October 6th 2020
The 2020 Nobel Prize in Physiology or Medicine has been jointly awarded to Harvey J. Alter, Michael Houghton, and Charles M. Rice, who have made a decisive contribution to the fight against blood-borne hepatitis, a major health problem that causes cirrhosis and liver cancer in people around the world.
Inflammation of the liver, or hepatitis is primarily caused by viral infections, although it can also be caused by alcohol abuse, environmental toxins, and autoimmune diseases.. In the 1940’s, scientific evidence highlighted two main types of infectious hepatitis. The first, hepatitis A, is transmitted from the ingestion of polluted water and food. The second type, to which Hepatitis B and C belong, is transmitted through blood and other bodily fluids. It is much more serious than Hepatitis A, as it may present as a chronic condition resulting in cirrhosis of the liver and/or liver cancer.
Baruch Blumberg, in the 1960’s, determined that one blood-borne form of hepatitis was caused by a virus–later termed the Hepatitis B virus–and the discovery led to the development of diagnostic tests and an effective vaccine. Blumberg was awarded the Nobel Prize in Physiology or Medicine in 1976 for this discovery.
Knowledge about the cause of Hepatitis B as well as the development of a preventive vaccine owes much to #animalresearch. Formative research including the first vaccine trials were performed with chimpanzees, and subsequently in other non-human primates, ducks, tree-shrews, woodchucks, and several mouse models.
This year’s Nobel Prize was awarded to Harvey J. Alter, Michael Houghton and Charles M. Rice, for their discovery of another blood-borne form of hepatitis, Hepatitis C. After the 1960’s discovery of Hepatitis B, Dr. Alter was studying the occurrence of hepatitis in patients who had received blood transfusions. Even after accounting for transfusion-related hepatitis cases from Hepatitis B, a large number of post-transfusion hepatitis cases remained unexplained. Moreover, tests for Hepatitis A failed to account for these cases.
Alter and his colleagues demonstrated that blood from the patients of these unexplained blood-transfusion related cases could transmit the disease to chimpanzees. They later showed that the agent was indeed a virus and a variant of chronic viral hepatitis. The mysterious illness became known as “non-A, non-B” hepatitis.
Michael Houghton, one of the shared winners of this year’s Nobel Prize, set out to isolate the genetic sequence of the virus. Houghton and his colleagues created a collection of DNA fragments from nucleic acids found in the blood of an infected chimpanzee. They predicted that within these fragments they would find the virus. On the assumption that antibodies against the virus would be present in blood drawn from hepatitis patients, the investigators used patient sera to identify cloned viral DNA fragments encoding viral proteins. Following a comprehensive search, one positive clone was found. Further work showed that this clone was derived from a novel RNA virus belonging to the Flavivirus family and it was named Hepatitis C virus. The presence of antibodies in chronic hepatitis patients strongly implicated this virus as the missing agent.
The discovery of Hepatitis C virus was decisive; but one essential piece of the puzzle was missing: could the virus alone cause hepatitis? To answer this question the scientists had to investigate if the cloned virus was able to replicate and cause disease. Charles M. Rice, the third recipient of this year’s Nobel Prize, along with other groups working with RNA viruses, noted a previously uncharacterized region in the end of the Hepatitis C virus genome that they suspected could be important for virus replication. Rice also observed genetic variations in isolated virus samples and hypothesized that some of them might hinder virus replication. Through genetic engineering, Rice generated an RNA variant of Hepatitis C virus that included the newly defined region of the viral genome and was devoid of the inactivating genetic variations. When this RNA was injected into the liver of chimpanzees, virus was detected in the blood and pathological changes resembling those seen in humans with the chronic disease were observed. This was the final proof that Hepatitis C virus alone could cause the unexplained cases of transfusion-mediated hepatitis. There is currently no vaccine for Hepatitis C; although early testing and treatment with antivirals, which were also developed using animal models, can cure Hepatitis C within 8-12 weeks.
Importantly, the chimpanzee is the only immunocompetent animal fully susceptible to Hepatitis B and C. Until 2011–when chimpanzee research was banned from biomedical research in the US–the chimpanzee was a major component of research on this virus, possessing the potential to evaluate vaccine candidates due to their close genetic relatedness to humans; we possess greater than 98% genetic similarity. Thereafter, the search for surrogate viruses in other animals were employed in research, for example: the George Baker virus B (GB Virus B, GBV-B), the guereza hepacivirus (GHV) found in black-and-white colobus monkeys, the GBV-B-like virus in Old World Monkeys, hepaciviruses found in African bats, and in North American rodents, canine hepacivirus (CHV), equine hepacivirus (EqHV) and non-primate hepaciviruses (NPHVs); to name a few.
Worldwide in 2015, hepatitis A occurred in about 114 million people, chronic hepatitis B affected about 343 million people and chronic hepatitis C about 142 million people. The Nobel Prizes in Physiology or Medicine in 1976 and 2020 highlight the important role that animal research played in our discovery of and ameliorative strategies for these forms of hepatitis. But, more importantly, it highlights the desperate need for continued animal research in these areas.
~Speaking of Research