I. Biology of Apicomplexan Parasites
II. The Apicomplexan Plastid: Something Old, Something New, Something Borrowed, Something Green
IIIA. Designing and Mining Pathogen Genome Databases: From Genes to Drugs and Vaccines
IIIB. Designing and Mining Pathogen Genome Databases: From Genes to Drugs and Vaccines
IIIC. Designing and Mining Pathogen Genome Databases: From Genes to Drugs and Vaccines
Part I: Biology of Apicomplexan Parasites
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There are more than 5000 species of single-celled eukaryotes in the biological phylum known as the Apicomplexa, including the parasites responsible for malaria, neurological birth defects, and opportunistic infections associated with HIV/AIDS. These ancient protozoa provide a unique window into the evolution of subcellular organelles that have long fascinated cell biologists. Familiar features help to elucidate the origins, functions and design parameters for the secretory pathway, endosymbiotic organelles, the cytoskeleton, and cell cycle control. Conversely, parasite-specific organelles highlight the evolutionary diversity of eukaryotes, and suggest novel targets for treating disease.
Antibiotics are effective because they kill bacteria without harming humans and other eukaryotes (organisms with cells that contain nuclei). So why are the eukaryotic parasites responsible for malaria and toxoplasmosis killed by drugs like clindamycin? Multidisciplinary studies integrating molecular genetics, cell biology, biochemistry, pharmacology and computational genomics reveal that such drugs target an unusual organelle. The "apicoplast" was acquired when an ancestral organism 'ate' a eukaryotic alga, and retained the algal plastid -- a relative of plant chloroplasts derived from a bacterial ancestor. Although no longer photosynthetic, the apicoplast is essential for parasite survival, providing new targets for drug development.
With the emergence of genomic-scale datasets representing all of the genes in the genome, all of the proteins in a cell or tissue, and all of the interactions and signals in an organism, biologists are increasingly faced with the challenge of how to store, integrate, and interrogate this information. How can we effectively mine large-scale datasets to expedite biological discovery, for example in the identification of new targets for anti-parasitic drug and vaccine design? Computational biology and genome informatics provide tools of growing importance for all biologists. Internet-based access makes such information available to scientists and the interested public worldwide.
David S. Roos is the E. Otis Kendall Professor of Biology at the University of Pennsylvania, and Founding Director of the Penn Genomics Institute. He earned his undergraduate degree at Harvard College, a PhD at The Rockefeller University, and joined the University of Pennsylvania in 1989 after a post-doctoral stint at Stanford University.
Dr. Roos' work seeks to integrate diverse disciplines, from molecular cell biology and pharmacology, to computer science and international public health. Current interests focus on protozoan parasites, including Toxoplasma (a prominent congenital pathogen and opportunistic infection associated with AIDS) and Plasmodium (which causes malaria). Research in the Roos laboratory has yielded genetic tools for the dissection of parasite pathogenesis and drug resistance mechanisms, new insights into the evolution and function of subcellular organelles, and computational tools including databases making genomic-scale datasets accessible to scientists worldwide.
Dr. Roos has published numerous research reports in leading scientific journals, and received honors including the Presidential Young Investigator Award from the National Science Foundation, the Burroughs Wellcome Scholar Award, and the Ellison Medical Foundation Senior Scholar Award in Global Infectious Diseases. Deeply committed to education, Roos has taught courses for both general and specialized audiences, at Penn and elsewhere, and travels widely as a lecturer and consultant for the WHO and other organizations.
- Norma Andrews iBioSeminar: Intracellular parasitism by Trypanosoma cruzi and Leishmania
- David Botstein iBioSeminar: Fruits of the Genome Sequence
- Joe DeRisi iBioSeminar: Malaria: Disease, Research and Drug Development
- Joseph DeRisi iBioEducation: Genome Sequencing for Pathogen Discovery
- David Haussler iBioMagazine: What Can We Learn From Sequencing Our Genomes
The cell biology of apicomplexan parasites
Roos, DS. 2005. Themes and variations in apicomplexan parasite biology. Science 309:72-73. PDF
Sibley, LD. 2004. Intracellular parasite invasion strategies. Science 304:248-253. PDF
Joiner, KA & DS Roos. 2002. Secretory traffic in Toxoplasma gondii: Less is more. Journal of Cell Biology 156:1039-1050. PDF
Nishi, M, K Hu, JM Murray & DS Roos. 2008. How to build a parasite: Organellar dynamics during the cell cycle of Toxoplasma gondii. Journal of Cell Science 121:1559-1568. PDF
Discovery and characterization of the apicoplast
Köhler, S, CF Delwiche, PW Denny, LG Tilney, P Webster, RJM Wilson, JD Palmer & DS Roos. 1997. A plastid of probable green algal origin in apicomplexan parasites. Science 275:1485-1488. PDF
Roos, DS, MJ Crawford, RGK Donald, JC Kissinger, LJ Klimczak & B Striepen. 1999. Origins, targeting, and function of the apicomplexan plastid. Current Opinions in Microbiology 2:426-432. PDF
Roos, DS, MJ Crawford, RGK Donald, M Fraunholz, OS Harb, CY He, JC Kissinger, MK Shaw & B Striepen. 2002. Mining the Plasmodium genome database to define organellar function: What does the apicoplast do? Philosophical Transactions of the Royal Society of London, series B (Biological Sciences) 357:35-46. PDF
Ralph, SA, GG van Dooren, RF Waller, MJ Crawford, MJ Fraunholz, BJ Foth, CJ Tonkin, DS Roos & GI McFadden. 2004. Metabolic pathway maps and functions of the Plasmodium falciparumapicoplast. Nature Reviews in Microbiology 2:203-216. PDF
Designing & mining (pathogen) genome databases
Kissinger, JC et al. 2002. The Plasmodium genome database: Designing and mining a eukaryotic genomics resource. Nature 419:490-492. See also http://PlasmoDB.org. PDF
Bahl, A et al. 2002. PlasmoDB: The Plasmodium genome resource. An integrated database providing tools for accessing and analyzing mapping, expression and sequence data (both finished and unfinished). Nucleic Acids Research 30: D87-90. See also http://PlasmoDB.org. PDF
Drug target discovery / Global access to genomics & bioinformatics
Roos, DS. 2001. Bioinformatics -- Trying to swim in a sea of data. Science 291: 1260-1261. PDF
deGrave, W, C Huynh, DS Roos, A Oduola & CM Morel. 2002. Bioinformatics for disease endemic countries: Opportunities and challenges in science and technology development for health. IUPAC Journal. PDF
Agüero, F et al. 2008. Genomic-scale prioritization of drug targets. Nature Drug Discovery, in press. See also http://TDRtargets.org.