The 2020 Nobel Prize in Physiology or Medicine Awarded for the Discovery of the Hepatitis C Virus

The 2020 Nobel Prize in Physiology or Medicine was awarded to three scientists who made a decisive contribution to the fight against blood-borne hepatitis, a major global health problem causing cirrhosis and liver cancer in people worldwide: hepatitis C.

Harvey J. Alter, Michael Houghton and Charles M. Rice made seminal discoveries leading to the identification of a new virus, the Hepatitis C virus. Before their work, the discoveries of Hepatitis A and B viruses had been critical steps forward, but most cases of blood-borne hepatitis remained unexplained. The discovery of Hepatitis C virus revealed the cause of the remaining cases of chronic hepatitis and made blood tests and new drugs possible, saving millions of lives.

Hepatitis — A Global Threat to Human Health

Liver inflammation, or hepatitis, combines the Greek words for liver and inflammation. Hepatitis is mainly caused by viral infections, but alcohol abuse, environmental toxins and autoimmune diseases are also important causes.

In the 1940s, it became clear that infectious hepatitis had two main types. The first, called Hepatitis A, is transmitted by contaminated water or food and generally has little long-term impact on the patient. The second is transmitted through blood and bodily fluids and poses a much more serious threat because it can become chronic, leading to cirrhosis and liver cancer (Figure 1). This form is insidious, as healthy individuals may be silently infected for years before serious complications appear. Blood-borne hepatitis is associated with substantial morbidity (illness) and mortality (death), causing more than one million deaths annually worldwide and making it a global health problem on a scale comparable to HIV infection and tuberculosis.

Figure 1. Hepatitis has two main forms. One is an acute disease caused by Hepatitis A virus, transmitted through contaminated water or food. The other is caused by Hepatitis B or Hepatitis C virus (this year's Nobel Prize). This blood-borne form is often a chronic disease that may progress to cirrhosis and hepatocellular carcinoma (liver cancer).

An Unknown Infectious Agent

The key to successful intervention against infectious diseases is identifying the causative agent. In the 1960s, Baruch Blumberg determined that a form of blood-borne hepatitis was caused by a virus known as Hepatitis B virus, leading to diagnostic tests and an effective vaccine. Blumberg received the Nobel Prize in Physiology or Medicine in 1976 for this discovery.

At the time, Harvey J. Alter at the US National Institutes of Health was studying hepatitis in patients who had received blood transfusions. Although blood tests for the newly discovered Hepatitis B virus reduced transfusion-related cases, Alter and colleagues showed that an alarming number remained. Tests for Hepatitis A virus infection were also developed during this period, revealing that Hepatitis A did not cause these unexplained cases.

It was a major concern that a substantial proportion of transfusion recipients developed chronic hepatitis from an unknown infectious agent. Alter and colleagues showed that blood from these hepatitis patients could transmit the disease to chimpanzees, the only susceptible host other than humans. Subsequent studies also showed that the unknown agent had the characteristics of a virus. Alter's methodical investigations thus defined a new, distinct form of chronic viral hepatitis. The mysterious disease became known as “non-A, non-B” hepatitis.

Identifying the Hepatitis C Virus

Identifying the new virus was now a high priority. All traditional techniques were used to detect it, but the virus nevertheless evaded isolation for more than a decade.

Michael Houghton, working for the pharmaceutical company Chiron, undertook the demanding work needed to isolate the virus's genetic sequence. Houghton and colleagues created a collection of DNA fragments from nucleic acids in the blood of an infected chimpanzee. Most fragments came from the chimpanzee's genome, but the researchers predicted that some would derive from the unknown virus. Assuming that antibodies produced against the virus by our immune system would be present in blood from hepatitis patients, they used patient sera to identify cloned viral DNA fragments encoding viral proteins. An extensive search found one positive clone. Further studies showed that the clone derived from a new RNA virus belonging to the Flavivirus family, which was named Hepatitis C virus.

Figure 2 Summary of the discoveries honored by this year's Nobel Prize. Harvey J. Alter's methodical studies of transfusion-related hepatitis showed that an unknown virus was a common cause of chronic hepatitis. Michael Houghton used an untested strategy to isolate the genome of the new virus, named Hepatitis C virus. Charles M. Rice provided the final evidence that Hepatitis C virus alone could cause hepatitis.

The discovery of Hepatitis C virus was decisive, but a key piece of the puzzle was missing: could the virus alone cause hepatitis? To answer this question, scientists needed to investigate whether the cloned virus could replicate and cause disease. Charles M. Rice, a researcher at Washington University in St. Louis, and other groups working with RNA viruses highlighted a previously unidentified region at the end of the Hepatitis C virus genome that they suspected might be important for viral replication: variations in isolated virus samples and the assumption that some might inhibit replication. Through genetic engineering, Rice produced a Hepatitis C virus RNA variant containing the newly identified region and lacking inactivating genetic variations. When this RNA was injected into chimpanzees' livers, virus was detected in the blood and pathological changes resembling those in humans with chronic disease were observed. This was the final evidence that Hepatitis C virus alone could cause the unexplained cases of transfusion-mediated hepatitis.

The Importance of This Nobel-Winning Discovery

The Nobel-recognized discovery of Hepatitis C virus is a major achievement in the ongoing battle against viral diseases (Figure 2). Thanks to these discoveries, highly sensitive blood tests are now available, preventing post-transfusion hepatitis in many parts of the world and greatly improving global health. They also enabled the rapid development of antiviral drugs against hepatitis C. For the first time in history, this disease can now be cured, raising hopes of eliminating Hepatitis C virus from the world's population. Achieving this goal will require international efforts to facilitate blood testing and make antiviral drugs available worldwide (Figure 3).

Figure 3. The process of discovering Hepatitis C virus made 3 scientists Nobel laureates. This discovery enabled sensitive blood tests to be designed, eliminating the risk of transfusion-transmitted hepatitis in much of the world. The breakthrough also enabled antiviral drugs capable of curing the disease. Hepatitis C remains a major global health problem, but there is now an opportunity to eliminate it.

Harvey J. Alter

Born in New York in 1935. He earned his medical degree at the University of Rochester Medical School and trained in internal medicine at Strong Memorial Hospital and the University Hospitals of Seattle. He joined the US National Institutes of Health (NIH) as a clinical associate in 1961. After several years at Georgetown University, he returned to the NIH in 1969 as a senior investigator in the Clinical Center's Department of Transfusion Medicine.

Michael Houghton

Born in the United Kingdom. He earned his PhD at King's College London in 1977. He joined GD Searle & Company before moving to Chiron Corporation in Emeryville, California, in 1982. He moved to the University of Alberta in 2010 and is currently Canada Excellence Research Chair in Virology and Li Ka Shing Professor of Virology there. He is also Director of the Li Ka Shing Applied Virology Institute.

Charles M. Rice

Born in Sacramento in 1952. He earned his PhD in 1981 at the California Institute of Technology, where he trained as a postdoctoral researcher from 1981-1985. He established his research group at Washington University School of Medicine, St Louis, in 1986 and became a professor in 1995. He has been a Professor at Rockefeller University in New York since 2001. From 2001-2018, he served as Scientific and Executive Director of Rockefeller University's Center for the Study of Hepatitis C, where he remains active.

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