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Le Cong

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2 papers

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NeurIPS Conference 2025 Conference Paper

Securing the Language of Life: Inheritable Watermarks from DNA Language Models to Proteins

Zaixi Zhang
Ruofan Jin
Le Cong
Mengdi Wang

DNA language models have revolutionized our ability to design and manipulate DNA sequences—the fundamental language of life—with unprecedented precision, enabling transformative applications in therapeutics, synthetic biology, and gene editing. However, this capability also poses significant dual-use risks, including the potential creation of harmful biological agents. To address these biosecurity challenges, we introduce two innovative watermarking techniques: DNAMark and CentralMark. DNAMark employs synonymous codon substitutions to embed robust watermarks in DNA sequences while preserving the function of encoded proteins. CentralMark advances this by creating inheritable watermarks that transfer from DNA to translated proteins, leveraging protein embeddings to ensure detection across the central dogma. Both methods utilize state-of-the-art embeddings to generate watermark logits, enhancing resilience against natural mutations, synthesis errors, and adversarial attacks. Evaluated on a therapeutic DNA benchmark, DNAMark and CentralMark achieve F1 detection scores above 0. 85 under diverse conditions, while maintaining over 60\% sequence similarity to ground truth and degeneracy scores below 15\%. A case study on a CRISPR-Cas9 system underscores CentralMark’s utility in real-world synthetic biology. This work establishes a vital framework for securing DNA language models, balancing innovation with accountability to mitigate biosecurity risks.

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NeurIPS Conference 2022 Conference Paper

Bandit Theory and Thompson Sampling-Guided Directed Evolution for Sequence Optimization

Hui Yuan
Chengzhuo Ni
Huazheng Wang
Xuezhou Zhang
Le Cong
Csaba Szepesvari
Mengdi Wang

Directed Evolution (DE), a landmark wet-lab method originated in 1960s, enables discovery of novel protein designs via evolving a population of candidate sequences. Recent advances in biotechnology has made it possible to collect high-throughput data, allowing the use of machine learning to map out a protein's sequence-to-function relation. There is a growing interest in machine learning-assisted DE for accelerating protein optimization. Yet the theoretical understanding of DE, as well as the use of machine learning in DE, remains limited. In this paper, we connect DE with the bandit learning theory and make a first attempt to study regret minimization in DE. We propose a Thompson Sampling-guided Directed Evolution (TS-DE) framework for sequence optimization, where the sequence-to-function mapping is unknown and querying a single value is subject to costly and noisy measurements. TS-DE updates a posterior of the function based on collected measurements. It uses a posterior-sampled function estimate to guide the crossover recombination and mutation steps in DE. In the case of a linear model, we show that TS-DE enjoys a Bayesian regret of order $\tilde O(d^{2}\sqrt{MT})$, where $d$ is feature dimension, $M$ is population size and $T$ is number of rounds. This regret bound is nearly optimal, confirming that bandit learning can provably accelerate DE. It may have implications for more general sequence optimization and evolutionary algorithms.

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