2020 · Medicine

Catching the hidden virus in the blood supply

Q: What did Harvey Alter prove about the mystery hepatitis spreading through blood transfusions?

It was caused by a new, unknown agent that behaved like a virus. Alter showed the disease was neither hepatitis A nor B, and that blood from these patients could transmit it to chimpanzees. That marked it as a new infectious agent, named non-A, non-B hepatitis.

Q: How did Michael Houghton's team find the virus when standard methods had failed?

They cloned genetic fragments from infected blood and used patient antibodies to fish out a piece of the virus. Houghton's team built a library of cloned DNA fragments from an infected chimpanzee's blood, then screened it with antibodies from patients. A clone whose protein those antibodies recognised pointed straight to the virus, which they named hepatitis C.

Q: Why was Charles Rice's experiment the final piece of proof?

He built a working copy of the viral genome that, injected alone, caused hepatitis in chimpanzees. Cloning the genes showed the virus was present, not that it alone caused disease. Rice engineered a functional full-length RNA, free of disabling mutations and including the missing tail region, and showed it alone triggered hepatitis. That sealed causation.

Awarded to Harvey J. Alter, Michael Houghton and Charles M. Rice “for the discovery of Hepatitis C virus”.

What was the 2020 Nobel Prize in Medicine awarded for?

The 2020 Medicine prize honours the detective work that unmasked the hepatitis C virus, the hidden cause of a liver disease people were catching from blood transfusions. Three scientists proved that a single unknown virus was to blame and then read out its genetic code. Their work made it possible to screen blood and to cure an infection that used to last a lifetime.

Predict first

Doctors in the 1970s kept seeing patients catch hepatitis from blood transfusions, but tests for the two known hepatitis viruses, A and B, came back negative. What was going on?

A third, still-unknown virus was hiding in the blood. Harvey Alter showed the cause was neither A nor B and that blood from these patients could pass the illness to chimpanzees, so it behaved like a real virus. It was named non-A, non-B hepatitis until its identity was finally cracked a decade later.

Predict first

The virus's genes had been copied and a blood test already existed. Why did scientists still not feel sure that this one virus, on its own, caused the disease?

Finding a virus's genes in sick patients is a strong clue, not final proof. Something else could have been riding along. Charles Rice settled it by building a clean, working copy of the viral genome and injecting that alone into the liver. It caused hepatitis, which proved the single virus was the culprit.

Four steps from a mystery illness to a curable virus. Alter showed it was a new virus, Houghton cloned and named it, and Rice proved the virus alone causes the disease.

Picture doctors in the 1970s with a mystery on their hands. Some patients who received a blood transfusion came down with hepatitis, a liver illness, weeks later. Doctors could test for the two hepatitis viruses they knew about, called A and B. The tests kept coming back negative. So what was making people sick?

It turned out a third, hidden virus was riding along in the blood. Catching it took detective work by three scientists. First they showed the cause really was a new virus. Then they pulled the virus's genes out of infected blood and gave it a name, hepatitis C. Finally they proved that this one virus, all by itself, was enough to cause the disease.

Why it matters

From hidden to curable

Once scientists could name the virus, they could test donated blood for it and keep it out of transfusions. Later they built pills that clear the virus from the body. A disease that used to be a lifelong threat can now be cured.

By the 1960s and 1970s, two viruses were known to cause hepatitis. Hepatitis A spreads through contaminated food and water and causes a short illness. Hepatitis B spreads through blood and can become chronic, and once a blood test for it existed, infected donations could be screened out. Yet many people still caught hepatitis after a transfusion, and tests for both known viruses were negative.

Step 1: Alter

A new virus, defined

At the US National Institutes of Health, Harvey Alter showed that most of this transfusion hepatitis was caused by neither A nor B. Crucially, blood from these patients could transmit the illness to chimpanzees, the only susceptible animal besides humans, and the agent behaved like a virus. The mystery disease got a placeholder name: non-A, non-B hepatitis.

Step 2: Houghton

Cloning the culprit

The virus was too scarce to catch under a microscope, so Michael Houghton's team at the Chiron Corporation took an untested route. They built a library of DNA copies from the nucleic acid in infected blood, then screened those clones with antibodies taken from patients. A clone whose protein the patient antibodies recognised had to come from the virus. That fragment led to the full genome, and the virus was named hepatitis C.

Risk of chronic hepatitis after surgery or many transfusions

Before any blood screening existed, versus after donated blood is screened for the hepatitis viruses.

Before virus testing (until the 1960s)up to 30%

Up to roughly 1 in 3 patients went on to develop chronic hepatitis.

After screening for hepatitis B and Cvery low

Screening donated blood for the viruses made transfusion-acquired hepatitis rare.

1960s to 1970s

Hepatitis A and B viruses are known, and donated blood can be screened for hepatitis B.

Mid-1970s

Alter shows transfusion hepatitis is neither A nor B, infects chimpanzees, and behaves like a virus. It is named non-A, non-B hepatitis.

1989

Houghton's team clones the virus straight from infected blood, names it hepatitis C, and a blood test soon follows.

Late 1990s

Rice builds a working copy of the viral genome and shows it alone causes hepatitis in chimpanzees.

One question still hung in the air. Finding the virus's genes in sick patients was a powerful clue, but it did not prove that this virus, on its own, caused the disease. That final proof came from Charles Rice.

The case for hepatitis C was built the way causation in infectious disease usually is, by steadily ruling out alternatives and then meeting the bar of Koch's postulates at the molecular level. Each laureate supplied one link, and only the three together amount to proof.

