A LAVISH lifestyle might be the downfall of three parasites that affect millions of people in poor countries. The sequencing of the DNA of the parasites that cause sleeping sickness, Chagas鈥� disease and leishmaniasis has revealed that they have a unique and wasteful way of making proteins.
The single-celled trypanosome parasites, collectively known as the 鈥渢ritryps鈥�, evolved from a common ancestor at least 200 millions year ago, and still share many characteristics. They are probably so careless about how they make proteins because they enjoy an endless free lunch, plundering nutrients from their hosts. 鈥淢etabolically, they don鈥檛 care,鈥� says Peter Myler of the Seattle Biomedical Research Institute, one of the three main labs involved in the sequencing effort. 鈥淭hey can waste as much as they want.鈥�
Most organisms switch genes on only when they need to make a protein, to avoid wasting energy. Myler鈥檚 genome analysis, one of seven papers on the trityps in last week鈥檚 Science, showed that they make an indiscriminate range of proteins by activating hundreds of genes at once.
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In parts of each parasite鈥檚 genome, a single gene switch, or promoter, will turn on many genes. 鈥淥n one chromosome, there may be only one promoter for more than 300 genes,鈥� he says. So if a drug could be created that interferes with the RNA polymerase enzyme that initiates protein manufacture when it binds to the promoter, it could cripple all three trityps by depriving them of hundreds of different proteins. Although all organisms have polymerase enzymes, the polymerase in trityps and its associated machinery are quite different, so it should be possible to target them without killing human cells too.
But there is a snag. Two of the parasites 鈥� Leishmania major, which causes the debilitating skin disease leishmaniasis, and Trypanosoma cruzi, which causes Chagas鈥� disease 鈥� live hidden in cells, and so are difficult to hit with drugs. The third of the trio 鈥� Trypanosoma brucei, which causes sleeping sickness 鈥� might be more vulnerable, because it lives in the bloodstream.
If Myler鈥檚 approach does not work, there are other potential targets. The sequencing revealed that the three parasites share 6200 genes, many of them in the gene clusters that get activated en masse. Now the teams want to find out which of these shared genes are vital to the parasites, but have no equivalent in humans. Targeting proteins encoded by these genes should not harm human cells.
New drugs are desperately needed, as the existing ones are very toxic and expensive. Melarsoprol, the major drug for combating sleeping sickness, kills 5 per cent of recipients. And in some areas a third of patients have parasites resistant to the drug.
The sequencing of the three genomes should boost efforts to develop new treatments. 鈥淚t鈥檚 a major milestone for all of us, and the first big step towards finding solutions to these diseases,鈥� says Najib El-Sayed of the Institute for Genomic Research in Maryland, another of the sequencing labs. 鈥淭he main concern is to convince the international community to use these new possibilities,鈥� adds Jean Jannin of the World Health Organization鈥檚 sleeping-sickness control programme. 鈥淏ut the route from genes to a new drug is very long.鈥�
