LI Mao
Junior Principal Investigator
Institute of Chemical Biology
"Perseverance" is how Mao Li characterizes himself. While many children dream of becoming scientists, only a rare few pursue this path with unwavering dedication, year after year. These individuals, like stars in the night sky, illuminate the darkness with their persistence, preserving the childlike wonder that first inspired their journey into science.
01 Li, the Young Tinkerer
"I owe a lot to my mom for her patience. It only took me three minutes to take things apart, but it could take three or four days to put them back together," Mao Li chuckled. As a child, he assembled all the small tables, stools, and cabinets at home. Naturally, the first step was always to dismantle them. In his boyhood, Mao Li often armed with a screwdriver, left a trail of dismantled parts. Components were strewn across the floor, and his mother's belongings were relegated to a corner. "I loved taking things apart. Anything within my reach, I had to dismantle it to understand how it was constructed and see if I could use the principles behind it to create something new."
Driven by this curiosity, Mao Li excelled in physics and chemistry, read broadly on politics and history. Ultimately, he was admitted to Nankai University with a major in Materials Chemistry for his undergraduate studies. During his graduate studies, he encountered his master's advisor, Professor Xi Zhen from the Department of Chemical Biology at Nankai University, who became his first mentor on his scientific journey.
"Before meeting Professor Xi, I hadn't found a research direction I was passionate about." At that time, the focus was on small molecule drugs and antibody drugs, targeting proteins. Professor Xi, however, told him, "RNA is the future. Shifting from proteins to RNA represents the future of research; it's a paradigm shift." Mao Li idolized Charles Darwin and had been captivated by the theory of evolution in "On the Origin of Species" since childhood. He was deeply interested in genetic materials like DNA and RNA. Professor Xi's words ignited a lasting passion in him. This enthusiasm has fueled his research for fourteen years.
02 Staying Grounded and True to His Aspirations
Since the 1960s, when the structures of DNA and RNA were first elucidated, there has been a significant surge in the pursuit of drug development centered around genetic material. Despite this, designing drugs that target RNA molecules, whether through nucleic acids or small organic molecules, has proven exceptionally challenging. Nucleic acid molecules struggle with delivery issues, while organic small molecules face difficulties in effectively and selectively binding to target RNA. By the early 2000s, little substantial progress had been made, leading many researchers to abandon the field disheartened. It was during this low point for RNA research that Mao Li went to Germany to pursue his Ph.D.
In 2011, just before graduating with his master's degree, Mao Li reached out to Professor Carsten Schmuck at the University of Duisburg-Essen in Germany, seeking an opportunity for further study. Professor Schmuck, who had notable achievements in both RNA research and new materials, suggested that Mao Li choose a topic in the direction of new materials. However, Mao Li was already determined to focus on improving the delivery efficiency of peptide-based delivery vectors. To convince Professor Schmuck, he wrote an extensive letter, detailing his dedication to RNA research and his comprehensive research plan. He also pointed out the potential of one of Professor Schmuck's research findings in the RNA field. Impressed by Mao Li's determination and sincerity, Professor Schmuck accepted his doctoral application and supported his continued research in RNA.
The journey of scientific research is rarely smooth. Typically, to develop a drug carrier, it’s essential first to demonstrate that the carrier can enter cells, which requires labeling the carrier with fluorescent molecules to track its entry process. In Professor Schmuck's lab, Mao Li tried numerous methods without success for six months.
"Sometimes, a change of scenery helps clear the mind." After many failed attempts, Mao Li and a few colleagues decided to take a break and headed to a nearby mountain. They planned to relax for a night at a bar on the mountaintop. Surrounded by the summer mountain breeze and lush greenery, the fatigue from their research journey melted away. As the sun set, they decided to skip a small hill along the way and head straight to their destination. At that moment, Mao Li had a sudden inspiration and made a decision.
The next day, back in the lab, Mao Li decided to skip the fluorescent labeling step and directly conduct drug delivery experiments with nucleic acid molecules. To his surprise, the experiment was successful on the first try.
