AI Meets the Pathway Database: React-to-Me Brings Trustworthy Chat to Cell Biology

Ask a chatbot how a growth factor signal travels from a cell membrane receptor down to the nucleus, and you will often get an answer that sounds fluent, confident, and subtly wrong. General-purpose large language models, for all their conversational charm, routinely blur the line between well-established biology and plausible invention. That mismatch between fluency and reliability has been one of the most stubborn obstacles to bringing conversational AI into serious scientific work. A team at the Ontario Institute for Cancer Research and the University of Toronto, led by Helia Mohammadi and Lincoln Stein, now reports a way to close that gap, at least for one corner of biology, in a study published in BMC Biology.

Their system, called React-to-Me, is a conversational assistant built on top of the Reactome Pathway Knowledgebase, one of the most rigorously maintained curated resources in molecular biology. Reactome, stewarded by a team of expert biologists, documents human biological pathways, molecular interactions, and disease mechanisms with a level of care that ordinary web search cannot match. Yet the knowledgebase has a usability problem: its data model is intricate, and its search interface rewards people who already know the vocabulary and structure of the underlying database. For a graduate student, a clinician, or a researcher crossing into a new field, that learning curve can be discouraging. React-to-Me was designed to let such users ask questions in plain natural language while still receiving answers that are traceable, verifiable, and anchored in curated content.

The engineering heart of the system is a hybrid retrieval-augmented generation pipeline, a technique that constrains a language model to answer only from documents fetched at query time rather than from its internal memory. In React-to-Me, an incoming question triggers two complementary searches over the Reactome corpus. The first is a semantic vector search, which uses neural embeddings to match the meaning of the question against the meaning of database entries, capturing paraphrases and conceptual overlap that keyword matching would miss. The second is a lexical keyword search, of the BM25 variety familiar from classic information retrieval, which excels at pinning down precise identifiers, gene names, and chemical terms. The two ranked lists are merged with reciprocal rank fusion, a method that rewards documents appearing near the top of both lists, and the fused evidence is handed to a language model that is instructed to generate an answer grounded strictly in that retrieved material.

Grounding alone is not enough; the system also insists on provenance. Every response is directly linked to the corresponding Reactome entries from which it was assembled, so users can click through and inspect the curated pathways behind the answer. And when the retrieved evidence is thin or absent, React-to-Me is designed to defer rather than improvise: it declines to speculate and instead points users toward trusted external biomedical sources. This refusal behavior, the authors argue, is a feature rather than a failure, because an honest admission of limited coverage is far more valuable to a scientist than a fabricated pathway. The team tested how well that refusal logic worked in the wild by manually classifying logged instances where the system declined to answer, finding that out-of-scope biology questions were the largest category, accounting for 31.9 percent of refusals.

Before any human saw the system, the researchers put the retrieval engine itself through computational benchmarking using the Ragas evaluation framework, scoring configurations on context utilization, relevance, and faithfulness across several query types: simple factual lookup, mechanistic reasoning, multi-context synthesis, and conditional logic. The results showed a clear pattern. Semantic retrieval on its own preserved relevance but faltered on faithfulness, letting unsupported statements slip through, while pure keyword retrieval weakened on complex reasoning tasks that required synthesizing multiple sources. The combined hybrid approach, ranked by reciprocal rank fusion, delivered the highest and most stable scores across every metric and every query type, confirming that the two retrieval strategies compensate for each other’s blind spots.

Real-world deployment brought a second wave of evidence. Analyzing user queries logged during October 2025 and March 2026, the team found that factual lookup and mechanistic or relational biology questions dominated, together accounting for 56.1 percent of classified logged-in queries. Notably, the mix shifted over time: factual lookups rose from 24.7 percent to 33.7 percent of classified queries, while mechanistic and relational questions declined from 32.7 percent to 21.2 percent, a pattern suggesting that as users became comfortable with the tool, they leaned on it increasingly as a rapid reference rather than a reasoning partner. The study received ethics approval from the University of Toronto Research Ethics Board under protocol number 47192, and all survey participants provided informed consent.

The most demanding test was a blinded head-to-head comparison against a general-purpose model, GPT-4o-mini, judged by ten external molecular biology experts who did not know which system produced which answer. The verdict favored grounding decisively. Grounded React-to-Me responses were more likely to receive higher quality ratings than their ungrounded counterparts, with an overall odds ratio of 2.01. The gains were strongest where scientific rigor matters most: factual accuracy improved with an odds ratio of 2.97, biological specificity with an odds ratio of 2.88, and mechanistic depth with an odds ratio of 1.83. Individual evaluator preferences, recorded in the supplementary data, showed consistent majority favoring of the grounded system across question-level comparisons, an exploratory mixed-effects ordinal regression accounting for variation among evaluators and questions.

User sentiment reinforced the expert verdict. In a survey of 25 consenting users drawn from the publicly deployed system, 92 percent expressed strong satisfaction with ease of use, 88 percent with citation reliability, and 85 percent with factual accuracy. Strikingly, perceived accuracy showed the strongest association with overall confidence in the system, with a correlation of r = 0.81, meaning that users who trusted the answers did so primarily because the facts checked out, not because the interface was pretty. Respondents spanned organization types and research fields, with human biology research most represented, followed by computational biology, cell biology, and genetics, and satisfaction held up across education levels and levels of prior Reactome experience.

Beyond the headline numbers, the study offers a practical template for institutions wrestling with how to deploy AI responsibly. The team published monthly operating costs, the full survey instrument, benchmark questions, and analysis code as supplementary materials, an unusual degree of transparency for a production AI deployment. The willingness to defer to trusted sources when coverage runs out, the insistence on clickable citations for every claim, and the hybrid retrieval architecture that balances conceptual breadth with lexical precision together sketch what credible scientific AI might look like. As funders and publishers grapple with hallucination risks in research tooling, React-to-Me demonstrates that domain-specific grounding is not a theoretical nicety but a measurable design choice, one that nearly triples the odds that an expert will judge an answer factually accurate. The broader lesson may extend well beyond pathways: for specialized knowledge, the future of conversational AI belongs to systems that know the boundaries of what they can honestly say.

Subject of Research: A grounded conversational AI interface for querying the Reactome Pathway Knowledgebase

Article Title: React-to-Me: real-world experience of a grounded conversational interface to the Reactome Pathway Knowledgebase

Article References: Mohammadi, H., Almodaresi, F., Hogue, G. F. J., Wright, A., Orlic-Milacic, M., Li, N. T., Mawani, A., & Stein, L. (2026). React-to-Me: real-world experience of a grounded conversational interface to the Reactome Pathway Knowledgebase. BMC Biology. https://doi.org/10.1186/s12915-026-02740-2

Image Credits: AI Generated

DOI: 10.1186/s12915-026-02740-2

Keywords: Reactome Pathway Knowledgebase, conversational AI, retrieval-augmented generation, large language models, knowledge grounding, biological pathways, biomedical question answering, hybrid retrieval, language model evaluation, computational biology, expert evaluation, responsible AI