Vaccines and me
My work with LAC showed that unlike rhabdo and paramyxo viruses, LAC, a bunya virus, utilized a remarkably similar transcription and replication pattern to the recently described cap-snatching mechanism of initiating transcription of influenza viruses.
Abstract
I started my scientific career thinking I wanted to be an ecologist. I did some field work where I was an undergraduate at Miami University in Ohio but it became clear I wasn’t particularly suited for that type of research. I received a Ph.D. in Biology at the University of Notre Dame working on physiological adaptations to cold, isolating a thermal hysteresis protein (antifreeze protein) from Tenebrio molitor, the meal worm. I then went on to hone my skills as a biochemist at the University of Wisconsin, Department of Biochemistry, but soon got the opportunity to move to the Microbiology Department at the University of Geneva, Switzerland. It was 1981 and molecular biology had suddenly come of age with the ability to sequence DNA. It was an exciting time but also a very na€ıve time thinking that for instance the cloning of complicated enzymes, like the ones I had worked on at Wisconsin, was going to be simple and questions easily answered. I found myself in the laboratory of Daniel Kolokofsky. He was for all intent and purposes a molecular virologist. I knew little of microbiology much less of virology. After a period of time he asked me to consider working on a segmented RNA virus La Crosse Encephalitis Virus (LAC) (Bunyaviridae). His lab was mostly focused on mechanisms of transcription of VSV (Rhabdoviridae) and Sendai virus (Paramyxoviridae). His lab would complete the sequence of Sendai virus while I was there, a milestone at the time. I thought working on a different family of viruses and seeing how they compared to our understanding of their transcription and replication would be interesting. Coincidentally one summer, while I was a graduate student at Notre Dame, I had participated in a survey of mosquitoes in the South Bend, IN area because of an outbreak of LAC. At the time, it was simply to help subsidize my salary. My work with LAC showed that unlike rhabdo and paramyxo viruses, LAC, a bunya virus, utilized a remarkably similar transcription and replication pattern to the recently described cap-snatching mechanism of initiating transcription of influenza viruses. While flu viruses cap-snatched in the nucleus, bunyaviruses and subsequently arenaviruses all initiated transcription in the cytoplasm. It was an exciting time to be starting to work with viruses as the new molecular techniques allowed us to ascertain aspects of their molecular mechanisms much easier than previously. Although if one asks graduate students today what they think of the techniques we were using, I believe primitive might be a word that would be mentioned! In any case I was hooked as a virologist and remain hooked today. After leaving Dan’s lab I moved to Harvard Medical School and Boston’s Children’s Hospital. It was there that I really became a virologist interested in not just understanding their molecular mechanisms but pursuing ways to stop their infections. Boston’s Children’s Hospital, like all pediatric hospitals, has specific interests in diseases of infants such as Respiratory Syncytial virus (RSV). In the 1960s an RSV vaccine developed by NIH was used and had the unexpected consequence of causing more harm than any protection. The vaccine caused disease enhancement. This result was one of the first where vaccines which previously would be automatically considered safe, now had to be tested for the possibility that they might cause worsened disease. There was no good animal model to examine RSV pathogenesis and it remains that way today. The 1980s also saw the outbreak of HIV, including in infants. The first AIDS patient was seen at Boston’s Children’s Hospital sometime between 1983 and 1985. It left an indelible mark on those of us who were there and suddenly realized the extent of the outbreak and that it was nothing like we had ever seen or hopefully see ever again in our lifetime. The history of HIV vaccine development is well documented and has served as an example of how complicated a virus can be that infects the immune system. It became clear that in order to develop a vaccine we need first to understand the virus, the correlates of protection and how to manage such a complicated pathogen. Most of the work I did at Children’s focused on anti-viral treatments such as ribavirin. I also became intrigued by single cell parasitic infections and how little was known of these organisms and their cellular functions. I started to wonder how viruses could play a role in understanding host-cell machinery. Eventually my lab developed a hypothesis that testing the protozoan parasite Leishmania extracts for RNA-dependent RNA-polymerase activity would identify any single, double, segmented or non-segmented virus. We tested the hypothesis and identified a dsRNA virus now known as Leishmaniavirus. There are several strains of this virus and other single-cell organisms are now known to be infected with dsRNA viruses. In 1996, I accepted the job of Chair of Virology and Immunology at Texas Biomedical Research Institute (Texas Biomed) previously known as Southwest Foundation for Biomedical Research. My new job was to rebuild a department of virology and immunology. It was a challenging time to be building a new department. Funding at the National Institute for Allergy and Infectious Diseases (NIAID) was hovering at less than 10%