Harbin Institute of Technology

Reported by: Yan Mingxing
Photographed by: Lan Rui
Translated by: Zhao Lingqi
Date: 2017.5.1

In just three years, a team led by Professor Huang Zhiwei from the School of Life Science solved three world scientific problems from 2014 to 2017, sending out the strongest sound of HITers in the frontier of life science research field.
In January 2014, they revealed the structure of AIDs virus a goal that world first-class structural biologists had been longing for, and their research paper “ Vif ‘hijacking’ CBF-β and CUL5 E3 ligase compound structural mechanism” was published on line in Nature.

In April 2016, they revealed the working mechanism of Cpf1, providing the structural foundation for a specific and efficient new gene editing system. Their paper “ Crystal Structure of CRISPR-Cpf1 combining crRNA complex” was published on line in Nature.

In April 2017, they revealed the molecule mechanism of Anti-CRISPR protein suppressing SpyCas9 activity, which offers the structural basis for SpyCas9 gene crediting activity tools in designing time,space specificity and conditionally precise control.Their paper “Anti-CRISPR Protein Suppressing SpyCas9 Activity” （shorten as “Anti-CRISPR”）was published on line in Nature.

As the team leader, Huang Zhiwei came back from the Harvard University as a talent of a very high level. Since he came to HIT in 2012, he started from scratch to construct the structural and molecule biology and innate immunity signal transduction lab. Huang Zhiwei now is the director of the School of Life Science, academic leader of structural and molecule biology, and Ph.D instructor.

Why can Huang Zhiwei’s team continually make new progress and make breakthroughs in the S&T research field in such a short time? Is there some secrets? Recently, one reporter visited their labs placed with experiment equipment, full of busy people, got closer to know this team, and found out their secrets.

Aims the most meaningful and the most important research

“We, researcher, should build a belief in climbing the heights of science, and keep in mind that our responsibility is to benefit the humankind, sacrifice for the society improvement and do the meaningful things.” These words are impressive.It is with this kind of responsibility that Huang leads his team in overcoming difficulties.

Their research results “Vif ‘hijacking’ CBF-β and CUL5 E3 ligase compound structural mechanism” first revealed the Vif structure puzzling scientists for 30years, and providing the structural basis for reasonable designing a new AIDs medicine targeted compound . This research marks Harbin Institute of Technology being the leading place on AIDs virus structural and molecule biology research field.

On February 6th, 2014, the deputy director of the Nature Structural & Molecular Biology in studying highlights column reporting on Huang Zhiwei team's paper pointed out: HIV virus Vif plays a vital role in the process against host virus limiting factor APOBEC3G. The study not only reveals the structural basis of Vif activity, but also will play a role in the development of anti-AIDS drugs.

In January 2016, Huang Zhiwei team first revealed the working mechanism of Cpf1, which explored the mechanism of CRISPR-Cpf1 recognition of crRNA and cleavage of pre-crRNA by structural biology and biochemical research. This was of great scientific importance for studying virus molecule mechanism how bacteria resists the virus evasion through the CRISPR system, successful reform of Cpf1system providing the structural foundation for a specific and efficient new gene editing system. It will make people can efficiently perform “close” , “recover”, and “modification” operation on targeted genes like plant, animal, and human cells. Therefore, it has a broader and far-reaching significance. In article published in less than a year, there are well-known foreign research groups based on the complex structure designed a Cpf1 identifying other DNA substrate, making the system has a wider range of applications.

The study of the molecular mechanism of anti-CRISPR protein inhibition of CRISPR-SpyCas9 activity is not only important for the co-evolutionary molecular mechanism that reveals phage and bacterial immunity (CRISPR) and the "anti-CRISPR" system "armed race", but also provides a structural basis on designing time, space-specific or conditionally precise control of SpyCas9 gene editing activity . It is like a car, there are two systems that are particularly important, one is the power system, and the other is the braking system. This study reveals the molecular mechanism of the "braking system" of the SpyCas9 gene editing system, which is currently the most widely used, provides a basis for controllable and more precise editing of genes.

