The future science prize winner: a joy of basic research is unparalleled

Interviews Shi Yigong & amp; Future Forum keywords
2017 Future Science Award / Life Science Award / Shi Yigong 2017 Future Science Award Winners announced, the future forum youth director Wang Haoyi the first time by telephone connection to the Life Science Award Obtain a special interview with the public. 2017 May 5, 1967 was born in Zhengzhou City, Henan Province, graduated from Tsinghua University in 1989, 1995 in the United States Johns Hopkins University won the University of Science and Technology, Doctorate. Chinese Academy of Sciences, American Academy of Arts, academician biologist, Tsinghua University professor. He is currently the vice chairman of the Ninth National Committee of the Chinese Science and Technology Association, the first president of the Tsinghua University and the first president of the West Lake Institute of Advanced Studies. Forum for the Future youth director Wang Haoyi telephone connection, Professor Shi Yigong The following is the interview: 01 significance Wang Haoyi awarding achievements: Hello, Professor Shi, first of all congratulations on your award won the 2017 Future Science Life Science Award! We would like to ask you a few simple questions on behalf of the future forum and the public. Your winning reason is mainly about the structure of the RNA splicing body and some of the work of the mechanism. Please use the more popular or simple words to the public to explain the significance of this work where? Shi Yigong: Yes. This recognition of the “Future Science Award” is primarily a contribution to the analysis of the structure of the key complex of eukaryotic cell messenger RNA splicing, revealing active sites and molecular mechanisms. I try to use the more popular language to explain the meaning of our study. Every life, including our human behavior, language, thinking and all life activities are controlled by our genes, which is a common sense we are familiar with. Parents’ genetic inheritance of children is achieved by DNA as a vector. The genetic information carried by DNA determines that we develop from one fertilized egg into an embryo, become a baby born, develop step by step mature and aging. So how does the gene control the life process of each organism? DNA storage of genetic information must first be converted into a specific function of the implementation of the protein, the vast majority of known life activities are carried out by the protein to complete. This genetic information from the stored DNA into a variety of structures, the implementation of various functions of the protein process, called the central law. Speaking of this non-biological professional friends may have been a bit obscure. If I say that life is a movie, then DNA is a script written in a password, the protein is the actors and props, the common interpretation of the completion of the film. But from the encrypted script to the final film, but also need to be decoded, the need to edit the script to become a mature script, this is the messenger RNA to do. In the life of the earth called “eukaryotes”, the implementation of the central law can be broken down into three steps: the first step is to pass our genetic information from DNA to precursor messenger RNA, that is, the process of decoding The This precursor messenger RNA and DNA are in a one-to-one relationship. In eukaryotes, the vast majority of precursor messenger RNAs can not be translated directly into proteins because they often contain fragments of length or sequence, which do not encode proteins, which are called As intron. The insiders are not able to enter the final script, they are to be cut off. Precursor fragments, in addition to introns other fragments are called exons. Imagine that each precursor messenger RNA is interlocked by introns and exons with different lengths and sequences. Cut the introns in the precursor messenger RNA and splice the exons containing the valid information into mature messenger RNAs. This process is called “splicing”, as the name suggests, cutting introns, connecting Exon. Mature messenger RNA can be translated into protein. Proteins are hard work, to achieve our movement, thinking, perception, sleep and so on physiological processes. Splicing such a simple word, but to achieve it is very complicated. Because the intron is too much change, an intron can only a few short nucleotides, there may be thousands of nucleotides; and introns and exons are relatively speaking , An intron in another splicing way to become the protein can be encoded exon, and vice versa. Expositions of exons are also very complex, not only can the order of 12345 stitching, but also disrupting the sequence of splicing, and even from different precursor messenger RNA exons can also “cross-border” connection. Thus, the same DNA template, the same precursor messenger RNA, because of the different splicing, the meaning of the transfer is completely different. This is just a simple analogy, in fact, the precursor of the messenger RNA in the cell world is more complex. The same precursor messenger RNA splicing method is different, resulting in mature messenger RNA on the ever-changing, resulting in the final product protein with the ever-changing. It sounds like insiders are disorganized, splicing arbitrary, of course not! The splicing of each cell for each precursor messenger RNA is very accurate in time and space. Cut off, how long to cut, when the cut, in accordance with what order to exon splicing together, which each may be the key to change the fate of cells. Think about it, step by step wrong, the results of different, life activities will be chaotic sets. So it is not surprising that about 35% of human genetic diseases are caused by splicing anomalies. It is precisely because splicing is so complex and so important that this process, whether in single-celled yeast or in our complex human, is made up of a giant molecular weight, consisting of tens to hundreds of proteins and five RNAs Of a super-large molecular machine, known as the “splicing body” (spliceosome)). Biochemical textbook will be described as the most complex cells in the complex super-large molecular complex, not too.
