In biological systems, there are billions of biomolecules orchestrating together to maintain cellular functions. Those biomolecules contain different levels of molecular information, such as primary sequence, folded structures, biological function, and chemical connectivity, from the single cell to the tissue scale. To better understand biological mechanisms and improve human healthcare, it is critical to visualize and manipulate these biomolecular activities in cells and tissues to study and control their behaviors. The development of biomolecular tools is one of the key pillars to achieve these goals. Designed biomolecular probes for bio-imaging can help massively visualize biomolecules in cells and tissues, which is necessary to reveal complex cellular organizations and behaviors to understand how they work and malfunction. Beyond visualization, the design of functional biomolecular regulatory tools enables us to manipulate cellular activities, from regulating gene expression and modulating metabolism to recording cellular events and reprogramming cell fates, ultimately building new therapeutics.
Motivated by the scientific challenges to decode and regulate complex biological systems, the research at Hong Lab will move along on the following tracks:
(1) Decoding molecular systems in biology: Biological systems are self-organized biomolecules with different species, quantities, and spatial locations within cells and tissues. We aim to develop next-generation molecular technologies with novel molecular probes for fluorescence microscopy （e.g., DNA Thermal-plex imaging) and next-generation sequencing to analyze cellular targets in cells and tissues with high sensitivity, high multiplexity, and high throughput to access the bio-molecular information untapped before. We'll then use the collected biomolecular information to understand how cell regulates its function, how they communicate with each other, and how their collective behavior is related to human health and diseases.
(2) Bio-programming: A cell is a complex genetically coded life system with its DNA sequence, which performs computation with principles we have yet to understand. We aim to develop principles and computational algorithms (e.g., crowder-oxDNA) to first understand the biomolecular folding from sequence to structure and how it relates to its biological function, particularly RNA folding and its biological function at the current stage. The developed algorithm can then be used to design functional and structural biomolecules, such as RNA gene expression control motifs (e.g., SNIPR) and molecular recognition motifs (e.g. FARSIGHT). Those computer-designed molecules will be used to interface the biology to program cellular behaviors within the cell and cross the cells, eventually building living cellular devices to monitor environmental signals or cure human diseases.
(3) Control/understand biomolecular dynamic circuits: Biomolecules are not static in cells; they interact with each other to have signal exchange and maintain cellular functions. We aim to understand and control the dynamic structural change of biomolecules to program cellular gene expression circuits. Those dynamic circuits will sense, process, and actuate to cellular and molecular signals. They can be used for cell reprogramming to develop new paradigms of therapeutics and diagnostics (e.g., SNIPR).
(4) Control/understand biomolecular assembly: Molecular self-assembly is everywhere. Biomolecules also self-organize in cells, and the collective self-organization relates to their functions and diseases. We aim to understand and control the complex collective assembly behavior of nucleic acids that emerged from individual molecular interactions both in vivo and in vitro (e.g., layered framework DNA architectures for DNA origami and DNA crystals), from nanoscale to macroscale, to build new forms of matter. We'll then study how those new matter forms in living systems can be used to advance the understanding of human healthcare and be used for biomedical applications.
(1) Decoding molecular systems in biology: Biological systems are self-organized biomolecules with different species, quantities, and spatial locations within cells and tissues. We aim to develop next-generation molecular technologies with novel molecular probes for fluorescence microscopy （e.g., DNA Thermal-plex imaging) and next-generation sequencing to analyze cellular targets in cells and tissues with high sensitivity, high multiplexity, and high throughput to access the bio-molecular information untapped before. We'll then use the collected biomolecular information to understand how cell regulates its function, how they communicate with each other, and how their collective behavior is related to human health and diseases.
(2) Bio-programming: A cell is a complex genetically coded life system with its DNA sequence, which performs computation with principles we have yet to understand. We aim to develop principles and computational algorithms (e.g., crowder-oxDNA) to first understand the biomolecular folding from sequence to structure and how it relates to its biological function, particularly RNA folding and its biological function at the current stage. The developed algorithm can then be used to design functional and structural biomolecules, such as RNA gene expression control motifs (e.g., SNIPR) and molecular recognition motifs (e.g. FARSIGHT). Those computer-designed molecules will be used to interface the biology to program cellular behaviors within the cell and cross the cells, eventually building living cellular devices to monitor environmental signals or cure human diseases.
(3) Control/understand biomolecular dynamic circuits: Biomolecules are not static in cells; they interact with each other to have signal exchange and maintain cellular functions. We aim to understand and control the dynamic structural change of biomolecules to program cellular gene expression circuits. Those dynamic circuits will sense, process, and actuate to cellular and molecular signals. They can be used for cell reprogramming to develop new paradigms of therapeutics and diagnostics (e.g., SNIPR).
(4) Control/understand biomolecular assembly: Molecular self-assembly is everywhere. Biomolecules also self-organize in cells, and the collective self-organization relates to their functions and diseases. We aim to understand and control the complex collective assembly behavior of nucleic acids that emerged from individual molecular interactions both in vivo and in vitro (e.g., layered framework DNA architectures for DNA origami and DNA crystals), from nanoscale to macroscale, to build new forms of matter. We'll then study how those new matter forms in living systems can be used to advance the understanding of human healthcare and be used for biomedical applications.
References:
- Zhaoqing Yan, Yudan Li, Amit Eshed, Kaiyue Wu, Zachary M. Ticktin, Vel Murugan, Efrem S. Lim, Fan Hong*, Alexander Green*. Programmable Fluorescent Aptamer-Based RNA Switches for Rapid Identification of Point Mutations. Nature Chemistry, 2025,17, 1826–1838
- Fan Hong, Jocelyn Y. Kishi1, Ryan N. Delgado, Jiyoun Jeong, Sinem K. Saka, Hanquan Su, Constance L. Cepko, Peng Yin*. Thermal-plex: Fluidic-free, rapid sequential multiplexed imaging with DNA encoded thermal channels. Nature Methods, 2024, 21, 331–341
- Fan Hong, Duo Ma, Kaiyue Wu, Lida A. Mina, Rebecca C. Luiten, Yan Liu, Hao Yan*, Alexander A. Green*. Precise and Programmable Detection of Mutations Using Ultraspecific Riboregulators, Cell, 2020, 180, 1018-1032.
- Fan Hong, John Shreck, Petr Sulc, Understanding DNA interactions in crowded environments with a coarse-grained model, Nucleic Acid Research, 2020,48,10726.
- Fan Hong, Shuoxing Jiang, Xiang Lan, Raghu Pradeep Narayanan, Petr, Sulc, Fei Zhang, Yan Liu, Hao Yan, Layered-Crossover Tiles with Precisely Tunable Angles for 2D and 3D DNA Crystal Engineering, J. Am. Chem. Soc. 2018, 140, 14670-14676.
- Fan Hong, Shuoxing Jiang, Tong Wang, Yan Liu, Hao Yan, 3D Framework DNA origami structure with layered crossover motifs. Angew Chem Int Ed, 2016,55, 12832-12835.