CAREER: Robust heterochiral molecular computing in mammalian cells

DNA双螺旋是最具标志性和广为人知的分子结构之一。所有自然产生的DNA双螺旋都朝同一个方向旋转：向右。这些被称为D-DNA。由D-DNA制成的分子装置可以直接与自然产生的核酸相互作用，但这种装置很容易被识别自然产生的D-DNA的细胞防御系统识别和降解。近年来，人们开发了一系列的D-DNA分子传感器、电路和致动器，但它们在活细胞和生物体中的应用受到这个问题的限制。这一职业项目将通过包括镜像“左手”脱氧核糖核酸(L-脱氧核糖核酸)在内的工程系统来增强基于脱氧核糖核酸的分子器件的实用价值。L-脱氧核糖核酸的双螺旋与D-脱氧核糖核酸的方向相反，因此可以抵抗细胞环境中的降解。特别是，这个项目将研究在这些新颖的电路设计中L脱氧核糖核酸和D-脱氧核糖核酸之间的分子信息传输，结合实验和计算研究来优化这些系统的行为，并展示它们在生物系统传感和控制中的用途。该职业项目还将通过与新墨西哥州阿尔伯克基的一家实践科学博物馆--探索！合作，加强新墨西哥州的生物技术教育渠道。这项合作将为当地高中生开发生物技术迷你课程，重点是代表人数不足的群体的成员。因此，该项目将加强新墨西哥州的科学和工程培训基础设施。这个跨学科的职业项目将研究新颖的分子电路设计，这种设计利用DNA手性来产生可以在活的哺乳动物细胞中执行计算的强大的分子电路。该项目将制定一个混合系统中L DNA和D DNA成分之间有效信号传递的设计规则，其中L DNA成分用于信息处理，D DNA成分用于与周围生物环境的接口。它还将研究活细胞中此类系统对降解的稳健性。最后，将开发基于分子计算的输出来控制细胞行为的创新机制，这些机制将被用于基于对特定生物标志物组合的感知来定向控制特定细胞类型。这些结果将推动分子电路设计的发展，提高基于DNA的分子器件在生物医学和生物技术行业中的实际应用。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The DNA double helix is one of the most iconic and well-known molecular structures. All naturally occurring DNA double helices twist in the same direction: to the right. These are called D-DNA. Molecular devices made from D-DNA can interact directly with naturally occurring nucleic acids, but such devices are easily recognized and degraded by cellular defenses that recognize naturally occurring D-DNA. A wide range of D-DNA molecular sensors, circuits and actuators have been developed in recent years, but their utility in living cells and organisms is limited by this issue. This CAREER project will enhance the practical utility of DNA-based molecular devices by engineering systems that include mirror-image “left-handed” DNA (L-DNA). The L-DNA double helix twists in the opposite direction to D-DNA and can therefore resist degradation in the cellular environment. In particular, this project will study the transmission of molecular information between L-DNA and D-DNA in these novel circuit designs, combining experimental and computational research to optimize the behavior of these systems and to demonstrate their use for sensing and control of biological systems. This CAREER project will also strengthen the biotechnology educational pipeline in New Mexico via a collaboration with ¡Explora!, a hands-on science museum in Albuquerque, NM. This collaboration will develop biotechnology minicourses for local high school students, with a focus on members of underrepresented groups. This project will thus enhance the scientific and engineering training infrastructure in the state of New Mexico.This interdisciplinary CAREER project will study novel molecular circuit designs that exploit DNA chirality to produce robust molecular circuits that can execute computations within living mammalian cells. The project will develop design rules for efficient signaling between L-DNA and D-DNA components in a mixed system where the L-DNA components are used for information processing and the D-DNA components are used for interfacing with the surrounding biological environment. It will also study the robustness to degradation of such systems in living cells. Finally, innovative mechanisms will be developed to control cell behavior based on the output from a molecular computation, and these will be used for targeted control of specific cell types based on sensing of specific biomarker combinations. These results will advance the state of molecular circuit design and enhance the utility of DNA-based molecular devices for practical applications in biomedicine and biotechnological industry.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.