William Robinson, who made fundamental hepatitis B discoveries, dies at 89

William “Bill” Robinson, MD, emeritus professor of infectious diseases and a leading figure in virology, succumbed to congestive heart failure at a custodial-care home in San Mateo, California, on March 19. He was 89.

Robinson’s laboratory was the first to definitively isolate the virus that causes hepatitis B, a global scourge that affects 300 million people and can lead to liver cancer and cirrhosis. His work laid the foundation for a deeper understanding of the virus’s constituent genes and its life cycle and led to a vaccine and treatments for the disease.

“Driven by a strong desire to improve people’s lives through patient care and research, Bill Robinson made enduring contributions to medical science,” said Lloyd Minor, MD, dean of the Stanford School of Medicine. “His use of advanced chemistry to unlock the tightly held secrets of viruses will have a lasting and profound impact on the health of the world. He will be missed.”

Robinson’s scientific rigor was matched by his athletic rigor. Colleagues described Robinson as a hard-driving molecular virologist, a deep thinker, an affable colleague and a lanky mountaineer who, during his lifetime, scaled not only mountains including Denali in Alaska and Gangapurna in Nepal, but also the heights of scientific discovery. Robinson was known for his cordiality and his sly sense of humor, as well.

“He was incredibly strong, very athletic, like a mountain man,” said Harry Greenberg, MD, the Joseph D. Grant Professor in the School of Medicine, active emeritus, who collaborated closely with Robinson in the 1970s. “I would want to be with him if I was out in the woods and there was a bear.”

Working with Greenberg and Thomas Merigan, MD, now the George E. and Lucy Becker Professor of Medicine, emeritus, Robinson developed the antiviral substance interferon as the first effective treatment for hepatitis B.

“He pioneered molecular virology,” said Merigan, who hired Robinson in 1967, when Merigan was the new chief of the infectious disease department. “But he wanted to see it extend beyond the lab to affect the lives of people who were infected.”

Robinson was a multifaceted professional.  

“He was a world-class scientist, an excellent and caring clinician, and an inspiring teacher,” said Stanley Cohen, MD, the Kwoh-Ting Li Professor in the School of Medicine and professor of medicine and of genetics.

Class president and Eagle Scout

William Sidney Robinson was born Nov. 24, 1933, to Sidney and Aline (nee Hewitt) Robinson in Bloomington, Indiana, where he grew up. An Eagle Scout and president of his high school senior class, Robinson matriculated at Indiana University in 1952. After obtaining his bachelor’s degree in chemistry, he began medical school at the University of Chicago in 1956. He received his medical degree as well as a master’s degree in physiology in 1960, then served his medical internship at Columbia University and residency training at Columbia and the University of Chicago. In 1965, after a year as a postdoctoral scholar at the University of California, Berkeley, he became an assistant professor in molecular biology at UC Berkeley.

Hired at Stanford’s School of Medicine as assistant professor in the division of infectious diseases in 1967, Robinson was promoted to associate professor in 1970 and in 1976 obtained a full professorship. After going emeritus in 1999, he resided mostly on the San Francisco Peninsula and engaged in numerous biotechnology business projects.

Hepatitis B was a major focus of his career. Discovered in 1966, the hepatitis B virus posed a daunting problem for researchers. Unlike the virus responsible for hepatitis A, which also infects the liver, the hepatitis B virus couldn’t be grown in cell culture, making it difficult to study, let alone treat.

A particle that had the look of a virus under a microscope had been identified in hepatitis B patients’ blood, but it hadn’t been substantiated as the actual virus. Robinson proved that it was. In so doing, he also found a way to estimate the amount of the virus present in patients’ blood.

In the absence of molecular biology tools that are taken for granted today but were then in their infancy, Robinson used centrifugation of patients’ blood to concentrate the mysterious particles.

“In 1973, Bill figured out that the particle in the serum of people with hepatitis B is the virus,” Greenberg said. “If you put a patient’s blood in a test tube and spin it around very hard, the particulate material goes to bottom of the test tube. Once you pour off all the liquid, you’ve got a very small particulate plug at the bottom of the tube.” That plug consisted mainly of Dane particles, the medical term for the mystery particles found in hepatitis B patients’ but not non-infected people’s blood.

