Academician Chen Runsheng: Thirty years of enlightenment and inheritance of bioinformatics in China are "big rivers"

Editor | Li Yuchen

Chen Runsheng remembered this day for more than 30 years, April 6, 1990, when he was 49 years old.

It was an ordinary day. It had been more than two years since Chen Runsheng returned to China from the University of Nuremberg in Germany and joined the Institute of Biophysics of the Chinese Academy of Sciences. During this period, he received funding from the "863 Protein Engineering" and was promoted to researcher.

He has been thinking about future research directions and read a lot of reports and discussions about the Human Genome Project (HGP).

On this day, Chen Runsheng saw an article published in Science by James Watson (known as the "Father of DNA"): "The Human Genome Project: Past, Present, and Future".

At the beginning of the paper, Watson wrote, “HGP will cost an order of magnitude less than the moon landing, but its impact on human life will be greater... When we can finally decipher the genetic information encoded in DNA molecules, it will not only It can help us understand what functions normal people have, and it can also explain at the chemical level the role of genetic factors in many diseases, such as cancer, Alzheimer's disease, and schizophrenia that kill thousands of people."

These descriptions made Chen Runsheng very excited - someone on the other side of the world had worked on the human genetic code. He decided to write a letter to Watson to express his understanding and support for this remarkable scientific event.

Chen Runsheng was just an ordinary scientific researcher at the time and had no reputation, while Watson had won the Nobel Prize as early as the mid-20th century and was the first director of the Human Genome Research Center of the National Institutes of Health (NIH).

The two were strangers and their identities were very different. "I wrote the letter without expecting any feedback or repayment. I couldn't find any colleagues in China. I just wanted to vent my emotions."

A month later, Chen Runsheng received an email from NIH. The letter was commissioned by Watson and written by the director of the U.S. Human Genome Project Office. Two materials were attached to the letter. One of them was the official text of the first five-year plan for the U.S. Human Genome Project, which had been treasured by Chen Runsheng for many years and had a wrinkled cover.

This text that traveled across the ocean opened up an important career direction for Chen Runsheng in the second half of his life, and also opened an important page in China's human genome research.

In 1987, Dr. Hwa A. Lim, a Malaysian Chinese working in the United States, first coined the term bioinformatics. He gave the definition of Bioinformatics: Bioinformatics is a new discipline that collects, analyzes and distributes genetic data to research institutions.

In October 1990, the Human Genome Project was officially launched in the United States, and the new discipline of bioinformatics also developed accordingly. In the official text of the U.S. Human Genome Project, genomic informatics is highlighted: it is a subject area that encompasses all aspects of the acquisition, processing, storage, distribution, analysis, and interpretation of genomic information.

In 1991, Chinese scientists discussed how to participate in genome research, and the burden fell on Wu Min, then 66 years old.

Wu Min returned to China after studying in the Soviet Union in 1961 and began to establish modern human cytogenetic research in China. In the 1970s, he devoted himself to the field of genetic etiology of esophageal cancer. He initiated and carried out gene therapy for human diseases in China. In 1986, he participated in the "863" Gene therapy research was carried out with funding.

By the 1990s, Wu Min held multiple positions, was elected as a member (academician) of the Chinese Academy of Sciences, and served as deputy director of the Department of Biology, Chinese Academy of Sciences. Motivated by the current situation, Wu Min became the leader of China's human genome project and bioinformatics.

In May 1991, Wu Min was appointed Director of the Life Sciences Department of the National Natural Science Foundation of China, a position he held until 1995.

Wu Min wanted to complete his participation in the HGP during his term. At the end of 1991, he submitted a proposal for a major project of the Chinese Human Genome Project to the NSFC, proposing and organizing a major project of the Chinese Human Genome Project.

Wu Min

This initiative won the support of many famous scientists in China, including Tan Jiazhen (the founder of modern genetics in China), Zou Chenglu (one of the founders of modern Chinese biochemistry, and then director of the Department of Biology, Chinese Academy of Sciences), Qiang Boqin ( Mainly engaged in research on the structure and function of genes related to brain development and neurological diseases), Chen Zhu (engaged in research on human leukemia and genes), Luo Liaofu (from physics to theoretical biophysics in the early 1980s), Zhang Chunting (from the mid-1980s to Physics turned to computational biology and bioinformatics), to name a few.

Zou Chenglu, Tan Jiazhen, Qiang Boqin, Chen Zhu, Luo Liaofu, Zhang Chunting

On the second day of the National Day in 1992, Wu Min slipped while getting dressed after swimming. He fell forward and landed on his face, which was covered in blood. X-rays later taken by the hospital revealed that the bridge of his nose was broken in two places and there was a seam on the tip of his left eyebrow. I took 5 shots and a tetanus shot.

At this time, it is a critical moment for the review of major project proposals of the China Human Genome Project. Four days later, there will be another defense before the Fund Committee. Zhao Zongliang, then deputy director of the Department of Life Sciences, was anxious but could not take his place.

