A Turning Point
Life's transformative moments often occur on a seemingly ordinary afternoon. Stepping out of Professor Olaf Schneewind's room, Xinhai Chen couldn't recall much of the conversation. "Olaf was very kind, but I was so nervous because my spoken English wasn't fluent back then," he said. At the time, Olaf Schneewind, a renowned expert from Department of Microbiology at the University of Chicago, was visiting China for academic exchange. Through a senior professor's introduction, Chen had the chance to meet this leading figure in microbiology. “Olaf is one of the world's foremost experts in Staphylococcus aureus (S. aureus) research. Back then, I was just an associate research fellow in China, with little recognition in the field,” Chen said. “I never expected him to later tell my friend how impressed he was with me.”
Not long after, Chen received a postdoctoral offer from Olaf's lab. Yet he remained anxious about whether he could fully seize the opportunity. “I've seen many researchers had to give up overseas opportunities due to family obligations. When I shared the news with my wife, she gave me unwavering support,” Chen said with gratitude. “I am deeply thankful to her. Her understanding and sacrifices enabled me to wholeheartedly pursue my academic aspirations.”
During his undergraduate, master's, and doctoral trainings, Chen developed a strong foundation in biochemistry, microbial infection, and immunology. Upon joining Olaf's lab in the U.S., he was tasked with studying bacterial infection and immunity. “At the time, Olaf was focused on developing vaccines and antibodies to prevent and treat S. aureus infections. He had a few candidates in hand and asked me to take the lead on them,” Chen explained. The beginning was far from easy. “Initially, I thought antibodies were mainly an applied research topic, and I struggled to find ways to connect them with fundamental science. It was a frustrating period. Olaf patiently guided me, recommending insightful literature. After diving into extensive reading, I realized how complex the problem was. Although antibodies are often viewed as an applied tool, many underlying mechanisms remain poorly understood. What lay ahead felt like navigating an unexplored ocean,” Chen reflected.
A Group Photo of Xinhai Chen’s Research Team
Riding the Waves
During his work on antibody expression in different cells, Chen made a surprising discovery: some cells expressed non-functional antibodies. “The sequences were identical, so why could certain cells express functional antibodies while others could not?” Chen pursued this question further, uncovering a key glycosylation modification in antibodies. “Although the amino acid sequences were the same, glycosylation patterns varied across cells. Then we did a mass spectrometry to confirm this finding,” Chen explained. With Olaf's support, Chen invited a leading expert in glycosylation Professor Lai-Xi Wang from the University of Maryland for their collaboration. Through in vitro glycosylation editing of antibody constant regions, they identified high-galactose and afucosylated glycosylation as optimal types. Their study revealed that differences in constant region glycosylation could significantly affect anti-infective activity, even for antibodies with identical amino acid sequences. This work was published in PNAS in 2020 and laid the foundation for developing more effective antibody-based therapies against S. aureus.
In 2019, over one million deaths worldwide were attributed to S. aureus infections, and MRSA was ranked among the WHO's top ten most dangerous superbugs. Yet, progress in immunotherapies targeting S. aureus has been slow. While working on antibody modification against S. aureus, Chen identified a critical challenge: the antibodies struggled to maintain a stable half-life in hosts. "The SpA protein (Staphylococcal Protein A) binds to the Fcγ region of antibodies, neutralizing their activity. We addressed this by redesigning the Fcγ region to prevent SpA binding and restore the antibody's functional integrity. However, while these antibodies exhibited no half-life issues in animal models, the modified binding sites overlapped with another receptor, potentially reducing efficacy in humans," Chen explained. Undeterred, Chen and his team explored multiple approaches. After months of experimentation, a serendipitous encounter with a research article revealed potential key sites for modification. Rigorous testing pinpointed 3-4 mutation sites that, when re-mutated based on existing designs, restored the desired function. "Our initial excitement was short-lived when we found the antibodies worked in human-focused assays but failed in mouse models," Chen noted. This setback led to the adoption of a humanized mouse model for further refinement. Eventually, the team developed an optimized Fcγ strategy that effectively shielded antibodies from SpA interference while preserving their activity. Comprehensive in vitro and in vivo experiments confirmed this approach as a breakthrough for reversing immune evasion associated with the antibody's constant region. Moreover, this strategy presented a novel framework for designing both therapeutic antibodies and vaccines targeting constant-region inhibitory factors. This work was published in PNAS in 2022 and drew widespread acclaim, including recognition from Dr. Rino Rappuoli, a prominent member of the National Academy of Sciences.
