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Signs of vigor

Agreement with Institut Pasteur and article in international magazine evidence Brazilian advances

The competence that Brazil has built up in biotechnology applied to healthcare could be glimpsed in two recent happenings without any apparent connection. One was the signature of an agreement between the Institut Pasteur, of Paris, and FAPESP, by means of which a group of  Brazilian researchers is going to take part in the international effort to sequence the genome of the Aedes aegypti mosquito, the vector of such diseases as dengue and yellow fever. The Brazilian group, headed by Sergio Verjovski-Almeida, from the Chemistry Institute of the University of São Paulo, will have the task of identifying fragments of active genes from the mosquito, called technically ESTs (expressed sequence tags).

These bits of genes, which carry the recipe to be used by the cells for making their proteins, can be of great use for the development of forms of prevention of the diseases transmitted by the Aedes aegypti. “It is still rare for Brazil to be invited to take part in a venture like this one”, says Verjovski, who in 2002 led a similar effort to map the fragments of active genes of the Schistosoma mansoni, a parasite that causes schistosomiasis.  The invitation of the Brazilian group is important, because it recognizes its contribution towards mapping the Schistosoma and comes from an institution, founded in France in 1887, that is a global landmark for health research.

The second good news was a five-page article about Brazil, published in a special supplement of the Nature Biotechnology magazine about seven developing countries (South Africa, Brazil, China, South Korea, Cuba, Egypt and India) that have been achieving advances in biotechnology applied to healthcare. The inclusion of Brazil in this team does not constitute a novelty. In mid-2002, a report from the World Health Organization about the benefits of genetic research in public health was already pointing out the contribution of four countries (Cuba, India, China and Brazil) as exceptions to the supremacy of the First World. Nature Biotechnology’s supplement went further and spelt it all out.

It highlighted, amongst others, India’s success in the production of cheap medicines, Cuba’s prowess in developing a vaccine against meningitis B, Egypt’s capability in producing recombinant insulin, and South Korea’s success in transferring technology to the private sector. South Africa and Brazil also called attention for publishing the results of their researches in scientific magazines of great impact, compared with other countries in the survey. Some contradictions were identified. In Brazil, the access of the poor population to medicines is relatively low, unlike what happens in China, Egypt, South Africa, Cuba and South Korea.

The article on Brazil was written by a group of researchers from Chile and from Canada that interviewed 33 persons in Brazil in the course of the last three years. The text does an inventory of the contributions from the 1970s, when the National Council for Scientific and Technological Development (CNPq) launched pioneer programs in biotechnology, to the recent creation of a database of DNA of threatened species, in the Botanical Gardens of Rio de Janeiro. Between one feat and another, the successes of companies like Biobras, from Minas, are recalled, which in the 1990s started producing recombinant human insulin, and FK Biotechnology, of Porto Alegre, in the area of immunodiagnostics. Or the excellence in the manufacture of vaccines acquired by public institutions, like the Butantan Institute, in São Paulo, and the Oswaldo Cruz Foundation  (Fiocruz), in Rio de Janeiro. The article highlights, in spite of the changes of government, the consistent investment in biotechnology, but ponders that, although it has been translated into a noteworthy increase in the publication of scientific articles, the effort has not materialized in an equivalent quantity of patents.

None of the advances, says the text of Nature Biotechnology, was so notable in Brazil as the sequencing of the Xylella fastidiosa bacterium, a program coordinated by FAPESP. “Acting as a launch platform, this public venture instilled national confidence and brought international recognition to the competence of  Brazilian genomics. More important, it is catalyzing post-genomic research into ills like Chagas’s disease and cancer, with vaccines and stem cells”, says the text. In the final paragraphs, the article makes reference to two pioneers who, according to the interviewees, had a fundamental role in the development of the sector.

One of them is Marcos Luiz dos Mares Guia (1935-2002), a professor from the Federal University of  Minas Gerais and a founder, in the 1990s, of  Biobrás (see box). The other is FAPESP’s scientific director, José Fernando Perez, for the coordination of the efforts in the Xylella fastidiosa project. “We are at a moment of great ebullience in biotechnology, and Brazilian musculature in this field cannot be regarded as episodic”, explains Perez. “FAPESP’s role was central, and the institution will always be recognized as a great catalyst.”

It is at this point that the article in Nature and the FAPESP-Institut Pasteur agreement converge and intermingle. To map the Xylella fastidiosa genome, FAPESP organized the ONSA network, a virtual consortium of genome laboratories from the state of São Paulo, made up originally of 30 institutions. It was in the ambit of this consortium that, in the last few years, various programs were set off, amongst them the identification of the fragments of the expressed genes of the Schistosoma mansoni, under the leadership of Sergio Verjovski-Almeida.