"Why do we need to climb the small hills if our goal is to reach the bar on the third mountain? Similarly, why insist on fluorescent labeling if the objective is drug delivery?" Mao Li acknowledged his good fortune, but this also confirmed the "First Principles" approach popularized by Elon Musk—challenging existing operational models, eliminating assumptions, and analyzing from the essence and structure to find problems and opportunities.
By 2016, having earned his Ph.D., Mao Li had published three papers in the prestigious journal Angew. Chem. Int. Ed. and had achieved his initial goal set before going abroad—developing a modification method that significantly improved the delivery efficiency of peptide vectors for nucleic acid drugs.
03 Reaching for the Stars, Integrating Diverse Disciplines
To expand his understanding of interdisciplinary fields, Mao Li decided to continue his studies in Switzerland after earning his Ph.D.
"Techniques from the field of materials science, such as electron microscopy and spectroscopy, can help us characterize the structure and properties of carriers more deeply. This clarity is crucial when designing drug delivery systems. Hence, I joined Professor Helma Wennemers' research group at ETH Zurich (Swiss Federal Institute of Technology Zurich) for my postdoctoral research. Professor Wennemers' lab explores various research directions, including biology, chemistry, and materials science. This environment allowed me to learn extensively and apply new knowledge to drug delivery."
During his postdoctoral research, Mao Li aimed to design carriers at the molecular level that could deliver drug molecules directly into the cell nucleus. "Scientific research is about trial and error; this makes it fascinating, like unveiling surprises that challenge previous knowledge." In one serendipitous experiment, Mao Li observed that at high concentrations, the mixture of their carrier with the target substance precipitated. Recognizing the significance, he immediately used various detection techniques and discovered that the molecule exhibited a conformational folding phenomenon upon entering the cell. His intuition suggested that this was more than a trivial occurrence. Through repeated experiments, Mao Li and his colleagues demonstrated that this conformational folding could facilitate precise delivery to the cell nucleus. This finding was published in Angew. Chem. Int. Ed., marking the fourth paper of Mao Li's academic career in this prestigious journal.
In Switzerland, the melting snow from the Alps flows into the majestic Lake Geneva. The Swiss summer is often described as "a paradise between earth and heaven". On a typical afternoon in 2021, sitting amidst the picturesque landscape of snow-capped mountains and shimmering lakes, Mao Li watched the sunlight play on the blades of grass and quietly bid farewell to this place, "though it is indeed beautiful, it is not my homeland, and I cannot linger here".
He had resolved to return to his homeland.
"After studying abroad for ten years, returning home has always been my unwavering dream. I have kept an eye on job opportunities in China, and the research environment at Shenzhen Bay Laboratory (SZBL) was particularly inviting. Here, Principal Investigators (PIs) have the freedom to explore their research interests," said Mao Li. "When I joined the lab, I found many PIs from various fields who, like me, share similar backgrounds. This common ground not only facilitates communication but also opens up ample opportunities for collaboration."
Opportunities often come with challenges. As a new PI, balancing time between academic research and team management is a fresh challenge for Mao Li. "In the early stages of building my research team, I need to focus heavily on team management. However, I also aim to remain at the cutting edge of my research field. It will be tough at first, but I am confident that I will find a balance," Mao Li acknowledged.
Mao Li's colleagues describe him as "rigorous, efficient, tolerant, and patient". Beyond teaching scientific research methodologies, Mao Li hopes to instill the spirit of being a researcher. "I welcome team members from diverse disciplinary backgrounds, as the continuous exchange of ideas generates sparks of inspiration. I want everyone in the team to make progress, in whatever form that may take. Maintaining a positive and forward-thinking attitude is the key."
When discussing his research goals, Mao Li stated, "My immediate goal is to produce highly original research findings, contribute to the field of nucleic acid drugs, and publish noteworthy papers. In the future, I hope that my research can be translated into practical applications to genuinely address health needs."
The road ahead is both long and promising. From his mother's furniture to the intricate mechanisms of nature (RNA), this dedicated researcher who never misses an opportunity for discovery will undoubtedly continue to astonish the world. Let's look forward to what he will unveil next!
Editor: Paula Bao
Executive Editor: Winston
For more information, please contact media@szbl.ac.cn
