When a self-improving AI-for-science system claims a new capability, the evidence is usually a benchmark delta, a description-length gate, or a p-value. None separates a real gain from extra search, from a changed verifier, or from adaptation to a fallible oracle. We build a two-sided audit whose negative side is a formal fact: a pseudoknot-free oracle provably cannot represent a crossing base pair, so the prior verifier's range is bounded exactly, offline, before any run. "New" is relative to the agent's prior self, never to the base model. First, how far a single fallible oracle can inflate a capability claim. An invented, solver-free operator solves 43/60 crossing RNA targets under the predictor it optimizes, above a context-free floor of 0/60; under three predictors, 1/60 survives. Paired on the same 43 targets, a predictor the operator never saw confirms 2 of its designs against 26 for a minimum-free-energy solver (p = 8e-7). No statistic computed from the system and its own oracle sees that gap. Second, agent-written procedures can beat a human-written one under a judge no objective can flatter, at a fraction of the compute. Of six frontier models, the two whose operators ran without timeouts carry over at 0.293 against our 0.095 (n = 951 paired units, target-clustered [+0.108, +0.297], p = 5e-5) while spending 4.6-10x fewer oracle calls. Three rungs: difference under an outside adjudicator (reached), not bought with compute (reached, both directions), mechanism identified and transferable (not reached; seven candidates tested, none moves the statistic). The ceiling is the panel itself: its three predictors share nearest-neighbour thermodynamic parameters, two agreeing at kappa = 0.673. The audit is as unsparing about our own system: matched undirected search is an exact zero, and a search-free probe puts 84% of our headline effect on targets a random sequence already solves.
Richard Zhu, Kento Nishics.AI cs.LG q-bio.BM stat.ML
Variational autoencoders (VAEs) trained on multiple sequence alignments (MSAs) have emerged as powerful generative models for biological sequences, with applications ranging from disease variant prediction to functional RNA design. However, standard biological VAE training treats all sequences as exchangeable, ignoring the rich evolutionary structure that organizes homologous sequences from evolutionarily close to highly divergent. We propose Evolutionary Curriculum Learning (ECL), a training strategy that exploits this structure by progressively exposing the model to sequences of increasing evolutionary distance from sampled anchors, following a power-law expansion schedule. Applied to two architecturally distinct VAE models and two biological domains--protein variant effect prediction with EVE and RNA family sequence generation with RfamGen--ECL improves downstream task performance across five random seeds per configuration. Mean ClinVar classification AUROC rises from 0.981 to 0.989 for p53; for PTEN, ECL attains 1.000 in every seed whereas the baseline is unstable (mean 0.905, falling as low as 0.54). For RNA, ECL raises mean covariance-model bit scores on all three families tested and exceeds its seed-matched baseline in 12 of 15 training runs, though with only three families the effect cannot be established as significant at the family level. Ablation experiments show that progressively expanding the sampled sequences by evolutionary distance outperforms fixed-size neighborhood sampling in addition to uniform random sampling. Evolutionary distance is therefore a useful inductive bias for ordering the training curriculum in biological sequence modeling.