Kehan Wu

Qizhi Pei, Wei Zhang, Jinhua Zhu et al.

Recent advancements in biological research leverage the integration of molecules, proteins, and natural language to enhance drug discovery. However, current models exhibit several limitations, such as the generation of invalid molecular SMILES, underutilization of contextual information, and equal treatment of structured and unstructured knowledge. To address these issues, we propose $\mathbf{BioT5}$, a comprehensive pre-training framework that enriches cross-modal integration in biology with chemical knowledge and natural language associations. $\mathbf{BioT5}$ utilizes SELFIES for $100%$ robust molecular representations and extracts knowledge from the surrounding context of bio-entities in unstructured biological literature. Furthermore, $\mathbf{BioT5}$ distinguishes between structured and unstructured knowledge, leading to more effective utilization of information. After fine-tuning, BioT5 shows superior performance across a wide range of tasks, demonstrating its strong capability of capturing underlying relations and properties of bio-entities. Our code is available at $\href{https://github.com/QizhiPei/BioT5}{Github}$.

Kehan Wu, Yingce Xia, Yang Fan et al. · microsoft-research

Structure-based drug design is drawing growing attentions in computer-aided drug discovery. Compared with the virtual screening approach where a pre-defined library of compounds are computationally screened, de novo drug design based on the structure of a target protein can provide novel drug candidates. In this paper, we present a generative solution named TamGent (Target-aware molecule generator with Transformer) that can directly generate candidate drugs from scratch for a given target, overcoming the limits imposed by existing compound libraries. Following the Transformer framework (a state-of-the-art framework in deep learning), we design a variant of Transformer encoder to process 3D geometric information of targets and pre-train the Transformer decoder on 10 million compounds from PubChem for candidate drug generation. Systematical evaluation on candidate compounds generated for targets from DrugBank shows that both binding affinity and drugability are largely improved. TamGent outperforms previous baselines in terms of both effectiveness and efficiency. The method is further verified by generating candidate compounds for the SARS-CoV-2 main protease and the oncogenic mutant KRAS G12C. The results show that our method not only re-discovers previously verified drug molecules , but also generates novel molecules with better docking scores, expanding the compound pool and potentially leading to the discovery of novel drugs.

Zequn Liu, Kehan Wu, Shufang Xie et al.

Emerging reasoning models hold promise for automating scientific discovery. However, their training is hindered by a critical supervision gap: experimental outcomes are abundant, whereas intermediate reasoning steps are rarely documented at scale. To bridge this gap, we propose DESRO, a framework for deciphering scientific reasoning from outcomes. By analyzing shared patterns and key differences within grouped data, a large language model (LLM) can recover the underlying logic. We instantiate this framework in molecule optimization, a pivotal stage in drug discovery that traditionally relies on the iterative reasoning of medicinal chemists. Across 2.3 million molecular property records, our framework infers optimization rationales by grouping molecules with shared fragments, then using an LLM to analyze how structural variations correlate with property differences. Based on the derived data, we train a model that conducts molecule optimization through an interpretable reasoning process. DESRO achieves the highest success rates on 15 out of 18 tasks, spanning both single- and multi-property optimization of bioactivity and ADMET properties. The reasoning process enables robust generalization to out-of-distribution scenarios, including novel property combinations, unseen biological targets, and unseen properties defined solely by natural language descriptions. In retrospective case studies under strict temporal splits, the model autonomously reconstructs expert-level lead optimization trajectories. Additionally, our framework extends beyond molecule optimization to reaction ligand selection. Our results establish deciphering reasoning steps from outcome data as a viable paradigm for enabling scientific reasoning, providing a scalable approach to accelerate scientific discovery.

Renqi Chen, Xinzhe Zheng, Haoyang Su et al.

Accurate segmentation of ultrasound images is essential for reliable medical diagnoses but is challenged by poor image quality and scarce labeled data. Prior approaches have relied on manually designed, complex network architectures to improve multi-scale feature extraction. However, such handcrafted models offer limited gains when prior knowledge is inadequate and are prone to overfitting on small datasets. In this paper, we introduce DeNAS-ViT, a data-efficient NAS-optimized Vision Transformer, the first method to leverage neural architecture search (NAS) for ultrasound image segmentation by automatically optimizing model architecture through token-level search. Specifically, we propose an efficient NAS module that performs multi-scale token search prior to the ViT's attention mechanism, effectively capturing both contextual and local features while minimizing computational costs. Given ultrasound's data scarcity and NAS's inherent data demands, we further develop a NAS-guided semi-supervised learning (SSL) framework. This approach integrates network independence and contrastive learning within a stage-wise optimization strategy, significantly enhancing model robustness under limited-data conditions. Extensive experiments on public datasets demonstrate that DeNAS-ViT achieves state-of-the-art performance, maintaining robustness with minimal labeled data. Moreover, we highlight DeNAS-ViT's generalization potential beyond ultrasound imaging, underscoring its broader applicability.

Yingce Xia, Peiran Jin, Shufang Xie et al. · microsoft-research

Foundation models have revolutionized natural language processing and artificial intelligence, significantly enhancing how machines comprehend and generate human languages. Inspired by the success of these foundation models, researchers have developed foundation models for individual scientific domains, including small molecules, materials, proteins, DNA, RNA and even cells. However, these models are typically trained in isolation, lacking the ability to integrate across different scientific domains. Recognizing that entities within these domains can all be represented as sequences, which together form the "language of nature", we introduce Nature Language Model (NatureLM), a sequence-based science foundation model designed for scientific discovery. Pre-trained with data from multiple scientific domains, NatureLM offers a unified, versatile model that enables various applications including: (i) generating and optimizing small molecules, proteins, RNA, and materials using text instructions; (ii) cross-domain generation/design, such as protein-to-molecule and protein-to-RNA generation; and (iii) top performance across different domains, matching or surpassing state-of-the-art specialist models. NatureLM offers a promising generalist approach for various scientific tasks, including drug discovery (hit generation/optimization, ADMET optimization, synthesis), novel material design, and the development of therapeutic proteins or nucleotides. We have developed NatureLM models in different sizes (1 billion, 8 billion, and 46.7 billion parameters) and observed a clear improvement in performance as the model size increases.

Meixi Zheng, Kehan Wu, Yanbo Fan et al.

The transfer-based black-box adversarial attack setting poses the challenge of crafting an adversarial example (AE) on known surrogate models that remain effective against unseen target models. Due to the practical importance of this task, numerous methods have been proposed to address this challenge. However, most previous methods are heuristically designed and intuitively justified, lacking a theoretical foundation. To bridge this gap, we derive a novel transferability bound that offers provable guarantees for adversarial transferability. Our theoretical analysis has the advantages of \textit{(i)} deepening our understanding of previous methods by building a general attack framework and \textit{(ii)} providing guidance for designing an effective attack algorithm. Our theoretical results demonstrate that optimizing AEs toward flat minima over the surrogate model set, while controlling the surrogate-target model shift measured by the adversarial model discrepancy, yields a comprehensive guarantee for AE transferability. The results further lead to a general transfer-based attack framework, within which we observe that previous methods consider only partial factors contributing to the transferability. Algorithmically, inspired by our theoretical results, we first elaborately construct the surrogate model set in which models exhibit diverse adversarial vulnerabilities with respect to AEs to narrow an instantiated adversarial model discrepancy. Then, a \textit{model-Diversity-compatible Reverse Adversarial Perturbation} (DRAP) is generated to effectively promote the flatness of AEs over diverse surrogate models to improve transferability. Extensive experiments on NIPS2017 and CIFAR-10 datasets against various target models demonstrate the effectiveness of our proposed attack.