Biomedical knowledge is uniquely complex and structured, requiring distinct reasoning strategies compared to other scientific disciplines like physics or chemistry. Biomedical scientists do not rely on a single approach to reasoning; instead, they use various strategies, including rule-based, prototype-based, and casebased reasoning. This diversity calls for flexible approaches that accommodate multiple reasoning strategies while leveraging in-domain knowledge. These triplets are then verified against a grounded KG to filter out erroneous information and ensure that only accurate, relevant data contribute to the final answer. Unlike RAG-based models, this multi-step process ensures robustness in reasoning while adapting to different models of medical reasoning. Medical reasoning involves making diagnostic and therapeutic decisions while also understanding the pathology of diseases (Patel et al., 2005). Unlike many other scientific domains, medical reasoning often relies on vertical reasoning, using analogy more heavily (Patel et al., 2005). For instance, in biomedical research, an organism such as Drosophila is used as an exemplar to model a disease mechanism, which is then applied by analogy to other organisms, including humans. In clinical practice, the patient serves as an exemplar, with generalizations drawn from many overlapping disease models and similar patient populations (Charles et al., 1997; Menche et al., 2015). In contrast, fields like physics and chemistry tend to be horizontally organized, where general principles are applied to specific cases (Blois, 1988). This distinction highlights the unique challenges that medical reasoning poses for question-answering (QA) models. While large language models (LLMs) (OpenAI, 2024; Dubey et al., 2024; Gao et al., 2024) have demonstrated strong general capabilities, their responses to medical questions often suffer from incorrect retrieval, missing key information, and misalignment with current scientific and medical knowledge.

A long-standing ambition for artificial intelligence (AI) in biomedicine is the development of AI systems that could eventually make major scientific discoveries, with the potential to be worthy of a Nobel Prize--fulfilling the Nobel Turing Challenge [1]. While the concept of an "AI scientist" is aspirational, advances in agent-based AI pave the way to the development of AI agents as conversable systems capable of skeptical learning and reasoning that coordinate large language models (LLMs), machine learning (ML) tools, experimental platforms, or even combinations of them [2-5] (Figure 1). The complexity of biological problems requires a multistage approach, where decomposing complex questions into simpler tasks is necessary. AI agents can break down a problem into manageable subtasks, which can then be addressed by agents with specialized functions for targeted problem-solving and integration of scientific knowledge, paving the way toward a future in which a major biomedical discovery is made solely by AI [2, 6].

With the increasing use of Graph Neural Networks (GNNs) in critical real-world applications, several post hoc explanation methods have been proposed to understand their predictions. However, there has been no work in generating explanations on the fly during model training and utilizing them to improve the expressive power of the underlying GNN models. In this work, we introduce a novel explanation-directed neural message passing framework for GNNs, EXPASS (EXplainable message PASSing), which aggregates only embeddings from nodes and edges identified as important by a GNN explanation method. EXPASS can be used with any existing GNN architecture and subgraph-optimizing explainer to learn accurate graph embeddings. We theoretically show that EXPASS alleviates the oversmoothing problem in GNNs by slowing the layer wise loss of Dirichlet energy and that the embedding difference between the vanilla message passing and EXPASS framework can be upper bounded by the difference of their respective model weights. Our empirical results show that graph embeddings learned using EXPASS improve the predictive performance and alleviate the oversmoothing problems of GNNs, opening up new frontiers in graph machine learning to develop explanation-based training frameworks.