Shi Yigong We look back again, the central law refers to the genetic material from the control of life to the process of protein such a message transfer process, inside the eukaryote is a three-step, each step has macromolecular complex Catalytic completion: the first step of transcription, from DNA to precursor messenger RNA, catalyzed by RNA polymerase, this step basically in 2006 before the molecular structure from the clear; the third step from the mature messenger RNA into protein, By ribosomal catalysis, this step is basically in 2006, 2007 before the understanding is more clear. I am here to say “more clear” refers to the structure of the analysis, so at the atomic, molecular level can be very clear to see how this step is completed. RNA polymerase structure analysis obtained the 2006 Nobel Prize in Chemistry, ribosome structure analysis was the 2009 Nobel Prize in Chemistry. But this step in the middle, that is, splicing, from immature precursor messenger RNA to mature messenger RNA is relatively clear at the molecular level. In fact, the phenomenon of splicing as early as 1977 by two American scientists PhillipSharp and Richard Roberts found that they therefore in 1993, has been Nobel Prize in Physiology or Medicine. But how this step is done, before 2015 we still only in genetic and biochemical research there are some clues and evidence, but the structure and molecular mechanism is not clear. As mentioned earlier, this step should also be the most complex step in the three-step rule of the whole center. 02 Future research direction Wang Hao Yi: You explained very clearly. Do you think the current second step on the molecular mechanism of understanding, you and some other international counterparts on the basis of the work, we are close to perfect, or that there is still a lot of work to do? What is the most central issue in your direction now? Shi Yigong: From 1977 onwards, after nearly 40 years of research, to the beginning of 2015, we have the genetic point of view and biochemical point of view has been sorted out of these RNA splicing process, the chemical principle also know, which protein, RNA The implementation of the splicing process is also found almost. But we do not see what is real, we do not know how such a complex splicing process is precisely controlled the orderly occurrence, we do not know how many components of the splice is arranged in combination. Each component is not a fixed tile, some specific components in the specific process of splicing arm stretched legs, so as to accurately find the intron boundaries, at the right time appropriate place, Cut a knife or make a knot. This process is so complicated. To understand it, it is necessary to capture the structure of each state of the splice body at work. However, by 2015, let alone one, even if it is a state that is also considered by the structure of biology and RNA splicing as mission impossible (impossible to complete the task). I studied DNA and RNA protein from the doctoral study, chose postdoctoral researcher had also interviewed the laboratory to study the structure of ribosomes, and during Princeton I have been concerned about the progress of the research progress, because I think this is structural biology One of the ultimate topics, very challenging. But I think the technology development at that time is very different, so there has been no pain to start. Until 2007 back to Tsinghua, I noticed the rapid progress of the field of frozen electron microscopy and great potential, so I am very confident of the future of the mirror, to determine is a very good time. Tsinghua University has a good basis for good bio-electron microscopy, the school approved the purchase of high-end electron microscopy request. Frankly, I predicted that there will be advances in the technology of electron microscopy, but did not think of this revolutionary progress so swiftly. So far, my lab has been in this field for ten years. In the world, by 2015, we know the structural information, including my own laboratory to do out of the previous, are fragments, are individual proteins or individual protein complexes in the splicing of some of the structural information, like Is a big three-dimensional puzzle, you only see jigsaw puzzle in one or two small tricks where, never put the puzzle together to read. In May 2015, my lab first analyzed the spatial three-dimensional structure of an endogenous splicing body from yeast to 3.6 Angstroms at near-atomic resolution, which was the first time a man had completed this great puzzle. To the other pieces of puzzles around each other, how they are combined together into a pretty machine. The results in August the same year in two back-to-back articles published in the “Science” magazine. From then on, my lab and other research groups in the world that study the structure of the splice structure explored the various working states of the splicing body. There are two other teams in the world, one in the German Mapo, a molecular biology laboratory at the University of Cambridge, UK, led by German scientist Reinhard Luhrmann and Japanese-born British scientist Kiyoshi Nagai. After a breakthrough in 2015, the two labs have been working with us to make a series of important results in the structure of different splicing structures. So far, my Tsinghua lab has captured a high-resolution structure in which the yeast splice is in five working states, and Nagai has obtained two similar states and one at an earlier stage. So in yeast, six key states have been captured, and I personally