Zhang Qi is doing experiments. Reporter Liu Changrong of China Youth Daily and China Youth Daily/Photo by
Zhang Qi (first from the left) takes a photo with the experimental data, and the second from the left is Zhang Linqi . Photo provided by the interviewee
Assistant researcher Zhang Qi’s desk is located at the innermost part of the A205 laboratory of Tsinghua University School of Medicine, squeezed together with the students’ workstations, and one step away is the experimental console. There are no decorations on this slightly cramped desk. There are two A4 papers taped on the partition, which are "mutant strains and single-point mutation S clones in the laboratory" and amino acid chemical formula diagram. The
A205 laboratory has the same style as Zhang Qi's desk. The experimental console is filled with experimental equipment and instruments, and the written sticky notes are hastily posted on the cabinet door of the console. The whole laboratory is like a "science and engineering man", simple and pragmatic, without any fancy. It was in this laboratory that Zhang Qi found the two antibodies in my country's first specific drug for the new coronavirus.
The two antibodies are BRII-196 (ambavirumab) and BRII-198 (romisevirumab). On December 23, 2021, Columbia University published a new research result in the international science and technology journal "Nature". Researchers found 19 representative strains of new coronavirus antibodies around the world and tested them against Austria. Competencies of Mixon strains , 18 of which are resistant The neutralizing activity of the antibody is negative, and only the BRII-198 antibody found by Zhang Qi has a positive neutralizing activity of 2.2, which means that in the face of Omicron , which has plunged the world into a new round of panic, For the new coronavirus mutant strain, the neutralizing activity of BRII-198 antibody increased 2.2 times compared with before.
On December 8 last year, my country’s first specific COVID-19 drug, developed by Tsinghua University Professor Zhang Linqi’s team, received emergency approval from the China Food and Drug Administration for marketing. Zhang Qi is a member of Zhang Linqi’s team. Zhang Linqi said that the focus and difficulty of the entire drug research and development is to find the most effective antibodies, and this work is mainly completed by Zhang Qi.
First find the BRII-196 antibody
After the new coronavirus enters the human body, it needs to infect cells before it can continue to reproduce and attack the human body. If there are neutralizing antibodies to intercept the virus outside the cells, then the virus cannot survive in the human body. The development of COVID-19 specific drugs is based on this seemingly simple principle.
Zhang Linqi’s team’s work on developing specific drugs for COVID-19 began on January 12, 2020. On the same day, my country released the genome sequence information of the new coronavirus to the world. Also on the same day, Wuhan reported a total of 41 confirmed patients, including one death. This war without gunpowder has begun in Wuhan and has begun to attract national attention.
htmlThirteen days later, at 9 pm, in the Tsinghua University campus in Beijing, more than 1,000 kilometers away from Wuhan, Zhang Linqi and Professor Wang Xinquan of the School of Life Sciences jointly convened a team meeting to start the search for neutralizing antibodies for the new coronavirus. Highly efficient neutralizing antibodies that specifically intercept the new coronavirus are mixed among hundreds of millions of antibodies in the human body. The first problem the team encountered was to find these antibodies.Through cooperation with Shenzhen Third People’s Hospital Party Committee Secretary Liu Lei, Professor Zhang Zheng, and Associate Researcher Ju Bin, on February 9, 2020, Zhang Linqi’s team obtained the preliminary screened 206 new coronavirus antibody genes. Zhang Qi took over the task of finding the antibody with the best neutralizing activity.
Before getting the antibody, Zhang Qi had already set up a system that could test the neutralizing activity of the antibody, and tested it with other small molecule drugs, making preliminary preparations in a short period of time.
At that time, there was no structural information about anti-COVID-19 monoclonal antibodies in the world. Zhang Qi was one of the first people to cross the river by feeling for the stones. Since there was no structural information to suggest the target of the antibody, Zhang Qi could only repeatedly conduct cross-competition experiments and fumble forward.
After more than a year, Zhang Qi recalled her state at that time and said that her entire mental state at that time was highly concentrated. What she ate and wore every day was no longer important at all. She only thought about the timetable of the experiment. , "Whatever time you have to do, you must do it, and you must do everything you need to do."