On October 6, the defense was held as scheduled. Wu Mintou reported on the importance and far-reaching significance of the implementation of my country's Human Genome Project.

After many twists and turns in the defense, Wu Min finally passed the defense successfully. In his article “Me and the Science Foundation”, Wu Min mentioned: Fortunately, I was not infected.

On the other side, Chen Runsheng is also always paying attention to clues from domestic human genome research. This 42-year-old (1983) member of the Communist Party of China was eager to join the academic community.

Chen Runsheng carefully read the official text of the US HGP. He believes that information analysis, including sequence assembly and identification of functional elements, is the key to this project.

In 1992, Chen Runsheng learned that Wu Min was organizing a human genome research project in my country, but he did not know Wu Min, and did not know how to tell him his idea.

Chen Runsheng thought about it for a long time and was very afraid of being rejected. He learned that the team organized by Wu Min mainly came from medical research departments and there were no units or personnel from the Chinese Academy of Sciences.

At that time, Chen Runsheng was a researcher at the Institute of Biophysics of the Chinese Academy of Sciences. He was afraid of not meeting Wu Min directly and was afraid of being rejected, so there was no room for maneuver.

After much deliberation, Chen Runsheng asked his graduate student Xu Jun to give it a try.

Xu Jun studied at Tsinghua University as an undergraduate (now working in Los Angeles, California, USA). He is not only smart but also astute. Regarding the door-to-door visit, Chen Runsheng told him that if he could meet Mr. Wu, he would only talk about two points:

"First, they said in my name that I had contacted Watson and obtained the official text of the US HGP, and I had always wanted to return to the team. We do theoretical biological research, which is necessary and complementary to the genome research institute. They hope that we can participate and make up for the sequence assembly and data analysis. Second, we know that funding is tight, and we can do theoretical research with just computers and brains, regardless of funding."

Unexpectedly, Wu Min met Xu Jun smoothly and told Xu Jun to go back and wait for news. Here Wu Min immediately approached Qiang Boqin and Chen Zhu to discuss, and finally Qiang Boqin came forward to welcome Chen Runsheng's team to join.

Everything is difficult at the beginning, Chen Runsheng lamented: "If Mr. Wu had not met Xu Jun, I would definitely not have the opportunity to be the first to engage in bioinformatics research in China, nor would I become an expert in genomics and bioinformatics."

In March 1993, an important "China Human Genome Review Seminar" was held at the Institute of Radioactive Atoms in Wuxi, Jiangsu.

After full discussion, the NSFC committee finally approved Wu Min's proposal. After the meeting, Wu Min said, "This project has finally been approved after more than a year of multiple reviews."

Wu Min was 67 years old at that time. Considering that human genome research was a long-term task spanning centuries, young scientists should be entrusted with this important task. Therefore, he recommended Chen Zhu and Qiang Boqin, who were still young at the time, as the leaders of this project, and recruited a group of young and middle-aged scientific and technological backbones to undertake the main tasks of the project.

On September 28, 1993, an expert group organized by the Department of Life Sciences of the National Natural Science Foundation of China and headed by Professor Tan Jiazhen demonstrated and approved the "Chinese National Genome" application by Professor Qiang Boqin and Researcher Chen Zhu in Shanghai. "Research on the Gene Structure of Several Loci in China" major project, the China Human Genome Project (CHGP) was officially launched.

Although China's funding is only 3 million yuan compared with the US$3 billion that the United States spent to launch HGP, the project team still allocated funding for Chen Runsheng's project.

The task of Chen Runsheng's research group is to study methods for splicing, assembling and identifying functional elements (mainly coding genes) of DNA sequences.

To this end, they established various methods such as statistical analysis of DNA sequences, fractal dimension analysis, neural networks, complexity, local degeneracy, etc. In particular, they proposed cryptography methods for the first time in the world, and combined these methods to use For gene identification, etc., it improves the success rate of prediction.

Being able to apply cryptographic knowledge to DNA sequence analysis is also a coincidence.

Around the second half of 1991, Chen Runsheng heard that Professor Zeng Kencheng and Professor Pei Dingyi were organizing a cryptography training class. He wanted to see if the genetic code was related to codes used in the military or business, so he participated with Xu Jun.

It took Xu Jun about a year to fully participate in the training, while Chen Runsheng only attended the lectures.

Although they understood the basics, they also learned some methods and tried to change some formulas to be able to calculate the DNA sequence of four characters (CGAT), and the results were quite good. Therefore, cryptographic analysis technology also uses genome analysis.

Although Chen Runsheng's team developed and applied a variety of algorithms, only a few coding regions were found in the genome sequence. Through communication with colleagues at home and abroad, everyone gradually came to a consensus: there are very few sequences used to code proteins in the human genome.

Chen Runsheng said, "Initially the discussion was about 10%, but we soon discovered that 10% was also an overestimate."

Today, what the industry knows is that the gene sequences encoding proteins in the human genome only account for about 3% of the human genome. But in the early 1990s, although the proportion of coding sequences was not known precisely, "the concept that it was a small part was very clear."