think that we have learned about 70-80% of the molecular mechanism of the yeast for the splice. Compared to the lower yeast, we humans in the splicing body composition from composition or structure, are larger and more complex. The first breakthrough in high-resolution structural analysis of human splicing is also made by our labs – for the first time in the May issue of “Cell” magazine, we first reported three-dimensional structures from near-atomic resolution of human splicing ;shouldIt is noted that the Luhrmann laboratory reported earlier this year that the medium state of the same state of the human splice structure. In August, Luhrmann Laboratories also reported a medium-resolution human splice structure in another state. To sum up, in the molecular mechanism of the phenomenon of splicing, in the yeast we have made great progress, more than half of the journey; in the human beings although we have just started, but because the yeast and human in the process of splicing the same chemical mechanism and Conservative protein sequence, I believe that the structure of the human splice structure, as well as the entire precursor of the messenger RNA splicing mechanism, within a year will make great progress in two to three years should be roughly clear the main problem. I am very optimistic about this. Wang Hao Yi: Thank you. So now you are the main research is the mechanism of human shear, right? Shi Yigong: Yes, we yeast cut the body is still doing, still one or two key state. Although the more technically more difficult, but I believe that we and other friendly cooperation and competition of several laboratories will eventually cut all the key steps of yeast structure of the structure are captured, the reconstruction of a relatively complete RNA splicing film The Yeast cut the body, if it is coming as a big battle, the rest is the local fight. But these fighting will take years, it is no longer two years and three years of tough battle, may be five years, ten years, or even two decades of protracted war, because we analyzed the normal structure of the splice, it is necessary to use yeast To facilitate the introduction of mutations to study the structure of the mutations associated with the disease, to see how they become abnormal, how to cause disease; but also to study the mechanism of regulation of splicing, to understand their temporal and spatial regulation and so on. So even in the yeast there are many years of work to do, steady, but the yeast splicing structure itself, the strategic progress I think is nearing the end. And has been launched for the more complex human body splicing structure of biological exploration is another battle. Wang Hao Yi: You are now using the frozen electron microscope technology, should be a certain moment of a photo. Is there a possibility that a technology in the future will allow us to see the movement of living body molecules at the molecular level? Shi Yigong: frozen electron microscopy technology in the past ten years has gone through a revolution, for structural biology, and even other life-related disciplines have brought great changes. Frozen electron microscope with everyone imagined with an electron microscope can only be observed a protein macromolecule outline has been completely different. Because a few years ago, frozen electron microscopy made a breakthrough in technology, first, hardware, that is, a revolutionary breakthrough in the detector or camera, the second is the progress of software computing methods. Previously acquired electron microscopy images, similar to our daily cameras, have experienced film and CCD two generations of detectors, but there are such and such problems, limiting the resolution of the increase. In the last ten years, advances in modern science and technology, such as materials science, physics, computer science, including data storage technology, have spawned detectors that can record electrons directly, supplemented by advances in image processing techniques and algorithms. The structure obtained from the image is propelled from a resolution of several nanometers to 2-4 angstroms, which is 0.2-0.4 nanometers, which is the atomic resolution that we often speak. Now the latest progress is already reached 1.5 angstroms, perhaps in a few years, with frozen electron microscopy to see the fine structure of the atomic level will become the norm, will be the most accurate level of understanding of the life process. The life process is dynamic, and we now see the photos are static. But you can imagine that these samples must be dynamic before freezing, then a picture should eventually be able to restore the various states before freezing, and now there is Professor Joachim Frank as the representative of the electron microscope expert theory and methods of exploration , Trying to restore a dynamic process from a static photo. I believe that in the future with the frozen electron microscope hardware and software technology to further breakthrough, combined with other imaging methods, we will observe the dynamic changes in intracellular biological macromolecules. 03