In the fight against the COVID-19 epidemic, doctors on the frontline of the clinic went retrograde, wearing white suits and armor, to fight the virus at close range, while scientific researchers were racing against the virus in another way in the laboratory. During that time, Zhang Qi often worked until one or two o'clock in the night before going home, and came to the laboratory at 6 o'clock in the morning to continue working. "If the experiment had been completed one day earlier and applied for it one day earlier, (the drug) might have been approved one day earlier. , use it on patients one day earlier."
On March 2, 2020, General Secretary Xi Jinping came to Tsinghua University to inspect and investigate scientific research and development work on the prevention and control of the COVID-19 epidemic. He walked into the A206 laboratory and encouraged and entrusted the team: "The most powerful weapon for mankind to fight against diseases is science and technology."
html Thirteen days later, Zhang Qi found the BRII-196 antibody with the strongest neutralizing activity. The computer on her desk recorded gratifying data about this antibody. On the same day, Zhang Linqi, Zhang Qi and several students also took photos with the data on the monitor to record this historic moment.The BRII-198 antibody that can fight against Omicron
After finding the BRII-196 antibody, Zhang Linqi’s team did not stop, but decided together with Dr. Zhu Qing of Tengsheng Huachuang Medical Technology (Beijing) Co., Ltd. and other R&D personnel, Continue to look for another antibody and fight together to deal with mutated strains that may appear in the future. From the Alpha strain, Delta strain to the Omicron strain that is now raging around the world, all prove the correctness of this decision at that time.
It is worth mentioning that the SARS virus and the MERS virus , which are also coronaviruses, do not actually have very active mutations. Zhang Linqi’s team has also conducted relevant research on these two viruses. In the very tense environment at the beginning of 2020, it is reasonable to choose only one antibody and not spend more time selecting "spare antibodies". However, Zhang Linqi’s team chose a safer and more secure solution. The screening of
"spare antibodies" was not smooth sailing. After the first antibody is identified, the second antibody that is used together with it needs to meet a certain standard in neutralizing activity and must not compete with the first antibody. Two antibodies should achieve the effect of 1+12. The competitiveness of the two antibodies
means that the two antibodies compete with each other to intercept the virus. High competition will affect the joint use of the antibodies. After repeated screening, Zhang Qi eliminated many antibodies with more than 50% competitiveness, and one of the few remaining antibodies was 40% competitive with the BRII-196 antibody. This antibody was selected as a "spare tire".
But the "40%" figure has always been a hurdle in Zhang Qi's heart. "40%, is this real competition or fake competition? In fact, it's a bit unclear. It's like something is scratching you. You know it shouldn't be a big problem, but you just feel a little worried." After struggling for a long time, Zhang Qi decided Try to find new antibodies again.
At the critical juncture of the race against time, Zhang Qi was patient and spent an extra two or three weeks to find an antibody that was basically 0% competitive with the BRII-196 antibody - the BRII-198 antibody. After more than a year, the new coronavirus has mutated into the Omicron strain. Faced with this mutant strain with 37 mutation sites (the Delta strain has 11 mutation sites), many antibodies have been defeated. came, but the neutralizing activity of BRII-198 antibody was stronger.
In the process of searching for BRII-198 antibodies, Zhang Qi also added some "little thoughts" of her own. On the premise of ensuring neutralizing activity, Zhang Qi chose a relatively "niche" antibody. "During the mutation process, the virus will target more types of antibodies to mutate in order to successfully escape, and the probability of 'niche' is much lower." Zhang Qi explained the "niche" here in
: " The neutralizing activity of this antibody is definitely relatively good, but it is not the best. In addition, compared with most antibodies, its target position when it binds to the virus is relatively niche."
In late November last year, the World Health Organization announced the genetic information of the Omicron strain, which has significantly more mutation sites than all new coronavirus variants that have been circulating in the past two years.
Zhang Qi told a reporter from China Youth Daily and China Youth Daily that after she saw the target position of the combination of virus and cells in the genetic sequence information of the Omikron strain, she probably knew that the BRII-198 antibody she had been looking for was against it. It will be effective, "I am quite confident." In addition, because of concerns that the new coronavirus mutant strain will cause the inactivation of antibodies, Zhang Qi and other members of the team have previously tested a single mutation site, and the antibodies have maintained good activity. The 37 mutation sites of the Omicron strain this time are equivalent to the synthesis of single mutation sites.
