Advances in Virology — Weller and Robbins
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《新英格兰医药杂志》
Book Review: This article reviews the book Growing Pathogens in Tissue Culture: Fifty Years in Academic Tropical Medicine, Pediatrics, and Virology, by Thomas H. Weller, published by Science History Publishers, Canton, Mass., 2004.
"Birds, fishes, worms, and viruses" — so runs the taxonomic summary of a life's work that opens the autobiography of Thomas H. Weller, Growing Pathogens in Tissue Cultures.1 Weller, a driven, curious, committed research physician, combined his interests and talent with a profound desire to improve the human condition through the prevention of diseases caused by viruses and parasites. He descended from several generations of physicians, and his father was a pathologist at the University of Michigan. The timing and circumstances of his career, he asserts, permitted the discovery of the growth of poliovirus in tissue culture, but was it synchronicity, or was it that chance favored the prepared mind? This his readers will decide.
(Figure)
Weller first studied parasitic disease as an undergraduate at the University of Michigan, where he identified a nematode of perch. In 1936, he entered Harvard Medical School, where his interest in microbes was stimulated by a microbiology course taught by Dr. Hans Zinsser and where he met Frederick Robbins, who became his roommate. During visits to the Rockefeller Institute, Weller was exposed to studies of malaria and to the cultivation, in chick-embryo tissue culture, of a mutant strain of yellow fever virus. These experiences laid the foundation for a research career spanning more than 40 years — a period that saw great advances in the prevention and control of viral diseases.
During his fourth year in medical school, Weller began a tutorial research project with Dr. John Enders, an associate of Zinsser's, from whom he learned to use tissue cultures in roller tubes to grow viruses; the model was vaccinia virus. Weller and Robbins began their internships at Children's Hospital, Boston, but these were soon interrupted by World War II. Both served in the war, Weller in Puerto Rico, focusing on the diagnosis and control of malaria and schistosomiasis among inductees, and Robbins in North Africa and Italy, leading the virus and rickettsial disease section of the 15th Medical General Laboratory and investigating Q fever and typhus. After the war, the pair completed their pediatric training and joined Enders, who had become chair of the newly established Research Division of Infectious Diseases at Children's Hospital. The primary focus of Enders's laboratory was viruses that cause paralysis in mice, including the mouse-adapted Lansing strain of poliovirus.
Weller guides the reader through the intricacies of the refinement of the techniques of tissue-culture growth and maintenance, the study of the specificity of virus–cell interactions, and the development of methods for identifying viral multiplication. At the Enders laboratory, Weller endeavored to isolate varicella virus in cultures of human embryonic skin. A crucial experiment took place almost by chance: after inoculating 16 tissue-containing flasks with samples of throat washings from a child with varicella, Weller had 4 flasks left over. He thought it would be interesting to inoculate them with a mouse-brain suspension that contained the Lansing poliovirus. He failed to isolate varicella virus, but fluid from the cultures of the poliovirus destroyed the tissue-culture cells and subsequently paralyzed mice. Robbins later showed that this fluid would also paralyze monkeys. Mixing the infected fluid with antibodies against the virus prevented the growth of virus in tissue culture and protected the monkeys from paralysis.
The technology rapidly improved, so that cells could be grown in a monolayer in test tubes; these could be observed under the microscope, where the cytopathic effect could be visualized. Robbins showed that polioviruses could be isolated from fecal samples from patients, and the group quickly found that all three types of poliovirus could be grown in the same cultures. Soon, they isolated other viruses — which would later be identified as coxsackievirus and echovirus — from patients with aseptic meningitis. Monkey kidney cells replaced human foreskin as the culture medium. With the discovery of antibiotics, it became possible to isolate many viruses from contaminated body fluids and feces. Finally, Enders, Weller, and Robbins showed that multiple passages in tissue culture led to a decrease in the virulence of poliovirus. This observation led to the development of live attenuated vaccines for polio and other viruses.