“Doing research, to better to challenge the forefront of the discipline and the most scientific direction". "It is natural to publish your paper in high-level journals if your research project is significant, innovative and strong." Those words uncover the secret of Huang Zhiwei’s publishing paper in Nature. He always insisted on targeting "the most meaningful and most important" on choosing the direction of research, which reflects Huang Zhiwei’s pioneering spirit and the courage to challenge. This is evident from his study experience, from majoring Chemical Engineering and Technology in his university, to studying the the life sciences structure and function in postgraduate stage, to the immunization and infection of the disease in the postdoctoral stage. Huang Zhiwei crossed big leaps from different majors as well as faced many unknown challenges, but he was happy to face these challenges, which contributed to his current research work. Huang Zhiwei said, "No matter what kind of challenge, I always have a beginner 's mind, and boldly try the frontier issues related to life, and I try to develop my own vision, and to explore the mysteries of life.”

Deep accumulation is a guide for the scientific research "maze"

People engaged in life science research know that life science experiments are very complex and time-consuming. Usually, an experiment has to go all night long without stop in the middle. Meanwhile, it also needs to test different experimental conditions and different methods, so the number of experiments for a project is often very alarming, but failure is common. Like the structure of the AIDS virus Vif, some research institutions have spent more than 30 years without progress.

Huang Zhiwei team seems different, just three years making so many important results. For achieving progress in such a short time, teachers and students felt incredible, but Huang Zhiwei thought it was "lucky". Is it really just the help of lucky god? Of course not, with the words of Li Yu, the party secretary of School of Life and Science, all of these cannot leave with the team's efforts, the scientific methods, especially scientific literacy of its leader Huang Zhiwei. Li Yu said, "creative work requires accumulation of knowledge and theory, and a certain sense of consciousness on this basis. Huang Zhiwei’s rich learning and work experience bring him the reserve of knowledge. He has a strong sense of consciousness in the frontier issues, moreover, with fast execution, rigorous work attitude, and assiduous spirit, success is inevitable.

Huang Zhiwei also said: "It is like going into a maze when doing scientific research sometimes. How to choose the line is very critical, which requires scientific judgment and logical thinking, while the scientific judgment is based on your decades of research experience and accumulated knowledge. "Indeed, he was eager to absorb knowledge during school days, and he accumulated a lot of knowledge. Until now he also adhered to reading literature every day, including the world famous magazine Natural , Science, and Cell. Huang Zhiwei read every issue timely, on which relevant research papers he carefully studied and read repeatedly.

Accurate judgment and keen insight are features of Huang Zhiwei. Students really admire him. "Anti-CRISPR" research paper’s common first authors, doctoral student Guo Minghui mentioned Huang Zhiwei's ability to judge, had to give it a thumbs up. Once, she was doing protein purification but the polymers were too many, and she did a number of experiments still unsolved. Huang Zhiwei carefully analyzed the experimental phenomenon, pointed out the problem and put forward a solution. In the next experiment, Guo Minghui obtained the ideal protein after just one time. She admitted: "Huang's eyes are very accurate. Once there is a problem or the next step how to go, we always ask Huang's advice, and Huang 's guidance is always so helpful that we suddenly understand and escape a lot of detours.

That is the case, Huang Zhiwei always be able to keenly find the problem, and lead the team to the scientific research, which makes the scientific results bear many fruits.
Team member favors the “Experiment Notes”

In the interview, the reporter found each member has a thick experimental record note on the desktop or the bench. Opening the notes, the reporter saw the recorded images, processes, results, formulas and many other contents.

Why do team members have a special twink to the lab notes? As an undergraduate, Ren Kuan has wrote down two books of notes within a short period of 4months. Ren Kuan is the "CRISPR-Cpf1" co-first author. He felt that the notes are the specific embodiment of the HIT motto. He said: "under the strict requirements of professor Huang, we have developed a note taking habit.Now I think that notes are really useful. Once I have a problem, I can always view notes to find out the problem. "

When leading the team, Huang Zhiwei asked and even ordered the students to recognize the importance of notes. Every morning, the first thing he went to the laboratory is to check students’ notes. He said: "The experimental record must record the details. It should be clear.If you do not take a good lab notes, in the future some of the experiment can not be repeated , and it is difficult to find the problem." In his view, science is rigorous, not half-sloppy. In particular, in the process of biological experiments, sometimes to verify a problem, they need to test various methods, and try different ways. If you do not remember the experimental process and the notes, it will be very troublesome. Like a Chinese old saying, “sharpening the knife helps the work of firewood workers.” At the request of Huang Zhiwei, members all develop a careful note-taking habit. A team member Guo Yingying once in the experiment found the protein precipitation, and she did not know why. Finally, by looking through the experimental record, combined with Huang Zhiwei's proposal, with the team's efforts, she finally found the reason.

