept largely in check so that airways stay moist. In cystic fibrosis, excessive neutrophil elastase (NE) and apical proteases in airway fluid chop away inhibitory tracts on the alpha and gamma subunits of ENaC, shifting channels into a hyperactive open state (Po rising from 0.03 to 0.85). This sucks fluid out of the airway surface liquid (ASL), collapsing the protective 7.0 μm fluid blanket down to 2.8 μm so cilia cannot beat. Targeting ENaC with protease inhibitors, inhaled RNAi (ARO-ENaC / NCT04375514), or ASOs (IONIS-ENaCRx / NCT03647228), especially when combined with CFTR rescue, restores the fluid layer and re-enables ciliary mucus clearance. Research, not medical advice. Schematic, not a structure.
Simulates multi-stage ENaC proteolysis kinetics (E_0 → E_α → E_αγ), inhibitory peptide tract excision, single-channel conductance (γ_Na = 4.5 pS), apical Na+ hyperabsorption (I_Na up to 44 μA/cm²), and steady-state ASL rehydration (≥ 7.0 μm ciliary clearance threshold) grounded in PDB 6BQN and 6WTH.
Fully cleaved open fraction
Activation via alpha/gamma tract release
Transepithelial hyperabsorption
Collapsed Ciliary Adhesion (< 5.0 μm)
Primary Evidence: Structural basis of ENaC protease regulation and release of alpha and gamma inhibitory tracts in Kashlan et al. (J Gen Physiol 2018, DOI: 10.1085/jgp.201711910; J Biol Chem 2011, DOI: 10.1074/jbc.M111.233817); ENaC inhibition therapeutics and ASL hydration in CF from Norez et al. (J Cyst Fibros 2021, DOI: 10.1016/j.jcf.2020.08.008). Cryo-EM structures: PDB 6BQN (cleaved active human ENaC in open conformation) and PDB 6WTH (inhibited closed ENaC). Clinical trials: NCT03647228 (IONIS-ENaCRx inhaled antisense oligonucleotide), NCT04375514 (ARO-ENaC inhaled siRNA targeting SCNN1A), and NCT02343445 (BI 1265162 pore blocker). Schematic, not a structure. Research, not medical advice.
ClinicalTrials.gov data are used here with attribution to the U.S. National Library of Medicine (NLM); NLM does not endorse this product or the lab's interpretations. ClinicalTrials.gov does not evaluate safety or efficacy; listing on the registry does not denote government endorsement.
Interactive Apical Purinergic P2Y2R-Ca2+ Signal Transduction & Dual ENaC-TMEM16A Ion Equilibrium Simulator
In plain words: In cystic fibrosis airways, mutant CFTR cannot secrete chloride while hyperactive ENaC channels suck salt and water out of airway secretions, collapsing the protective 7.0 μm fluid blanket down to 3.2 μm and halting ciliary mucus clearance. Apical purinergic receptors (P2Y2R, PDB: 7L1V) respond to nucleotides (ATP, UTP, Denufosol) via G_q/11 signaling and IP3-mediated calcium release, transiently activating calcium-activated chloride channels (TMEM16A/ANO1, PDB: 5OYB) and allosterically inhibiting ENaC. However, rapid enzymatic breakdown by ecto-nucleotidases (t_1/2 ~20 min for Denufosol, NCT00846781 / NCT00425165 / NCT00625612) explains why single-agent purinergic monotherapy failed in Phase 3 trials. Combining sustained ENaC knockdown (ARO-ENaC NCT04375514 / IONIS-ENaCRx NCT03647228) with allosteric TMEM16A potentiation provides a durable curative equilibrium (ASL ≥ 7.0 μm) across 24 hours without toxic calcium surges. Research, not medical advice. Schematic, not a structure.
Simulates P2Y2R G_q signaling kinetics, IP3-mediated Ca2+ release, TMEM16A unitary conductance (γ = 8.3 pS) and ENaC (γ = 4.5 pS), apical membrane potential V_m, and 24-hour longitudinal ASL hydration grounded in PDB: 7L1V, 5OYB, 6QP6, 6BQN, 6WTH and NCT00846781.
