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In 2006, the first cancer vaccine in human history, the cervical cancer vaccine, was launched. Experts pointed out that the use of new vaccines may eradicate cervical cancer in a generation.

99.8% of cervical cancers occur due to human **nabioma virus (HPV), but today's cervical cancer vaccine is not produced with real viruses, but is produced with virus-like particles that were invented by Dr. Ian Fraser and Dr. Zhou Jian in 1991. This particle does not contain viral infection components but can stimulate the body to produce an immune response. This is a breakthrough in the history of human medicine. However, Zhou Jian failed to see this research results with his own eyes to benefit mankind. In 1999, he died of a sudden illness while visiting his country at the age of 42.

Zhou Jian’s wife Sun Xiaoyi was his assistant for 8 years. In 1991, Sun Xiaoyi personally synthesized the first virus-like particle. After many twists and turns, the reporter contacted her who was attending an academic conference in Europe. In a telephone interview for nearly two hours, she reviewed Zhou Jian’s life journey. She said: “Zhou Jian is actually just an ordinary researcher and a very simple person. To me, a competent husband, a good father to my son, and a serious researcher to scientific work.”

"I'm really standing on the shoulders of giants."

Zhou Jian and Sun Xiaoyi are both from Hangzhou. After graduating from high school, he went to the factory to work as a worker, and she went to the countryside to work in the lineup. In 1977, the college entrance examination was resumed, and the two were admitted to the medical major of Wenzhou Medical College at the same time. After five years of university, they met, got to know each other, and fell in love.

"We have completely different personalities. I am quite active. I either run on the playground or participate in various cultural and entertainment activities all day. He is very quiet and uses a tape recorder to concentrate on learning English every day. He likes my lively personality very much, and I also envy him for being dedicated to achieving excellent results." Sun Xiaoyi said: "After graduating from college, I naturally got together, which is also a kind of fate."

After graduating from university in 1982, Zhou Jian was admitted to Zhejiang Medical University to pursue a master's degree, studying pathology under the pathologist Professor Xu Yinghan, and worked very late in the laboratory every day. At this time, Sun Xiaoyi worked as an ophthalmologist at Zhejiang Provincial People's Hospital, and her home was across the street from the Medical University, so she often went to the laboratory to help Zhou Jian with cell culture work at night.

Zhou Jian completed his master's degree in two years and was admitted to Henan Medical University to pursue a doctorate. His supervisor Professor Shen Qiong is the founder of esophageal cytology in my country and uses histological methods to study esophageal cancer. Two or three months later, Zhou Jian had an idea: no longer study esophageal cancer from the perspective of molecular biology, but Sun Xiaoyi was worried that Shen Qiong was not a researcher in molecular biology. Will he oppose Zhou Jian's idea? But Shen Qiong said to Zhou Jian: "You are very good at breaking my ideas and doing molecular biology. I don't understand molecular biology at all, but I can send you to the Beijing Institute of Viruses to study."

Shen Qiong immediately introduced Zhou Jian to his classmate, Zeng Yi, who was the director of the Beijing Institute of Virology at the time. Zeng Yi introduced him to Gu Shuyan, deputy director of the Beijing Institute of Virology. At that time, Gu Shuyan had just returned from studying in Germany and was undertaking several projects of the national "Seventh Five-Year Plan" key research plan, specializing in HPV research. Sun Xiaoyi said: "Zhou Jian is very lucky. Teacher Gu likes him very much and teaches him step by step. Teacher Gu is an enlightener who really brought him into the enlightenment of using molecular biology methods to study HPV."

In 1986, after graduating from a doctorate, Zhou Jian entered the postdoctoral mobile station of the Institute of Biochemistry, Beijing Medical University, and followed the virologist Professor Zhang Naiheng to continue to do HPV research. At this time, his son Zhou Zixi was just born, and Sun Xiaoyi was seconded to the ophthalmology department of Peking University Third Hospital.

In 1988, Zhou Jian applied for research at the tumor and virus laboratory of the British Imperial Cancer Research Foundation (ICRF) at the University of Cambridge, and became the first Chinese researcher accepted by Professor Crawford, a pioneer in international HPV research. Sun Xiaoyi said: "Zhou Jian is extremely lucky that Lionel's laboratory is one of the top laboratories in the field of HIV and molecular biology in the international field. Lionel also likes him very much because he is a very creative person."

