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Yu-Hsuan TSAI: A Painstaking Journey - Finding the Key to Target Protein Inhibition

2021.08.11


The great strides in science discovery and development have been achieved no longer by the solitary search of individual but teamwork and collaboration in every segment of the science community. And so does Yu-Hsuan Tsai believes, that excellent teamwork is indispensable to the delivery of successful outcomes, with the open visions, innovative minds, active thoughts and interdisciplinary backgrounds of each team member. In the Tsai group, being encouraged to explore science freely and independently does not prevent each member from collaboration. When it comes to their collective research goal, the group marched as a unit, bravely towards the unexplored hinterland of science.

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Tsai Yu-Hsuan

SZBL Institute of Molecular Physiology

Junior Principal Investigator

Research Areas:

Our research focuses on development of new chemical biology tools that address challenging biological questions. We are particularly interested in developing new tools to control protein function and their biomedical applications, such as therapeutics and diagnostics. The group has expertise in chemical biology, organic synthesis, therapeutic development, gene editing, and genetic code expansion.


Peptides and proteins are the building blocks of life. Comprised by 20 amino acids, peptides and proteins perform life-sustaining activities in our bodies. The abnormalities of peptides and proteins are associated with almost all human diseases, which means that they can serve as very promising bases for targeting diseases. However, there are tens of thousands of different proteins in the human body, many of whom the physiological roles have not yet been fully understood, including some possess very similar structures or amino acid sequences, adding to the difficulty of research on protein.

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Selective inhibition of protein function through a genetically incorporated unnatural amino acid barring a bioorthogonal functionality.

Rapid and selective inhibition of target protein enables the elucidation of protein function and its association with diseases, providing new approaches for therapeutics. However, since many proteins have closely related family members with similar sequences and structures, selective inhibition of a target protein without affecting other members in the same protein family remains challenging.

To address this, the Tsai group developed a strategy that confers specificity to pan inhibitors, enabling differentiation of two proteins differed by a single amino acid. This strategy has been used to selectively inhibit kinases MEK1, MEK2 and LCK that regulate the signaling pathways in the growth and development of tumors, as well as reversibly regulate protein activity by optical switching (Nat. Chem. 2015, 7, 554). 

The strategy is based on genetic incorporation of a unnatural amino acid barring a bioorthogonal functionality into the target protein. This enables covalent tethering the small-molecule inhibitor containing the complementary bioorthogonal group. Consequently, the activity of the tethered protein is inhibited. Therefore, developing new approaches for site-specific protein modifications will expand the scope of this selective inhibition strategy, realizing the concurrent regulation of two enzymes. Through collaboration with Prof Chuanliu Wu at the Xiamen University, they reported a new bioorthogonal reaction for site-specific protein modification. The reaction can be used for site-specific modification of proteins on the surface of phages without affecting the viability and infectivity. Also, the reaction contributed to the site-specific modifications on synthetic peptides, purified proteins and proteins on mammalian cells. 

Tsai and his collaborators hope that in the future, they will be able to break new paths for rapid and selective inhibition of any proteins in vivio. 

Yu-Hsuan Tsai did his undergraduate study in the Department of Chemistry at the National Taiwan University. He met Professor Peter Seeberger, a renowned expert in glycosciences, in a conference. He then joined theSeeberger group at the Swiss Federal Institute of Technology (ETH) Zurichfor masters study and Max Planck Institute of Colloids and Interfaces for doctoral study. In the Seeberger group, Tsai focused on synthesis of glycoconjugates and their biomedical applications. While his original project was on elucidating the effect of glycosylation on the infectivity of prion protein, the collaborator working on the recombinant proteins failed to provide the material, hampering the research progression. Therefore, Tsai took on a different research direction with which more efforts were demanded. In 2012, after doctoral graduation, Tsai joined the group of Jason Chin at the MRC Laboratory in of Molecular Biology, working as a postdoctoral researcher on protein research. In 2015, Yu-Hsuan Tsai established his independent research group in the School of Chemistry at Cardiff University and obtained the tenure in 2018. In 2020, Tsai joined the Institute of Molecular Physiology at SZBL. Tsai is also an Academic Editor of PLOS ONE and Fellow of the Higher Education Academy. 

Research experience gained over the years has taught Yu-Hsuan Tsai a valuable lesson, that good teamwork is an integral part for scientific success. Scientific research often presents complex and arduous tasks that require collaborative works by team members. The intersection and fusion of modern sciences requires even greater connection and collaboration for scientists in a team. Taking the leadership of a team, Yu-Hsuan Tsai hopes that everyone in it can work and fight cohesively towards their common destination; also, seeing the idea of “Wuwei” (无为) from the great ancient Chinese philosopher Laozi, Yu-Hsuan Tsai never interferes much on the daily business of his member, letting them work and research in an unconstrained environment. By doing so, he tries to bring out the best potential of his team.

Joining SZBL, Yu-Hsuan Tsai feels much more stimulated with his pursuit of giving scientific contribution back to the society. In his point of view, the laboratory has created an ideal ecosystem for doing research. Sufficient research resources, leading facilities, professional technical support and efficient administrative service, all making more concentration and less distraction for researchers at SZBL. Moreover, the laboratory has convened topmost scientists and groups, which greatly benefits higher-level exchange and interaction among different segments of life sciences and will surely setup new research, innovation and collaboration within the science community. 

Research at the group of Yu-Hsuan Tsai focuses on the development of new chemical biology tools that address challenging biological questions. The group is particularly interested in developing new tools to control protein function and their biomedical applications, such as therapeutics and diagnostics. They have expertise in chemical biology, organic synthesis, therapeutic development, gene editing, and genetic code expansion.

In the Tsai group, all members envision the goal to serve and contribute to the society through science, and transfer more scientific results into intellectual support for social development. In his anticipation, SZBL will develop he potential to establish a globally influential profile as a Chinese scientific institute, telling the world that in China, we not only have the famous CAS, but the burgeoning community of Shenzhen Bay Laboratory.


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Biography:

Yu-Hsuan Tsai did undergraduate study at the National Taiwan University and obtained his BSc with Honors in 2006. He then worked as a research assistant on isolation, characterization, and synthesis of bacterial glycoconjugates in the group of Shih-Hsiung Wu in the Institute of Biological Chemistry at the Academia Sinica. He later joined the group of Peter Seeberger at the Swiss Federal Institute of Technology (ETH) Zurich in 2007 and moved with the group to Max Planck Institute of Colloids and Interfaces in 2009. During this time, he worked on different aspects of carbohydrate research, including carbohydrate dendrimers, carbohydrate-antibody interactions, synthetic inositol phosphoglycans as insulin mimetics and total synthesis of glycosylphophatidylinositol anchors. In 2012 he joined the group of Jason Chin at the MRC Laboratory of Molecular Biology working on genetic code expansion and its applications in mammalian cells.

In 2015, Dr Tsai established his independent research group in the School of Chemistry at Cardiff University. To date, he has published 37 peer-reviewed papers (25 as an independent researcher), including articles in Nat. Chem., J. Am. Chem. Soc., Angew. Chem. and Chem. Sci. Published works from his lab have been reported as feature news by various agents, such as Science, The Conversation, etc. He is also a co-inventor of two patents and a recipient of different distinctions, such as Cardiff Futures (2019), British Science Association Media Fellow (2018), GW4 Crucible (2017), EMBO Fellow (2014), MCR Career Development Fellow (2012). He has also been an Academic Editor of PLOS ONE since 2020.


Explore more about Yu-Hsuan Tsai: https://tsai-lab.org/