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Genomics

Fascinating and terrifying

Scientists detail out the strategies for the survival of three parasites that infect illions of inhabitants in poor countries

The biochemist Santuza Teixeira had to interrupt her holidays twice last month and run to her laboratory at the Biomedical Sciences Institute of the Federal University Minas Gerais (UFMG). By luck, it was not to solve problems, but to celebrate with her team two happenings that were out with their normal routine. On the 5th of the month Santuza got to know that her study proposal on the genetic variability of the protozoa Trypanosoma cruzi, which is responsible for Chagas’ disease, had been selected by the Howard Hughes Institute, in the United States, and would receive funding to the tune of US$ 70,000 per year over the next five years – a privilege granted to few research groups in Brazil. Ten days later there came out in the magazine Science a scientific article of wide medical and scientific interest, in which her group had participated, scrutinizing the grouping of genes – the genome – of the parasite portrayed at the side of this article.

The genome of Trypanosoma cruzi is the most complex among the three described in the 15th of July edition of Science – there also outlined were the Trypanosoma brucei, that causes sleeping sickness, and the Leishmania major, responsible for one of the types of leishmaniosis. The result of an international research effort led by American, English and Swedish specialists, with the participation of groups from the states of Minas Gerais, São Paulo and Rio de Janeiro, these studies should, from here onwards, direct the studies dedicated to these protozoa, since a series of similarities, peculiarities and probable vulnerabilities of each one of them, has become clearer.

These discoveries could accelerate the search for methods and diagnostic reagents or of medicines that reduce the scope of these illnesses caused by this parasite the T. cruzi, transmitted by an insect known as the kissing bug, which infects 18 million people in Latin America, and brings about heart problems; the T. brucei, which is spread by way of the tsetse fly, installing itself in the organism of 500,000 people in 36 African countries, causing fever, headache, sleep disturbances and neurological problems; the Leishmania major, also transmitted by flies, which serves as a model for the study of around 30 species that affect 12 million inhabitants in 88 countries, among them Brazil, and can bring about disfiguring lesions or attack the intestines. Together, the three illnesses kill around 150,000 people per year in the world.

“The fact that the genes of these parasites have been identified is an incentive for the pharmaceutical companies and even for state owned medical companies to invest in the development of new anti-parasitic drugs, because they can now begin at a more advanced stage”, says José Franco da Silveira Filho, a researcher at the Federal University of São Paulo (UNIFESP), who worked on the identification of the telomeres – the end of chromosomes – of Trypanosoma cruzi. It is exactly at the telomeres that the genes responsible for the production of the surface proteins are concentrated, and these facilitate the invasion of mammal cells and help to deceive the defenses of the organisms and install themselves within.

The three parasites, although they had separated from a common ancestor around 200 million years ago, still show some 6,158 common genes, associated to metabolic functioning and basic structures – the genes exclusive to each species are relatively few, varying from 910 for the Leishamia major to 3,736 in the Trypanosoma cruzi. “Starting from this common nucleus, it’s possible to begin to think about compounds that would serve for all three”, suggests Angela Cruz, from the Medical School of Ribeirão Preto, of the University of São Paulo (USP), who participated in the sequencing and analysis of chromosome 2 of the Leishamia major.

“But the greatest problem”, she adds, “is that we’re talking about neglected illnesses, those of poor countries”. Up until now, the pharmaceutical industry has shown little interest in the development of medicines that are more efficient and less toxic than the rare ones in use today because the revenue might not even cover the costs, since the purchasers would be governments or the inhabitants of poor countries. According to a report published on the 3rd of July in the New York Times newspaper, the development costs for a new medicine have gone up from US$ 800 million in 2000 to almost US$ 1 billion today. The jump in the expenses is making the drug companies concentrate their search on variations of products in which they already have experience or those that can count upon a secure market such as diabetes, cancer, mental disturbances and some heart problems.

Among the researchers things are different. “For us, and for many other scientists who work with the Tripanossomas, there is a genuine interest in enlisting in the fight against neglected illnesses”, comments to this magazine Najib El-Sayed, a molecular biologist from the Institute for Genomic Research (Tigr), in the United States, who in this current edition of Science signed for two of the articles as first author and another as the senior researcher – as well as the three studies describing the genomes, there was another comparing them and a further two commenting upon the discoveries. “This research is important from the medical point of view, because good, available medicines don’t exist”, states Bjorn Andersson, from the Karolinska Institute of Sweden, who has been studying Chagas’ disease since 1996. “I hope that new medicines will truly come about.”