At that time, many people in the academic circles at home and abroad called about 97% of "non-protein coding sequences" "junk" DNA, but Chen Runsheng had a bold idea: such a large proportion of "junk" is uncomfortable and illogical! I firmly believe that "junk" DNA must have a function.

At the end of 1993, Chen Runsheng decided to focus his research team's main efforts on the research of "genome non-coding sequences".

Although this research was constantly talked about at the Institute of Theoretical Physics, the Institute of Biophysics and some academic conferences, the external response and the progress of the research team were not significant in the first few years. The reason is simple: lack of experimental data.

At the same time, China's human genome research, promoted by Wu Min and led by Chen Zhu and Qiang Boqin, was still small in scale and only examined certain specific gene loci without conducting whole-genome sequencing.

In any case, China's human genome research has taken an important first step.

The development of China's human genome project and bioinformatics cannot be separated from the efforts of another group of people. They are Yang Huanming, Yu Jun, Wang Jian and Liu Siqi who later became the early backbone of BGI. They are younger and are witnesses and participants of the international HGP.

Since 1994, four people have returned to China one after another, prompting CHGP to begin to integrate with international HGP.

The four founders of BGI, from left: Wang Jian, Liu Siqi, Yu Jun, and Yang Huanming

In 1993, Yu Jun resigned from his position as a research assistant professor at New York University and joined the University of Washington Genome Research Center, where he became colleagues with Maynard V. Olson, one of the planners and leaders of the Human Genome Project.

There, Yu Jun participated in co-building the key physical mapping technology required by HGP, becoming the only Chinese scientist who participated in the project in the early stages and the person closest to HGP among the four.

Maynard V.Olson

In 1993, Yu Jun first found Wang Jian. They were both at the University of Washington. After discussing, they agreed that human genome research should be promoted in China. To this end, they also contacted Yang Huanming in Denmark and Liu Siqi in Texas.

In 1994, Wang Jian was the first of the four to return to China and founded Beijing GBI Biotechnology Co., Ltd. (GBI). He is an activist and full of challenges. This can be seen from his leadership in establishing the Seattle Chinese Biomedical Association in 1991 to his trips to the highest and deepest places in the world, as well as the North and South Poles.

Wang Jian made his first pot of gold through the hepatitis C and AIDS reagent business, and this money also became the start-up capital for the development of HGP in China.

Yang Huanming also returned to China in 1994 and entered the Institute of Basic Sciences of the Chinese Academy of Medical Sciences.

Back to Chen Runsheng. Chen Runsheng, who has been rooted in China for a long time, has noticed that China’s genome research team is growing. With the trend of scholars studying abroad returning home, he went abroad to exchange technical experiences with foreign colleagues.

In the ten years since 1994, Chen Runsheng has visited the Chinese University of Hong Kong, the University of California, Los Angeles, Harvard University, the Protein Research Institute of Osaka University in Japan, and the Taiwan Theoretical Science Center.

Most of these visits last for three months. Chen Runsheng explained, "Three months can accomplish something. Otherwise, if you go and chat with others, nothing will be accomplished."

Successive visits broadened Chen Runsheng's horizons. He became a scholar who turned to structural simulation very early and did a lot of analysis of electronic structures and spatial structures.

In September 1996, for his work in the fields of protein spatial structure simulation and DNA sequence analysis, he was invited by CODATA (the International Committee on Scientific and Technological Data, a first-level academic institution under the International Federation of Sciences) to give the "Masao Otani Memorial Ceremony" at the University of Tsukuba, Japan. speech" .

He became one of the three people who received the "Masao Otani" Award that year (named after the Japanese scientist. In 1960, Masao Otani founded the Japan Biophysical Society and was elected president of CODATA in 1978).

On the other hand, domestic genetic research is on the right track, and my country's bioinformatics has also made progress.

In 1996, two schools in northern Qing Dynasty took the lead in offering bioinformatics courses. Because it is a new subject, teachers and students do not have formal teaching materials, and the materials for reference are even scarce.

In order to promote the popularization of biotechnology disciplines, Chen Runsheng has focused on sorting out teaching handouts since he taught at the National University of Science and Technology in 1988. In eight years, Chen Runsheng's series of theoretical deduction manuscripts, foreign technical texts he consulted, and his work with colleagues at home and abroad became the most complete and detailed teaching handouts at the time.

In 1997, two heavyweight scholars joined: Academician Li Yanda, Director of Tsinghua Bioinformatics, and Academician Hao Bailin, Director of the Institute of Theoretical Physics, Chinese Academy of Sciences.

Chen Runsheng commented: They are people who have truly developed "shengxin" .

Since then, Sun Zhirong from Tsinghua School of Life Sciences also participated and became the number one person in organizing domestic bioinformatics academic conferences.

Today, Sun Zhirong is 75 years old and is still busy in the construction of disciplines ( this story will be a separate article, add the author WeChat icedaguniang to share and communicate in advance )

Li Yanda, Hao Bolin, Sun Zhirong

In November 1997, Yang Huanming, then director of the Youth Committee of the Chinese Society of Genetics, organized a seminar in Zhangjiajie, Hunan.

