Three scientists’ rocky journey from unknown pathogen to Nobel Prize.
Author: Maja Bronowska
Editor: Sophie North
Artist: Zach Ng
Hepatitis C virus, an agent that currently infects over 70 million people worldwide, remained unidentified until three decades ago. The infection can lead to chronic inflammation of the liver, which may eventually progress to cirrhosis or even liver cancer. In some cases, liver damage is so gradual and surreptitious that patients show no clinical symptoms for years. The Nobel Prize in Physiology or Medicine for 2020 was awarded to three scientists who discovered hepatitis C virus ‒ Harvey J. Alter, Charles M. Rice and Michael Houghton.
Hepatitis infections were first identified at the beginning of the 20th century. They were thought to be accounted for by two strains of the virus: hepatitis A, transmitted via contaminated food and water, and hepatitis B, transmitted by blood. In the 1960s and 70s, advancements were made in the field with the development of diagnostic tests for hepatitis A and B infections and a vaccine for hepatitis B. But many patients presenting clinical symptoms of hepatitis appeared not to be infected with the known strains of the virus, leaving those infections unexplained.
Alter and his team, in the mid-1970s, made a breakthrough when they demonstrated that the cryptic infections were caused by an unidentified infectious agent. Originally, he studied hepatitis cases in blood transfusion recipients, and proved that screening for hepatitis B reduced the risk of the infection. However, even with well-developed screening protocols for hepatitis B in place, many transfusion patients still contracted the infection. Hepatitis A couldn’t be responsible as it is not a blood-borne infection. Alter transfused plasma of those patients to chimpanzees, who subsequently developed the disease. This experiment proved that the unexplained cases of hepatitis were caused by an infectious agent, very likely a new hepatitis virus.
In the 1980s, knowing that the infection could be induced in chimpanzees, Houghton and his team isolated DNA fragments from infected chimpanzees’ blood, which they anticipated would contain unfamiliar sequences of the new hepatitis virus. They then took sera from hepatitis patients, as they believed it must contain antibodies for the virus. After numerous attempts, they successfully cloned the virus by inserting the viral chimpanzee-derived DNA into a bacterial vector and using human antibodies to screen for the virus. This innovative molecular technique had never been used before to search for a new viral genetic sequence. It pioneered the development of effective blood screening for the presence of the virus.
Nevertheless, whether the hepatitis C virus alone could account for the disease was undetermined. The third scientist, Rice (and his colleagues), put considerable effort into answering this question. They attempted to inject the cloned pathogen into animals and induce the disease, but this was unsuccessful as viral replication was not triggered. The scientists conducted a thorough analysis of viral DNA sequences, in which they discovered that the clones had acquired mutations, making the virus defective. After repairing the mutations, Rice demonstrated that hepatitis C virus alone was capable of inducing the disease in host organisms.
The three lead scientists entered the battle against hepatitis C virus and have made a tremendous contribution towards its decline. Their discoveries facilitated the development of highly sensitive blood tests that to this day make blood transfusion safer by eliminating the risk of post-transfusion hepatitis. Moreover, a better understanding of the pathogen and how it works led to the discovery of antiviral drugs targeting the hepatitis C virus. Since 2011, direct-acting antivirals (DAAs) that cure the infection have been made available. In 2016, 86% of patients who started treatment worldwide received DAAs, with Egypt accounting for 40% of these. In 2017, access to DAAs increased, so more low-income countries joined the programme and many more lives have been saved. Although hepatitis C has been present in society for a long time, the identification of the pathogen has given us a real possibility of eradicating the disease.
The World Health Organization set a goal to eliminate hepatitis C as a major threat to public health by 2030. Further development of drugs and screening programmes are promising, and survival rates are significantly increasing. Although the drugs can cure more than 95% of infected patients, they might not be enough to fully eradicate the virus. Ultimately, we need an effective vaccine ‒ but with the COVID-19 pandemic ongoing, priorities have changed, and hepatitis C virus research has taken a backseat. The virus has now been known for 30 years, yet there is still no vaccine. This Nobel Prize victory brings hope that this will change, as hepatitis C has become a focus of attention once again.
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