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<p>Generative modeling offers a robust framework for designing functional DNA, RNA and protein sequences. However, physical synthesis of these sequences at scale is prohibitively expensive. We introduce a method to efficiently synthesize DNA designs from generative models. The method integrates machine learning and wet lab procedures, implementing generative sampling algorithms physically through controlled stochastic chemical reactions using DNA oligosynthesis. We synthesize ~10<sup>16</sup> designs from a generative model of human antibodies, with realism and diversity comparable to state-of-the-art protein language models, and verify the designed DNA by sequencing. Translation and expression of the designed antibody scFvs in human cell lines, combined with high-throughput screening against multiplexed human leukocyte antigen (HLA)-presented intracellular proteins, yields potential therapeutic chimeric antigen receptors. We further synthesize ~10<sup>16</sup> DNA designs from models of Taq polymerase and the HLA-presented peptidome, confirming the method’s generalizability.</p>

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Manufacturing-aware generative models enable petascale synthesis of designed DNA

  • 期刊论文

  • 发表日期：

    2026年3月17日

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  • Eli N. Weinstein,
  • Mattia G. Gollub,
  • Andrei Slabodkin,
  • Kerry Dobbs,
  • Xiao-Bing Cui,
  • Cameron L. Gardner,
  • Ryan J. Grant,
  • Kristina Gurung,
  • Amira Bailey,
  • Alan N. Amin,
  • George M. Church,
  • Elizabeth B. Wood

摘要

Generative modeling offers a robust framework for designing functional DNA, RNA and protein sequences. However, physical synthesis of these sequences at scale is prohibitively expensive. We introduce a method to efficiently synthesize DNA designs from generative models. The method integrates machine learning and wet lab procedures, implementing generative sampling algorithms physically through controlled stochastic chemical reactions using DNA oligosynthesis. We synthesize ~1016 designs from a generative model of human antibodies, with realism and diversity comparable to state-of-the-art protein language models, and verify the designed DNA by sequencing. Translation and expression of the designed antibody scFvs in human cell lines, combined with high-throughput screening against multiplexed human leukocyte antigen (HLA)-presented intracellular proteins, yields potential therapeutic chimeric antigen receptors. We further synthesize ~1016 DNA designs from models of Taq polymerase and the HLA-presented peptidome, confirming the method’s generalizability.