about the splicing body Wang Hao Yi: cut the body of this battle in the future to complete, the most interesting for you personally, the most important structural biology problem will be what? Shi Yigong: Three years ago, the famous British academic journal “Nature” made a comment to celebrate the X-ray crystallography for a hundred years. At the end of the year, two major “holy grails” of structural biology were proposed: one is the cut , The author who wrote the comment may be pessimistic, did not expect a year later we put the high-resolution structure of the splicing body made out; another called the nuclear pore complex, its molecular weight of more than 100 million Dalton, Dozens of times the body. Of course, the difficulty of splicing is that it is highly dynamic and has a variety of working conditions. We say that splicing the body does not refer to a complex, but refers to a series of different composition and structure of the complex, artificially classified to about 10 different macromolecule complex, every two between the great Composition and structural changes, which are collectively referred to as splicing bodies. For the nuclear pore complex I have just said, it is relatively relatively static relatively fixed supramolecular complex, and has eight symmetry. This complex is another major and unresolved problem in structural biology. Many of the world’s laboratories have been working on this issue, and now the best resolution has reached 20 Angstroms, of course, compared to the 3 -4 Egyptian resolution, it still has a great distance. In addition, as we understand the fine structure of the cell, there may be a number of supramolecular complexes that we may not have known before that, and together with the nuclear pore complexes become the new work of structural biology Direction, their atomic fine information will be gradually captured by our structural biologists, fundamentally deepen our understanding of life, fundamentally promote the process of precision pharmaceuticals. But in my case, the most interesting thing should be the splice. As I said earlier, this is a protracted war. We not only want to get their in vitro structure, we also want to see them in the cell within the dynamic combination and change, we want to design according to structural informationScreening of possible drugs. And I think that in the field of structural biology, how to obtain the high resolution structure of the molecule in situ, including its dynamic information will be a major direction. 04
Winner Feelings and “New People” Message Shi Yigong Award Reason
Wang Hao Yi: Then I put the two questions together, the first is that you get this year’s future science prize after the impression. The second is for the newly entered the field of life science research newcomers, what kind of your message or advice? Thank you. Shi Yigong: After winning the experience in fact quite a lot, of course, the first feeling is very excited, very excited, thanks to my nominees, peripheral review experts, as well as the award committee recognized my work; thanks my wife I also thank the two children for their sensible work and began to understand my father. I thank the Natural Science Foundation for reviewing the trust of the experts and the long-term funding of my research work. But the feeling is the biggest, which reflects the past decade of China’s long-term investment in basic research and development of China’s science and technology. Shear body structure of biological exploration, I was completely back to Tsinghua after the start from scratch, to explore the stalemate, and ultimately a breakthrough. I returned to Tsinghua University in 2007, Tsinghua University, undergraduate basic education is already a world-class, there is no doubt that the overall level of undergraduate education in Tsinghua University, the world leader. But tell the truth, even 10 years ago, even in Tsinghua Peking University, China’s best colleges and universities, we are still facing great difficulties in basic research, far behind the first-class universities in Europe and America, and the world’s leading level of the overall difference. So that schools like Tsinghua, if we want to recruit foreign first-class young talent to come back to serve as a teacher is very difficult. 2007, 2008, when I often feeling, if Tsinghua and the United States better research-based state university competition for young talent, our odds I think that was less than 10%, we are at a serious disadvantage. Ten years later, for example, in the field of life science, Tsinghua soldiers strong horse, we now the overall size than four years ago expanded four times, from the scientific research strength to expand more than one order of magnitude. I often encourage our teachers and students to say that Tsinghua is now more than the United States in general research-based state universities, both from the scientific research facilities or competitive strength is not just a little better, the outstanding young talent winners should be in the Eighty percent A few years ago in Tsinghua has just started an independent research career six or seven young professors by foreign first-class universities and first-class research institutions competing recruitment, which did not dare to think ten years ago! Now we have a lot of opportunities for teachers and students to communicate abroad, many people come back feeling the strength of domestic scientific research support, scientific research conditions. I walked all the way, looking back is indeed the past, compared with ten years ago has been turned upside down This progress is due to the country’s long-term investment in basic research in research universities, which makes us have such research conditions, to be able to make such achievements, to stand out, so I engaged in the field of structural biology, we are still Tsinghua’s structural biology center was selected in Beijing’s first high-tech center, even more powerful, and further strengthened