Renato Dulbecco and the Beginnings of Quantitative Animal Virology

In an earlier posting [Max Delbruck, Lisa Meitner, Niels Bohr, and the Nazis], we mentioned that when James Watson was a graduate student in Salvatore Luria’s lab at the University of Indiana in the late 1940’s, he shared a lab bench with another future Nobel laureate, Renato Dulbecco. Dulbecco happened to be in Luria’s lab because earlier, in 1936, when Dulbecco was studying for a medical degree at the University of Torino in Italy, he favorably impressed Luria, who was then a professor at Torino. Later, in 1947, after Dulbecco had spent a short stint in politics in Italy, Luria invited Dulbecco to join his Indiana group to study bacteriophages. Hence, Dulbecco came to share a lab bench with Watson. In the summer of 1949, Dulbecco moved on to the California Institute of Technology, to join Max Delbruck’s phage group to further his inquiry into bacteriophages. But, providence was to intervene, as follows.

In the late 1940s, a wealthy Californian became ill with shingles; a late complication of chickenpox, caused by varicella-zoster virus, a herpesvirus. The man’s physician explained that nothing could be done for his shingles, and moreover, that virtually nothing was known about the viruses that infect humans. Auspiciously, the physician knew of the studies being done on bacteriophages at Caltech, and he also was aware that Caltech was the great center for such work. So, after explaining to his well-heeled patient that bacteriophages were only of theoretical interest regarding human disease, he suggested that the patient might help to develop a center at Caltech that might begin to study medically important viruses. The patient agreed, and since virology at Caltech was headed by Delbruck, the former physicist found himself with an endowment to study human viruses, with virtually no background for how to use it. So, Delbruck summoned to his office Dulbecco, who had trained to be a physician, and proposed that Dulbecco give animal viruses a try. Dulbecco was delighted by the idea and, together with Marguerite Vogt (also in Delbruck’s group) he developed procedures to grow poliovirus in cell culture. Additionally, Dulbecco and Vogt developed a plaque assay procedure to measure the titer of animal viruses grown in cell culture. Importantly, the plaque assay also made it possible to plaque-purify attenuated poliovirus variants; crucial to the development of the Sabin live-attenuated polio vaccine. And, apropos the major point of this vignette, this is how quantitative animal virology came to be.

Plaques produced by Western equine encephalitis virus on chick embryo fibroblasts (left) and by poliovirus on HeLa cells, a line of cells derived from a human cervical carcinoma (right). Photo by R. Dulbecco; Figure 1.6, page 18, From Virology: Molecular Biology and Pathogenesis, by Leonard C. Norkin, ASM Press, 2010.
Plaques produced by Western equine encephalitis virus on chick embryo fibroblasts (left) and by poliovirus on HeLa cells, a line of cells derived from a human cervical carcinoma (right). Photo by R. Dulbecco; Figure 1.6, page 18, From Virology: Molecular Biology and Pathogenesis, by Leonard C. Norkin, ASM Press, 2010.

Dulbecco, remarking on the importance of the plaque assay for animal viruses, noted that subsequent biochemical and molecular studies would have been much less meaningful without reference to the multiplication cycle revealed by the plaque assay. Interestingly, although this was apparent to the phage workers, it was not equally obvious to most animal virologists of the day.

Before moving on, we might note that Marguerite Vogt came to Caltech in 1950 to work with Delbruck, who introduced her to Dulbecco, thus initiating the long and productive collaboration of Dulbecco and Vogt. Following their ground-breaking poliovirus studies, they went on to study the tumorigenic mouse polyomavavirus, demonstrating that infection of normal cells in culture with mouse polyomavirus resulted in neoplastic transformation of the cells into tumor cells. What’s more, this transformation was associated with the integration of the viral genome into that of the host cell. Moreover, a subset of the viral genes continued to be expressed in the transformed cells. Importantly, these studies gave credence to the notion that cancer has an underlying genetic basis. Indeed, the subsequent identification by others of those viral genes that are expressed in virally transformed cells led to singularly important insights into the molecular basis of cancer. [In 1973, Vogt established her own research program, looking into the immortalization of cancer cells, and the roll of telomeres in the origin of cancer.]

Renato Dulbecco.  Image via the National Library of Medicine (image in public domain).
Renato Dulbecco. Image via the National Library of Medicine (image in public domain).

For his studies revealing the link between genetic mutations and cancer, Dulbecco shared the 1975 Nobel Prize for physiology or medicine with his former student, Howard Temin, and David Baltimore. The latter two individuals simultaneously and independently discovered the enzyme, reverse trancriptase, which enables retroviral genomes to be reverse-transcribed and then incorporated into cellular genomes (another of my favorite stories and the subject of a future posting). Dulbecco took no part in these studies, but he did teach Temin and Baltimore approaches that led to their discoveries. Vogt was never recognized by the Nobel Committee for her contributions, which many regard as an oversight.

Bearing in mind events recounted in the earlier posting, Max Delbruck, Lisa Meitner, Niels Bohr, and the Nazis, note that Dulbecco served as a medical officer in the Italian Army during the Second World War, eventually being ordered to the Russian front. During a stopover in Warsaw, he happened to see Jewish slave laborers wearing yellow stars, and was horrified to learn that they would be killed when their work was completed. He later referred to that episode as his “turning point.” In Russia he was wounded and sent back to Italy to recuperate. After his recovery, and the collapse of Italian fascism, he joined the resistance against the German occupation, attending to wounded partisans.

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