This is the first time that my country's academic community has held a seminar related to genomics. Yang Huanming, Wang Jian, Yu Jun and others proposed the strategic concept of China's Human Genome Project (HGP), which became the starting point of their common cause.

In 1998, Chen Shouyi, then director of the Institute of Genetics of the Chinese Academy of Sciences, and Zhu Lihuang, deputy director, invited Yu Jun, Yang Huanming and others to come to the Institute to establish an institute-level human genome center.

Yu Jun and Liu Siqi returned to China that year.

On August 12, 1998, the Human Genome Center (now the Beijing Institute of Genomics, Chinese Academy of Sciences), which Wang, Yang and Liu participated in, was established in Beijing at the Institute of Genetics of the Chinese Academy of Sciences. Yang Huanming was the director, Wang Jian was the executive director, and Yu Jun, Liu Siqi serves as deputy director.

Chen Shouyi, Zhu Lihuang

Chen Runsheng attended the founding meeting of the center.

After 24 years, he still vividly remembers the scene at that time: "I remember that the meeting was held in the yard in front of the main building of the Institute of Genetics. There was a small building on the side, which was specially vacated for the genome center. There were only tables and chairs in the room. Some of the tables and chairs are not complete, and there are no instruments and equipment. It can be said that they are in a state of poverty. "

All efforts are aimed at realizing China's genomic research and integrating it with international standards, but we must ensure that every penny is spent wisely.

Although Wu Min retreated to the second line at this time, his words are well known to everyone: " No one is allowed to engage in profit-making or commercial scientific research, and we must maintain the position of basic science. "

Therefore, before large-scale human genome sequencing, in order to prepare and train the team, in 1998, Tan Huarong’s team at the Institute of Microbiology, Yang Huanming’s team at the Institute of Genetic Development, and Chen Runsheng’s team at the Institute of Biophysics agreed to first conduct a complete microbial genome sequence determination.

This is the "research on deciphering the genome of Tengchong heat-resistant bacteria", which is regarded as "training" before the study of the human genome.

Before deciding to use Thermosporin B4, which was screened out from the Tengchong hot springs in Yunnan, as the research object, the three teams held a key meeting in the second-floor conference room of the Zhongguancun Institute of Microbiology's office building.

At that time, the Institute of Microbiology prepared four or five candidate microorganisms, the largest of which was about six million bases and the smallest of which was about three million bases. We analyzed various factors, such as whether it could lead to new discoveries, whether it could help explain the evolution of life, whether it had intellectual property rights, and most importantly, the lowest cost.

But a wise man will make a mistake after careful consideration, because he did not consider that the AT base content of this bacterial genome is very high (up to 62.4%) and the GC content is very low (only 37.6%). In the end, the total sequencing volume is not at all higher than that of a genome with a high GC content. A genome of six million bases is less.

This greatly increased the amount of sequencing required by Yang Huanming's team, as well as the difficulty of splicing and assembly.

Additionally, at the outset of this work, off-the-shelf software tools were not available. All the algorithms and programs for splicing, assembly and gene labeling were built from scratch by Chen Runsheng and his team and modified as they went.

Chen Runsheng’s students Xuan Zhenyu, Li Wei and Yang Jian became the main participants in this project, which also laid the foundation for their future participation in the work of the international HGP.

In September and October 1998, the National Genome Northern Research Center (directed by Academician Qiang Boqin, and the Honorary Director of the Academic Committee Academician Wu Min), and the Southern Research Center (directed by Academician Chen Zhu) were established one after another.

The establishment of the three research centers has officially launched the large-scale sequencing of CHGP , and has finally made China's journey to become an international HGP possible.

In the summer of 1999, Yang Huanming came to Wu Min's laboratory. He decided to participate in the International Genome Conference in Cambridge, England, and hoped to fight for 1% of the international genome sequencing work at the meeting.

This is the last meeting of the International HGP Cooperation Group to determine the tasks of each country.

Yang Huanming and the others knew that this might be their last chance to join. If we don’t fight to the death, the historic opportunity may be missed.

This idea received the support of Wu Min, and with the help of experts such as Maynard V. Olson, on September 1, 1999, Chinese scientists were invited to attend the fifth large-scale human genome sequencing strategy seminar.

Representative Yang Huanming attended the meeting alone with the 700,000 base pair sequencing results of the human genome sequence done 13 times, indicating that China was capable of undertaking 1% of the sequencing task and completed it in the late spring of 2000.

On September 5, 1999, the International Human Genome Sequencing Collaboration Group officially announced that China had become a member of the Human Genome Project and was responsible for a region of about 30 centimoles (equivalent to about 30 million base pairs) on the telomere side of the short arm of human chromosome 3. of sequencing and analysis tasks (also known as the "China volume"), which accounts for 1% of the human genome sequencing effort.

On this day, China finally became the sixth country to participate in the HGP after the United States, Britain, Japan, Germany and France.