In 1998, when Zhou Jian's career was developing smoothly and had nearly 10 invention patents, he said: "I can achieve some success all depend on these teachers. I am really standing on the shoulders of giants."

Professor Crawford's laboratory has a lot of funds and good equipment. As long as he has ideas, he can do it. Zhou Jian's experiments in Cambridge are very meaningful, but he is too busy to get busy. He hopes that Sun Xiaoyi can come to the laboratory to help. In 1989, Crawford gave Sun Xiaoyi a visiting scholar position. Ten months after Zhou Jian arrived in Cambridge, Sun Xiaoyi came to him and became his assistant. But what she didn't expect was that this would take 8 years and experience the most exciting moments in their lives together.

Cambridge Encounter

In 1985, when Zhou Jian was concentrating on HPV in his doctoral stage, on the other side of the earth, after Ian Fraser obtained a doctorate degree from the University of Melbourne, Australia, he learned through reading the literature that cervical cancer is caused by HPV infection, so "I hope to develop a vaccine...to prevent this cancer."

In the same year, Fraser founded his own Immune and Cancer Research Laboratory at Princess Alexander Hospital, a teaching hospital in the University of Queensland, and decided to join the research of HPV and cervical cancer vaccines. At this time, Fraser held several positions: teaching, clinician and research. In 1989, he decided to use his academic leave to study in the laboratory of the Department of Pathology at Cambridge University. Professor Margaret Stanley's laboratory was right next to Lionel Crawford's laboratory. Therefore, "I was lucky enough to meet Dr. Zhou Jian from China not long ago," he said.

Fraser said that in Cambridge, Zhou Jian and his wife were called "magical fingers". Any difficult things can always be done in their hands. Sun Xiaoyi said: "At that time, Zhou Jian was just starting out, and I focused on being his assistant. We complement each other, he was very creative, had many ideas, I was more organized and skillful, and I had never contaminated cell culture. I could complete all the tasks I gave me carefully. Not only did we understand each other in life, but we also cooperated in the laboratory. As long as he looked at him, I knew what he needed. My colleagues said that we were working perfectly."

"Ian and Zhou Jian are very similar in many ways, and they work very hard," said Sun Xiaoyi. "Every morning, they must be the first to arrive at the laboratory, and they must be the last to leave at night. They are very compatible."

"We often meet at coffee time and talk about how we work together to achieve and validate some new ideas," Fraser said.

However, due to various reasons, the two did not have the conditions to cooperate in Cambridge. When Fraser was about to return to Australia, he kindly invited Zhou Jian and his wife to work at the University of Queensland's laboratory to work together. He had applied for a lot of funds and had the conditions to continue in-depth research. In 1990, Zhou Jian and his family came to Queensland.

Sun Xiaoyi said: "After we arrived at Kunming University, we continued to do the same topic, without wasting time at all, changing the laboratory did not bring any impact, and the progress was very smooth. Ian also supported us. In less than a year, Zhou Jian, the most important invention, had a bright future."

"We really synthesized a virus!"

HPV is a very small virus with a diameter of 45 to 55 nanometers. Scientists have been studying this virus for hundreds of years, but have never been successfully cultivated in the laboratory. And once it is stored in the host cell, it will fuse its genes with the host cell's genes. Therefore, it is impossible to see complete virus particles in vitro, and its research progress has been limited.

In the past, scientists have tried many methods to cultivate this virus in vitro. Zhou Jian and Sun Xiaoyi have been trying every possible way, but they have not succeeded. Sun Xiaoyi said: "We have tried many different methods, which is indeed difficult. There are still some progress in basic research and there are articles to publish, but I am really helpless about how to see this virus particle." If you can't get the virus, how can you start with the vaccine?

The couple is used to going out for a walk after their children go to bed. Zhou Jian often suddenly comes up with an idea after walking a few steps. Sometimes Sun Xiaoyi remembers it in the palm of her hand and returns to the laboratory for the experiment. One day at the end of 1990, they went out for a walk as usual. Zhou Jian suddenly said: "Our existing L1 and L2 (HPV late-stage protein, the main component of the virus shell membrane) is well expressed and purified well. Why not put these two proteins in the test tube and add certain conditions to see if there are any results?" Sun Xiaoyi said: "I laughed at him at that time. How could it be that possible? Just put two things together? If it were so simple, others had seen virus particles for hundreds of years. Is it still our turn?"