235 researchers from 21 countries participated of this enterprise – not only from Brazil, Argentina and Venezuela, where these problems are old, but also from France, Scotland, the United States and Singapore, in which a case of leishmaniosis would cause more panic than the arrival of a Martian. This consortium of institutions began to be formed in 1994 when the World Health Organization (WHO) approved the modest funding of US$ 20,000, the so-called seed money, for the proposal of the sequencing of the genome of the parasites that cause tropical illnesses, presented by Carlos Morel, from the Oswaldo Cruz Foundation (Fiocruz), of Rio de Janeiro, which released a further US$ 20,000. Starting from there, the challenge was taken up by more scientists and in 1998 they managed to seduce the Tigr, which then became one of the leading institutions driving the consortium. Upon receiving funding estimated at US$ 32 million, essentially from the National Institutes of Health (NIH), in the United States, and from the Wellcome Trust, of the United Kingdom, the work took off.

Transition beings
The mobilization size is also due in truth to the interest in the biology of these single cellular microorganisms. “Some phenomena, such as the RNA edition and the antigenic variation, were identified or well characterized in the tripanossomas”, exemplifies El-Sayed, with whom the Brazilian Daniela Bartholomeu worked. Although they are eukaryotes (cells with a true nucleus, just like those of animals and higher level plants), they present some characteristics of prokaryotes, as the single cell organisms with out a nucleus are called, which are more primitive, such as bacteria.
“These parasites are extremely fascinating”, says Franco da Silveira, who worked in collaboration with other groups from UNIFESP, such as that of  Nobuko Yoshida and Renato Mortara. “They’re a type of living fossils, as if they were experiments from nature that had survived but had originated being that were much more refined.” In the three, they have shown the order of genes to have been highly conserved – or genome synteny –, on a scale more accentuated for the L. major, as if it had been the oldest organism and in their chromosomes, duly jumbled up or segmented, had given origin to the other two species of protozoa.

One of the surprising findings in the Trypanosoma cruzi is a family of genes called MASP, Mucin Associated Surface Proteins, with some 1,300 members, but whose functions are as yet unknown. This was, by indication, the most indomitable of the three parasites, from the point of view that it demanded modifications in the mounting and analysis programs of the genes. “The genome of T. cruzi is highly complex and repetitive, more than unusual”, recognizes Andersson. At least half of the genetic sequences have a copy and the other half might well have more than two copies. “Because of these repetitive sequences”, tells group leader Santuza, “it was not possible to carry out a complete mounting of the genome”. Another reason for which one cannot give to the genome the form of a long tape is that it is not known for certain how many chromosomes there are – the structures that contain the genes – in T. cruzi: there should be something close to 28; the problem is that some chromosomes have only one copy and others two or more.

Dribbling antibodies
These repetitions of genes and of chromosomes, Santuza ponders, should facilitate genetic recombination and the perfecting of artificers that will permit these parasites escaping from the defenses of the organisms that they invade – even with a vast stretch of common genome, the tritryps, as they are known, guard subtle but essential differences. The Trypanosoma brucei lives in the blood of mammals and escape from the antibodies by producing different surface proteins – this is the antigenic variation: the antibodies recognize the invaders that have a protein A, let us say, but allow to escape those that had exchanged protein A for another protein B. Curiously enough, the genes linked to the surface proteins are generally truncated – only 7% work directly.

However, the T. cruzi invades the cells – first those of the skin and afterwards the heart – and it makes use of the so called antigenic variability: the reason for producing Chagas’ disease, and at the same time, dozens of variations of the surface proteins, which allows them not only to dribble the antibodies but also to link onto the mammal’s cells in which it lives throughout the length of its lifecycle. “Perhaps we’re closer to understanding how these parasites have such success and survive in organisms so different”, comments Angela Cruz, from USP of Ribeirão Preto, “but we have to make use of this knowledge for something useful. Whoever works with the genetics of these organisms should get together with those who work with the structure of proteins or those who design medicines in order to optimize the search for better targets in the parasites and to generate compounds for testing. We have to carry out a concentrated and concerted effort to arrive at medicines or at operable preventative methods in combating these illnesses”.

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