(Figure)
Thomas Weller (left) with Frederick Robbins (center) and John Enders (right) at the Nobel Prize Ceremony in Stockholm, December 10, 1954.
Photograph from Growing Pathogens in Tissue Cultures, courtesy of the Boston Medical Library.
As others began to apply the team's work with poliovirus to the race for a vaccine, Weller forged ahead to isolate the virus responsible for rubella, which later also led to the development of a vaccine. Weller went on to isolate cytomegalovirus and to demonstrate its virulence in the fetus. And he was finally successful in isolating varicella virus, which showed homology with viruses isolated from herpes zoster. A live attenuated varicella vaccine was licensed in 1995, and today varicella, with its bacterial complications, is rapidly becoming a scourge of the past; moreover, we have seen a decrease in the incidence of herpes zoster among vaccinees.
Weller's second career in tropical medicine included the directorship of the Section of Tropical Medicine at the Harvard School of Public Health, where he was a mentor to many young physician-scientists who went on to distinguished research careers in tropical medicine. During his tenure, research programs were established in Brazil and St. Lucia for schistosomiasis control. Weller credits the awarding of the team's Nobel Prize with his ability to spark worldwide collaborations for the control of parasitic diseases.
Robbins, for his part, pursued a career in academic pediatrics and studied the efficacy and use of polio vaccine. He was an active participant in the laboratory evaluation of the Salk vaccine field trial and later in studies of Sabin vaccines in infants — studies in which I participated as a fellow in Robbins's laboratory. He studied the epidemiology and clinical syndromes of enteroviruses and respiratory agents, served as dean at Case Western Reserve University Medical School, and provided direction in the campaign to eradicate poliomyelitis. He also chaired the Institute of Medicine and launched programs in adolescent health in collaboration with community agencies in Cleveland. Like Weller, Robbins believed that it was the Nobel Prize that enabled him to become a leader in the prevention of infectious diseases.
Source Information
From the Department of Pediatrics, Albany Medical College, Albany, N.Y.
References
Weller TH. Growing pathogens in tissue cultures: fifty years in academic tropical medicine, pediatrics, and virology. Canton, Mass.: Science History Publishers, 2004.(Martha L. Lepow, M.D.)
"Birds, fishes, worms, and viruses" — so runs the taxonomic summary of a life's work that opens the autobiography of Thomas H. Weller, Growing Pathogens in Tissue Cultures.1 Weller, a driven, curious, committed research physician, combined his interests and talent with a profound desire to improve the human condition through the prevention of diseases caused by viruses and parasites. He descended from several generations of physicians, and his father was a pathologist at the University of Michigan. The timing and circumstances of his career, he asserts, permitted the discovery of the growth of poliovirus in tissue culture, but was it synchronicity, or was it that chance favored the prepared mind? This his readers will decide.
(Figure)
Weller first studied parasitic disease as an undergraduate at the University of Michigan, where he identified a nematode of perch. In 1936, he entered Harvard Medical School, where his interest in microbes was stimulated by a microbiology course taught by Dr. Hans Zinsser and where he met Frederick Robbins, who became his roommate. During visits to the Rockefeller Institute, Weller was exposed to studies of malaria and to the cultivation, in chick-embryo tissue culture, of a mutant strain of yellow fever virus. These experiences laid the foundation for a research career spanning more than 40 years — a period that saw great advances in the prevention and control of viral diseases.
During his fourth year in medical school, Weller began a tutorial research project with Dr. John Enders, an associate of Zinsser's, from whom he learned to use tissue cultures in roller tubes to grow viruses; the model was vaccinia virus. Weller and Robbins began their internships at Children's Hospital, Boston, but these were soon interrupted by World War II. Both served in the war, Weller in Puerto Rico, focusing on the diagnosis and control of malaria and schistosomiasis among inductees, and Robbins in North Africa and Italy, leading the virus and rickettsial disease section of the 15th Medical General Laboratory and investigating Q fever and typhus. After the war, the pair completed their pediatric training and joined Enders, who had become chair of the newly established Research Division of Infectious Diseases at Children's Hospital. The primary focus of Enders's laboratory was viruses that cause paralysis in mice, including the mouse-adapted Lansing strain of poliovirus.