On November 10, 1999, the 1% Plan was included in my country's national projects, and it was decided that BGI would take the lead, with the participation of the National Genome Southern Center and the National Genome Northern Center.

Just four days after the official announcement of the collaboration group, Beijing BGI Gene Research Center was officially established and moved to Building 6, Area B, Airport Development Zone, Shunyi District, Beijing.

In this factory, everyone has a grid work station (about 2 meters x 2 meters). The environment is open and the work station is the same no matter who it is.

At that time, the bioinformatics team had about 20 people, led by Wang Jun (former CEO of BGI and later founder of Carbon Cloud Intelligent Technology). Chen Runsheng's doctoral student Li Wei temporarily became Wang Jun's assistant.

Their primary focus is the integration and development of algorithms for large-scale genome splicing, assembly, and gene identification.

In order to complete the sequencing task on schedule, the sequencer was running day and night, and the people were divided into two groups, working day and night shifts. There was no laboratory table or duty room, and the night shift colleagues were responsible for several machines alone.

Calculate the time for each machine to be disconnected, set the alarm clock, put together a few small round stools from the laboratory, lie on them and cover them with clothes to sleep for a while. When the alarm clock rings, you get up to operate it. After all the tossing, you no longer feel sleepy.

In this team of mostly young people, Chen Runsheng is also one of them. At this time, Chen Runsheng held multiple positions. He was still a researcher at the Institute of Biophysics, Chinese Academy of Sciences. He also participated in the HGP project and became a member of the BGI team.

In addition, since 1999, he has been hired as a part-time doctoral supervisor by Li Guojie, then director of the Institute of Computing Technology of the Chinese Academy of Sciences, to help establish a computational biology team.

Although he had little time to do, Chen Runsheng took into account the urgency of HGP and gave it most of his time. "I spent 4 out of 5 days at the airport."

At that time, BGI was short of space, funds, equipment, and personnel. There are many difficulties and great pressure, but the only thing that is not lacking is determination.

They placed three corn cobs on the top of the sequencer, with a line of red letters printed on white paper underneath: The spirit of the poor cob will always shine!

A corner of the laboratory

In May 2000, Chinese scientists finally completed the determination of the draft genome sequence of the "China Volume". Among the six countries, it was the latest to participate and the earliest to complete.

On June 26, 2000, then-U.S. President Bill Clinton announced that “the most important and astonishing map ever created by mankind—the draft of the human genome—was completed.”

At the same time, a small celebration ceremony was held in Building 6, Zone B, Airport Industrial Zone. There were no flowers, no cheering crowds, and not even a group photo. The young people who participated in the China Volume calculated the time of the press conference, ate some fruit, and then dispersed.

After that, Chen Runsheng started the next research.

From the early 1990s to the beginning of the new century, the more he participated in genome analysis work, the more Chen Runsheng became convinced that non-coding sequences have biological functions. The reason why his research has made little progress is that there is too little experimental data.

At that time, there were not many people engaged in non-coding research internationally. To understand the functions of non-coding was equivalent to making a meal without rice. Chen Runsheng had an idea. At the end of 1999, he saw the vigorous development of domestic human genome sequencing experiments and the process of BGI achieving large-scale sequencing from scratch.

This gave him the idea of ​​setting up a wet lab to capture uncoded research data.

However, it is not easy to conduct molecular-level biological experiments for those who are engaged in theory. Talents, funding, and equipment are all problems.

Funding is best solved. After returning from studying in Germany, Chen Runsheng was absorbed into the Ministry of Science and Technology's "863 Protein Project" and later the CHGP project. Most of the funds allocated to him were not spent. In more than ten years, he saved 60 Ten thousand yuan.

With this funding, it will be easier for Chen Runsheng to start his work.

He invited Deng Wei from the Institute of Biophysics, who was good at experiments, to use the multicellular model animal C. elegans with up to 70% non-coding sequence as the entry point, and limited the length range of the transcript to 50-500 bases. Study the sequence.

In fact, there was no precedent for this experimental method at the time. Chen Runsheng's team designed the experimental process from scratch and explored experimental conditions and parameters. In order to save funds, Chen Runsheng took advantage of his position at the Institute of Computing Technology of the Chinese Academy of Sciences and borrowed the large computers there to conduct large-scale sequencing analysis.

This stay lasted for four years. In 2004, Rao Zihe, then director of the Institute of Biophysics of the Chinese Academy of Sciences, teased Chen Runsheng more than once, "You should return to the team soon, why do you always drift outside?"

Rao Zihe

It was these "wandering" experiences that led Chen Runsheng to establish two teams (currently more than 30 people in total) in the Institute of Computing and the Institute of Biophysics, and finally found a way in the non-coding field.

On the experimental side, Deng Wei recorded various explorations related to the experiment into more than 400 documents; on the theoretical side, Chen Runsheng's team established a set of its own non-coding gene prediction methods.