"SpA proteins exhibit selective and preferential inhibitory effects. While they don't easily allow bacteria to escape immune defenses, once the bacteria manage to evade, the antibodies become ineffective. Since human and mouse receptors differ in sequence and binding affinity for antibodies, modifications must be meticulously designed to accommodate both species," explained Chen. After several rounds of refinement, Chen and his team successfully transformed the wild-type antibody into a multifunctional variant. This achievement secured three patents and garnered significant attention from leading biopharmaceutical companies. The patents were subsequently licensed to Janssen Pharmaceuticals (a Johnson & Johnson company) and IMMUNARTES in the United States, supporting the development of vaccines and antibody therapies against S. aureus infections.
Although Chen had already published several first-author articles in prestigious journals, one long-standing scientific question continued to elude him. "In 2016, I observed that the same antibody displayed varying efficacy across different mouse strains, but I couldn't pinpoint the cause," he recalled. Over the next five years, Chen explored a wide range of experimental conditions without success. "One day, I had a sudden realization: innate immune cells, which play a critical role in antibacterial activity, have numerous antibody-related receptors on their surfaces. Could receptor expression patterns explain the differences?" Through persistent experimentation, Chen eventually identified FcγRIV and CR3 expression levels on neutrophils as key determinants of antibody functionality. This breakthrough was published in PNAS in 2023, provided critical insights into how downstream genetic diversity impacts antibody performance. Moreover, it established a foundational framework for improving the design, optimization, and selection of vaccines and antibody-based therapies across diverse biomedical applications.
In Memory of a Great Mentor
Signs often precede unfortunate events. “Before I went abroad, I already knew that Olaf was battling cancer and undergoing treatments. However, his immense enthusiasm for work and his energetic presence made it difficult to see him as a patient,” recalled Chen. At the time, Olaf's research group consisted of more than ten postdoctoral fellows, and he could eloquently discuss each person's research focus. “Olaf frequently engaged with us on project updates. His memory for scientific literature was extraordinary—almost photographic. In our conversations, he could effortlessly weave together insights from various papers, which was profoundly inspiring,” Chen noted.
In 2018, Olaf Schneewind was elected to the U.S. National Academy of Sciences in recognition of his groundbreaking work in bacterial infection research. "An unforgettable moment was when Olaf, on his way to the ICU, called me over and said, 'Come here, let's talk about the project.' On another occasion, after undergoing brain surgery due to tumor metastasis, he attended a lab meeting the very next day, with his head still bandaged.”
Chen fondly recalled Olaf's mentorship. “Olaf would introduce me to specific techniques and provide a stack of relevant papers, but his focus was never just on the methods. Instead, he emphasized broader ideas and principles, encouraging me to reach out whenever I faced challenges. He was always willing to offer his full support. Olaf's presentations were equally inspiring—his logical reasoning and charisma left an indelible mark on everyone.” Tragically, Olaf passed away in 2019 due to complications from an infection that led to sepsis and organ failure. After his passing, Chen and other lab members transitioned to the research group of Olaf's wife, Professor Dominique Missiakas.
Professor Missiakas granted the new team members considerable autonomy, enabling Chen to continue his research uninterrupted. Reflecting on his mentors, Chen expressed deep gratitude: “I've had the privilege of learning from exceptional mentors. My master's advisor, He Huaqin, worked tirelessly to create optimal experimental conditions for us, sparking my passion for research and launching my scientific journey. Olaf and Dominique encouraged me to step out of my comfort zone, become more confident, and explore uncharted territories. Without their guidance, I wouldn't be where I am today.”
Carrying the Torch Forward
Having benefitted from exceptional mentorship in his own career, Chen is committed to supporting the younger scientists in his group. In 2022, Chen joined the Institute of Infectious Diseases at Shenzhen Bay Laboratory (SZBL) as a Junior Principal Investigator, establishing his own research lab. Danzhi Wu, a technician in the lab, reflected on her experiences: “At one point, our experiments were not progressing as planned, and I started doubting myself. Dr. Chen noticed my discouragement and, instead of criticizing me, shared his own research challenges and patiently encouraged me. His guidance helped me overcome that low point.” Postdoctoral fellow Qianyu Duan added: “Dr. Chen prioritizes the comprehensive development of every team member. In addition to training us in experimental techniques, he places great emphasis on improving our academic presentation skills. He holds weekly group meetings to hone our public speaking and encourages us to step outside our comfort zones and advocate for our ideas.”
