Never before have we known so much about proteins. Their sequences can be determined in hours, and their structures predicted computationally or visualized experimentally at near-atomic resolution. Yet one of biology's most fundamental questions remains: How do proteins perform their biological functions?

The consequences extend far beyond basic biology. In the field of pain, numerous molecular targets have been identified, including thermoTRP ion channels that detect heat and other painful stimuli. When TRPV1 was cloned nearly three decades ago, it was widely anticipated that understanding its molecular mechanisms would rapidly lead to a new generation of highly specific, non-opioid analgesics. Today we possess detailed structural information for TRPV1 and many other pain receptors, yet effective non-opioid pain therapies remain scarce.

This experience with pain receptors exemplifies a broader challenge facing modern biology. Knowing what a protein looks like does not necessarily reveal how it performs its biological function. Bridging molecular structure and biological function has therefore emerged as one of the central challenges in modern biology.

Our Vision: Observe Biology in Motion

We believe that bridging structure and function requires observing biology in motion. Our goal is not simply to determine what proteins look like, but to understand how they work. Protein function emerges through transient structural states that are often invisible to conventional experimental approaches. Our laboratory integrates structural biology, biophysics, thermodynamics, and computation to reveal these dynamic processes and uncover the physical principles governing protein function.

Guided by this vision, our research has continually evolved as each discovery exposed the limitations of existing approaches. We began by combining patch-clamp electrophysiology with mutagenesis to define structure-function relationships. When functional measurements alone proved insufficient tot explain the mechanisms of temperature sensing, we introduced differential scanning calorimetry to directly measure heat absorption during channel activation. More recently, we expanded into cryo-EM and are now developing millisecond time-resolved cryo-EM to capture protein motions in real time.

Together, these advances have uncovered fundamental mechanisms governing thermoTRP channel function, including lipid regulation of temperature receptors, molecular mechanisms of desensitization, and the structural basis of thermal sensing. More recently, integrating electrophysiology, thermodynamics, and structural biology led us to propose a new thermodynamic framework in which temperature activation arises through progressive conformational destabilization rather than conventional allosteric transitions. This framework offers a new way of thinking about temperature sensing and may represent a broader conceptual mechanism by which biological receptors harness structural destabilization to perform biological work.

Over three decades of research, we have learned that major biological discoveries are often driven by new ways of observing nature. Guided by this philosophy, our laboratory has developed innovations ranging from the QuB software suite for single-channel kinetic analysis, to submillisecond temperature-clamp electrophysiology, differential scanning calorimetry, and now millisecond time-resolved cryo-EM. We believe that revealing the transient molecular states connecting structure and function is essential for understanding how proteins perform their biological functions. When existing methods cannot answer important biological questions, we build new ones.