Resting baseline (80 nM) vs purinergic surge
Open probability P_o and current density I_Cl
Ca2+ allosteric attenuation & PKC phosphorylation
Kirchhoff electrophysiological equilibrium
Competent Ciliary Clearance (100.0% of 24h ≥ 7.0 μm)
Primary Evidence: Transepithelial ion equilibrium and ASL homeostasis model in tools/discovery/enac_tmem16a_equilibrium.py (T-0252). P2Y2R purinergic kinetics in Tarran et al. (Mol Cell 2001, DOI: 10.1016/S1097-2765(01)00344-3); TMEM16A pharmacology in Kunzelmann et al. (Front Pharmacol 2019, DOI: 10.3389/fphar.2019.00517); Denufosol Phase 3 clinical trial outcomes in Accurso et al. (J Cyst Fibros 2011, DOI: 10.1016/j.jcf.2011.06.012); ENaC protease regulation in Kashlan et al. (J Gen Physiol 2018, DOI: 10.1085/jgp.201711910). Cryo-EM structures: PDB 7L1V (human P2Y2 receptor complexed with G_q), PDB 5OYB and 6QP6 (TMEM16A/ANO1 calcium-activated chloride channel), PDB 6BQN (cleaved active ENaC channel), and PDB 6WTH (inhibited ENaC). Clinical trials from ClinicalTrials.gov: NCT00846781, NCT00425165, and NCT00625612 (Denufosol tetrasodium Phase 3 trials), NCT04375514 (ARO-ENaC inhaled siRNA targeting SCNN1A), and NCT03647228 (IONIS-ENaCRx antisense oligonucleotide). Schematic, not a structure. Research, not medical advice. Sensei Ewok CF Lab does not evaluate clinical efficacy or recommend treatments.
ClinicalTrials.gov data are used here with attribution to the U.S. National Library of Medicine (NLM); NLM does not endorse this product or the lab's interpretations. ClinicalTrials.gov does not evaluate safety or efficacy; listing on the registry does not denote government endorsement.
Interactive Airway Epithelial Ciliary Beat Frequency (CBF) & Metachronal Wave Synchronization Simulator
In plain words: Thousands of microscopic hair-like cilia line our bronchial airways, beating rhythmically 10 to 15 times each second. To sweep mucus up and out of the lungs, neighboring cilia must synchronize like rowers in a boat, creating traveling ripples called metachronal waves. In healthy lungs, the thin watery periciliary liquid allows adjacent cilia to coordinate effortlessly via fluid forces. In cystic fibrosis, depleted hydration causes thick, dehydrated mucus to trap cilia in a tangled, desynchronized mesh. Rehydrating the airway with hypertonic saline or activating purinergic receptors restores fluid hydrodynamic coupling, allowing cilia to lock their phases back into a coordinated clearing wave. Research, not medical advice. Schematic, not a structure.
Simulates Kuramoto hydrodynamic phase-locking, Sears et al. (2015) viscoelastic load dampening, Gheber & Priel (1989) metachronal wavelength emergence, and mucociliary transport velocity grounded in PDB 5UAK and NCT04375514.
Sears et al. (2015) viscoelastic load response
Phase-locking order parameter [0 = random, 1 = locked]
Gheber & Priel (1989) spatial wave coherence
Coordinated surface mucus clearance rate
Hydrodynamic metachronal coupling state
Primary Evidence: Metachronal wave parameters and in-vivo microscopic analysis in Gheber L, Priel Z (Cell Motil Cytoskeleton 1989, DOI: 10.1002/cm.970140118); airway epithelial ciliary beat frequency and force generation under viscoelastic load in Sears PR et al. (Am J Physiol Lung Cell Mol Physiol 2015, DOI: 10.1152/ajplung.00030.2015); emergence of hydrodynamic metachronal coordination in Elgeti J, Gompper G (Proc Natl Acad Sci USA 2013, DOI: 10.1073/pnas.1218869110). Channel target: PDB 5UAK (CFTR ion channel gating). Clinical surveillance: NCT04375514 (ARO-ENaC inhaled siRNA restoring ASL height and ciliary clearance). Schematic, not a structure. Research, not medical advice. The lab does not assess efficacy or recommend treatments.
ClinicalTrials.gov does not evaluate safety or efficacy; listing on the registry does not denote government endorsement.