Toward Auditable AI Scientists: A Hypothesis Evolution Protocol for LLM Agents

Large language model (LLM)-based systems are increasingly deployed to conduct scientific research autonomously, yet whether their reasoning adheres to the epistemic norms that make scientific inquiry self-correcting is poorly understood. Here, we evaluate LLM-based scientific agents across eight domains, spanning workflow execution to hypothesis-driven inquiry, through more than 25,000 agent runs and two complementary lenses: (i) a systematic performance analysis that decomposes the contributions of the base model and the agent scaffold, and (ii) a behavioral analysis of the epistemological structure of agent reasoning. We observe that the base model is the primary determinant of both performance and behavior, accounting for 41.4% of explained variance versus 1.5% for the scaffold. Across all configurations, evidence is ignored in 68% of traces, refutation-driven belief revision occurs in 26%, and convergent multi-test evidence is rare. The same reasoning pattern appears whether the agent executes a computational workflow or conducts hypothesis-driven inquiry. They persist even when agents receive near-complete successful reasoning trajectories as context, and the resulting unreliability compounds across repeated trials in epistemically demanding domains. Thus, current LLM-based agents execute scientific workflows but do not exhibit the epistemic patterns that characterize scientific reasoning. Outcome-based evaluation cannot detect these failures, and scaffold engineering alone cannot repair them. Until reasoning itself becomes a training target, the scientific knowledge produced by such agents cannot be justified by the process that generated it.

Scientific agents contribute to hypothesis discovery by synthesizing evidence, assessing proposals, and developing new explanations. Recent systems combine scientific agents with evolutionary search through critique, comparison, and revision. However, how different forms of agent collaboration affect hypothesis quality remains an open question. Answering this question requires separating the effects of agents' scientific capabilities from those of their collaboration. A framework must therefore preserve agents' scientific roles and support rules for combining, revising, and retaining hypotheses. Building on this view, we introduce HypoEvolve, which makes collaboration explicit through successive updates to a hypothesis population. Specifically, we propose a generational genetic algorithm to coordinate specialized large language model (LLM) agents that integrate mechanistic arguments, reconsider assumptions, and assess evidence and testability. Each generation specifies how scientific judgments and new proposals reshape the population, making collaboration effects on hypothesis quality directly testable. Moreover, we design our evaluation around scientifically meaningful hypotheses that explain how a proposed intervention could work. Drug repurposing links these explanations to target-level biological claims assessed against external evidence. Specifically, we adapt DepMap and Open Targets into complementary external measures grounded in experimental, genetic, and clinical evidence. Across 34 cancer types, HypoEvolve achieves the highest scores against six baselines on both measures. DepMap selectivity reaches 0.171, versus 0.115 for the strongest baseline. Gains over single-pass generation also generalize to held-out cancer types. HypoEvolve advances a vision of autonomous science in which AI research teams achieve a capacity for discovery beyond that of individual models.

LLM systems for scientific discovery increasingly assist with ideation, literature synthesis, experiment planning, and report generation, but the first research question they propose can remain difficult to audit: it may sound plausible without exposing the mechanism, falsifier, or assumption that a scientist should inspect. We introduce FirstResearch, a first-principles research-question formation framework for scientific LLM agents whose core artifact is a structured Research Question Certificate. The certificate records primitive definitions, assumptions, a mechanism model, a tension or contradiction, a falsifiable hypothesis, a minimal decisive test, and a failure update rule, making the proposed question inspectable before downstream execution. On ten LLM-agent research topics, FirstResearch outperforms controlled prompt-level baselines inspired by AI co-scientist, Agent Laboratory, and AI Scientist-v2 under a primary DeepSeek-blind-judge protocol. A Gemini-2.5-Flash independent-judge rescore of the same 40 baseline packages preserves the system-level ranking, with FirstResearch scoring 4.86/5 versus 4.38/5 for the strongest baseline and Pearson agreement of 0.865 on average score. A one-repeat ablation checkpoint further suggests that the certificate-centered core is the strongest component: certificate-only scoring reaches 4.90/5 under DeepSeek and 4.88/5 under Gemini, while removing certificates drops below 1/5 under both judges. These results are preliminary and use LLM judges rather than human domain experts, but they support a narrow scientific-discovery claim: explicit derivation constraints are a promising mechanism for making LLM-generated scientific questions more auditable. Code, prompts, saved outputs, and reproduction scripts are available at https://github.com/louiswang524/FirstResearch.