A Blind Spot in Alignment: Quantifying Biosecurity Risks in Large Language Models

Frontier large language models (LLMs) are increasingly integrated into scientific workflows, yet their growing biological capabilities may outpace current safeguards. To assess the biological risks of frontier models, we develop Intern-BioBreaker, a specialized bio-red-teaming model, together with an integrated computational-to-physical framework that couples model-level stress testing with wet-lab validation. Within this framework, Intern-BioBreaker generates targeted jailbreak prompts to test whether aligned models can be induced to provide operational guidance for safety-sensitive biological tasks or produce sequence-level outputs with potentially harmful properties. Selected sequence outputs are then carried forward for DNA synthesis, host expression, and orthogonal protein verification to assess whether model-generated designs can yield the intended biological products. Our evaluation reveals a concerning gap between text-level safeguards and the risks posed by capable scientific models: (i) Intern-BioBreaker outperforms baseline attack models and reveals widespread bio-risk jailbreak vulnerabilities across both open-weight and proprietary frontier LLMs, with several targets reaching near-saturated or 100% task-level attack success rate (ASR); (ii) in sequence-level case studies, GPT-5.5 can be induced to generate modified viral candidate sequences with pathogenic potential; the corresponding translated proteins may exhibit even stronger receptor-binding affinity and thus enhanced infection potential; and (iii) end-to-end verification shows that selected model-generated biological designs are not merely textual artifacts, but can be physically realized under controlled experimental settings. These findings underscore the need for stronger biological red-teaming, nucleic acid synthesis screening, and safety mechanisms that keep pace with model capabilities.

Large language models (LLMs) are rapidly acquiring capabilities relevant to biological research, from literature synthesis to interpretation of experimental data. Increasingly, LLM agents can also perform in silico biology tasks that previously required experienced human biologists. These emerging AI capabilities offer new opportunities for scientific discovery and biomedical advances, but they also shift the landscape of biosecurity risks. To address this, we introduce the Agentic Bio-Capabilities Benchmark (ABC-Bench), a suite of tasks to measure agentic biosecurity-relevant capabilities. ABC-Bench evaluates LLM agents on both benign and dual-use biology tasks: writing code to operate liquid handling robots, designing DNA fragments for in vitro assembly, and evading DNA synthesis screening. These tasks require a combination of biology and software expertise. All tested LLM agents outperformed the median expert human baseliner on all three tasks. Agents performed highly on tasks drawing on published knowledge and well-documented protocols, and more weakly on a task requiring novel bioinformatics reasoning. In three wet-lab validation experiments, we found that OpenAI's o4-mini-high produced scripts that, when run on an OpenTrons liquid handling robot, successfully assembled DNA with expected sequences.

Large language models (LLMs) are increasingly used for medical and health-related questions, yet their safety in high-risk medical scenarios remains poorly understood. We introduce \textsc{MedHarm}\footnote{Code and data will be released upon acceptance. Due to the sensitive nature of high-risk medical queries, data access will be available to qualified researchers upon request.}, a high-risk medical safety benchmark with 1,100 medically grounded queries across 10 safety-critical categories, including toxicology, pharmacology, covert poisoning, anesthesia, and fetal harm. Unlike broad medical QA benchmarks, \textsc{MedHarm} targets realistic clinical, educational, and technical prompts that require refusal, caution, or safe redirection rather than direct helpfulness. We evaluate 15 LLMs spanning general-purpose, medical-purpose, closed-source, and downstream SFT models, together with 4 representative guardrail models. Results reveal a substantial gap between apparent alignment and medical safety: aligned models can still produce unsafe or actionable responses, medical fine-tuning can amplify harmful specificity, and external guardrails reduce some failures while introducing brittle blocking and weak safe helpfulness. These findings show that medical safety cannot be inferred from general alignment or medical capability alone, highlighting the need for domain-specific stress testing before deploying LLMs in safety-critical medical applications.