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Yonghui Zhang, Ph.D.
Associate Professor, School of Pharmaceutical Sciences, Tsinghua University

On one winding path, come what may

A chemist by training, Yonghui Zhang took a leap of faith and entered the unfamiliar world of tumor immunotherapy without much support. However, his love for science and perseverance for research guided him through the unconventional path. Chemistry provided him with unique perspectives on cancer research, leading him to tackle immunology from a distinctive angle — lipid metabolism. His findings demonstrated how lipid metabolism is crucial to immune cells, which may one day help boost immune responses to vaccines and act as a target for tumor immunotherapy.

In 2013, Yonghui Zhang returned to Beijing from the United States and joined the School of Pharmacy at Tsinghua University as an Assistant Professor. Having initially trained as a chemist, the last 7 years have taken him on a sometimes bewildering journey deep into the heart of a notoriously complex biological field: tumor immunity. This transition has been so wide ranging in scope that some of his colleagues still express frank shock that he has pulled it off; he is now publishing elite immunology papers and collaborating on clinical efforts to deploy immune-cell-based onco-therapies.

“What you have to understand is that my deep and abiding interest in isoprenoids has brought me where I am.”

“What you have to understand is that my deep and abiding interest in isoprenoids has brought me where I am. My current research program—while now full of complex immunology experiments with various experimental models and clinical samples—is still focused dead-square on isoprenoid metabolism and on the mevalonate pathway in particular.”

Upon returning to China and starting his lab at Tsinghua, he repeatedly heard colleagues express surprise about his seemingly narrow focus on a very well-studied pathway. There has been more than a half-century of groundbreaking and Nobel-prize-winning science about the mevalonate pathway (three prizes), and some folks were initially skeptical about whether he was wasting his time (and his new lab’s resources) on well-trod ground. Zhang recalls, “It was difficult and challenging back then.” At the time, he had never worked on protein expression and didn’t understand the details, assumptions, and conventions for using various mouse models for immunology research.

Out of the wilderness

Happily,  his “all-in” bet on that the mevalonate pathway affects tumor immunity was right.  Zhang credits his stubborn perseverance for keeping him going during those early days of immunometabolism research. Five years on, he reaped some initial success with a paper in one of the top academic journals, Cell, which also published a Leading Edge Preview article that ventured his study might have “a potentially huge impact” for advancing both anti-infection and anti-tumor immune defenses.

The Cell paper from Zhang’s team in 2018 demonstrated proof-of-principle for targeting the mevalonate pathway for drug development, including for new vaccine adjuvants and for improving tumor vaccine activity. Ultimately, the enabling insights for the discovery in the Cell paper stemmed from a clinical observation: patients with a rare immune disease developed pyrexia and fever due to a disorder in metabolizing lipids (isoprenoid synthesis pathway dysfunction). Moreover, clinicians had reported the puzzling fact that these patients generated aberrantly high antibody titers when they received vaccinations. This elevated immune response was foundational evidence lending support to Zhang’s theory that “some lipid metabolism pathways can regulate immunity.” This was the scientific and medical context underlying the launch of Zhang’s lab at the Tsinghua School of Pharmacy, and the basic insights uncovered in the Cell study have helped explain how deficiency for particular lipids can directly disrupt antigen presentation in dendritic cells. This has implications well beyond a single immune disease, clearly extending to current (and emerging) onco-immunology treatment concepts: antigen presentation is central to all of adaptive immunity.

Holding up the spirit of science

Taking paths that may seem unpromising is essential for innovative discoveries and breakthroughs in research. Zhang defines himself as “a scientist studying tumor immunity through the lens of chemistry.” His work has emphasized the power of using chemistry to deeply probe the molecular mechanisms through which the immune system targets antigens from pathogens and from tumor cells. In particular, Zhang has used his chemistry background—he trained at the elite Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences before going to work in the US—and continually invested the time needed to develop sets of inhibitor analogs to provide multi-layered insights about how lipid metabolism affects immune responses.

Further, rather than using a single chemical agent to shut down some metabolic process, Zhang’s team tries to target multiple distinct steps in metabolic pathways, and this has enabled comparisons yielding insights not evident when using a single inhibitor alone. “I get the feeling that some of my research colleagues still think it’s bizarre that I spend so much time running additional sets of experiments with apparently overlapping metabolic modulations (i.e., use of bisphosphonates and statins when both types of drug would ultimately block the mevalonate pathway).”