A key feature of every working virus is an enzyme called a polymerase that’s able to replicate the virus’s genetic material so the virus can make copies of itself. By incubating the centrifugation plug with the component subunits of DNA, the virus’s genetic material, Robinson was able to show that an enzyme in the Dane particles had the ability to stitch these subunits into lengthy strings of DNA: In other words, it was a polymerase. And the particle was the virus.

Unlike its subunits, a string of DNA is insoluble and can be separated from the incubation mixture. By starting with radioactive versions of its subunits, Robinson was able to count the radioactivity in the resulting DNA strings. The bigger the count, the more the polymerase activity — and, presumably, the greater the number of infectious viral particles providing that activity in a patient’s blood.

Robinson had, in short, found an effective biomarker for “viral load” that didn’t require growing the hepatitis B virus in culture. Different amounts of polymerase activity in different patients’ blood samples would correspond to the levels of the hepatitis B virus circulating in their blood.

“You could tell how many viral particles a patient’s blood was carrying,” Greenberg said. This discovery set the stage not only for diagnosing infection severity but for evaluating potential antiviral treatments’ effectiveness.

Bill was a person who tackled all kinds of challenges most people would find overwhelming.

Enter interferon

A promising candidate was interferon, a protein that’s made by our white blood cells and that stimulates the immune system’s antiviral capability. This substance is now manufactured in bioreactors and is available commercially in bulk. But at the time it could be obtained only in minuscule amounts from human blood cells, and it had to be supplied by the National Institutes of Health.

“Tom Merigan had a small supply of interferon to test for treating the virus,” Greenberg said. “Bill Robinson had the enzymatic reaction you could use to detect the amount of virus in patients’ blood.” Greenberg, who had trained in Robinson’s lab in 1975 and 1976, had hepatitis B patients.

In 1978, the trio published an article in The New England Journal of Medicine about their success in treating an initial set of patients with interferon. They showed it suppressed viral replication, as measured by Robinson’s viral-load assay, for the relatively short time the researchers’ supply of interferon held out.

In 1979, Robinson got around the inability to grow the hepatitis B virus in bulk in a laboratory dish. With Cohen, who six years earlier had been a member of the scientific duo that first transferred genes from one living organism into another organism, and two younger colleagues, he cloned its genome — that is, transplanted it into a laboratory-workhorse bacterial strain that’s easily grown in culture. They described their results in a paper published in Nature.

Their discovery made it possible to harvest myriad copies of the virus’s genome inside of those bacterial cells — rendering its component genes, as well as the functions of the proteins they encode, accessible to scientific study. It also laid the groundwork for developing a vaccine against the virus, which became a reality in 1982.

“Bill was a person who tackled all kinds of challenges most people would find overwhelming,” Cohen said. “And he succeeded.”

Robinson was also a master of understatement, recalled Cohen, who became a lifelong friend. Cohen said, “One time, our families were on a camping trip together at Tenaya Lake in Yosemite. He and I were in our late 30s then. Sitting around the campfire, he said to me, ‘Let’s take a little walk tomorrow morning, just you and me. We can pack sandwiches and bring some water, and be back by afternoon.’ That little walk ended up being a steep, 15-mile hike. Eleven hours later I stumbled back into camp. Bill strode in. He turned to me and said, ‘We can take another little walk tomorrow if you like, Stan.’”

Author or co-author of some 200 scientific publications, Robinson was a fellow of the American Association for the Advancement of Science and a member of the American Society for Microbiology, the American Society for Virology, the Infectious Disease Society of America, the American Society for Clinical Investigation and the American Federation for Clinical Research. He served on the board of the Journal of Medical Virology, the Journal of Virology and the Journal of Infectious Diseases and Hepatology. He held honorary professorships at Hunan Medical University and Chongqing Medical University in China, where the prevalence of hepatitis B is very high.

Survivors include his wife, Keting Chu; his children, William, Allen, Thomas and Sophie; five grandchildren; and his sister, Jean.