Award Abstract # 2044838
CAREER: Robust heterochiral molecular computing in mammalian cells

NSF Org: CCF
Division of Computing and Communication Foundations
Recipient: UNIVERSITY OF NEW MEXICO
Initial Amendment Date: January 29, 2021
Latest Amendment Date: June 17, 2025
Award Number: 2044838
Award Instrument: Continuing Grant
Program Manager: Stephanie Gage
sgage@nsf.gov
 (703)292-4748
CCF
 Division of Computing and Communication Foundations
CSE
 Directorate for Computer and Information Science and Engineering
Start Date: April 1, 2021
End Date: March 31, 2026 (Estimated)
Total Intended Award Amount: $650,000.00
Total Awarded Amount to Date: $659,990.00
Funds Obligated to Date: FY 2021 = $253,574.00
FY 2023 = $262,817.00

FY 2024 = $9,990.00

FY 2025 = $133,609.00
History of Investigator:
  • Matthew Lakin (Principal Investigator)
    mlakin@unm.edu
Recipient Sponsored Research Office: University of New Mexico
1 UNIVERSITY OF NEW MEXICO
ALBUQUERQUE
NM  US  87131-0001
(505)277-4186
Sponsor Congressional District: 01
Primary Place of Performance: University of New Mexico
NM  US  87131-0001
Primary Place of Performance
Congressional District:
01
Unique Entity Identifier (UEI): F6XLTRUQJEN4
Parent UEI:
NSF Program(s): FET-Fndtns of Emerging Tech
Primary Program Source: 01002122DB NSF RESEARCH & RELATED ACTIVIT
01002324DB NSF RESEARCH & RELATED ACTIVIT

01002425DB NSF RESEARCH & RELATED ACTIVIT

01002526DB NSF RESEARCH & RELATED ACTIVIT
Program Reference Code(s): 1045, 7931, 7946, 9150, 9251
Program Element Code(s): 089Y00
Award Agency Code: 4900
Fund Agency Code: 4900
Assistance Listing Number(s): 47.070

ABSTRACT

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.

PUBLICATIONS PRODUCED AS A RESULT OF THIS RESEARCH

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Lakin, Matthew R and Kumar, Sarika "Geometric Enumeration of Localized DNA Strand Displacement Reaction Networks" , v.314 , 2024 https://doi.org/10.4230/LIPIcs.DNA.30.1 Citation Details
Mallette, Tracy L. and Lakin, Matthew R. "Protecting Heterochiral DNA Nanostructures against Exonuclease-Mediated Degradation" ACS Synthetic Biology , v.11 , 2022 https://doi.org/10.1021/acssynbio.2c00105 Citation Details
Mallette, Tracy L. and Lidke, Diane S. and Lakin, Matthew R. "Heterochiral modifications enhance robustness and function of DNA in living human cells" ChemBioChem , v.25 , 2024 https://doi.org/10.1002/cbic.202300755 Citation Details

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