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<p>Designing single molecules that compute general functions of input molecular partners is a major unsolved challenge in molecular design. Here we demonstrate that high-throughput, iterative experimental testing of diverse RNA designs crowdsourced from the online game Eterna yields sensors of increasingly complex functions of input oligonucleotide concentrations. After designing single-input RNA sensors with activation ratios beyond our detection limits, we created logic gates, including challenging XOR and XNOR gates, and sensors that respond to the ratio of two inputs. Finally, we describe the OpenTB challenge, which elicited 85-nucleotide sensors that compute a score for diagnosing active tuberculosis based on the ratio of products of three gene segments. Building on OpenTB design strategies, we created an algorithm, Nucleologic, that produces similarly compact sensors for the three-gene score based on RNA and DNA. These results expand the possibilities for using compact, single-molecule sensors in a range of applications previously constrained by design complexity.</p><p></p>

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Compact RNA sensors for increasingly complex functions of multiple inputs

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月12日

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  • Christian A. Choe,
  • Johan O. L. Andreasson,
  • Feriel Melaine,
  • Wipapat Kladwang,
  • Michelle J. Wu,
  • Fernando Portela,
  • Roger Wellington-Oguri,
  • John J. Nicol,
  • Hannah K. Wayment-Steele,
  • Michael Gotrik,
  • Purvesh Khatri,
  • William J. Greenleaf,
  • Rhiju Das

摘要

Designing single molecules that compute general functions of input molecular partners is a major unsolved challenge in molecular design. Here we demonstrate that high-throughput, iterative experimental testing of diverse RNA designs crowdsourced from the online game Eterna yields sensors of increasingly complex functions of input oligonucleotide concentrations. After designing single-input RNA sensors with activation ratios beyond our detection limits, we created logic gates, including challenging XOR and XNOR gates, and sensors that respond to the ratio of two inputs. Finally, we describe the OpenTB challenge, which elicited 85-nucleotide sensors that compute a score for diagnosing active tuberculosis based on the ratio of products of three gene segments. Building on OpenTB design strategies, we created an algorithm, Nucleologic, that produces similarly compact sensors for the three-gene score based on RNA and DNA. These results expand the possibilities for using compact, single-molecule sensors in a range of applications previously constrained by design complexity.