Benefiting from this extensive cross-research, they discovered 161 new non-coding genes in C. elegans, thus identifying two non-coding gene families and discovering three specific non-coding gene promoters.

More importantly, they confirmed that non-coding genes, like coding genes, each have an independent transcriptional regulation system.

By then, all the non-coding genes discovered by Chen Runsheng's team were included in GenBank (the most well-known nucleic acid and protein sequence database), and the paper was published in Genome Research with an impact factor of 11+ on January 6, 2006.

Three days later, "EurekAlert", a scientific review magazine affiliated with the American Association for Science and Technology (AAAS), also published a long article introducing the research results. It not only affirmed the above findings, but also pointed out that the efficiency of the experimental technology was 10 times higher than internationally.

Then, relying on the complete set of non-coding gene identification methods established in the nematode research, Chen Runsheng's team independently undertook the task of identifying non-coding genes in the human chromosome 3 map and discovered nearly 900 non-coding genes of various types.

These results were included in the paper on the complete map of chromosome three published in Nature in 2006.

Every achievement is hard-won, and there are still too few people willing to engage in non-coding research.

Since 2000, Chen Runsheng's team has begun collecting NcRNA genes and non-coding transcripts that have been experimentally confirmed internationally, developed corresponding software and retrieval tools, and built the NcRNA database - NONCODE.

This is currently the most comprehensive NcRNA database in the world and has become a basic data source for many studies. The academic contribution of this work is to propose a classification system for non-coding genes.

As soon as the article was published, "Science" introduced the work on January 21, 2005. Since then, Chen Runsheng's team has constructed a non-coding RNA and protein interaction database - NPInter, which has provided a data basis for international non-coding gene research.

Due to some experimental and theoretical achievements, the non-coding research of Chen Runsheng's team has had some impact both internationally and domestically, and future research has become easier to carry out.

Today, Chen Runsheng's research is still non-coding, but it focuses more on "practical application", such as nucleic acid vaccines and nucleic acid drugs. The long-chain non-coding nucleic acid drugs he led in the development are aimed at tumors, virulent viruses and infectious diseases, and aging.

Chen Runsheng has clearly pointed out in many reports and papers: The human genetic code represents all the information of the human body. Now only 3% can be used. Can the diagnosis and treatment of diseases be accurate? In fact, deciphering the genetic code has brought us countless new targets. If you could decipher the remaining 97% of non-encoded information, that would be a fundamentally original innovation.

During the conversation with Leifeng.com, Chen Runsheng answered a phone call midway. He said, "In the afternoon, the Beijing Development Zone will talk about building a base for nucleic acid drugs and vaccines. Basic research must be transformed at a certain stage, and we are busy with transformation now."

Following the country's "Four Orientations", Chen Runsheng has been engaged in non-coding research for 30 years, and gradually began to serve society and economic development because of the importance of the subject.

Recalling his decision to switch to non-coding fields in 1993, Chen Runsheng lamented the difficulty of getting started: he could not apply for funds from the National Science Foundation, and the reviewers declared that the work was meaningless and unfounded; he was not allowed to participate in the long-term funded "863 Protein Engineering" project.

"It was not until the late 1990s that we obtained the 973 project in the non-coding field. In recent years, as the chief researcher, I and my peers have obtained the National Key Research Program of the National Natural Science Foundation of China, which shows that we are on the right track in the non-coding field."

In the 1990s, the development of bioinformatics in China was almost synchronized with the international level, and the foundation was that China had an academic team of theoretical biophysics.

Chen Runsheng's establishment of bioinformatics courses in China and his brilliant performance at the HGP are closely related to China's theoretical research and the passing on of the torch from its predecessors.

In September 1959, Chen Runsheng was admitted to the Department of Biophysics of the University of Science and Technology of China (hereinafter referred to as "USTC"), becoming one of the 1,600 students admitted to the University of Science and Technology of China that year.

This group of students from all over China are not only the best in their respective provinces, but also have a common name, " the first batch of national unified examination students of USTC ."

Because USTC had just been established the year before, but missed the enrollment period, so students had to be "seconded" from other universities. Therefore, Chen Runsheng's class was particularly valued, and it was said that the admission score was slightly higher than that of Peking University and Tsinghua University.

The first president of the University of Science and Technology of China was Guo Moruo. He proposed the establishment of a science and technology university, determined the name of the school, established a university preparatory committee, and drafted the lyrics of the school song. He made all the decisions.

At the beginning of its establishment, the University of Science and Technology of China carried the common vision of my country's political and scientific circles. Yan Jici, Hua Luogeng, Qian Xuesen, Bei Shizhang, Qian Linzhao, Zhao Zhongyao, Guo Yonghuai, Zhao Jiuzhang, Wang Yuan, Gong Sheng and other scholars from the Chinese Academy of Sciences mobilized to form the teaching lineup of the University of Science and Technology of China.

Bei Shizhang, who was elected as the first academician of Academia Sinica and a member (academician) of the Chinese Academy of Sciences, is the core figure who has since promoted the development of biophysics in China.

