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Brazil?s Collaboration with the World

Integrated action in the public and private sectors has pushed forward research in biotechnology

Eduardo Geraque

On the 1st of May 1997 research into genomics was inaugurated in Brazil. At a meeting on a ranch in the town of Piracaia, in the interior of the State of Sao Paulo, the biochemist Fernando Reinach, today the executive director the Alellyx, the Brazilian biotechnology company set up just over a year ago, and FAPESP?s scientific director, José Fernando Perez, agreed that the moment had arrived in Brazil to sequence the genome of a bacterium. The proposal, put forward by Reinach, who is also with the Chemical Institute of the University of Sao Paulo (USP), would be going to only begin to flourish.

At another meeting at FAPESP?s headquarters some time afterwards, the researcher from USP refined his idea: having found it interesting to study the genome of some bacterium involved in the agricultural sector. “People from Fundecitrus (the Fund for the Defense of Citrus Farming ) were at that moment in time complaining about CVC (Citric Variegated Chlorosis). I looked at the size of the genome and reckoned that it would do (for sequencing)”, Reinach recalls. The fact that the choice had fallen upon a bacterium was for no special motive. “A bacterium is sufficiently large to get many people involved and sufficiently small to make it possible to carry out”, he says.

“At that time, the genome of the bacterium was the largest that had ever been sequenced” Today, after the sequencing of the human genome, it wouldn?t be such an arduous task. The sequencing of theXylella fastidiosa genome, the bacterium that causes CVC or the yellowing, one of the worst pests for orange trees in Brazil, became the largest scientific project to have been carried out in the country. FAPESP invested US$ 12 million and managed to mobilize some thirty laboratories in the state of Sao Paulo, coordinated by two central laboratories. The interest to participate in this project was surprising: there were thirty vacancies and some seventy laboratories showed up as applicants. Not only was this scientific approach considered to be innovative for that time, but the springing up of the virtual network of laboratories also opened up a new chapter in scientific collaboration in the state of Sao Paulo.

Without the simultaneous efforts of a gathering of research groups, it would not have been possible to anticipate the completion of theXylella project, as it ended up happening. On the 6th of January 2000, all of the genome had been completed. Before this, at exactly 17:46 on the 9th of November 1999, the researchers were already certain that the most complex parts of the genome of the bacterium had already been sequenced.Xylella was the fourteenth bacterium to have been unraveled in the world. But Brazil entered into history as the country that sequenced the first phytopathogen ? a bacterium that causes pestilence in a plant of economic importance. On the back ofXylella , other new projects came forward.

The second, begun in the same year of 1998, was the sequencing of the sugarcane genome, another agricultural plant relevant to the state. This time the objective was not to identify all of the genes, as was done withXylella , but only fifty thousand of them. The researchers? goal was to discover the genes especially involved with growth, development, production and the level of the plant?s sugar.

By the end of 1999, the research into sugarcane had attracted close to US$ 30 million, counting upon the participation, once again, of Fundecitrus, with US$ 1 million, and a new partnership with Copersucar with a further US$ 500,000. To demonstrate that the initial focus of genomics in Sao Paulo was truly in the agricultural field, a third project was started during 2000: the sequencing of a further bacterium,Xanthomonas citri , that causes citric canker, made possible through an investment of around US$ 5 million. Brazilian science had most definitely integrated itself into the cutting edge of world scientific knowledge.

Rapid expansion

Restricted in the first instances to research institutions in the state of Sao Paulo, the projects on the sequencing of genomes quickly spread throughout Brazil. Currently there are research groups in all of the regions (North, Northeast, Central-West, South and Southeast) qualified to set up libraries of DNA and complementary DNA (cDNA), in the preliminary stage of sequencing, and analyzing the sequences of the organisms that they have resolved to study. This is the case of Embrapa Genetic Resources and Biotechnology, located in Brasilia, in the Federal District. In the face of the argument surrounding genetically modified animals throughout the world, last year Embrapa literally managed a victory: the birth of the calf Vitoria, the first Brazilian clone via nuclear transfer.

Vitoria is one of the most recent milestones of biotechnological research in the area of Brazilian animal reproduction. “The calf is healthy, without a single health problem”, Luiz Antônio Barreto de Castro, the head of Embrapa Genetic Resources and Biotechnology, explains. The essential difference between the Brazilian animal and the famous sheep Dolly, the first mammal to be cloned in 1996, is that the European clone was born from adult cells and it so happens that the Brazilian researchers made use of embryonic cells introduced into cells missing a nucleus. According to Dr. Castro, the intention is not to clone animals simply and exclusively as a genetic objective.

The aim in Brazil, which has yet not used the technique used for Dolly, is to advance in the research of the so called bio-factories ? plants or animals capable of producing medicines for human use. “We want to arrive at a genetically modified animal that has the expression of the genes that interest us”, he explains. After a period of more than twenty years in the genetic improvement of plants, Embrapa is also yearning to incorporate the new methods into the animal farming sector. “The Canadian example stands out”, Castro observes. “They have bred a spider that weaves its web with a strand that is more resistant than steel.”

