CAREER: Robust heterochiral molecular computing in mammalian cells

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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.