“Step outside your comfort zone and make your voice heard.”were words Olaf often spoken to Chen. Though Olaf is no longer here, his influence endures. His legacy is carried forward by his students, whose names are now listed alongside his in top-tier scientific journals and whose work contributes to the fight against S. aureus. Truly exceptional scientists leave behind not just discoveries but a spirit of inquiry that continues to illuminate human progress.
Reflecting on his research contributions to the S. aureus field, Chen remarked with a smile: “So far, our work holds its own within the scientific community.” At SZBL, Chen and his team focus on unraveling the co-evolutionary dynamics between hosts and microbes. Their current projects span three key areas: 1. Mechanisms regulating the functional activity of antibacterial antibodies; 2. Development of antibodies targeting specific antigenic epitopes; 3. Adaptability studies of bacterial pathogens. With a resolute gaze and an optimistic smile, Chen is fully dedicated to advancing this prolonged battle between humans and microbes. Inspired by the values instilled by Olaf, he continues to push boundaries in his field. “I hope that one day, I can mentor and inspire others the way Olaf inspired me,” Chen said with a smile.
Dr. Xinhai Chen earned his Ph.D. from Sun Yat-sen University in 2015. From 2015 to 2016, he served as an Associate Research Fellow at the School of Medicine, Sun Yat-sen University. He subsequently joined the Department of Microbiology at the University of Chicago in July 2016, working in the laboratories of Professors Olaf Schneewind and Dominique Missiakas on infection immunology. In 2022, he was appointed Junior Principal Investigator at the Institute of Infectious Diseases, Shenzhen Bay Laboratory.
Dr. Chen has dedicated his career to investigating the interactions between bacterial infections and host immune protection. His research focuses on elucidating the mechanisms of bacterial immune evasion and host immune defense from various perspectives. Furthermore, he develops novel immunotherapies targeting these mechanisms, thereby laying a biological foundation for the prevention and treatment of significant bacterial infections. Over the past five years, he has published as the first or corresponding author in prestigious journals, including PNAS, Annu Rev Microbiol, EMBO Rep, J Infect Dis. Dr. Chen holds four patents, three of which are licensed to Janssen Pharmaceuticals (a Johnson & Johnson company) and IMMUNARTES for the development of vaccines and antibody therapies against Staphylococcus aureus.
Selected Publications：
1. X Chen, D Missiakas*. Novel Antibody-Based Protection/Therapeutics in Staphylococcus aureus. Annu Rev Microbiol. 2024 Aug 15.
2. X Chen, H Gula, T Pius, C Ou, M Gomozkova, LX Wang, O Schneewind, D Missiakas. Immunoglobulin G subclasses confer protection against Staphylococcus aureus bloodstream dissemination through distinct mechanisms in mouse models. PNAS, 2023, 120(14): e2220765120.
3. J Ye, X Chen(Corresponding author). Current Promising Strategies against Antibiotic-Resistant Bacterial Infections. Antibiotics, 2023; 12(1):67.
4. X Chen, O Schneewind, D Missiakas. Engineered human antibodies for the opsonization and killing of Staphylococcus aureus.PNAS, 2022, 119(4): e2114478119.
5. X Chen, M Shi, X Tong, HK Kim, LX Wang, O Schneewind, D Missiakas. Glycosylation-dependent opsonophagocytic activity of Staphylococcal protein A antibodies. PNAS, 2020, 117(37): 22992-23000.
6. R Pang, H Zhou, Y Huang, Y Su, X Chen (Corresponding author). Inhibition of host arginase activity against staphylococcal bloodstream infection by different metabolites. Front Immunol, 2020, 11, 1639.
7. X Chen, Y Sun, D Missiakas, O Schneewind. Staphylococcus aureus decolonization of mice with monoclonal antibody neutralizing protein A. J Infect Dis, 2019, 219(6):884-888.