Half a month later, Zhou Jian asked Sun Xiaoyi if he had done the experiment. Sun Xiaoyi said, "I wrote it down at that time, but I don't think you are joking, right?" At the second urging of her husband, she "had a try-out mentality, and according to his ideas, put two existing HPV late-stage proteins in the test tube, add a little one and a little one, just like a kindergarten kid doing games, it's that simple."

About two weeks later, the two took the synthetic thing to an electron microscope to observe. "After seeing it, we were both stunned. It was really a virus particle synthesized. We actually saw a virus particle synthesized in vitro! This was a really pleasant moment."

Sun Xiaoyi said: "This is really lucky. We quickly told Ian about this result. He was so happy that he couldn't even close his mouth. This was a moment when we were very excited all our lives, and we inadvertently achieved this breakthrough."

Virologists all know the importance of this virus-like particle: this particle is an empty shell with no viral DNA core inside, so it is not infectious, but there are many antigens on the shell, which will stimulate the immune system and produce antibodies after entering the body, so it is a vaccine itself.

They used this HPV virus-like particle for animal tests, and an immune response appeared in the animal's body. Fraser and Zhou Jian published this result in the journal Virology, No. 185, 1991. In June 1991, the University of Queensland applied for a patent for this invention. In July of that year, the two reported the result at the International Conference on Taxovirus held in Seattle, USA. After the animal test was successful, they began to transfer to human clinical trials.

die young

When the clinical trials reached one stage, the University of Queensland was no longer able to pay the expensive scientific research costs, so it sold part of the patents to CSL, an Australian biotechnology company, and the company continued to do it. But it could not support it a few years later, because clinical trials were conducted in many countries around the world, requiring more funds, so some of the patents were sold to the stronger American Merck Pharmaceuticals.

Sun Xiaoyi said: "In every vaccine patent purchase and sale, these companies have to give Kunda a large amount of funds to continue the research. Our laboratory has received more funds and can do more experiments, so this is a positive cycle, which is very exciting."

With Fraser's encouragement, Zhou Jian was also studying for a doctorate in medicine from the University of Queensland while doing research. In 1994, a German professor established a new HPV laboratory at Loyola Medical University in Chicago, USA. Zhou Jian went to challenge him again, saying: "People should keep moving, learn new knowledge, and arm themselves." In Chicago, Zhou Jian had his own doctoral student and postdoctoral student, and he encouraged Sun Xiaoyi to take the Chicago Ophthalmology Qualification Examination, so Sun Xiaoyi returned to ophthalmology clinical.

In 1996, the University of Queensland provided Zhou Jian with a higher position. He returned to Australia with his family and established his own laboratory. In 1998, he received three funds from the Australian National Health and Medical Commission (NHMRC), plus the company's funding for vaccine research, and became the researcher who applied for the most NHMRC in the history of the University of Queensland at that time.

Clinical trials of cervical cancer vaccine are still being conducted around the world. Every March, Zhou Jian returns to Wenzhou Medical College to see the clinical trials conducted there. March 1999 is no exception, but no one would have thought that this became a journey without a return.

"Zhou Jian has always been in good health. He has not taken a day off for more than ten years abroad. His diligence is obvious to all. He often works 7 days a week and works day and night. In February 1999, he sat there all day writing fund application. After writing, he said, 'Why am I so tired?'" Sun Xiaoyi said, "I advised him to rest and not go to Wenzhou in March. But he insisted on going."

On the evening of March 8, 1999, Zhou Jian, who had just arrived in Hangzhou, called his home. His son said on the phone: "Dad, what gift do you buy for me when you come back this time? Buy me the latest lego (Liaogao assembly toy)!" Zhou Jian said: "No problem, I will definitely buy it for you." Sun Xiaoyi said to his son: "Dad is too tired, let him rest early."

On March 9, Zhou Jian was seriously ill due to septic shock. On March 10, when Sun Xiaoyi took Zhou Jian's mother and son to Hangzhou from Australia, he closed his eyes forever. 8 years later, Sun Xiaoyi was still sad: "It's too sudden. It's hard to believe that he really left me and it's hard to accept."

"The pain of water in the world is hard to write"
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