Another big success occurred in 2019 when Zhang’s team revealed the antigen-recognition mechanism of γδ T cells in a study published in the journal Immunity. Beyond focusing attention on the unique functions of γδ T cells and using structural data to clarify a longstanding debate about “inside-out” or direct activation of γδ T cells, the Immunity study provided theoretical support for making use of immune cells in allogeneic cell therapy.

Intra-Beijing collaborations between the basic researchers like Zhang and his team with medical scientists doing clinical research are really speeding up the translation of biological discoveries into medicine.

Zhang’s γδ T cell work also highlights the fast-moving nature of cancer research in Beijing. Intra-Beijing collaborations between the basic researchers like Zhang and his team with medical scientists doing clinical research are really speeding up the translation of biological discoveries into medicine. “An allogeneic γδ T cell treatment for solid tumors has already entered the pre-clinical research stage, and we are also working with three hospitals to carry out clinical research on both blood cancer and solid tumor treatments,” says Zhang.

Teaching and mentoring

Zhang’s persevering attitude has been shaped by his professors and research mentors. “My mentor, Eric Oldfield from the University of Illinois at Urbana-Champaign, is the most research-focused scientist in my mind. I remember my realization that this man has clearly devoted his whole being to science.” Fortunately, the Zhang lab has received strong support from the Tsinghua University School of Pharmacy. In particular, Professor Xuebin Liao was a key factor in recruiting Zhang back to China to join Tsinghua University’s effort in pharmaceutical research and has remained a stalwart colleague through ups and downs.  With his lab now well-established at Tsinghua, Zhang is grateful for its full support. “Looking back, I’m fortunate that I chose to return to China.

The leading edge of scientific research is a very high-pressure environment, and immunotherapy is undoubtedly one of the hottest and fastest-moving research topics in cancer research. Zhang entered this increasingly crowded area because his scientific inquiries brought him there: he clearly thinks that the body’s immune system holds the answers to his most personally compelling scientific questions. His advice to young researchers would be focus on asking compelling research questions with a big upside and to worry much less about defined fields or chasing hot topics. “If you are asking interesting questions, you can recruit top talent.”

“You must have enough passion for science and remember why you stepped into this field. Even if you’re not studying the seemingly hottest topic, you persist and devote yourself to it whole-heartedly.”

Zhang’s team is a combination of talented scientists from biochemistry, drug design, structural biology, immunology, and other disciplines and he says these young researchers are his “right-hand man” in the lab. He remains especially grateful for the early members of the lab who had some faith in the big vision of his mevalonate-pathway-focused research program.  Zhang praised his students as “hardworking” and “reliable.” Amid the 2020 pandemic, they have overcome many difficulties and continue to pursue their research, and he tries to encourage his students and keep them moving towards their goals. “You must have enough passion for science and remember why you stepped into this field. Even if you’re not studying the seemingly hottest topic, you persist and devote yourself to it whole-heartedly. Don’t overthink what others tell you. We must stick to the path that we believe in, even if it’s non-mainstream, even if it seems unpromising,” says Zhang.

A very bright future for finding cures in Beijing

Zhang strongly endorses Beijing as a hotspot for life science and biomedical research. “I spent many years abroad and had some achievements, but I always felt a sense of restraint back then. The research context in Beijing right now is very special; there are now opportunities that were simply not available to me or my colleagues in the USA. Provided that you have an original scientific idea to pursue, I would argue that the support available in Beijing might be peerless. There is a huge amount of creative research going on here, and the publication achievements are increasingly reflecting this.” 

He also praises Beijing for its investment in basic research and its major role in pushing cancer research progress. “I am especially grateful to the Beijing Municipal Science and Technology Commission for supporting the γδ T cell project during the most difficult time of my research,” says Zhang. The commission both provided research funding and also connected Zhang’s team to Tiantan Hospital and 301 Hospital for clinical collaboration, which has dramatically accelerated the translation of basic research findings.

Zhang has also noticed multiplier effects and increasing broad opportunities as more as more and top teams do innovative basic and clinical cancer research in China generally and in Beijing in particular. “In the next 5 to 10 years, we can expect China’s very rapid development in immunotherapy, especially with breakthroughs for new target drug development.” Regarding the future of his own lab, Zhang said, “We have made a name for ourselves in the field, but this is just the beginning. There is still so much knowledge for us to uncover.”