Experts explain: Why did the work on hepatitis C virus win the 2020 Nobel Prize? China aims to eliminate the threat of hepatitis C by 2030

This is the first time in human history that a chronic disease has been cured by medicine. It is a very classic example of basic research promoting the development of human medicine and humans using science as a weapon to defeat disease.

Written by | Fanpu

On October 5, 2020, three scientists, Harvey J. Alter, Michael Houghton and Charles M. Rice, jointly won the 2020 Nobel Prize in Physiology or Medicine for their discovery of the hepatitis C virus.

The three people's work is roughly as follows: Harvey J. Alter discovered hepatitis C; Michael Houghton isolated the RNA fragment of the hepatitis C virus (HCV-RNA), making it possible to detect the hepatitis C virus at the molecular level, which quickly made the hepatitis C virus almost extinct from blood transfusions and blood product supplies, avoiding a large number of hepatitis C infections. At that time, the bottleneck restricting the development of hepatitis C drugs was that the hepatitis C virus was extremely difficult to replicate in a laboratory environment, and Charles Rice found the "consensus sequence" of the hepatitis C virus and established a cell line that efficiently replicated the hepatitis C virus.

There are two noteworthy changes in this year's Nobel Prize: first, this year's Nobel Prize prize money has increased by 1 million Swedish kronor compared to last year, reaching 10 million Swedish kronor (about 7.6 million yuan); second, the traditional award ceremony and dinner to be held in December was cancelled due to the new crown epidemic and changed to an online event.

According to the Chinese Center for Disease Control and Prevention (CDC), hepatitis C is a contagious disease mainly transmitted through blood. After infection with hepatitis C virus (HCV), the chronicity rate is 55%~85%. The incidence of cirrhosis in the general population 20 years after infection is 5%~15%. The annual incidence of HCV-related hepatocellular carcinoma (HCC) in patients with cirrhosis is 2%~4%.

At the 69th World Health Assembly, the World Health Organization set the overall goal of "eliminating viral hepatitis by 2030". On World Hepatitis Day on July 28, 2020, Liu Zhongfu, Secretary of the Party Committee of the Center for STD and AIDS Prevention and Control of the Chinese Center for Disease Control and Prevention, said that hepatitis C is a serious public health threat. There are more than 7.6 million hepatitis C patients in my country. If they cannot receive timely treatment, 15-30% of them will develop a series of health problems such as cirrhosis, liver failure and even liver cancer within 30 years, which seriously threatens the life and health of patients. He said that with the advent of direct antiviral drugs (DAAs), the vast majority of hepatitis C patients can be cured in 3 months.

In recent years, Chinese authorities have intensively approved a number of direct-acting antiviral drugs for hepatitis C for domestic marketing, and a variety of direct-acting antiviral drugs have also entered the national medical insurance catalogue, which brings the overall goal of 2030 one step closer.

Fanpu Interview 1 Interview with Ding Qiang, a researcher at Tsinghua University School of Medicine Fanpu: The 2020 Nobel Prize in Physiology or Medicine was awarded to three scientists, Harvey Alter (USA), Michael Houghton (UK) and Charles Rice (USA), in recognition of their contributions to the discovery of the hepatitis C virus. Why did these three win the prize?

Ding Qiang: The first winner, Harvey Alter, was the first person to recognize this disease (hepatitis C). In the 1970s, he proposed that this was a new type of hepatitis, different from the previously discovered hepatitis A and hepatitis B, and caused by a new virus. In 1989, Michael Houghton finally discovered this virus and named it Hepatitis C Virus (HCV for short), which was the first time that humans used molecular biology technology to discover a new virus. In the following years, Charles Rice developed a series of systems to study this virus, which eventually gave scientists the tools to do basic research related to HCV and screen anti-HCV drugs, which led to the launch of hepatitis C drugs in 2013, which can almost 100% cure this chronic disease. As a new disease, it took almost 40 years from the discovery of hepatitis C to its complete cure. This is the first time in human history that a chronic disease can be cured by drugs.

Therefore, we can see that the work of these three award winners is a continuation of the past and a gateway to the future.

In 2016, Ralf Bartenschlager, Charles Rice, and Michael Sofia, a scientist who found the drug sofosbuvir to cure hepatitis C, won the Lasker Award. But Sofia did not win the Nobel Prize this time, which also reflects the Nobel Prize's emphasis on the most original work.

Fanpu: We know that you have worked in the HCV field for a long time and have had interactions with Professor Rice. Can you give us a detailed introduction to his work?

