Junior Principal Investigator
Institute of Systems and Physical Biology
Upon entering the office, we are immediately struck by the array of classic books from diverse fields such as philosophy, psychology, management, and political science neatly arranged on the shelves. The subtle fragrance of sandalwood fills the air, and under the bright sunlight, the entire desk is adorned with literature from biology, chemistry, and physics, each appearing to demand its own space—evidence of a well-rounded and erudite scientist's workspace.
"I originally majored in Electrical Engineering as an undergraduate," Chao Wu reminisced. "China Agricultural University offered an innovative Life Sciences Honors Program, and I wanted to push my boundaries, so I joined the program and graduated a year ahead of schedule. As my research progressed, I began exploring computational chemistry, biophysics, biochemistry, and virology."
Despite his intricate interdisciplinary background, Chao Wu spoke without a trace of pride and self-satisfaction.
Life is finite, but the pursuit of knowledge is endless
"Continuous self-improvement and overcoming activation barriers are fundamental qualities for researchers and are not something to boast about," said Chao Wu. "I don’t believe in simply being goal-oriented; life is more like a marathon. The process of learning itself is enjoyable, and we should savor the entire journey rather than just the moments of 'success.'" He added, "A mature personality is characterized more by self-recognition."
"The year I worked on my graduation thesis in Professor Niu Huang's lab at the National Institute of Biological Sciences, Beijing (NIBS) was the time when I was most actively exploring new frontiers in my academic career. I enjoyed it so much that I didn’t want to attend other classes anymore, so I decided to forgo the opportunity for graduate school and stayed on as a research assistant after graduation," Chao Wu recalled. In addition to reading a vast amount of literature every day, Chao Wu also studied computational chemistry, performed molecular dynamics simulations, and participated in cancer drug screening at the newly established BeiGene biotechnology company. "NIBS focuses more on fostering scientific thinking and developing a good scientific taste rather than on producing immediate results. This experience made me truly fall in love with scientific research." As his work progressed, Chao Wu aimed to master more experimental techniques, such as nuclear magnetic resonance (NMR) for studying protein dynamics, to validate his simulation predictions. "To close the research loop, after studying and working at NIBS for four years, I received an offer from Washington University in St. Louis to pursue a Ph.D. in Computational and Molecular Biophysics under the rising doctoral tutor in the field of protein dynamics."
During his Ph.D., one of Chao Wu 's tasks was to perform NMR on membrane proteins. This was challenging because NMR is typically used for very small molecules, but membrane proteins are quite large together with lipids and detergents. To minimize signal loss in NMR, Chao Wu needed large quantities of expensive heavy water to culture bacteria that express these proteins. To maximize the number of experiments within limited budgets, Chao Wu would distill the heavy water from the used culture medium and reuse it three or four times before discarding it. "So, besides my regular experimental work, I often spent day and night in the lab distilling heavy water and purifying these proteins." To others, Chao Wu 's four and a half years of almost no vacation during his Ph.D. might have seemed grueling, but he didn't feel that way: "I love vacations because when everyone else is away, I can use the expensive, idle equipment in the lab for many experiments. I labeled proteins in various ways, such as replacing all nitrogen atoms with nitrogen-15 or substituting a methyl group on an amino acid with carbon-13. This taught me a great deal about metabolism and labeling, and I gained immense knowledge."
The signal data derived from amino acids is vast, necessitating the integration of various theoretical knowledge to consolidate computational information for accurate peak assignment. At that time, Chao Wu's research focused on the transport mechanisms and multidrug resistance of bacterial multidrug transporters. To efficiently compare a large quantity of experimental data, he purchased a large monitor and spent his days analyzing data from morning until late at night, eventually completing the assignment of eight transmembrane helices. "Though it was arduous, we discovered that the ability of the protein to recognize different types of antibiotics and undergo conformational changes is linked to a kink in one of the transmembrane helices. Upon binding with protons and antibiotics, this transporter protein alters its 'gate-opening' direction from inward to outward, enabling it to expel harmful antibiotics from the bacterial cell by leveraging the proton gradient across the cell membrane."
During his Ph.D., Chao Wu also collaborated with the University of Cambridge, obtaining several mutant variants to study their conformational changes using NMR technology. He discovered that one particular mutation could slow down membrane transport by a factor of five. This deceleration was advantageous for observing the protein dynamics and structural analysis. Leveraging this finding, the research group subsequently resolved multiple proton-bound states, leading to a more comprehensive understanding of the transport cycle mechanisms.
Facing Life's Challenges with Equanimity
In 2015, Chao Wu 's doctoral advisor made the decision to leave Washington University in St. Louis (WUSTL) to lead the National Magnetic Resonance Facility at Madison (NMRFAM), resulting in the closure of the lab. Chao Wu faced a difficult decision: remaining at WUSTL would mean that most of his Ph.D. work might never be published, but relocating wasn't an option due to family commitments. With little hesitation, Chao Wu chose to stay at WUSTL. With the support of his doctoral committee, he successfully defended his dissertation and then joined the research group led by the committee chairman to embark on interdisciplinary postdoctoral research. "The intense effort during my Ph.D. laid a strong foundation in biophysics and biochemistry. Since I had already gained the most crucial knowledge, the potential loss of a few papers seemed less significant," he reflected. "Working in research is like playing a card game. If you always win with the best hand, it becomes monotonous. The excitement lies in not knowing the cards you'll be dealt and striving to play them to the best of your ability. Life is similar—finding joy in adapting to unpredictable circumstances is key. Becoming adept at this makes one unstoppable."