Weller guides the reader through the intricacies of the refinement of the techniques of tissue-culture growth and maintenance, the study of the specificity of virus–cell interactions, and the development of methods for identifying viral multiplication. At the Enders laboratory, Weller endeavored to isolate varicella virus in cultures of human embryonic skin. A crucial experiment took place almost by chance: after inoculating 16 tissue-containing flasks with samples of throat washings from a child with varicella, Weller had 4 flasks left over. He thought it would be interesting to inoculate them with a mouse-brain suspension that contained the Lansing poliovirus. He failed to isolate varicella virus, but fluid from the cultures of the poliovirus destroyed the tissue-culture cells and subsequently paralyzed mice. Robbins later showed that this fluid would also paralyze monkeys. Mixing the infected fluid with antibodies against the virus prevented the growth of virus in tissue culture and protected the monkeys from paralysis.
The technology rapidly improved, so that cells could be grown in a monolayer in test tubes; these could be observed under the microscope, where the cytopathic effect could be visualized. Robbins showed that polioviruses could be isolated from fecal samples from patients, and the group quickly found that all three types of poliovirus could be grown in the same cultures. Soon, they isolated other viruses — which would later be identified as coxsackievirus and echovirus — from patients with aseptic meningitis. Monkey kidney cells replaced human foreskin as the culture medium. With the discovery of antibiotics, it became possible to isolate many viruses from contaminated body fluids and feces. Finally, Enders, Weller, and Robbins showed that multiple passages in tissue culture led to a decrease in the virulence of poliovirus. This observation led to the development of live attenuated vaccines for polio and other viruses.
(Figure)
Thomas Weller (left) with Frederick Robbins (center) and John Enders (right) at the Nobel Prize Ceremony in Stockholm, December 10, 1954.
Photograph from Growing Pathogens in Tissue Cultures, courtesy of the Boston Medical Library.
As others began to apply the team's work with poliovirus to the race for a vaccine, Weller forged ahead to isolate the virus responsible for rubella, which later also led to the development of a vaccine. Weller went on to isolate cytomegalovirus and to demonstrate its virulence in the fetus. And he was finally successful in isolating varicella virus, which showed homology with viruses isolated from herpes zoster. A live attenuated varicella vaccine was licensed in 1995, and today varicella, with its bacterial complications, is rapidly becoming a scourge of the past; moreover, we have seen a decrease in the incidence of herpes zoster among vaccinees.
Weller's second career in tropical medicine included the directorship of the Section of Tropical Medicine at the Harvard School of Public Health, where he was a mentor to many young physician-scientists who went on to distinguished research careers in tropical medicine. During his tenure, research programs were established in Brazil and St. Lucia for schistosomiasis control. Weller credits the awarding of the team's Nobel Prize with his ability to spark worldwide collaborations for the control of parasitic diseases.
Robbins, for his part, pursued a career in academic pediatrics and studied the efficacy and use of polio vaccine. He was an active participant in the laboratory evaluation of the Salk vaccine field trial and later in studies of Sabin vaccines in infants — studies in which I participated as a fellow in Robbins's laboratory. He studied the epidemiology and clinical syndromes of enteroviruses and respiratory agents, served as dean at Case Western Reserve University Medical School, and provided direction in the campaign to eradicate poliomyelitis. He also chaired the Institute of Medicine and launched programs in adolescent health in collaboration with community agencies in Cleveland. Like Weller, Robbins believed that it was the Nobel Prize that enabled him to become a leader in the prevention of infectious diseases.
Source Information
From the Department of Pediatrics, Albany Medical College, Albany, N.Y.
References
Weller TH. Growing pathogens in tissue cultures: fifty years in academic tropical medicine, pediatrics, and virology. Canton, Mass.: Science History Publishers, 2004.(Martha L. Lepow, M.D.)