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Decoding the Dynamics of Life at the Molecular Limit
"Seeing is believing." At our laboratory, we believe that to truly understand the complex orchestration of life, we must observe it in action at its most fundamental limit: the single molecule.
Our research is driven by a profound curiosity about how cells are dynamically regulated in space and time. To uncover these secrets, we embark on a two-fold journey. First, we tackle compelling biological mysteries—such as how soluble proteins orchestrate liquid-liquid phase separation (LLPS) to control cell fate, how intrinsitcally disordered regions (IDRs) regulate LLPS and how single regulatory RNAs act as living messengers across organelles. Second, to see these phenomena clearly, we shatter the physical limits of optical resolution. We do not just use microscopes; we engineer the next generation of optical paradigms, including advanced STED nanoscopy and our groundbreaking, scan-less and pixel-less new imaging paradigm.
A Collaborative Playground for Biologists and Physicists/Chemists/Engineers
Tackling the most outstanding questions in life science requires a fusion of perspectives. However, you do not need to be an expert in both biology and physics to join us.
Our lab is designed as a highly collaborative ecosystem. Biologists bring the fundamental questions and biological models, while physicists, chemists and engineers design the state-of-the-art tools required to answer them. Whether your passion lies in uncovering the secrets of gene editing and molecular condensates, or in setting up ultrafast optical systems to build the future of microscopes, your unique strength will be the key to our collective breakthrough. Bring your passion in one, and we will help you master the rest.
To address the unseen mysteries of the cell, we focus on three exciting, interconnected areas:
LLPS (Liquid-liquid phase separation) Biology and Therapeutics
Liquid-liquid phase separation (LLPS) is a groundbreaking concept that explains how cells dynamically organize their internal space without membrane-bound organelles. Soluble proteins and nucleic acids separate from the aqueous protoplasm in response to physical and chemical cues, forming distinct biomolecular condensates. Strikingly, an enormous variety of cellular processes—including chromatin organization, temperature sensing, and amyloid formation in neurodegenerative diseases—are deeply governed by LLPS.
A key driving force behind this phenomenon lies in Intrinsically Disordered Regions (IDRs)—highly flexible protein domains that lack a fixed 3D structure. Interestingly, we focus on a fascinating principle of IDRs: their phase separation is governed less by the exact amino acid sequence, and much more by their overall molecular features (such as charge distribution, hydrophobicity, and specific amino acid patterning).
Despite its biological importance, there remains a huge gap in the quantitative, physical understanding of how these condensates regulate enzyme reaction rates and cellular responses. In our lab, we bridge this gap by employing advanced single-molecule biophysical techniques (such as smFRET and SiMPull) to unveil the genuine molecular dynamics and stoichiometry within condensates. We actively investigate LLPS phenomena in both plant models (e.g., how the GI-FKF1 complex undergoes phase separation to control flowering time) and mammalian cells (e.g., FUS and UBQLN2 in neurodegeneration).
Ultimately, our goal extends beyond basic biology. We aim to invent novel, orthogonal 'knobs' based on LLPS principles to modulate cellular functions at high temporal resolution. We believe these engineered condensates will pave the way for next-generation therapeutics targeting diseases that remain undruggable by conventional mechanisms.
RNA Biology and Gene Editing
Cells respond to environmental cues by dynamically controlling RNA localization, translation, and degradation. We aim to understand the complex regulatory networks of living cells by observing single RNA molecules in real-time. By utilizing multiplexed single-molecule fluorescence in situ hybridization (smFISH) and live-cell single-molecule tracking (e.g., SunTag, MS2/PP7 systems), we investigate the spatiotemporal dynamics of regulatory RNAs, including mRNAs, miRNAs, and long non-coding RNAs (lncRNAs).
Our research addresses fundamental questions: How do lncRNAs transcribed in the nucleus navigate the cell to regulate organelle functions, such as chloroplast transition via anterograde signaling? How is protein translation stochastically regulated in response to environmental stress?
Building upon our expertise in tracking single RNA and translation events, we are expanding our frontiers into advanced genetic manipulation. We are developing and applying CRISPR-based technologies to exert spatiotemporal control over gene editing. By combining high-resolution RNA tracking with targeted genetic manipulation, we seek to uncover the profound relationship between molecular movement, expression, and cellular necessity.
Super-resolution Optical Microscopy (STED, PALM/STORM)
Optical microscopy is an indispensable tool in biology, yet the fundamental optical diffraction limit restricts the observation of cellular structures smaller than 250-300 nm. Super-resolution optical microscopy, recognized by the 2014 Nobel Prize in Chemistry, breaks this barrier. Techniques like STED (using a donut beam for fluorescence depletion) and PALM/STORM (using photoactivatable fluorophores) have revolutionized our ability to investigate nanoscale cellular dynamics.
Our lab actively develops these state-of-the-art super-resolution methods. We push the limits of STED microscopy by pioneering techniques like 'background-free STED' via differential depletion, effectively overcoming the critical bottleneck of background noise and significantly enhancing the signal-to-background ratio.
We do not stop at overcoming the diffraction limit. To fully capture the rapid and complex dynamics of living cells, we are developing a completely new imaging paradigms (currently unable to disclose). We welcome physics and engineering talents to join us in building this ultimate tool for the future of life sciences.
See, Optics Express 31, 37549 (2023) and ACS Photonics 6, 1789 (2019).
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