During his time at the National Institute of Biological Sciences, Beijing, Chao Wu collaborated with Professor Wenhui Li, which sparked his interest in virology. His postdoctoral advisor recognized Chao Wu's interdisciplinary background and potential in virology, offering him extensive guidance and opportunities for collaboration with major research platforms. Chao Wu discovered the cunning behavior of viruses: their genomes hide within nucleocapsid proteins to avoid detection by the immune system when threatened, and once in a safe environment, these viral genomes quickly intereact with polymerase to replicate more progeny genomes. What regulates this process? Can the dynamic behavior of viruses be altered? Through multidisciplinary studies encompassing biochemistry, structural biology, and virology, Chao Wu identified that viruses possess another protein that specifically recognizes and encapsulates their nucleocapsid protein. During replication, these nucleocapsid proteins use a polymerase cofactor to open and replicate. Chao Wu reconstructed this dynamic remodeling process and proposed that targeting it could simultaneously inhibit viral replication and activate the immune system. This groundbreaking work provided a theoretical basis for designing antiviral drugs targeting nucleocapsid proteins and was published in the renowned molecular biology journal, Cell.
Scientific research is a journey of continuous learning, refinement, and discovery. After three years as a postdoctoral researcher, Chao Wu’s advisor, in an effort to keep him, promoted him to the position of lecturer. This provided Chao Wu with a prime opportunity to engage with prominent scientists across the entire research spectrum. He continued his in-depth studies on the replication and immune evasion mechanisms of highly pathogenic viruses like Ebola, coronaviruses, human metapneumovirus, and respiratory syncytial virus, and screened antiviral small molecule inhibitors. During the COVID-19 pandemic, Chao Wu investigated the specialized properties of the SARS-CoV-2 N protein (nucleoprotein) as a diagnostic marker. By analyzing different nucleoprotein fragments, he identified the CTD domain as the most specific and sensitive marker for serological detection. Collaborating with others, he developed high-throughput serological methods for COVID-19 antibody detection, laying the theoretical groundwork for Hong Kong's large-scale serological studies on the half-life efficacy of mRNA and inactivated vaccines used for public health policy decision making. By the time he completed his postdoctoral work, Chao Wu had co-authored over 20 high-impact papers in prestigious journals such as Annual Review of Virology, Cell, JMB, iScience, Respirology, ACS Infectious Diseases, and Antiviral Research.
"The real world is a highly optimized one, the outcome of countless gamings and adjustments. Though imperfect, this is a process in which it continually evolves towards the ideal." Chao Wu said, reflecting on his academic journey. "From the relatively loose guidance during my Ph.D. to the highly efficient postdoc stage, I've learned that every experience holds its worth. Having experienced diverse management styles, I now prioritize personalized mentorship for my students, offering tailored advice to help them navigate research more effectively and avoid some of the pitfalls I encountered."
Enlightened Minds Illuminate the Infinite Path
"Chao Wu is the most outstanding student I've had over the past decade," his postdoctoral advisor remarked in a glowing recommendation letter upon his completion of postdoctoral research. Joining the Shenzhen Bay Laboratory, Chao Wu was determined to impart not only the scientific techniques and management strategies he had mastered but also the life philosophies he had absorbed from his mentors. "I want my group members to feel free to share any challenges with me. Many invaluable experiences and practical wisdom are best conveyed through a mentor-apprentice relationship," Chao Wu noted.
Hou Jingyu, an assistant in the research team, described, "Professor Wu is incredibly responsible, visionary, and adept at problem-solving. His sense of responsibility extends beyond the scope of our projects, fostering personal and professional growth in each one of us. He invests in our holistic development, encompassing scientific thinking, interpersonal skills, mental models, and even instilling a sense of mission and conviction. Professor Wu is also exceptionally practical, guiding us away from impractical ideations and staying grounded in our research. He keenly oversees our experiments, providing iterative feedback and ensuring methodological rigor."
Chao Wu's research group is built on the pillars of "unity, friendship, seriousness, and diligence." He envisions a flat-team structure where collaborative efforts drive progress within major project frameworks, encouraging members to identify their unique strengths and pursue sub-projects aligned with their interests. "I often tell my team that mastering effective learning techniques allows you to grasp 80% of a field's key insights within 20 hours. However, to become a leader in that field, you need 10,000 to 30,000 hours of practice. Our team upholds two core principles: constantly evolving to be our best selves and fostering a collaborative, win-win environment," Chao Wu emphasized.
When Chao Wu joined the Shenzhen Bay Laboratory, he inscribed a concise yet profound motto on his personal homepage: "Tranquility leads to distant goals." "I aspire to pioneer a new field called 'Physical Virology.'" Chao Wu explained. "My extensive experience in biophysics and biochemistry over the past decade gives me a unique edge in virology research. Additionally, the advanced instrumentation platform at Shenzhen Bay Laboratory empowers us to leverage cutting-edge biophysical techniques to unravel complex biological systems. We're aiming to develop shape- and content-based sorting technologies for virus particles, and investigate how their morphology influences infectivity and pathogenicity, ultimately contributing to the design of antiviral drugs and vaccines."
Chao Wu holds the belief that age-old problems often bear age-old solutions. "Do good without seeking fame; avoid evil without fearing punishment. Adhering to moderation can ensure self-preservation, vitality, parental care, and longevity." In his leisure time, he finds solace in reading "Chuang Tze", engaging in timeless conversations with the ancient philosopher. "Both natural and human sciences, in the end, converge towards the same goal—to better understand the world and our own minds as we strive for greater heights." To see oneself, to see the world, to see all of humanity. In Chao Wu's laboratory, the intricate interplay of physics, biology, chemistry, and virology transcends conventional boundaries, transforming into a form of art wielded by this "scientific philosopher".
Editor: Paula Bao
Executive Editor: Winston
For more information, please contact media@szbl.ac.cn
