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Dual-Chassis EcN PDB + Uricase Additivity — Invalidated Prior (comp-031)

Status

INVALIDATED 2026-07-13. The original ΔSUA, substrate-competition, CBT2.0-derived butyrate, Q141K rescue, and dual-chassis additivity results must not guide engineering or clinical decisions.

The live comp-031 artifact is an invalidation record. The obsolete model and outputs remain available through Git history, not in the current corpus.

Why the prior failed

  1. Inherited unsupported UOX regime: comp-031 hard-coded comp-019's 32–1,300× saturation finding. comp-044 shows that classification is not robust to the tested substrate-occupancy and finite-window diagnostics; it does not identify the true physiological regime.
  2. Organism/product mismatch: the CBT2.0 paper establishes urate-pathway products through pyruvate in engineered EcN; it does not establish butyrate production. A C. sporogenes butyrate-yield assumption was transferred into EcN without measurement.
  3. False Basseville attribution: Basseville 2012 tested HDAC inhibitors including vorinostat-class compounds and valproate, not direct 1–5 mM butyrate rescue of Q141K in this system.
  4. Unmatched background: the model added 0.8 mM background crypt butyrate to the combination arm. Most of the modeled rescue therefore came from a background term not matched across comparators.
  5. Compartment error: UOX and PDB were modeled as well-mixed consumers even though oxidative UOX and anaerobic PDB are likely to occupy different longitudinal/radial gut niches.

What remains scientifically open

  • CBT2.0 may still lower urate through reductive purine degradation.
  • A full-pathway PDB organism may produce butyrate and create a colonocyte-hypoxia persistence loop.
  • UOX and PDB may be complementary when they access different spatial residual fluxes.
  • None of those possibilities supplies a quantitative human ΔSUA prior yet.

Replacement priors and experiments

  • comp-044: reopens the UOX dose/regime question.
  • comp-046: uses a conserved dietary fate ledger and a separate non-conserved endogenous capture comparison, providing a conditional architecture boundary without summing efficacy.
  • Validation §1.34: isotope-resolved sequential flux.
  • Validation §1.37: CBT2.0 carbon fate and actual butyrate measurement.

Current decision

Do not build a dual cassette or claim PDB-derived ABCG2/Q141K synergy. First measure CBT2.0 products and the spatial residual-flux terms. Separate strains remain an experimental option, not a computationally validated recommendation.