Jung-Chi Liao studied mechanical engineering as an undergraduate at National Taiwan University in Taipei. He was interested in mechanical vibration, so following his graduation he went to MIT to pursue a PhD working on understanding fluid-structure interaction of oil drilling pipes with Kim Vandiver. “Toward the end of my PhD studies around 2000 and 2001, I thought, is there any new research direction that would be challenging and exciting for a mechanical engineer?” he says. “The vibration research in solving real-world problems in the oil industry was pretty cool, but I wanted to explore some new stuff.”
He started attending a popular nanotechnology class taught by Christine Ortiz and became fascinated by molecular motors. “In one lecture, to my surprise, I found that the most amazing nano-machines are actually those ATP-driven molecular motors in biology, such as myosin, kinesin, dynein, F1 ATPase, helicase, and many others. They can walk, rotate, and translocate, much like mechanical machines, but in a super tiny 5–10 nm size,” he explains. “I was deeply intrigued by these machines — who wasn’t at that time? — and started to read a lot of books and papers related to molecular motors, including works by James Spudich, Steve Block, Ron Vale, Carlos Bustamante, Kazuhiko Kinosita, Joe Howard, George Oster, Michael Fisher, and Martin Karplus, to name a few. During that time, I also had a few chances to talk to Rob Phillips. He encouraged me a lot in moving toward biophysics.”
In 2001, he met George Oster at Berkeley. “At that time, I was just an ‘oil piper,’ while George’s lab had just published a few groundbreaking papers introducing the concepts of Brownian ratchets and power strokes at the framework of Fokker-Planck models. George gave me guidance on the molecular motor field when we first met,” he shares. “And the second time, he decided to give this mechanical engineer a try as a postdoc to model molecular motors.”
Oster suggested that he apply for postdoctoral fellowships, writing about a project modeling GroEL. “During those two to three months, I read more than 100 papers related to ATP-driven molecular motors and GroEL, bought a vegetable steamer to get hints on cooperative motion of different GroEL subunits, and discussed back and forth with George about the mechanochemical coupling of GroEL,” he says. “Finally, one day after finishing my PhD study in ‘Vortex-induced Vibration of Slender Structures in Unsteady Flow,’ I moved from Cambridge, Massachusetts, to Berkeley to pretend to be a biophysicist in October 2001.”
He caught up quickly due to a unique feature of Oster’s lab culture. “The famous thing about George’s lab was that all lab members went to a café outside of the Berkeley campus every morning to have a cup of coffee or tea and discuss modeling ideas on a couple of pieces of paper on the table. Every morning, we did the same thing. It was a unique training style of George’s and certainly benefitted me quite a bit to dive into the excitement of the field quickly,” Liao shares.
His first project in Oster’s lab was to model the conformational states of Mg-ATP in water using molecular dynamics simulation, with much help from his postdoc colleague Sean Sun. “We revealed that magnesium coordinates with either two (beta- and gamma-) phosphates or three (alpha-, beta-, and gamma-) phosphates with a similar free energy level. We also identified the conformational energy landscape of Mg- ATP and illustrated the corresponding conformational states of different Mg-ATP molecules in different protein-bound crystal structures,” he explains. “After that, we collaborated with Smita Patel’s lab to examine the mechanochemical coupling of hexameric T7 DNA helicase, my first mechanochemical study of an ATP-driven molecular motor. We found that the subunits move single-stranded DNA through the center of the ring in a sequential manner, and proposed a power-stroke model with the coupled ATP hydrolysis cycle that is consistent with all experimental results of kinetic studies. I then worked on modeling several other ATP-associated molecular motors, including F1 ATP synthase, Rho transcription termination factor, and hepatitis C virus NS3 helicase. These projects were completed with several outstanding colleagues, including Jianhua Xing, Joshua Adelman, and Wenjun Zheng.”