In fact, for Huang Zhiwei, note-taking not only involves the effect of the experiment, but the most important thing is to adopt such a thing to develop everyone rigorous, serious and meticulous habits and scientific attitude.

Harder thus more lucky

The first-year doctoral student Dong De has been keeping in mind "Harder thus more lucky", said to him by his instructor Huang Zhiwei. Dong De is the co-first author of two papers published in Nature. This sentence, as a motto, always inspire Dong De to study with great concentration.

In the three months of the most intense experiment, Dong De stayed in the laboratory 16 hours every day. It was common thing to go back to the dormitory at 3or 4 o’clock in the morning. Even he did an experiment continuously in two days and one night. He said: "I have long heard that the team is busy, but until joining the team I really realized what is busy!" Even in Chinese New Year, he only rest for 3 days, but he thought it was nothing. Because there are those more busy than him, that is his mentor Huang Zhiwei. Huang Zhiwei has always been convinced that "harder thus more lucky". He almost has no weekend and holiday, and he often stay up in the laboratory. Even in the New Year, he does not rest. On the first day of the lunar January, he wrote paper in the office. Huang Zhiwei said: "In addition to hard work on the road of science, there is no shortcut, only hard work, and then work hard."

Busy used to describe the team is appropriate. Under the leadership of Huang Zhiwei, all work very hard, and they could not bear to waste even a little time. Whether it is for himself or for students, Huang Zhiwei asked "things can be finished today must not be dragged into tomorrow."

"Genius is 1% of the inspiration plus 99% of the sweat, but that 1% inspiration is on the basis of 99% sweat in the early time." He said with deep feeling, to do a subject, it needs to study the background, to design routes and methods, and to continue to do experiments ... ... This process is very hard, but a sub-pay a little harvest, without some cold biting, which plum blossom incense. Do research work like this, do any work to be successful need to work hard and pay.

Huang operates the critical experiment, leading all work hard together

Huang Zhiwei works meticulously in the cultivation of students, he insisted in accordance with the "students" and "scientific research workers," the dual identity requirements, care and training them. He hopes that through their own "words and deeds", the spirit of science will be passed down, so that every student will be able to work independently, becoming the pillars of the country.

Therefore, in this group, you will often see Huang Zhiwei and students together in the experimental bench "fight together" scene, a lot of experiments Huang Zhiwei are hands-on hands to teach students how to do experiments. This makes the students feel very lucky. Dong De felt that the beginning of the experiment is not very clear, hands-on experimental heart is full of apprehension, but now has become an expert in experiments. He said: "very rare, we entered the laboratory from the first day to get the teacher's personal guidance Huang, while watching the notes, let us know how to do experiments, how to analyze the results, how to look at the data ... ... now feel so much at ease."

In order to learn the forefront of structural biology of frozen electron microscopy in the latest technology, 2015, Huang Zhiwei arranged for Dong De to enter the Chinese Academy of Sciences Institute of Biophysics. After he came back, at the very the beginning he worked to establish negative sample preparation, data processing, analysis and other new directions, and the College used advanced equipment effectively.

In this team, Huang Zhiwei personally arranged for the students to study the subject, for them to design experiments, personally guide students to do experiments, and at any time to read the students of the laboratory notebook, and students to discuss the problem every day. Encountered a key experiment, he always personally involved, such as in the latter part of the structure because of the need for experience and timely judgments, he personally do it yourself. Often in the evening put the next day to work the idea of finishing, the progress of the project to what extent, to do what experiment, which students want to do ... ... he will make timely arrangements. He said: "I was in the prime of life, in the experimental platform to do experiments to better understand the specific circumstances of scientific research in order to make judgments in a timely manner to make reasonable arrangements to achieve better results.

