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Science 309 (5733): 399-

Copyright © 2005 by the American Association for the Advancement of Science

Trypanosomatid Genomes

Caroline Ash and Barbara R. Jasny

We have committed the pages of this issue to an exploration of three genomes of ancient organisms. Why? There are two important reasons. First, the body of work represented here is the culmination of more than a century of labor on parasites responsible for severe human diseases; many of those who have contributed have done so from deep-seated humanitarian motives. Second, this work symbolizes a huge intellectual triumph; these organisms have been recalcitrant to methodologies developed for the standard model organisms, not least in the difficulties encountered in the sequencing effort itself, yet the rewards for persistence have been remarkable: RNA editing and RNA trans-splicing, the T helper cell paradox, innate immunity, immune evasion, antigenic variation, glycophosphoinositol membrane anchoring, metabolic compartmentalization and the glycosome, the kinetoplast and chromosome evolution, vector biology, and epidemiological modeling.

This work also represents a triumph of international collaboration. After independent origins and discussions in the 1990s, it became clear that there was more to be gained by sharing experiences across the groups of researchers interested in these parasites. The three original international networks for trypanosomatid genome projects held the first "Tritryp" meeting in 2000 (http://tryp-pc1.path.cam.ac.uk/trypanosome/report2000.htm). It was jointly funded by the World Health Organization, Wellcome Trust, the National Institutes of Health, and the Burroughs Wellcome Fund, and also marked the beginning of closer collaboration among the sequencing centers at the Sanger Institute, The Institute for Genomic Research, the Seattle Biomedical Research Institutet, and the Karolinska Institute. Another triumph of this collaboration was the extent of international involvement: Most of the ESTs (expressed sequence tags) for all three organisms were sequenced at institutions in Africa and South America. The participation of endemic countries also included studies on strain diversity, construction of large-insert libraries, and early stages of physical mapping of the genomes.

Figure 1

CREDIT: ELISBET CALER

Within the past 5 years, the sequencing of genomes per se has gone from being a revolutionary achievement to something commonplace. However, the sequences of Trypanosoma cruzi, Trypanosoma brucei, and Leishmania major (the so-called Tritryps) are revelatory. The desire to put the emphasis on biology led the authors of the Research Articles to adopt a somewhat unusual organization. Although there is nominally a comparative article and articles on each of the genomes, each article provides comparisons among the three organisms for different research themes. Hence, Berriman et al. (p. 416) emphasize metabolic and biochemical pathways of all three organisms within the article for T. brucei; Ivens and colleagues (p. 436) highlight fundamental aspects of molecular biology (such as transcription, translation, posttranslation modification, and proteolysis) while describing L. major; and El-Sayed et al. (p. 409) focus on repetitive elements, DNA replication and repair, and signaling pathways in T. cruzi and the other parasites. The comparative paper by El-Sayed et al. (p. 404) concentrates on gene content, genome architecture, composition, organization of protein domains, and rates of evolution. This special section also contains four fold-out plates (between pages 423 and 434), which are cross-referenced by all the Research Articles. Parasite invasion also depends on exploitation of host signaling pathways; an STKE Perspective by Burleigh discusses alternate models of T. cruzi invasion, highlighting the role of host phosphatidylinositol 3-kinases (PI3Ks) in this process.

Sequence information provides the launching pad for research into function which, in turn, can provide the forward thrust for the design of new therapeutics. We have included two examples here. From scrutinizing the proteome of T. cruzi, Atwood et al. (p. 473) have identified distinct energy sources used at different stages of its life cycle. Pérez-Morga et al. (p. 469) have resolved a long-standing conundrum, and present the mechanism by which apolipoprotein L-1, a factor in human serum, kills trypanosomes.

With so many unique tools and targets, why don't we have effective drugs? It is a terrible indictment that we have failed to support the translation of this work into cheap, safe products. Cross (p. 355) calls for something better than the standard modus operandi of the pharmaceutical companies and the academic promotions system. As Morel notes in his Viewpoint (p. 401), networks such as the one that led to the sequencing of these three organisms can enable developing countries to push forward in health innovation with their own energies and resources. Let's hope the genomes will fuel this process.



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Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882