The group generated 163,000 partial sequences of active genes in the main stages of the life cycle of the parasite of schistosomiasis, from the forms that live freely in fresh water to those that inhabit their intermediate host, the snail, and those that infect man. Before the publication of the results from the ONSA network, there were only 16,000 fragments of genes, or expressed sequence tags (ESTs), of the schistosomiasis worm in the public databases,  75% of which derived from the adult stage of the parasite. “The complete sequences of only 163 genes of the worm were known before. We raised this number to 510 complete genes and 14,000 with partial sequences”, says Verjovski.

This work, published in September 2003 in the Nature Genetics magazine, qualified Verjovski’s group for taking part in the mapping of Aedes aegypti, in the ambit of a program of the Institut Pasteur for South America, Amsud-Pasteur. The overall objective is the same as the study of the Schistosoma: to identify fragments of genes of  Aedes aegypti  that have a role in the dissemination of dengue and yellow fever. The group will have the task of generating  100,000 ESTs, which will be added to the other 170,000 tags generated by other groups. The process generates an infinity of repeated sequences – but, the larger the number of sequences generated, the greater the chance of finding fragments of as yet undiscovered genes. The Institut Pasteur will supply the raw material for the research: cDNA libraries – databases of stable sequences of  DNA obtained from messenger RNA, corresponding to the genes in activity.

To get an idea of the unprecedented nature of this venture, you might recall an extremely rare precedent that was the collaboration between Brazilians and Americans in the study of Xylella fastidiosa. The pathogen that attacks the citruses in Brazil has lineages that cause damage in vines, oleanders and almond trees in the United States. “These groups are extremely closed, hence the importance of our integrating ourselves with the international effort with Aedes aegypti”, says researcher Ana Lucia Tabet Oller Nascimento, from the Biotechnology Center of the Butantan Institute, who is taking part in the project. Besides her and Verjovski, the group is made up of  Carlos Menck, a geneticist from USP’s Biomedical Sciences Institute, Suely Lopes Gomes and Hamza El Dorry, both from the Chemistry Institute. Verjovski, Ana Lucia and Menck worked together in the Schistosoma mansoni project.

The sequencing of the gene fragments of Aedes aegypti should begin in January and promises to be concluded next year. The partnership between Brazil and France will be part of the international project of the mosquito genome, coordinated by the Institute for Genomic Research (TIGR), of the United States. This study started in 2004, under the leadership of David Severson, from the University of  Notre Dame, Indiana, who took part in the mapping of the Anopheles gambiae mosquito, which transmits malaria. The project received funding from the American government because it is part of the Microbial Sequencing Center network, a scientific task force charged with researching into pathogens and vectors potentially usable as weapons of bioterrorism. It is not even necessary to resort to conspiracy theories to realize the threat that Aedes aegypti embodies. The cyclical epidemics of dengue in Brazil and the threat of the return of yellow fever to the major urban centers are already crushing evidence.

Precursor of the leap

The article on the advances of  biotechnology in Brazil, published in Nature Biotechnology, rescued the contribution from researcher and businessman Marcos Luiz dos Mares Guia (1935-2002). A professor at the Federal University of Minas Gerais (UFMG), at the end of the 1960s he created Biobrás, an enzyme factory, in the city of Montes Claros, in the north of the state, built with financial support from Sudene. The nose for business had arisen two years previously. In partnership with his brother, the present Minister of  Tourism, Walfrido dos Mares Guia, in 1966, the researcher created the university entrance course Pythagoras, in Belo Horizonte. Biobrás kept on growing, thanks to the integration with the university and taking advantage of postgraduate students. In the 1980s, it began to produce insulin, by means of a technology transfer agreement with the multinational Lilly. When the agreement was breached, Mares Guia came out in defense of a new technology for production, which culminated with getting one of the four patents in the world for recombinant human insulin. “In 1990, when we transformed the insulin from a pig into human insulin, by chemical means, we won the IBM award for Technological Development”, the scientist and businessman recalled in a statement recorded by the website Gallery of Brazilian Inventors (http://inventa “We managed to develop the technology by enzymatic means with great efficiency, and from then on to do recombinant genetics. It was the team from Biobrás that did the work, I was the general.” Between 1991 and 1993, Mares Guia presided the National Council for Scientific and Technological Development (CNPq). Afterwards, he moved to Miami, to take care of the company’s international business, which, in 2001, ended up being sold to the Danish group Novo Nordisk. Until the end of his life, he maintained the link with the academic world, as the head of the Enzymology and Protein Physicochemistry Laboratory at UFMG. Mares Guia died in August 2002 in Belo Horizonte, at the age of  67, as a consequence of complications in the pancreas.