Mr. Bei Shizhang

In 1958, when the school was founded, Bei Shizhang did two major things: establishing the Department of Biophysics of the University of Science and Technology of China and establishing the Institute of Biophysics of the Chinese Academy of Sciences (hereinafter referred to as the "Institute of Biophysics").

At that time, biophysics was still a controversial subject, with some well-known scholars even asserting: "There is only physiology, not biophysics!"

Bei Shizhang founded the interdisciplinary field of biophysics despite opposition and established a separate theoretical biology research group. The team leader is Zheng Zhuying, and the members are: Yu Xianzhang, Wang Xiangsheng, Chen Chuanjuan, and Wang Yunjiu.

Bei Shizhang gave specific guidance to the group members on their business directions. For example, he asked Yu Xianzhang to pay more attention to the structure and function of biological macromolecules, and asked Wang Yunjiu to focus on control and information in biological systems.

Group photo of comrades from the theory group (first row from left: Xia Fafa, Du Pu, Gu Fanji. Second row from left: Sun Wenqi, Zhu Jieping, Zou Jiayu, Zheng Zhuying , Shi Shuzhen. Third row from left: Wang Xiangsheng, Wang Yunjiu , Wan Fu Yuan, Zhang Jianming), taken in 1961

At the same time, in order to cultivate real cross-disciplinary talents, Bei Shizhang is also unambiguous.

He arranged for students in the Department of Biophysics to take physics classes with the Physics Department, math classes with the Mathematics Department, chemistry classes with the Chemistry Department, and the exams were also ranked with other departments, without any discount.

The unique teaching method has allowed Chen Runsheng to be cultivated by many teachers. Chen Runsheng said, "We usually discuss cosmology, particle physics, and Green's function with Mr. Qian and Mr. Peng today, and biology with Mr. Bei and Shen Shumin tomorrow."

In all examinations taken during the five years of the university, Chen Runsheng was ranked among the top three regardless of department. In May 1964, Bei Shizhang recommended outstanding students to the Institute of Biophysics, Chinese Academy of Sciences, and Chen Runsheng was one of them.

Thanks to the basic mathematical skills he has developed in the past, it is easier for Chen Runsheng to get started in theoretical biophysics.

However, due to current circumstances, many academic research groups no longer exist.

In March 1978, the Central Committee of the Communist Party of China held a National Science Conference. Deng Xiaoping pointed out that the key to the four modernizations is the modernization of science and technology, and emphasized the Marxist view that science and technology are productive forces. Scientific research finally resumed.

Chen Runsheng's theoretical research did not stop there, and he did a lot of macromolecular structure simulation. At the end of 1978, in order to further understand the theoretical basis of structure simulation, Chen Runsheng was sent to Jilin University to study theoretical chemistry for one year.

The person who teaches this course is none other than Tang Aoqing, who is regarded as the pioneer and founder of modern theoretical chemistry in China.

This professor, who was from Jiangsu and Zhejiang provinces like Chen Runsheng, was transferred to a Northeastern university in the 1950s, where he spent the rest of his life. Xu Ying 's father, Xu Ruren, who also settled in the Northeast due to transfer reasons , was a student of Tang Aoqing.

Chen Runsheng had a particularly deep memory of Tang Aoqing, in fact he was shocked by his academic research.

"Mr. Tang's eyesight is not good. He is 3000 degrees short-sighted when he wears those glasses. He almost writes on the blackboard. He always brings a box of chalk, a chalk eraser, and nothing else to class. From eight to ten in the morning Continuously push the formulas at two points, then erase it on the blackboard and continue. This is a basic skill (how thick it is).”

Tang Aoqing

Inspired by Tang Aoqing, Chen Runsheng set stricter requirements on himself in theoretical research. Once he was invited to teach quantum chemistry at Huazhong University of Science and Technology, deriving the formula throughout the process without changing a word from beginning to end.

In Chen Runsheng’s view, this is a way to temper himself, “If you don’t really understand and can’t remember the development of the theory clearly, it will be impossible to teach this class, and you won’t be able to explain it, and you will be stuck there. ”

At the same time, after 1978, Bei Shizhang took many measures to promote the reorganization and development of the Theoretical Biology Laboratory.

First of all, Bei Shizhang invited famous scientists in other fields such as Peng Huanwu and Qian Xuesen to explain the development and intersection of disciplines to the researchers in the institute, and substantively established the connection between biophysics and the disciplines of each expert.

Next is the establishment of a theoretical biology research laboratory.

Around 1978 to 1979, Bei Shizhang invited researcher Xu Jinghua from the Shanghai Institute of Biochemistry (hereinafter referred to as the "Shanghai Institute of Biochemistry") to serve as the Institute of Theoretical Biology jointly established by the Shanghai Institute of Biochemistry and the Beijing Institute of Biophysics. Director of the Research Office (hereinafter referred to as the "Joint Office").

By then, Chen Runsheng, Ding Dafu, and Wang Baohan will all be the main members.