For Huang Zhiwei's personal guidance, any depth of feeling, he said: "In the teacher's guidance under the operation of the teacher, feel particularly practical.He personally took us to do experiments, but also infected everyone, the teachers are so invested, of course we also to this. "It is precisely because Huang Zhiwei moment fighting in the first line, personally led the team forward, only to create this now very fighting team. The whole team in close cooperation, we work together, we naturally progress quickly. At the same time, team members pay great attention to cooperation and communication. Once, "Anti-CRISPR" the first author of the paper Wang Sihan do not feel right during the experiment, contacted Dong in Germany to help check to find the problem. Guo Minghui in the experimental chart when the team members often work together. They believe that the team's close cooperation with the smooth development of the subject is very critical, they said: "Under the leadership of the teacher in the yellow, the team will be very good, encountering problems we help each other, together to solve them with the feeling that the whole group is a 'home'. "

If you want to do something, HIT will give you chance

In 2016 my first international youth scholar "Shenzhou" forum, Huang Zhiwei share their work in HIT, life story, talk about their own into the HIT, grow into a real work of the minds of young workers and sentiment, he exclaimed exclaimed: "HIT is concerned about the young talent, trust and support, as always, in the HIT, want to work will have a stage.

Although his time in HIT has only been five years, but from the beginning to set up a laboratory to overcome the difficulties of Huang Zhiwei has published three "natural" papers, a "cell research" papers, can be described as striking results. When it comes to why you can make so much scientific research in a short time, Mr Wong stressed that the achievement of a need requires a scientific approach that requires rigor and diligence and requires teamwork, but not just that. A system of engineering, including many aspects of the various aspects.

Among them, Huang Zhiwei specifically mentioned the support of young scientists and other schools. He said: "In the process of my growth, schools, colleges have been given a lot of help, young scientists studio for the team to carry out scientific research work provides a good platform; the school also pay great attention to the work of talent, research environment and academic The atmosphere is very good, so I can feel at ease to engage in their favorite work.

The school has been very concerned about, concerned about the growth of Huang Zhiwei team. School leaders Wang Juquan, Zhou Yu and many other to the studio research, understand the situation and give strong support to encourage him to create a studio-class, to achieve more and more significant innovations.

Indeed, in the growth of Huang Zhiwei road, can not do without the school's attention, support and trust. This concern, support and trust gave Huang Zhiwei growth and progress of the greater power.

In 2016, the school decided to set up a life sciences center. Life Science Center as a school scientific research system reform pilot, to the first-class potential young PI (academic director) as the center, to explore the establishment of efficient scientific research mechanism, scientific research, personnel training system reform and innovation.

As the person in charge of the life sciences center, Huang Zhiwei actively explored the implementation of the internationally accepted PI system (academic responsible person) scientific research organization management mode, employment and employment period for international peer assessment, life center all administrative services in PI and students, the current work is steadily advancing. Talking about the establishment and prospects of the Center for Life Sciences, he is both perturbed and excited: "In the domestic colleges and universities have to reform and development of the historical period, the establishment of the Center for Life Sciences can see the school's courage and vision, policy and other aspects of the great support and reform and innovation, but this is a new attempt, the school, for ourselves is a challenge, need to overcome many difficulties.As long as the school holds firm to innovation, the development of faith, we do not forget the beginning, Confidence in a few years time will be the life center into a world - class basic life science research institutions, making it the field of life science and HIT innovation and innovation of the cradle of talent.

"We are in a stage that the national scientific and technological innovation changing from quantitative to qualitative change of the critical moment. Young college science and technology workers should be more dream, more passionate to make more textbook level of original research results." In Huang Zhiwei words, we see a kind of science "love" and "dedication".

With the perseverance, lonely life journey can be companied by a blue sky; with dedication, loneliness can be interpreted as a row of wild goose; with dedication, science can bloom into the garden of flowers. In the interview, the reporter can see the whole team of Life Science affection and dedication, it is this love and dedication to science blooming the light of life, so that the team harvested a number of high levels of research results, while training a number of scientific, aspiring, capable graduate students.

team member