Source: People's Daily
2022 Future Science Prize Life Science Prize winner Li Wenhui——
Doing Difficult but Valuable Research (Telling and Promoting the Spirit of Scientists)
On November 27, three scientists, including Li Wenhui, Yang Xueming and Mo Yiming, were awarded the 2022 Future Science Award for Life Sciences, Material Science, and Mathematics and Computer Science. The Future Science Prize aims to reward original basic scientific research, and so far 27 scientists including Yuan Longping and Shi Yigong have been awarded.
The report of the 20th National Congress of the Communist Party of China put forward: "Adhere to the world's scientific and technological frontier, the main economic battlefield, the major national needs, and the people's life and health, and accelerate the realization of high-level scientific and technological self-reliance and self-improvement." In order to deeply implement the spirit of the 20th National Congress of the Communist Party of China and carry forward the spirit of scientists, our reporter conducted an in-depth interview with Li Wenhui and Yang Xueming, who won the 2022 Future Science Award, and introduced their innovative stories of brave climbing peaks and working hard to dedicate themselves. This issue introduces Lee Wenhui's story.
—Editor
Character business cards
Li Wenhui: Senior researcher at Beijing Institute of Biological Sciences and professor at the Institute of Biomedical Sciences, Tsinghua University. Born in Gansu in 1971, he received his Ph.D. degree from Peking Union Medical College in 2001, and then went to Harvard Medical School to engage in postdoctoral research in the field of molecular virology. In 2007, he returned to China and joined Beisheng Institute, focusing on the research of hepatitis B, hepatitis D and other viral infection research and the development of anti-hepatitis B and anti-new crown drug candidates. In 2021, he won the "Baruch Bloomberg Award", the world's highest award in the field of hepatitis B research and treatment, and won the Future Science Award Life Science Award in 2022.
"I'm sorry to keep you waiting, I've been a little busy lately, and I can't stop as soon as I wake up in the morning." At 9 p.m. on November 23, Li Wenhui (pictured above, courtesy of Beijing Institute of Life Sciences) finally returned a reporter's call. He said as he ate: "A few things are going quite well. ”
From the first interview in the winter of 2011, the reporter knew that "busy" was his daily routine. In recent years, he has been in a state of "several things" in parallel -
The "roadmap" for hepatitis B virus invasion of the human body is becoming clearer, and the results are being verified; He and his lover Sui Jianhua, director of the Biological Products Center of Beisheng Institute, developed the original hepatitis B and D drug candidate HH-003, which ushered in an important node in clinical research; The clinical study of the full-spectrum anti-coronavirus candidate HH-120 developed by him, Sui Jianhua and other colleagues has entered the sprint stage...
Advancing in the Face of Difficulties: Solving the World's Scientific Puzzles That Have Been Unsolved for Years
Wang Xiaodong, director of the Beijing Institute of Biological Sciences (hereinafter referred to as "Beisheng Institute"), still remembers a conversation with Li Wenhui when he first returned to China in the fall of 2007:
"I want to study the HBV (hepatitis B virus) receptor, which is a very difficult but urgent problem in this field."
"I have always supported scientists in doing the most difficult and valuable research, and as long as the subject is valuable, we should not be afraid of difficulties and risks. We will fully support you! ”
"Receptor" refers to a molecule on the surface of the host cell, and the virus can only enter the host cell if it binds to this molecule first. Finding HBV receptors is a key step in in-depth study of viral infection mechanisms and the development of therapeutic drugs. After the topic was selected, Li Wenhui first led the students to collect and study relevant papers published at home and abroad, looking for "clues". In the spring of 2008, they bought two squirrel-like primate critters, the tree shrew, from Yunnan Province, and worked with doctoral students such as He Wenhui and Huang Yi to try to feed them. It turned out that HBV only infected humans and tree shrews, and at that time, only tree shrews could be used as animal research models.
After that, they continued to explore and establish and optimize in vitro infection models for studying hepatitis B virus. With the help of Dr. Cai Tao of the High-throughput Sequencing Center of Beisheng Institute, the gene expression map of tree shrew hepatocytes was established.
