Thursday, April 5, 2012
Renato Dulbecco, February 22, 1914 – February 19, 2012
Last February 19 Nobel laureate Renato Dulbecco died at age 97. Dulbecco
discovered how viruses integrate their genomes into host cells, something I've often talked about when describing the HIV life cycle. Dulbecco was mostly interested in oncoviruses, (viruses that have the potential to trigger tumors) and, in particular, the molecular mechanisms through which this could happen. He studied a virus called SV40, or simian virus 40, a polyomavirus that infects both monkeys and humans. He was also among the scientists that launched the Human Genome Project.
Over about a decade between the late '50s and the late '60s, Dulbecco and his group showed that SV40 contains DNA in a circular form and that the virus is able to permanently integrate its DNA in the cellular DNA, forming what is called a provirus. Interestingly, they found that the virus could grow in certain cell cultures, but did not grow in others, where instead it induced a cancer-like state. Dulbecco was fascinated by how the virus could achieve this as he believed the key to this mechanism could shed light on tumorigenesis in general.
In cells where the virus does not replicate, the integrated viral DNA expresses one protein in particular, the "T antigen," which the virus uses for replication. The T antigen alters the cell's replication cycle (for example by inactivating the p53 tumor suppressant proteins) favoring cell replication. Since the viral DNA is integrated in the cell's DNA, by promoting DNA replication, the virus ensures its own replication. As this happens, though, mutations start accumulating increasing the likelihood of the cell line becoming carcinogenic. In other words, it's the accumulation of mutations that eventually leads to cancer.
What about HIV? HIV is an RNA virus, not a DNA virus like SV40, and yet it uses the same mechanism that SV40 uses to replicate: integration into the host's DNA. HIV achieves this by first transforming its RNA into DNA through an enzyme called reverse transcriptase. It was Howard Temin, a graduate student in Dulbecco's laboratory, who did his Ph.D. thesis on another oncovirus, the Rous sarcoma virus, that realized that this RNA virus was able to alter the host cell DNA (edited after Dr. Racaniello's comment below). This finding led to the discovery, a few years later, of the reverse transcriptase enzyme, for which Howard Temin, David Baltimore, and Renato Dulbecco shared the 1975 Nobel Prize in Medicine (David Baltimore made the same discovery independently).
Dulbecco R (1973). Cell transformation by viruses and the role of viruses in cancer. The eleventh Marjory Stephenson Memorial Lecture. Journal of general microbiology, 79 (1), 7-17 PMID: 4359401