Albert Lasker
Clinical Medical Research Award

Thirty years ago the blood transfusion intended to save your life might have caused your death. Each transfusion—now numbering more than 15 million in the U.S. annually—had about a one-in-three chance of being tainted by infection, leading to hepatitis (that is, inflammation of the liver) which often resulted in cirrhosis of the liver, a leading cause of liver failure and liver cancer. Today, thanks to the work of many, but particularly the work of Harvey Alter and his colleagues at NIH, and of Michael Houghton and his team at the Chiron Corporation, the risk of transfusion-associated hepatitis is virtually zero. This public health triumph resulted from medical research spanning the full range of approaches from basic to disease-oriented to patient-oriented, from molecular biology to immunology to epidemiology. Here's a glimpse of how this huge problem was solved.

In the 1970s, Alter and his colleagues initiated prospective clinical research studies using both human blood donors and blood recipients, with the goal of defining the causes of transfusion-associated hepatitis. Alanine aminotransferase is an enzyme found in liver cells which "leaks" into the blood when the liver is infected. Measurements of this enzyme enabled Alter to deduce that any transfusion had about a one-in-three chance of causing hepatitis. Most infected blood came from paid donors carrying the hepatitis B virus, one of two hepatitis viruses known at the time—the other being hepatitis A. As a result of these and other epidemiologic studies in the 1970s, the U.S. changed to an all-volunteer blood donation system and instituted antibody testing of all donors for hepatitis B. Hepatitis rates fell by half—a major advance but still subjecting transfused patients to an unacceptable risk of one chance in five of developing hepatitis.

The Alter group then asked: What was responsible for the remaining cases of transfusion-associated hepatitis? In a systematic study of more than 100 patients with transfusion-associated hepatitis shown not to have either hepatitis A or hepatitis B, they provided compelling evidence for another form of hepatitis which they called "non-A, non-B hepatitis." They infused chimpanzees with blood from these non-A, non-B patients and produced hepatitis in the animals. This proved that the disorder was caused by an infectious agent, presumably another virus. Between 1975 and 1985, non-A, non-B hepatitis was widely recognized as being both serious and remarkably common. Today it affects nearly 200 million people worldwide—about 4 million in the U.S.—and is very likely the leading cause of liver failure and liver cancer in the world.

The virus responsible, however, was frustratingly elusive until the work of Michael Houghton and his colleagues at Chiron. Many investigators had tried to find antibodies to the agent in the blood or to propagate the virus in the laboratory. All their efforts failed. Houghton chose a novel and risky strategy: to go after the organism's genetic material. He reasoned that if he could clone one or more genes from the virus, he might be able to make protein from them, and from the protein, an antibody. Some have likened this approach to looking for a needle in a haystack without being able to see or feel the needle. Others used the metaphor of a scientific fishing expedition in which the scientists weren't sure they had either bait or fish.

Yet Houghton and his colleagues prevailed. They extracted DNA and RNA from the blood of chimpanzees infected with non-A, non-B blood. Then they cloned pieces of genetic material, inserted them into bacteria, and programmed them to make proteins. Over two years they screened tens of millions of bacteria until they found a single sample of DNA that made a protein that bound antibody from infected, but not uninfected, blood. Then they painstakingly determined that the DNA was not of human or bacterial origin, meaning they were on the right track. In this way—in this systematic, repetitive, step-wise way—they finally convinced themselves and others that they had a collection of virus proteins from a new organism which they named hepatitis C.

At this point, the efforts of Alter and Houghton converged. Houghton asked Alter to send the panel of blood samples from patients deduced to have non-A, non-B hepatitis. Most of the samples contained antibodies to hepatitis C proteins, proving that hepatitis C was the cause of nearly all non-A, non-B hepatitis. Thus, the Chiron group discovered a clinically important organism without being able to grow it in the laboratory, visualize it under the microscope, or detect it serologically. This was a genuine scientific tour de force, and led to tests which routinely detect hepatitis C in donor blood.

Many dedicated scientists worked with, and independently of, Alter and Houghton but these two men and their colleagues, using widely different scientific technologies, were responsible for making the blood supply in our country safe and effective—the two fundamental requirements for any material worthy of being administered to people in need.