After the foundation and research system were gradually established, they began to look for proteins in tree shrew liver cells that might bind to HBV. He Wenhui, Gao Zhenchao, Xu Guangwei, Feng Xiaofeng and other team members worked day and night, using multiple methods such as "compound inhibition", "directional exploration" and "cross-capture", and the molecular images of HBV infection also shone bright light from the darkness. After comprehensive research and judgment, Li Wenhui's team was divided into two ways: one was led by doctoral student Yan Huan, using "fishing hooks" and "fishing"; Another route, led by postdoc Zhong Guocai, used exclusion to "screen" recipients.
However, months passed, and both sides failed. At this time, four full years have passed, and the students are in the question: "Is the receptor not there at all?" ”
Li Wenhui's pressure can be imagined. But experience told him that they had reached the darkest hour before dawn. He said to everyone: "The receptor definitely exists, but it is very hidden. Since we've come this far, why don't we go further? ”
"What if I can't find it in the end?" Some students asked. "Major discoveries in science are made through the exploration of generations or even generations of scientists. If we do our best, we will not regret not succeeding. He changed his tone, "We are actually not far from the goal, if we give up and let others find out, will everyone regret it?" After everyone listened, they gathered up enough energy to continue groping...
At this time, Sui Jianhua also returned to China to join Beisheng Institute. She and Yan Huan and others made creative improvements to the "fish hook" and continued to look for the "little goldfish".
After midnight on January 7, 2012, with the help of Chen Shen, director of the Proteome Center, through mass spectrometry identification, team member Jing Yi found a possible "small goldfish" among a number of "fish" with similar appearance. In the early morning of January 11, the initial verification results showed that this "little goldfish", the sodium ion-taurocholic acid cotransporter (NTCP), is likely to be the receptor. At this time, it was close to the Spring Festival, Yan Huan, Zhong Guocai, Xu Guangwei and others gave up going home for the New Year, and continued to tackle problems with Li Wenhui and Sui Jianhua. On the fifth day of the Lunar New Year on January 27, 2012, at 2 a.m., Yan Huan obtained a key result: the receptor was introduced into liver cancer cells that could not be infected by hepatitis D virus (HDV, which is a satellite virus of HBV, and the two share a receptor), and the result was infection.
After that, they tried a variety of schemes, and finally completed the verification of HBV function and the loss of function of NTCP on human liver cells, fully proving that NTCP is a receptor for HBV and HDV to specifically infect human liver cells. After the publication of the relevant paper in November 2012, it was highly recognized by international peers.
"I thought we would be the first to publish this study, but in fact you won the race. We will all benefit from this, especially those patients. Professor Steven Wooden of the University of Heidelberg, an international expert in the field of HBV infection and a leading international expert in the field of HBV infection, said in an email to Li Wenhui: "The impact of this outstanding achievement on HBV research cannot be underestimated, it will change the current research model, and may help the discovery of new drugs for hepatitis B treatment for the benefit of hepatitis B patients." ”
Research and application: research and development of original drugs to cure hepatitis B
"You quickly prepare the materials and send them to your international counterparts for the review of the 5-year assessment." At noon one day after the article was published, Wang Xiaodong saw Li Wenhui and reminded him with a smile, "Only after the international review can the institute give you a promotion, raise your salary, and increase experimental funds." ”
"Let this go first, I have more important things to do." Li Wenhui said. After finding HBV receptors, he led students to continue to study the mechanism of chronic infection of hepatitis B, and cooperated with Sui Jianhua to develop innovative drugs for the treatment of hepatitis B and D based on the existing research results.
"Of course, it is important to discover new knowledge, but what is even more meaningful is to turn new knowledge into medicine that can cure diseases." Li Wenhui said that none of the drugs currently used to treat hepatitis B can cure hepatitis B, and new drugs must be developed.
With the support of the Beijing Municipal Science and Technology Commission, Li Wenhui and Sui Jianhua, as the founders of science, established Huahui Anjian (Beijing) Biotechnology Co., Ltd. (hereinafter referred to as "Huahui Anjian") in 2015 to fully develop new drugs.
After several years of research, they developed the original (FIRST-IN-CLASS) ANTIBODY DRUG HH-003, AND COMPLETED VARIOUS PRECLINICAL EXPERIMENTS OF HH-003 IN 2016. Li Wenhui introduced that HH-003 is the world's first HBV-neutralizing antibody targeting the pre-S1 region of the large envelope protein on the surface of hepatitis B virus, which can directly realize the blockade of HBV and receptor NTCP, break the continuous infection and reinfection process of HBV in the liver, and achieve the goal of functional cure of hepatitis B.
