Shri Vinoba Bhave Civil Hospital
As the entire world is watching the pandemic of Covid-19 unfold in front of them, they have witnessed the speed at which the fight against the disease is progressing. Since the first genome sequence of SARS-CoV-2 was released online on January 10, 2020, various diagnostic tests have been developed. Different treatment options have been predicted virtually and tried, and vaccines have been developed and tested worldwide within a span of 10 months. So, when the Nobel Prize in Physiology or Medicine 2020 was announced for the discovery of hepatitis C virus, it was a surprise to the common public, few of the scientific community, and even to the reward recipients, the trio, Harvey J. Alter, Michael Houghton, and Charles M. Rice. The surprise because the discovery of Hepatitis C was 30 years ago and compared to the scientific discovery of SARS-CoV-2, the discovery of Hepatitis C took around 30 years of painstaking research collaboration. Nevertheless, many from the scientific community were not so surprised. The three scientists fought a similar kind of battle decades ago to discover Hepatitis C, but without the advancement of recent sequencing technology. As explained by one of the Nobel Committee, getting a blood transfusion before discovering the hepatitis C virus was a bit like Russian roulette. Their work has benefited millions of people by having a safe blood transfusion on safe blood products.
The hepatitis C virus is transmitted via blood. Most of the hepatitis C cases recover quickly, but some develop chronic inflammation of the liver that slowly destroys the organ over the years. It ultimately leads to cirrhosis or liver cancer, which are sometimes only treatable through liver transplantation. As per the latest report, the World Health Organization estimated over 70 million hepatitis C cases globally and 400,000 deaths annually. It is one of the most common cause of liver cancer and liver transplantation. In India, to combat various types of viral hepatitis, The National Viral Hepatitis Control Program has been launched by the Ministry of Health and Family Welfare, Government of India on the World Hepatitis Day 28th July 2018. Both the Indian Government and WHO has set a goal of eradicating Hepatitis C by 2030.
Around half a century ago, recipients of blood transfusions were at higher risk of liver disease. In 1967, Baruch Blumberg discovered the hepatitis B virus, which won him one half of the 1976 Nobel Prize in Physiology or Medicine. This was an important discovery, but it did not explain all the chronic hepatitis cases seen in patients who had a blood transfusion. It became clear that another agent was responsible for blood transmitted hepatitis, and an improved understanding was required to identify blood donors who were carriers for the diseases. In the late 1960s, Harvey J. Alter, who was then working at the blood bank, began to suspect an unknown pathogen responsible for causing the disease and became motivated to investigate the source of post-transfusion hepatitis. To find its cause, he tested the blood supply for the presence of known viruses and followed individuals who developed hepatitis after a blood transfusion. In 1978, Alter demonstrated using one of the principles of Koch’s postulate that plasma from patients with unexplained hepatitis could cause the disease when transferred to chimpanzees. Further work by Altar and colleagues over the following years showed that the diseases was likely caused by an agent having properties similar to that of the virus. This was one of the first steps of the puzzle solved by Alter’s work spanning over the years.
After determining the transmission, the next step was to isolate the virus, which was a challenge at that time and took several more years. In 1988, Houghton and his colleagues Qui-Lim Choo and George Kuo, working at Chiron Corporation, introduced genes from an infected animal to bacteria and, using human antibodies against the virus, screened for its genetic sequence. Out of 1 million bacterial colonies they screened, most of the genes belonged to apes, and they could find only one cloned which coded for a protein from the virus. According to Houghton, they must have tried 30 different approaches at least over seven or eight years in order to identify the virus. For the first time, this type of molecular biology and immunology approach had been used to identify the virus. The gene from the positive clone resembled sequences from flaviviruses, and they named the virus hepatitis C. Using this technique Houghton and his group further developed a blood test to identify hepatitis C. This allowed blood samples from around the world to be screened, leading to dramatic decreases in the number of post transfusion cases of hepatitis, making blood transfusion safe. Identification of the virus was the second step of the puzzle solved by Houghton and his group.
The third and last step of the puzzle was to replicate the virus and check whether the hepatitis C virus alone was responsible for causing the disease or if it needed assistance? Charles Rice and his colleagues working at Washington University used the initial version of the virus that was cloned by Houghton. However, the virus failed to replicate and caused diseases when infected in the chimpanzee.
On comparing the sequence of many viral clones, Rice found out that the virus contained many genetic mutations, as is the case with many RNA viruses and thus rendered them inactive. He then worked out a functional sequence by removing mutations, and this cloned virus was able to cause hepatitis C in chimpanzees. Rice used genetic engineering techniques to construct hepatitis C virus in the lab and demonstrate that it is solely responsible for the unknown post-transfusion liver diseases solving the last puzzle piece.
The research of all the three Nobel laureates and others has led to significant improvements in the diagnosis and treatment of Hepatitis C. Development of antiviral treatment can cure about 95 % of hepatitis C patients and thus have saved millions of lives worldwide. Hopefully, the Nobel prize will regain attention to hepatitis C and the need for vaccine development, raising hope that it would eventually be eliminated.
As mentioned by Rice, the effort of all the scientists involved in understanding hepatitis C is a beautiful story of a kind of chain of discovery over a long period of time where each team handovers their work to the next team and so on. A similar kind of story is going on against the fight for the COVID-19 pandemic. According to Alter, these stories need to be told to the next generation so that they, too become virus hunters.