Alter: defining the agent

A transmissible, virus-like agent

Alter's transfusion studies established that the residual post-transfusion hepatitis was a distinct clinical entity, not a variant of A or B. By transmitting disease to chimpanzees with patient plasma, and by showing the agent shared the physical properties of a virus, he converted an epidemiological puzzle into a defined, transmissible viral disease. The chimpanzee model he helped establish was the platform everything later depended on.

Houghton: isolating the genome

Immunoscreening a blind cDNA library

With no culture system and no visible particle, Houghton's group at Chiron extracted total nucleic acid from the plasma of an infected chimpanzee, copied it into DNA, cloned it into a bacterial expression vector, and screened the resulting clones with serum from non-A, non-B patients. A single reactive clone encoded a protein recognised only by antibodies from infected people. It traced to an RNA genome of roughly 9,600 nucleotides found only in infected samples. The agent was a positive-sense single-stranded RNA virus of the Flaviviridae family, named hepatitis C virus, and the same proteins became the basis of an antibody blood test.

Rice: proving causation

A functional full-length clone

Cloning showed the virus was present, not that it alone caused disease. Rice, drawing on his work with related flaviviruses, noticed that published HCV sequences lacked a conserved region at the end of the genome needed to start replication, and that lab isolates carried scattered mutations that would inactivate the virus. He engineered a complete RNA that restored the missing element and removed the disabling mutations, a consensus functional clone. Injected directly into the liver of chimpanzees, this RNA alone produced replicating virus, a specific antibody response, and the liver pathology of human disease. That closed the loop: hepatitis C virus by itself causes hepatitis C.

What the discovery delivered

Blood screening: donated blood is now tested for the virus, which made transfusion-acquired hepatitis C rare.
Direct-acting antivirals: pills that block specific viral enzymes now cure most infections in a matter of weeks.
Research tools: Rice's replication-competent clones, and the cell-culture systems that followed, let scientists dissect the full viral life cycle.
Open problems: there is still no vaccine, and many infected people remain undiagnosed, so the World Health Organization treats hepatitis C as an elimination target rather than a solved problem.

“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.”Nobel Assembly at Karolinska Institutet, 2020 prize announcement

Worth knowing

From mystery to cure in a single career

When Alter began his work, catching hepatitis from a transfusion was a real danger, with no test and no cure. Within a few decades the same virus could be screened out of the blood supply and cleared from the body with a short course of pills. Few diseases have travelled from unknown to curable so quickly.

Check yourself

What did Harvey Alter prove about the mystery hepatitis spreading through blood transfusions?

Why: Alter showed the disease was neither hepatitis A nor B, and that blood from these patients could transmit it to chimpanzees. That marked it as a new infectious agent, named non-A, non-B hepatitis.

How did Michael Houghton's team find the virus when standard methods had failed?

Why: Houghton's team built a library of cloned DNA fragments from an infected chimpanzee's blood, then screened it with antibodies from patients. A clone whose protein those antibodies recognised pointed straight to the virus, which they named hepatitis C.

Why was Charles Rice's experiment the final piece of proof?

Why: Cloning the genes showed the virus was present, not that it alone caused disease. Rice engineered a functional full-length RNA, free of disabling mutations and including the missing tail region, and showed it alone triggered hepatitis. That sealed causation.

Key terms

Hepatitis: Inflammation of the liver. It can cause fatigue, nausea and jaundice, and over years can scar the liver (cirrhosis) or lead to liver cancer.
Non-A, non-B hepatitis: The placeholder name given to transfusion-linked hepatitis that tested negative for both the hepatitis A and hepatitis B viruses. It was later shown to be caused by hepatitis C virus.
Hepatitis C virus (HCV): A small, enveloped, positive-sense single-stranded RNA virus of the Flaviviridae family. Its genome is about 9,600 letters long and it infects liver cells.
cDNA library: A collection of DNA copies made from the genetic material in a sample. Screening such a library let Houghton's team pull out a fragment belonging to the unknown virus.
Functional clone: A laboratory-built, complete and working copy of a virus's genome. Rice's functional clone of HCV could replicate and cause disease, which is what proved the virus was the cause.
Direct-acting antivirals: Drugs that block specific steps in the hepatitis C virus life cycle. A short course of these pills now cures most infections.

The laureates

Harvey J. Alter

National Institutes of Health, Bethesda, MD, USA

Alter, born in the United States in 1935, led transfusion-medicine research at the National Institutes of Health in Bethesda. In the 1970s he proved that most hepatitis caught from blood transfusions was caused by neither hepatitis A nor hepatitis B. By showing the disease could pass to chimpanzees, he established that an unknown virus was responsible and defined the new illness as non-A, non-B hepatitis.

Photo: Unknown author, Public domain (via Wikimedia Commons)

Michael Houghton

University of Alberta, Edmonton, Canada

Houghton, born in the United Kingdom in 1949 and now at the University of Alberta in Canada, isolated the virus's genes while at the Chiron Corporation. Rather than catch the virus under a microscope, his team cloned genetic fragments from infected blood and used antibodies from patients to fish out a piece of the unknown agent. They named it hepatitis C virus and turned the find into a blood test.

Photo: Kerry Angelo Piper, CC BY 2.0 (via Wikimedia Commons)

Charles M. Rice

Rockefeller University, New York, NY, USA

Rice, born in the United States in 1952 and now at Rockefeller University in New York, supplied the final proof through work begun at Washington University in St. Louis. He spotted a missing tail in the viral genome and disabling mutations in lab samples, then engineered a clean, complete RNA copy. Injected on its own into the liver, it caused hepatitis, showing that hepatitis C virus alone was the cause.

Photo: Bill Branson, Public domain (via Wikimedia Commons)

Sources

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