The 2020 Nobel Prize in Medicine, announced a day before the Physics prize we talked about last week, was awarded to Harvey J. Alter, Michael Houghton, and Charles M. Rice for their discovery of the blood-borne virus Hepatitis C. Hepatitis, a predominantly viral disease characterized by liver inflammation, can be caused by one of five different viruses (hepatitis A, B, C, D, or E). Hepatitis A (HAV) is commonly transmitted through contaminated food or water, and it usually resolves within six months without treatment. Similarly, Hepatitis E (HEV) is transmitted through unsanitary drinking water and usually clears up on its own. Hepatitis B (HBV) is commonly transmitted through direct contact with bodily fluids (typically through blood transfusions or shared needles). HBV can result in either an acute (<6 months) or chronic infection, and only the chronic form requires treatment to prevent serious liver damage. Hepatitis D (HDV) can only be contracted by people who have already been infected by HBV. Hepatitis C (HCV) is contracted primarily through infected blood or shared needles and similarly to HBV, it can result in chronic hepatitis that causes permanent damage to the liver.
The hepatitis B virus was discovered in the 1960s and shortly after, diagnostic tests and a vaccine significantly curbed its spread. Donated blood, a major source of HBV infections, could be easily screened for the disease before being used in transfusions. But, as Alter discovered while tracking the prevalence of hepatitis, this screening did not completely eliminate cases of hepatitis contracted from blood transfusions. It became clear that there was another form of Hepatitis virus responsible for these cases that was not identified by any of the existing screens. Individual work by Houghton and Rice eventually led to the identification and characterization of the hepatitis C virus, which enabled the creation of diagnostic tests that have effectively eliminated HCV risk in many countries.
The liver—a rounded, triangular-shaped organ that sits just above the stomach like a really bad toupee—is the primary organ responsible for controlling the chemical balance of your blood. Perhaps its most famous function is breaking down toxic chemicals, like alcohol, that get into the blood. The liver clears alcohol in two stages. First, it uses a protein called alcohol dehydrogenase (ADH) to convert ethanol (alcohol) to acetaldehyde. Aldehydes and the related chemical group, ketones, include chemicals like formaldehyde—the common embalming fluid—and acetone—the key ingredient in nail polish remover. Acetaldehyde is still fairly toxic, and it is responsible for many of the negative side effects of alcohol consumption, as well as some of the hangover side effects. The second stage of the breakdown process takes longer, which means if you drink too much too quickly, the liver falls behind and acetaldehyde builds up in your bloodstream. This second stage of the alcohol breakdown process uses a protein called aldehyde dehydrogenase (ALDH) to convert the acetaldehyde to acetic acid. Acetic acid is inactive and can be metabolized by the liver cell easily into carbon dioxide and water. (For more of the science of alcohol, check out this article I wrote on methanol poisoning.)
In addition to toxic chemical metabolism, the liver has many other vital functions. The liver is responsible for producing bile, which is stored in the gallbladder where it can be distributed to the duodenum (the first section of the small intestine after the stomach and a word I’ve always thought was funny to pronounce—if you pronounce it correctly). Here, bile is responsible for breaking down fats, which can’t be broken down by stomach acid. The liver also metabolizes fat-soluble vitamins (vitamins A, D, and E), and it manages the synthesis of many vital blood proteins, including clotting factors. The liver also plays a part in the breakdown of heme, the protein in red blood cells responsible for carrying oxygen. Through hemolysis, heme is metabolized into bilirubin, which is carried to the liver where it is processed and sent to the kidneys to be excreted.
Persistent overuse of toxic chemicals, like alcohol or other drugs that get metabolized by the liver (including the pain medication, Tylenol), over the course of a person’s life can result in permanent liver damage. Cirrhosis, the irreparable scarring and damage of the liver that leads to liver failure, is common in long-term alcoholics and chronic hepatitis sufferers. Early on, cirrhosis causes fatigue, weight loss, nausea, and mild abdomen pain. But as it progresses, it causes easy bruising/bleeding (because of the loss of clotting factors), confusion and memory loss, swelling and bloating from fluid build-up, itchiness, and yellowing of the eyes and skin (jaundice). Jaundice, perhaps the symptom most commonly associated with liver damage, occurs because of the build-up of bilirubin, the product of hemolysis.
In the early 1970s, shortly after the development of a reliable HBV screening method, Harvey J. Alter realized that HBV screening of transfusion blood only eliminated roughly 20% of hepatitis cases. He tracked several cases of this “non-B” hepatitis and concluded that it must originate from a different strain of virus not recognized by HBV screening. Further study and comparison revealed that this serum hepatitis wasn’t caused by the hepatitis A virus either. The mysterious virus came to be called “non-A, non-B hepatitis” (NANBH). Alter and his colleagues were able to thoroughly characterize NANBH, but its identity wasn’t discovered until years later.
In 1982, Michael Houghton began searching for the identity of the elusive NANBH virus. He isolated RNA from infected chimps and used it to generate a cDNA library (a collection of DNA fragments complementary to the isolated RNA). The cDNA library was transferred into bacteria and exposed to hepatitis antibodies (from a NANBH-infected patient). The antibodies sought out the bacteria containing DNA from the novel hepatitis virus. This method allowed Houghton to isolate and identify the unique RNA sequence associated with hepatitis C.
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After the identification of hepatitis C, it was still necessary to verify that the virus, on its own, was responsible for the development of transfusion-related acute or chronic hepatitis. Charles Rice was able to demonstrate this causality by creating a synthetic-RNA duplicate of the hepatitis C virus that he injected into the livers of chimps. His experiment proved that the viral-RNA by itself was sufficient to produce clinical symptoms of hepatitis.
The characterization, identification, and verification of hepatitis C provided by Alter, Houghton, and Rice were instrumental in enabling new anti-viral treatments and screening tests for the disease. As a result, post-transfusion hepatitis has been pretty much eliminated in most of the developed world. And antiviral treatments have been successful in curing over 95% of hepatitis patients.
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