He stayed in Oster’s lab for four years before joining Simbios, an NIH Center for Biomedical Computation headed by Russ Altman and Scott Delp at Stanford University, as a Research Associate. He worked with Altman, Delp, and Jim Spudich to model myosin, another ATP-driven molecular motor. “We used different approaches to understand the mechanochemistry of myosin. We revealed the allosteric communication pathway within the structure of myosin to couple the ATP binding and the movement of the lever arm, and we established a kinetic model to explain the dwell-time distribution of the myosin power stroke cycle,” he says. He realized that it would be even better if he could conduct both modeling and experimental work, so he began working in Spudich’s lab, learning experimental techniques for myosin studies. “Several people helped me a lot on learning experimental assays when I was at Spudich’s lab, including Zev Bryant, Alex Dunn, Mary Elting, Shiv Sivaramakrishnan, Ben Spink, and Shirley Sutton,” Liao shares. “I focused on a myosin VI project under the guidance of Jim and Zev with help from Mary and identified minimal structural determinants of myosin VI’s reverse directionality. We were able to replace myosin VI’s lever arm to change its moving direction.”
After three years at Stanford, he accepted a faculty position at Columbia University in 2008. Around that time there had been breakthroughs in fluorescence microscopy, specifically STED and PALM/STORM superresolution microscopy that broke the diffraction limit. He was inspired by these breakthroughs, led by Stefan Hell, Eric Betzig, and Xiaowei Zhuang, and decided to start his own lab with a focus on superresolution microscopy. “With help from Stefan Hell and his lab members, my PhD students Bhavik Nathwani and Tony Yang built a two-color continuous-wave STED microscopy system in my lab. We first used it to image dendritic spines in neurons by collaborating with Rafael Yuste, but found that a lot of labs were working on spine imaging using superresolution microscopy,” he says. “It was by chance that I got to know Dieter Egli and Rudolph Leibel, who are interested in ciliary functions and were trying to image primary cilia using superresolution microscopy. That was the starting point when my lab moved our focus toward understanding primary cilia using superresolution microscopy.”
In 2014, he moved back to Taiwan to accept a position as an Associate Research Fellow (equivalent to Associate Professor) at the Institute of Atomic and Molecular Sciences (IAMS) of the Academia Sinica. “I have been continuing my research focus on primary cilium research using superresolution microscopy incorporating more techniques including 2D and 3D dSTORM and sptPALM in addition to STED,” he says. “We revealed the molecular architecture of the transition zone and the distal appendages at the ciliary base. Our transition zone study provides a structural framework for functional studies related to transition zone proteins that are important for various ciliopathies. Our distal appendage study redefines the architecture of distal appendages as two different regions, that is, the distal appendage blades and matrix. Thus, instead of a nine-blade architecture, the appendage region is a cone-shaped structure essential for the regulation of transmembrane protein passage. In addition to using superresolution microscopy for studies of biological problems, we are now also developing a new microscopy-based method to be broadly useful for the cell biology community.”
“Since Dr. Liao joined IAMS, he has been active in promoting bioimaging research in Taiwan,” shares his institutional colleague Chia-Lung Hsieh. “He has always tried to make Taiwan a better place for bioimaging/biophysical research. He is willing to serve the community, to bridge the local community to the global.”
Jie Xiao, Johns Hopkins University School of Medicine, with whom Liao organized a Biophysical Society thematic meeting in Taiwan, says, “Jung-Chi is a great colleague that everyone would want be with. He is kind, gentle, considerate, and generous with his time; he does not talk much but he gets things done thoroughly and efficiently. I look forward to seeing Jung-Chi becoming a rising star in his research field, and at the same time taking on leadership roles reaching out to a larger scientific community.”
Liao advises young biophysicists to “attend the Biophysical Society Annual Meeting and listen to a lot of talks to figure out what may interest you the most. Once the direction of your interest is decided, attend some conferences in that focused area (Biophysical Society thematic meetings or small meetings held by other societies) and get to know people and their works in depth.”