Academic journal article Bulletin of the World Health Organization

Entering the Post-Genomic Era of Malaria Research

Academic journal article Bulletin of the World Health Organization

Entering the Post-Genomic Era of Malaria Research

Article excerpt

Bulletin of the World Health Organization, 2000, 78: 1424-1437.

Voir page 1434 le resume en francais. En la pagina 1434 figura un resumen on espanol


The development of genome sequencing technologies over the last five years has resulted in a wealth of sequence information, culminating in the recent announcement of a working draft of the human genome. Pathogen genomes, through their smaller size, have been even more tractable to these methodologies and are now well represented in genome science. Although not always suited as "model" organisms, the importance of pathogens in medicine and agriculture has made the exploitation of the sequence databases a high priority. But what does the production of long strings of As, Cs, Gs and Ts actually mean in terms of the alleviation of the burden of disease, particularly in developing countries? So far, genome sequencing has largely been the province of the developed world, where the resources and science infrastructure have allowed the formation of high-throughput sequencing centres. However, the use of sequencing information need not be restricted in this way, provided that resources for training can be met.

Probably the most important aspect of the post-genomic era (i.e. after the sequencing has been carried out) is analysis of the primary sequence data. This is called bioinformatics and embraces a range of theoretical analyses aimed at converting the DNA sequence into biological information. A major part of this discipline involves the identification of genes through a number of processes, from identifying similarities with previously identified genes from other organisms, to the use of computer-derived models based on existing data. Subsequently come predictions of biological function and molecular shape (structural genomics), both of which have scope for development.

Knowing the whole sequence of a pathogen genome also allows researchers to investigate the behaviour of organisms on a much broader basis than was previously possible. Now, instead of studying the effect of drug treatment or differentiation on one or two genes, it is possible to study variation in all the genes at the same time using global transcriptional analysis. Protein patterns may also be examined, or the organism may be genetically modified (transfection), providing a direct link between these biological effectors and gross phenotype. The technology for these experiments has been developed as a direct consequence of the desire to exploit the genome sequence data.

It is not hard to envisage that the ability to identify and characterize the genetic blueprint of pathogens will help us recognize critical elements in the development and pathogenesis of disease-causing organisms and target our research efforts in the production of new therapies. For Plasmodium falciparum, genes and proteins acting at specific stages in the life cycle can be identified, their roles tested by genetic modification and promising candidates used in vaccine production. Parasite metabolic pathways not present in the host could also be targeted with potent inhibitors that are non-toxic to humans; and parasite drug-resistance mechanisms could also be targeted, giving existing drugs a kroger effective lifetime. The sequence of the P. falciparum genome will provide many opportunities for research into malaria, but this is only a beginning, with the challenge being to turn those opportunities into effective treatments in the field.

The Plasmodium falciparum genome

The genome of P. falciparum consists of three discrete components: a linear repeat of a 6 kb element located within mitochondria; a 35 kb circle within a plastid-like structure (the apicoplast); and 25-30 Mb of nuclear DNA (genomic DNA). The nuclear DNA is organized into 14 chromosomes, between 0.75-3.5 Mb in size, as determined by pulse-field gel electrophoresis (PFGE) and electron microscopic counts of kinetochore structures. …

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