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July 28, 2003
In Search of a Vaccine: Proteins, Genes, and Giardia
Woods Hole, MA-Giardia, best known in the United States as a disease of backpackers and children in daycare, also kills about 2 million people around the world each year. It boasts a tenacity and adaptability that has allowed it to survive since its ancestors acted as the transition between cells with and without internal organelles millennia ago. Yet no one knows exactly what this bug does that makes people so sick, and no one knows how to create a vaccine for it. Andrew McArthur and collaborators with the new Global Infectious Disease program at the Marine Biological Laboratory in Woods Hole, Massachusetts, plan to change that. "A lot of people who get Giardia never get rid of it, and live lives of discomfort and lost productivity," says McArthur.
The MBL team uses state-of-the-art equipment to sequence DNA and RNAs (messengers for protein production) collected from Giardia at particular milestones in the bug's lifecycle. MBL researchers, who are nearing the end of a project to map the entire Giardia DNA code, then identify sequences of DNA responsible for producing specific RNAs. RNA is taken, for example, from Giardia cultures as the parasite transforms into a cyst to survive being shed from its host animal. The cysts form to survive in water outside that host and to survive the treacherous path to the intestine of a new host. Sequencing the RNA most conspicuously present as the cysts form and comparing those sequences to the Giardia genome shows what sequences of DNA are active genes during cyst formation. McArthur presumes that genes that are highly active at this time are responsible for producing the proteins that make cyst formation possible. Researchers have already discovered one gene used only late in cyst formation, but which may produce large quantities of protein on the cyst's surface. "Cysts may go into the water stream just covered in that protein," says McArthur. That protein, McArthur says, may be critical to simply surviving in water or important for infecting the next host. The latter case might lead to a target for a vaccine.
The MBL collaboration between world-class computational biologists and parasitologists has also shown that the difficult-to-study bug, during its residence in a host's intestine, becomes a cyst at a later point in its life cycle than previously suspected. The collaboration has also yielded new genes and proteins that appear responsible for distinct characteristics of its transmission and ability to survive in different hosts. "You never know what might end up being a vaccine target, " says McArthur.
The quick success of the Giardial project has led to other work on trypanosomes and amoebae. Analogous work on schistosomiasis, a disease caused by infectious worms, is under consideration.
"The Giardial project showed so clearly and so quickly how you can learn a great deal using this approach about an organism and its biology and activity," says McArthur. "These approaches are key, and done right, they can open up windows into almost any aspect of biology."
McArthur received his Ph.D. in Biology from the University of Victoria, British Columbia, in 1996, for a dissertation focusing on the evolutionary origins of hydrothermal vent gastropods. From 1996 until 1998, he worked in invertebrate zoology and molecular systematics at the National Museum of Natural History, part of the Smithsonian Institution in Washington, D.C. He joined the research staff at the Josephine Bay Paul Center of the Marine Biological Laboratory in 1998. He is currently an Assistant Scientist at the MBL. McArthur's work on Giardia and African trypanosomes is supported by the National Institute for Allergies and Infectious Diseases of the National Institutes of Health.
Recent Relevant Publications
Seshadri, V., A.G. McArthur, M.L. Sogin, & R.D. Adam. "Giardia lamblia RNA polymerase II: Amanitin-resistant transcription." Journal of Biological Chemistry, in press. 2003.
Nixon, J.E.J., J. Field, A.G. McArthur, M.L. Sogin, N. Yarlett, B.J. Loftus, and J. Samuelson. "The iron-dependent hydrogenases of Entamoeba histolytica and Giardia lamblia: activity of the recombinant entamoebic enzyme and evidence for lateral gene transfer." Biological Bulletin, 204, 1-9. 2003.
Nixon, J.E.J., A. Wang, H.G. Morrison, A.G. McArthur, M.L. Sogin, B. Loftus, and J. Samuelson. "A spliceosomal intron in Giardia lamblia." Proceedings of the National Academy of Sciences, USA, 99, 3701-3705. 2002.
Sun, C.-H., D. Palm, A.G. McArthur, S.G. Svard, and F.D. Gillin. "A novel Myb-related protein involved in transcriptional activation of encystation genes in Giardia lamblia." Molecular Microbiology, 46, 971-984. 2002.
The Marine Biological Laboratory is an independent scientific institution, founded in 1888, that undertakes the highest level of creative research and education in biology, including the biomedical and environmental sciences. In 2002 the Laboratory received a grant of $5 Million from the Ellison Medical Foundation of Bethesda, Maryland, to establish a new interdisciplinary Program in Molecular Pathogenesis and Global Infectious Diseases. This program creates a one-of-a-kind international center for research and training dedicated to studying disease-causing organisms and the complex relationships these pathogens have with their hosts. The program is part of the Josephine Bay Paul Center for Comparative Molecular Biology and Evolution at the MBL, and builds upon the Center's existing strengths in molecular evolution and comparative genomics.