Ding Qiang: My postdoctoral advisor is Professor Alex Ploss of Princeton University, who once worked in the Rice laboratory. I have been engaged in HCV virology research since my graduate studies, so I have come into contact with Charlie in many meetings and I am also good friends with many people in Charlie's laboratory.

Charlie started studying flaviviruses when he was a graduate student at Caltech. His most famous work was cloning the Yellow Fever Virus (YFV). Since 1986, Charlie has been an assistant professor at Washington University in Louis, where he established a reverse genetics system for YFV. In 1989, he noticed the new virus HCV discovered by Michael Houghton. Both HCV and YFV belong to the Flaviviridae family and have some similarities. At that time, the successful development of the YFV vaccine led to a gradual reduction in related research funding, so Charles turned to the study of HCV. He and Professor Ralf Bartenschlager of Heidelberg University in Germany independently established a system for studying the replication of hepatitis C, called the replicon system. It was with this system that people discovered the effective anti-HCV drug sofosbuvir. In 2001, Charlie joined Rockefeller University. After that, he established a system that could study the entire life cycle of the virus, discovered the receptor for HCV, and established a humanized mouse model for studying HCV infection. It can be said that Charles has done a series of groundbreaking work in this field.

Charles pays great attention to the cultivation of students and postdoctoral students in all aspects, and his students are all over the world. Many researchers in this field come from his laboratory, and many of them are professors at world-class universities. Some Chinese scientists have also been trained in his laboratory, such as Professor Yuan Zhenghong and Professor Yi Zhigang of Fudan University. Recently, Dr. Wu Xianfang from his laboratory has just been awarded a teaching position in Cleveland to establish his own laboratory. Charles likes to raise dogs and walk dogs. He has two dogs in the laboratory, and he also likes to make wine.

Fanpu: What do you think when you learn that this year's Nobel Prize in Physiology or Medicine was awarded to the field of hepatitis C virus research?

Ding Qiang: I am particularly encouraged by the award in the field of Hepatitis C, which fully demonstrates the contribution of basic research to human medicine. We first recognize a disease, then find the pathogen that causes the disease, and at the same time establish a research method for this virus, and finally find a drug to cure the disease - this is a very classic example of basic research promoting the development of human medicine and humans using science as a weapon to defeat disease.

2 Exclusive interview with Niu Junqi, President of the First People's Hospital of Jilin University and Editor-in-Chief of the Journal of Clinical Hepatobiliary Diseases: You have been working in the field of infectious diseases. Please talk about the significance of the work of the three winners from the perspective of infectious diseases.

Niu Junqi: It took about 29 years from the discovery of the complete sequence of the hepatitis C virus to the final cure. This is the fastest victory in the history of human beings against pathogenic diseases, and it is also a miracle to defeat the virus. From the perspective of infectious disease workers, we have always expected the research on hepatitis C virus to win the award, and we think this field should have won the award earlier. Therefore, the three winners today are well-deserved.

After the hepatitis B virus was discovered in 1965, people found that in addition to type A and type B, there was also a "non-A, non-B" hepatitis, which was Alter's contribution. Since then, people have used all the technical means at the time to study this new hepatitis. Finally, Michael Houghton, who worked at Chiron Pharmaceuticals, led a research team to cooperate with the US NIH, first isolated and identified the viral genetic sequence, and further found the antigen, and established an antigen-antibody dependent test kit, which provided a precise method for diagnosing hepatitis C virus infection. The research on hepatitis C virus has since entered the fast lane.

At the same time, the establishment of screening methods also solved the problem of transfusion-related hepatitis. Around 1993, China began to screen blood transfusion sources for hepatitis C virus, and since then, the problem of hepatitis C transmission caused by blood transfusion has been generally eradicated.

So far, HCV cannot replicate in cell models or animal models, but Charles M. Rice has established a pseudovirus particle that can simulate the replication process of HCV in cells. It is by using this model that people have found drugs to fight HCV. Now, for different target sites of HCV, such as NS3A\NS4A\NS5B, various small molecule drugs have been developed to effectively fight HCV, bringing the cure rate of HCV to 95%.

Fanpu: So what is the situation of hepatitis C screening and treatment in China?

Niu Junqi: Charles M. Rice once gave a speech at the American Association for the Study of Liver Diseases. He said that "the study of Hepatitis C virus has become a thing of the past", but this is not the case for China. China is still the country with the largest number of hepatitis C virus infections, and the number of diagnosed patients accounts for only 19% of all patients. There are still a large number of hepatitis C patients who have not been discovered. We also look forward to the continuous improvement of the country's screening policy.

Today's drug treatments are very cheap. It only costs about 14,000 yuan and takes about three months of treatment to cure a hepatitis C patient, and the cure rate can reach 95%, which is a remarkable achievement.