William J. Rutter
William Rutter in 2003. Photograph by Stuart Watson. CHF Collections.
Pioneering research in biotechnology has greatly influenced the development of vaccines, most notably for hepatitis B, a virus contracted by over a hundred thousand people each year in the United States. Hepatitis causes inflammation of the liver and in some cases can lead to liver cancer. Today there are seven known hepatitis viruses (A, B, C, D, E, F, and G), some of which are transmitted by contaminated food and water. Hepatitis B, like several of the other hepatitis viruses, is transmitted through bodily fluids. A revolutionary vaccine for hepatitis B was developed by a team of scientists led by William J. Rutter (b. 1928), in collaboration with both industrial and academic researchers, who used new recombinant DNA techniques.
Rutter grew up in Malad, Idaho. He attended high school there until the age of 15, at which point he spent a year at Brigham Young University. Perhaps influenced by stories told by his grandfather, who had been a British army officer in India, Rutter developed an early interest in medicine, particularly in parasitic diseases that abound in warm climates.
After his year at Brigham Young, Rutter claimed to be 18 and joined the navy, serving until the end of World War II. He then was admitted to Harvard University and received his B.A. in both biochemistry and chemistry in the winter of 1949. Once he graduated, his intention was to enroll in Harvard’s medical school in the fall. However, he returned to the West for a few months to be close to his family. During this time he took some medical classes at the University of Utah and did some biochemical research. On the basis of these experiences he quickly determined that his real scientific interest lay in basic research, not in medicine, and so he remained at the University of Utah, working with Gaurth Hansen on studies of metabolism. He earned his M.S. in biochemistry in 1950.
When Hansen was offered a position at the University of Illinois, Rutter traveled with him as a doctoral student. There he worked on galactosemia, a hereditary condition that prevents the normal metabolization of galactose, a constituent of lactose, the sugar found in milk. Infants with this condition are unable to consume milk or milk products, and they risk malnourishment, liver disease, and mental retardation. Rutter received his Ph.D. in biochemistry from the University of Illinois in 1952.
He took up a postdoctoral position at the University of Wisconsin, where he studied enzyme chemistry, and his interests led him to take a second postdoctoral position at the Nobel Institute in Stockholm before accepting a teaching position at the University of Illinois.
At Illinois, Rutter developed a greater interest in biological research, and in 1965 he decided to move to Seattle and take a position at the University of Washington, where he learned genetics and began to research mechanisms of gene transcription. Three years later he moved again, this time accepting the chair of the biochemistry department at the University of California at San Francisco (UCSF).
At UCSF Rutter became involved in a number of research endeavors, including cloning of the insulin gene. With the advent of recombinant DNA techniques (see Paul Berg, Herbert Boyer, and Stanley Cohen), and the resulting debates within the scientific community about the risks of such experiments, Rutter began to search for a project that would demonstrate the benefits of such technology. He chose production of a hepatitis B vaccine.
Rutter and his laboratory made a cooperative arrangement in 1978 with Merck and Company, which at that time also sought a hepatitis B vaccine by using recombinant DNA techniques. Merck had developed a hepatitis B vaccine (Heptavax-B) a few years earlier, but it was plasma based, which led to concerns about the potential contamination of plasma—a constituent of blood—by the newly discovered AIDS virus. The vaccine was also extremely difficult and expensive to produce. Because hepatitis cannot be cultivated in a cell culture, the hepatitis B vaccine could not be developed in the same way as the polio vaccine (see Jonas Salk and Albert Sabin) and other subsequent vaccine developments. However, Roy Vagelos, then president of Merck, Sharp and Dohme Research Laboratories, felt that recombinant DNA technology provided an excellent opportunity. Rutter and Merck agreed to collaborate on a method for producing the hepatitis B antigen in a microbial cell using recombinant DNA technology. For two years fellow researcher Pablo Valenzuela worked in Rutter’s UCSF laboratory on the necessary gene splicing and by 1981 was able to insert the spliced antigen gene into the bacterium E. coli. When expressed, however, this did not produce antigens that evoked the desired immunologic response. Later it was discovered that the molecules so produced, although equivalent in other respects to the natural antigen, failed because they did not have the proper three-dimensional shape.
In the meantime Rutter was becoming increasingly aware that UCSF could not compete with commercial enterprises, so he suggested to Vagelos that a separate lab be set up to conduct their hepatitis research. Vagelos agreed, and the biotechnology company Chiron Corporation was born. Founded in 1981 by Rutter, Valenzuela, and another researcher, Edward Penhoet, Chiron engaged in a wide variety of activities in such areas as vaccines, therapeutics, and diagnostics. The hepatitis researchers learned, soon after the failed E. coli attempt, that Genentech (see Berg, Boyer, and Cohen) and Benjamin D. Hall of the University of Washington had discovered plasmids in baker’s yeast. Plasmids—extrachromosomal DNA molecules capable of replicating independently—had previously been known to exist only in bacteria. Researchers felt that this discovery would provide a possible method of producing the hepatitis antigen. Further, culturing yeast in large quantities was a well-known technology that would lend itself relatively easily to scaling up production. The project then expanded to include Merck, Chiron, Rutter and his UCSF laboratory, and Hall and his laboratory. These collaborators were able to produce plasmids that included the DNA sequence of the hepatitis B antigen. The plasmids were transferred to yeast, which then produced the desired antigen. In turn, the antigen stimulated the correct antibody reaction. The researchers had solved their problem.
Clinical studies were done on the new hepatitis B vaccine, first on volunteers among the Merck employees and then on a larger scale. These studies concluded that the new vaccine provided protection comparable to that of Heptavax-B, and in 1986 Recombivax HB was licensed in the United States. Today the vaccine is administered to infants, children under the age of 18, and adults at risk for contracting the virus.
In 2006 Chiron was acquired by Novartis International.