our own research field to lead the world’s confidence. So I am very grateful to the state, Beijing and Tsinghua University perennial investment in basic research and attention. Another very strong feeling is that, although the future awards are rewarding individuals, but it really recognized is that we in the structure of the splicing structure of the breakthrough, and these breakthroughs of course I am not a person to do, I am only the team leader and Guidance only. Down to earth to contribute to my laboratory doctoral and postdoctoral students, a few stubble students, after ten years. We see the results of the present, but we do not see the early struggle, did not publish the results, behind it is also very good doctoral and postdoctoral, including from Wuhan University to Tsinghua postdoctoral, now in Huazhong Agricultural University Professor Yin Ping, Tsinghua University after graduation to join my laboratory for a doctorate, and now Harvard Medical School to do postdoctoral Zhou Lijun and her little assistant Zhou Yu Lin, as well as China University of Science and Technology after my doctoral students, and now the University of Washington, Seattle, Postdoctoral Lu Peilong, and so on, although their names did not appear in the article in the hatch structure of 2015, but they set up the system in front of a lot of way, in fact, the hero list should have their names. Then my doctoral and postdoctoral, especially after graduating from Tsinghua University, after graduating with my master’s degree postdoctoral Yan entrepreneurship, Sun Yat-sen University after joining my laboratory Wan Rui Xue, Wuhan University, Tsinghua University after joining the undergraduate, and then Followed by the white core, Zhang Xiaofeng, accounted for Xie Chao, Wang Lin, Huang Gaoxing Yu, and from the United States postdoctoral Lorenzo Finci, now have the latest generation to join in, they are really heroes. RNA operation for the technical requirements are extremely strict, they carefully designed experiments, meticulously analyze each of the results, fighting in our frozen electron microscope platform, cold room, sample, with biochemical, molecular biology means to optimize the best samples, Frozen electron microscopy to collect data. I am so lucky to have these students trust my judgment, willing to go with me to take risks and work hard to pay. They are really very good, without them can not get these breakthroughs. Professor Shi Yigong and his team based research, many young students may not understand when they feel very far away, and feel very esoteric, and even imagined too tall, it seems that every result is shaking ZZZZZZZZZZ The In fact, I would like to our undergraduate, our middle school students, our primary school students say, basic research is really esoteric, but also very simple. This process we can quickly adapt, not to say that you must be the number of math test points, how strong your physical basis of mathematics to do basic research, in fact, the basic research threshold is mainly from the interest and curiosity. I believe that when you are really interested in basic research, many people can do baseResearch, it is a threshold is not high, come in later can gradually through their own interest to develop a discipline of ability. And basic research once the entry, you will get endless happiness. I believe that not only me, all my research breakthroughs in the doctoral and postdoctoral will tell you to do basic research to get the joy and a sense of accomplishment. Especially after a breakthrough, this happiness is unparalleled, I think the world is a unique joy. I have a student once because the subject is not smooth, depressed to switch to work, work are good, in the South a consumer is not too high, the annual salary of 200,000. But in the last six months, he made a breakthrough, this kind of hard to let him change his mind, five years after graduation to the United States to continue to engage in postdoctoral research, recently told me he was very fortunate to adhere to the last. I understand his mentality, and there are more than one of these psychological changes, and I have experienced it when I was young. The world is the easiest thing that makes me fascinated by the unpredictable future, which is unknown to those parts. Every breakthrough in basic research has allowed us to step out our known boundaries of the human being in the universe, and that we have taken a step forward in the exploration of the unknown world; Researchers who break through this basic research, whether students, postdoctoral or professors, are part of the creation of history, and their research is linked to their names, which can not be described in words. I think many of my colleagues have experienced this feeling, I would also like to encourage our young students to maintain interest in scientific research. Wang Hao Yi: Thank you Shi Yigong teacher. Finally thank you again for your interview and once again congratulate you on winning this year’s Science Award for Life Science Award, thank you. Shi Yigong: Thank you everyone. 05 After the interview three scientists rigorous attitude is not only reflected in the scientific research, academic papers, etc., they also use a strict attitude to treat all aspects of life. Even time is an invaluable thing for them, but they will do their best to do everything that needs them to complete, even if only an interview. Praised the scientist with a grand prize, to pay tribute to the scientific spirit!

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