Junior Principal Investigator
Institute of Neurological and Psychiatric Disorders
Tingting Chu's lifelong dream has been to become a scholar and study significant human diseases. However, life's journey often brings unexpected challenges—sometimes delightful, sometimes daunting. "In the first 25 years of my life, the shocks definitely outnumbered the surprises," Tingting Chu confessed.
Chrysalis
Receiving a college entrance exam score over 40 points lower than her usual practice tests, Tingting Chu had little time for disappointment. Deciding between retaking the exam and moving forward, she opted for a biotechnology major at a typical first-tier university in Hebei. From the moment she enrolled, she dedicated herself to preparing for graduate school exams. She reminded herself, as long as you don't give up, there's always hope.
Four years later, the results came in. "Good news and bad news," Tingting Chu said with a wry smile. "The good news was that I scored 357 on the Chinese Academy of Sciences exam. Students who scored 30 points lower got into Peking University's cell biology program. The bad news was that due to an error on my application, I was placed in another college to study plants."
Tingting Chu aspired to combat major human diseases, yet she spent three years of graduate school researching photosynthesis in Arabidopsis, a model plant. "During that time, I found solace in the movie 'The Pursuit of Happyness' starring Will Smith, which tells the true story of Chris Gardner, an African-American investment specialist. The film’s portrayal of resilience and unwavering determination from people at the bottom of the society to overcome hardships inspired me deeply."
She told herself to endure for another three years, balancing her graduate studies while preparing for doctoral exams.
Receiving the Ph.D. acceptance letter from Li Yanmei's research team at Tsinghua University was a moment of immense relief for Tingting Chu. Seven years of dedication and perseverance had finally brought about a positive turning point.
"I am deeply grateful to Professor Li Yanmei for the opportunity to pursue a Ph.D., which allowed me to delve into neurodegenerative diseases and chemical biology, bringing me closer to my academic aspirations. This was the first significant turning point in my life."
Metamorphosis
Shifting from a biology background to chemical biology was a significant challenge for Tingting Chu. She leveraged her expertise to support her lab with tasks like plasmid construction, cell culture, and protein purification, while also humbling herself to learn peptide synthesis and chemical synthesis techniques from her senior colleagues.
While reviewing literature, Tingting Chu came across a groundbreaking strategy introduced by Craig Crews' team at Yale University in 2001, known as Proteolysis Targeting Chimeras (PROTACs). This method uses the body's natural protein degradation system to target and break down specific proteins, offering potential therapeutic applications. At the time, Tingting Chu was researching ways to degrade Tau protein to reduce its buildup in Alzheimer's disease patients. Enthused by her discovery, she proposed to Professor Li Yanmei a plan to design transmembrane peptides coupled with the PROTAC strategy for Tau protein degradation. Professor Li supported her idea and encouraged her to develop a series of peptides to test their effectiveness in degrading Tau protein in the mouse brain. After multiple rounds of testing, she successfully demonstrated that intravenous or nasal administration could achieve Tau protein degradation in mice, marking the world's first application of the PROTAC strategy to target Tau protein. In 2016, this work was published as the cover article in Cell Chemical Biology and earned a national invention patent. As the lead author, Tingting Chu received the "Young Peptide Scientist Award" from the Chinese Peptide Society at the 14th Chinese International Peptide Symposium.
After another seven years of dedication, Tingting Chu completed her Ph.D. and post-doctoral research and underwent a remarkable "metamorphosis" at Tsinghua University.
Unfolding new horizons
During her Ph.D., Tingting Chu's work on a project that used peptide synthesis to activate the immune system for cancer suppression ignited her interest in human immunity. Since the immune system is crucial for defending against pathogens and tumor cells while its overactivation can lead to autoimmune diseases like lupus and rheumatoid arthritis, Tingting Chu aimed to delve deeper into its regulatory mechanisms. This pursuit led her to embark on her second postdoctoral research at the University of Texas Southwestern Medical Center.
"Professor Nan Yan at UTSW MedCenter was already well-known in immunology when I joined his lab. The time I spent in Yan lab was one of the most memorable periods in my academic journey. On my first day, I whispered to myself that I came here to learn from the best and hoped to make Nan proud when I left," Tingting Chu recalled with a smile. "Nan didn't assign specific topics but provided directions and posed questions to guide our exploration and thinking. The comprehensive trainings I received there, from literature review to scientific research thinking training, from experimental details and lab management, was invaluable."
Early on, Nan gave Tingting Chu a challenging problem: STING, a pivotal protein in the DNA innate immune signaling pathway, has pathological mutations that cause it to activate and transport without binding to the ligand cGAMP. Can Tingting Chu try to explain how the spontaneous process happened? This was a world-class formidable challenge in the field.
To answer this question, after nearly two months of researches and discussions, Tingting Chu decided to use chemical biology techniques, specifically proximity labeling, to map out the regulatory factors involved in STING's activation and transport across various organelles. She initially screened over 2,000 targets, spending two months categorizing each one and investigating relevant literature. She narrowed it down to 50 critical genes for a second round of screening. Through meticulous analysis, Tingting Chu identified a strong link between the NPC1 protein and the innate immune cGAS-STING pathway, establishing NPC1 as a significant regulator. From a translational medicine perspective, she further demonstrated that Niemann-Pick disease, a neurodegenerative disorder, is caused by NPC1 mutation-mediated STING activation, leading to neuroinflammation. For the first time, she applied STING inhibitors in the lab to treat this condition. This breakthrough expanded the understanding of STING biology and offered new therapeutic targets and strategies for Niemann-Pick disease. In 2021, Tingting Chu published her findings as the first author in Nature, with Nature Cell Biology highlighting it in a special review, and it was widely reported by BIOART, Bioon, ScienceNet, and other media.
Soaring
"During a high school class meeting, our teacher asked us to record a message to our future selves. I said I wanted to become a scholar, research major human diseases, and travel the world for academic exchanges." Tingting Chu reflects, "Twenty years have flown by, and I often tell my students that you can't rush science. It has taken me two decades to get closer to my dreams."
In August 2022, Tingting Chu became a Junior Principal Investigator at the Greater Bay Biomedical InnoCenter of Shenzhen Bay Laboratory (SZBL). Her research over the past twenty years has covered various fields including biology, chemical biology, botany, molecular genetics, and innate human immunity. This diverse expertise has made her a sought-after PI. "I collaborate with many colleagues here. I work with Professor Zhang Ke on neurodegenerative diseases and with Professor Zheng Min on immunology. PIs at our center frequently share ideas and support each other."
Tingting Chu's goal is to uncover new regulatory mechanisms in innate immune signaling pathways, elucidate their roles in autoimmune diseases, neuroimmunity, cancer, and metabolism, and identify new therapeutic targets. This could revolutionize treatment strategies for these diseases. For her, SZBL is the perfect place to achieve these goals: ample funding, a liberal research environment, top-notch collaborators, and exceptional support. "I initially wanted to go to Beijing to be close to my family. However, after speaking with Academician Zhang Mingjie, the center's convener, I was convinced to come here. The opportunity to work with such talented teams and pursue scientific dreams together is exhilarating."
On her personal homepage at the SZBL, Tingting Chu has inscribed her motto: "The future is worth fighting for." She believes that life, like a butterfly, after enduring long periods of waiting and challenging transformations, will ultimately find freedom and a vast sky to soar in!