After the Joint Office was established in 1980, with the support of Peng Huanwu, Xu Jinghua led its members to frequently participate in academic activities of the newly established Institute of Theoretical Physics, and also organized many theoretical biology-related discussions at the Institute of Theoretical Physics. For example: chaos, entropy, dissipative structure and the structure of living organisms, chirality and self-organization of biological macromolecules; the representation and characteristics of genetic information in DNA molecules, etc.

It can be said that the theoretical biology research at the turn of the 1970s and 1980s was gradually formed and on the right track under the organization and guidance of Bei Shizhang and Peng Huanwu, and through many discussions among a group of researchers from the two institutes. .

However, China's real exploration of the physical and mathematical characteristics of DNA sequences did not begin until 1982.

The first group to focus on DNA sequencing was Luo Liaofu’s team at Inner Mongolia University.

In 1982, Luo Liaofu led the team from theoretical physics to theoretical biology research. Throughout the 1980s, this team published many research results on DNA sequences and genetic codes, such as: S_4 symmetry breaking of mutation rate and stop codon ; Statistical analysis of nucleic acid starting sequences, termination sequences and insertion sequences; base distribution, homology and Markov properties of nucleic acid sequences; information parameters and molecular evolution of nucleic acid molecules; degeneracy rules of genetic codes, etc., and even discussed Understand why the genetic code is made up of four bases.

It is very important that Luo Liaofu's team has researched and developed theoretical methods for DNA sequence analysis, such as the fractal method; especially information theory methods, such as the maximum information principle and the average mutual information method of gene sequences.

After the mid-1980s, Zhang Chunting of Tianjin University was also engaged in DNA theoretical research.

In May 1984, Zhang Chunting was transferred to the Department of Physics, School of Science, Tianjin University. After that, he switched from physics to computational biology and bioinformatics, and published his first theoretical biophysics paper in 1987.

Zhang Chunting has made two major contributions in the field of theoretical biology research:

First, it was proposed in the late 1980s to use a system of double Sine-Gordon partial differential equations to simulate the dynamic mechanism of base movement of DNA molecules during transcription and replication;

Second, in the early 1990s, the Z-curve theory of DNA sequences was proposed, opening up a new way to analyze DNA sequences using geometric methods. At present, Z-curve theory has been widely used in genomics and bioinformatics.

The third team is Chen Runsheng’s team.

In fact, Chen Runsheng did research on DNA theory in the 1980s.

In 1982, at a theoretical biology seminar, Luo Liaofu was invited to share a report on DNA sequence analysis, and Chen Runsheng discussed the analysis of nucleic acid sequences with him.

At the end of 1987, Chen Runsheng's two-year study tour in Germany ended. At this time, there was already an international trend to decipher the human genetic code (ie "DNA"). Chen Runsheng made an important judgment: genetic code will be a very important direction in the future. .

Funded by the "863" project, Chen Runsheng quickly turned to genome sequence research, and continued this part of the work into the CHGP project in the early 1990s.

In general, from the 1980s to the early 1990s, China has made great achievements in the theory of DNA sequence analysis. Particularly typical ones are: Luo Liaofu's team proposed the informatics theory of DNA sequence analysis, and Zhang Chunting's team proposed the DNA sequence analysis. Based on the geometric theory, Chen Runsheng's team proposed the cryptographic theory of DNA sequence analysis.

And if we look at it from a longer-term perspective, since the 1950s, Bei Shizhang, Peng Huanwu, Xu Jinghua, Jiang Shouping, Ding Dafu, Wang Baohan... these seniors have all contributed to China's participation in the human genome project in the 1990s. An important foundation has been laid in the career.

"I'm not depressed. People can achieve things through judgment and perseverance."

Talking about the choices he has made over the past few decades, Chen Runsheng's voice was clear and powerful, "Most of my decisions have not followed others' decisions, and have been doubted and opposed by many people. This requires your own persistence. Persistence lies in your own judgment, and the two are complementary." ’: His judgment is not firm enough, and many people suffer from this. He is smart enough and has thought about it, but if he doesn’t persist, he will not succeed due to various circumstances.”

Chen Runsheng is still used to clocking in at the office 365 days a year. One New Year's Day, Chen Runsheng went to the Institute of Biophysics, Chinese Academy of Sciences as usual, and met the only other person on that day, Wang Zhizhen.

Chen Runsheng recalled the scene that day and said, "From a distance I saw someone escorting another person. When I got closer I saw it was Wang Zhizhen. I asked her if she was here too, and she said she was here too."

Wang Zhizhen waved her hand to tell her colleagues not to follow. She and Chen Runsheng were classmates. They were both top students at the University of Science and Technology of China. Neither of them had been in the top three in five years.

Since then, Wang Zhizhen has made important contributions in the study of protein folding, the interaction and recombination of folding enzymes and molecular chaperones insulin A and B chains, and became academicians successively with Chen Runsheng.

That day, the two of them talked about teachers, students, and finally Chen Runsheng talked about himself and bid farewell to his old classmates with a smile.

He said, "There are still many things waiting for me to do."

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