The Nobel
Assembly at Karolinska Institutet has today decided to award the 2020 Nobel
Prize in Physiology or Medicine jointly to Harvey J. Alter, Michael Houghton
and Charles M. Rice for the discovery of Hepatitis C virus.
This year’s Nobel Prize is awarded to three scientists
who have made a decisive contribution to the fight against blood-borne
hepatitis, a major global health problem that causes cirrhosis and liver cancer
in people around the world.
Harvey J. Alter, Michael Houghton and Charles M. Rice
made seminal discoveries that led to the identification of a novel virus,
Hepatitis C virus. Prior to their work, the discovery of the Hepatitis A and B
viruses had been critical steps forward, but the majority of blood-borne
hepatitis cases remained unexplained. The discovery of Hepatitis C virus
revealed the cause of the remaining cases of chronic hepatitis and made
possible blood tests and new medicines that have saved millions of lives.
Hepatitis — a global threat to human health
Liver inflammation, or hepatitis, a combination of the
Greek words for liver and inflammation, is mainly caused by viral infections,
although alcohol abuse, environmental toxins and autoimmune disease are also
important causes. In the 1940’s, it became clear that there are two main types
of infectious hepatitis. The first, named hepatitis A, is transmitted by
polluted water or food and generally has little long-term impact on the
patient. The second type is transmitted through blood and bodily fluids and
represents a much more serious threat since it can lead to a chronic condition,
with the development of cirrhosis and liver cancer. This form of hepatitis is
insidious, as otherwise healthy individuals can be silently infected for many
years before serious complications arise. Blood-borne hepatitis is associated
with significant morbidity and mortality, and causes more than a million deaths
per year world-wide, thus making it a global health concern on a scale
comparable to HIV-infection and tuberculosis.
An unknown infectious agent
The key to successful intervention against infectious
diseases is to identify the causative agent. In the 1960’s, Baruch Blumberg
determined that one form of blood-borne hepatitis was caused by a virus that
became known as 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.
At that time, Harvey J. Alter at the US National
Institutes of Health was studying the occurrence of hepatitis in patients who
had received blood transfusions. Although blood tests for the newly-discovered
Hepatitis B virus reduced the number of cases of transfusion-related hepatitis,
Alter and colleagues worryingly demonstrated that a large number of cases
remained. Tests for Hepatitis A virus infection were also developed around this
time, and it became clear that Hepatitis A was not the cause of these
unexplained cases.
It was a great source of concern that a significant
number of those receiving blood transfusions developed chronic hepatitis due to
an unknown infectious agent. Alter and his colleagues showed that blood from
these hepatitis patients could transmit the disease to chimpanzees, the only
susceptible host besides humans. Subsequent studies also demonstrated that the
unknown infectious agent had the characteristics of a virus. Alter’s methodical
investigations had in this way defined a new, distinct form of chronic viral
hepatitis. The mysterious illness became known as “non-A, non-B” hepatitis.
Identification of Hepatitis C virus
Identification of the novel virus was now a high
priority. All the traditional techniques for virus hunting were put to use but,
in spite of this, the virus eluded isolation for over a decade. Michael
Houghton, working for the pharmaceutical firm Chiron, undertook the arduous
work needed to isolate the genetic sequence of the virus. Houghton and his
co-workers created a collection of DNA fragments from nucleic acids found in
the blood of an infected chimpanzee. The majority of these fragments came from
the genome of the chimpanzee itself, but the researchers predicted that some
would be derived from the unknown virus. On the assumption that antibodies
against the virus would be present in blood taken 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, a researcher at
Washington University in St. Louis, 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.
Significance of this Nobel Prize-awarded
discovery
The Nobel Laureates’ discovery of Hepatitis C virus is
a landmark achievement in the ongoing battle against viral diseases. Thanks to
their discovery, highly sensitive blood tests for the virus are now available
and these have essentially eliminated post-transfusion hepatitis in many parts
of the world, greatly improving global health. Their discovery also allowed the
rapid development of antiviral drugs directed at hepatitis C. For the first
time in history, the disease can now be cured, raising hopes of eradicating
Hepatitis C virus from the world population. To achieve this goal,
international efforts facilitating blood testing and making antiviral drugs
available across the globe will be required.
Harvey J. Alter was born in 1935 in New York. He
received his medical degree at the University of Rochester Medical School, and
trained in internal medicine at Strong Memorial Hospital and at the University
Hospitals of Seattle. In 1961, he joined the National Institutes of Health
(NIH) as a clinical associate. He spent several years at Georgetown University
before returning to NIH in 1969 to join the Clinical Center’s Department of
Transfusion Medicine as a senior investigator.
Michael Houghton was born in the United Kingdom. He
received his PhD degree in 1977 from King’s College London. He joined G. D.
Searle & Company before moving to Chiron Corporation, Emeryville,
California in 1982. He relocated to University of Alberta in 2010 and is
currently a Canada Excellence Research Chair in Virology and the Li Ka Shing
Professor of Virology at the University of Alberta where he is also Director of
the Li Ka Shing Applied Virology Institute.
Charles M. Rice was born in 1952 in Sacramento. He
received his PhD degree in 1981 from the California Institute of Technology
where he also trained as a postdoctoral fellow between 1981-1985. He
established his research group at Washington University School of Medicine, St
Louis in 1986 and became full Professor in 1995. Since 2001 he has been
Professor at the Rockefeller University, New York. During 2001-2018 he was the
Scientific and Executive Director, Center for the Study of Hepatitis C at
Rockefeller University where he remains active.
Source: https://www.nobelprize.org/prizes/medicine/2020/press-release/
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