Of course, whether the antibody can remain active ultimately depends on the laboratory test results. After the genetic information was released, Zhang Linqi's team also immediately conducted an antibody activity test against the Omicron strain. After more than a week of experimental work such as gene synthesis, chimeric virus packaging, and neutralizing activity testing, the experimental results were finally released. Report: my country’s first specific COVID-19 drug still maintains good activity against the Omicron strain.
Beyond the spotlight
When asked how the "careful thought" of selecting "niche" antibodies came about, Zhang Qi said that this may be inseparable from her many years of experience in researching antibodies, of which there are many There is no "waste effort" that produces no results.
After graduating from Wuhan University in 2005, Zhang Qi entered the University of Halle-Wittenberg in Germany to pursue her master's and doctoral degrees. During this period, she began research in the field of artificial antibodies. It is notoriously difficult for PhD students in Germany to graduate. Zhang Qi said: "The pace in Germany is relatively slow. Germans think that long time is not a problem, but the work must be done well and they will pay attention to every point in the work." "Especially consider it carefully." This is also what attracted Zhang Qi to apply for universities in Germany.
Zhang Qi's doctoral graduation defense took half a day. Her graduation thesis, which took her 4 years to write, withstood the "torture" of the professors. Not only did she successfully pass the defense, she also finally won the "Magna Cum Laude" (Magna Cum Laude) Cum Laude is translated into Chinese as "Excellent Class". Only the top 10% of graduates can receive this honor - reporter's note). This is an excellent result that few German students can obtain.
Halle-Wittenberg University is a famous comprehensive university in Germany. In this university with a history of more than 500 years, Zhang Qi received 8 years of systematic and solid scientific research training. In 2013, Zhang Qi joined Zhang Linqi's team and began to engage in research on infectious disease antibodies, mainly on AIDS antibodies. The mutation of HIV and the mutation of new coronavirus are completely different in magnitude. The former can often mutate into hundreds of mutant strains in a person's body. Before the COVID-19 epidemic, Zhang Qi’s daily work was mainly researching HIV.
However, many scientific researchers, including Zhang Qi, have not achieved particularly significant results in their research on HIV over the years. In terms of drugs, infected people need to continue taking drugs to temporarily suppress the virus. Once the drugs are stopped, the virus's attack on the human body will rebound. In addition, no vaccine to prevent and control HIV has been successfully developed in the world.
"Although AIDS research is difficult, the accumulated technologies, methods and accumulated knowledge are very useful." Zhang Qi explained that the methods and technologies used to search for new coronavirus antibodies this time are based on previous accumulation. The dual-antibody combination regimen initially determined was also based on the common "cocktail therapy" in the field of AIDS treatment.
In Zhang Qi’s view, behind the sparkling inspirations in the scientific research process are the accumulation of countless days and nights. "For us, this accumulation process is like using a small hammer to dig a mine in a cave. Most of the time it is dark." How does
persevere in the darkness? Zhang Qi said that there needs to be a belief to support.
Mid-to-late February 2020 was the most stalemate period in Zhang Qi's search for antibodies. At that time, the anti-epidemic situation in Wuhan was not yet clear. Looking at the large number of new confirmed cases every day, Zhang Qi always thought that she was researching If this drug can be used on patients and save lives, it will be very meaningful.
The opposite of the small probability of "just in case" is "nine thousand nine hundred and ninety-nine out of ten thousand".In Zhang Qi's view, this "nine thousand nine hundred and ninety-nine thousandths" does not mean that it is worthless. As a scientific researcher, it is your job to use your own knowledge reserves to explore the unknown. "You may not be the last to pick it." The one who gets the fruit, if I don’t make it, but I sue Telling others why I failed is also contributing to my own value."
Note: The title of the paper published by Columbia University is "The Omicron variant of the new coronavirus shows severe antibody escape" (Striking). Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2) (Reporter Liu Changrong)
Source: China Youth Daily