After several years of hard work, HH-003 finally reached a milestone in research and development: on June 14, 2018, the Center for Drug Evaluation of the State Medical Products Administration accepted its clinical research application. At this time, 6 years had passed since they discovered the HBV receptor.
"Progress is really slow." Li Wenhui explained, "Making medicine is first of all a scientific problem and must be reliable. HH-003 is our self-developed global original drug, which must be constantly explored, improved and optimized, and cannot be sloppy at all. Medicine is used to treat patients and save people, we must be responsible for the health of patients, we cannot blindly rush time and catch up with progress. ”
"The safety performance of HH-003 is good, and all enrolled subjects have no problems!" One day in January 2019, Li Wenhui called a reporter with a rare relaxed tone, "Because it was the first time it was used on the human body, I didn't sleep well for a while, until I saw the preliminary clinical results of phase I.a done by Peking Union Medical College Hospital, and the stone in my heart fell to the ground." ”
In June 2019, HH-003 launched phase I.b clinical studies in the First Affiliated Hospital of Jilin University and Beijing Friendship Hospital Affiliated to Capital Medical University to test the efficacy and dosage of drugs.
"HH-003 exhibits good safety and antiviral activity. In the immunoclearance group, the decrease of HBV DNA and hepatitis B virus surface antigen was clearly observed after three administrations by intravenous injection of HH-003 every two weeks. Not long ago, Professor Jia Jidong of Friendship Hospital reported the safety, tolerability, pharmacokinetics and preliminary efficacy data of the phase I b clinical study of HH-003 at an international conference.
"From the current results, HH-003 has good potential." Li Wenhui said that the phase II clinical trial has been launched in many hospitals in September 2021, and it is progressing smoothly. "The clinical results of hepatitis D are also very good, and it may be the best in its class."
Excellence: Develop highly effective full-spectrum original anti-coronavirus drugs
In the past two years, Li Wenhui has been particularly busy because he has added a temporary task to himself - to develop new anti-coronavirus drugs.
As early as 2003, Li Wenhui, who was doing postdoctoral research in the United States, with the support of his mentor Mike Fazan and his colleague Sui Jianhua, found the world's first receptor for SARS, angiotensin-converting enzyme 2 (ACE2, which is also a receptor for the new coronavirus). In June of the same year, the related paper was published in the journal Nature.
After the outbreak of the new crown pneumonia epidemic, Li Wenhui realized that the mutations of the new crown virus are increasing rapidly, and the performance after infection is also diversified. He approached Wang Xiaodong and said: "We should hurry up to develop a full-spectrum drug, just in case." Wang Xiaodong quickly transferred a special fund from the institute and fully supported it. In this way, Li Wenhui and Sui Jianhua quickly invested in the development of anti-new crown drugs and made excellent efforts in drug design: in view of the characteristics of strong variability of the new crown virus, with its receptor ACE2 as the target, a special drug molecular structure was designed to block its access to human cells; Fully considering the drug safety of the elderly, pregnant women, lactating mothers and other groups, the drug with a diameter of 40 nm is designed as a mist spray, and the drug is only evenly covered on the surface of the lungs and upper respiratory tract through aerosolized inhalation or nasal spray... More than a year later, they successfully achieved their design goals. Preclinical studies have shown that HH-120 has a very good safety and efficacy and can cope with various variant viruses.
The Ministry of Science and Technology and the Beijing Municipality have allocated special funds for this research. However, like other new drugs, the clinical development of HH-120 is expensive, and the financial funds are only a drop in the bucket. Moreover, the new crown virus is unpredictable, and everyone has different opinions on drug research and development. Li Wenhui told colleagues: "We can't just think about money, we have the responsibility and ability to develop effective drugs just in case." "They have carried out clinical research abroad and domestically.
"It's almost there now." Li Wenhui said on the phone that under the vigorous promotion of Beijing and relevant departments, the nasal spray type HH-120, which is more convenient and efficient than the atomized inhalation type, is also progressing smoothly, and is currently being accelerated in Beijing Ditan Hospital and other places, and the effect is exciting. "With this weapon, we don't have to panic."
"I have spent a lot of energy on the research and development of anti-new crown drugs in the past two years, which is indeed quite a toss." Li Wenhui said, "Valuable things are definitely difficult, but as a scientific researcher, it is a responsibility and luck to use your research results to solve practical problems." ”