Historically genomics began in Brazil in the year 2000 and spread throughout all regions with the creation of the Brazilian Genome Program (BRGene) by the Ministryof Science and Technology (MCT). The first study to mobilize the network of scientific cooperation that was formed was the mapping of the genome ofChromobacterium violaceum , a bacterium found in tropical regions that produces compounds such as violacein and others that, in principle, the scientists believe can be used in the treatment of some illnesses.

This first national project absorbed investments to the order of R$ 26 million, half coming from the MCT itself and the other half divided between the institutions involved. One hundred and sixty researchers and twenty-five laboratories participated in this sequencing. In January of last year, the National Council for Technological and Scientific Development (CNPq) invested a further R$ 3 million for the improvement of the network established through the sequencing project ofChromobacterium violaceum , integrating some two hundred and forty researchers in four hundred and eighty Brazilian institutions.

Through this effort it was possible to start last year a study on the virusMycoplasma synoviae , which attacks bovine animals. They have advanced in regional projects, an example being the genome of the guarana plant (Paullinia cupana ) by teams from the Northern region, among them those of Embrapa and the Amazonian National Research Institute (INPA), which should be concluded by the end of 2004. Also started last year was the study into the genome of another economically important plant for Brazil, coffee. It is being analyzed by a consortium formed by FAPESP and Embrapa.

The expectation is that, at a cost of some R$ 1.92 million, two hundred thousand gene sequences will be generated, with which it will be possible to create strains of that plant that are more productive and/or resistant to pests. Both Embrapa, who have accelerated their genomic research over the past few years, and the Votorantim Group, who last year invested some US$ 300 million in establishing the company Alellyx, are casting an eye on the market that moves millions of dollars every year. The economic importance of research in this area, which can lead to more productive plants and animals, can be measured in numbers: US$ 50 billion. This is the sum that the biotechnology market, strengthened through genomic innovations, should annually move throughout the world.

Only within the market of the agricultural sector the Embrapa Genetic Resources and Biotechnology is working with an estimate of US$ 30 billion. The Embrapa researchers are looking towards genomics in order to identify, isolate, and characterize genes that are involved in biological processes that control the productivity of characteristics of economic importance in plants, animals and microorganisms. Besides the libraries of DNA and cDNA, the efforts of the groups who work out of Brasilia are directed towards obtaining fragments of genes, the so-called expressed sequence tags or ESTs.

“It is important that all of this effort in genomics has a focal point”, Castro emphasizes. For him after the respectable work of sequencing carried out over the last few years, “it is fundamental that the research groups in Brazil also have the capacity to interpret the information found up until now”. Without this interpretation the data could be lost. “It would be no surprise if the more developed countries went on to make use of our work on genomics”, the head of Embrapa Genetic Resources and Biotechnology warns. One of the ongoing research lines at Embrapa reflects the spirit that biotechnology has for the institution. “We are studying some plants and the worms that attack these vegetable plants”, Castro comments.

The goal of this project, which as yet has not analyzed a plant of economic importance, is to identify, also from the genetic point of view, how the mechanisms of the vegetables? defenses work when they are attacked by determined pathogens. As they collect these results, the Embrapa researchers imagine that it will be possible to transfer these mechanisms of defense in one plant to another species that already has economic importance. It is due to scientific studies such as this that over the last few years Embrapa has obtained appreciable standing in Brazilian agriculture. “More or less half of the genetic techniques currently used with soya have come from our laboratories”, Castro informs.

New phase

Announced during November 2001 and effectively started in 2000, the project for the sequencing of the eucalyptus genome, officially named FORESTS, acronym forEucalyptus Genome Sequence Projects Consortium , marked a new phase for genome research in Brazil.Through it, after the initiative of a small group of researchers at the end of the 90s, the clear intention was to bring together capable people to work with genomes and with the prospect that this data could find practical use, by way of biotechnology, thus opening up a new form of research.FAPESP entered into the venture with an initial investment of US$ 500,000 in the eucalyptus genome project, but is not alone. The consortium made up by Votoratim Celulose and Papel, Ripasa Celulose and Papel, Suzano de Papel and Celulose and by Duratex is going to invest a further R$ 500,000 in this study.

As the companies are very interested in the eucalyptus genome, the fundamental raw material for the production of paper, they themselves, in a second phase of this enterprise, must invest a further R$ 1.2 million. This is a clear example of what should begin to occur in the very near future with research in the genomic area. Companies are going to begin to invest together with the other development agencies interested in the theme, so that scientific results of quality are generated. Not one of these projects that is currently ongoing, be it through public research, be it via industry, could have occurred if it had not been for the tools and the procedures installed via a genomic revolution that began in São Paulo and spread itself throughout the country starting at the back end of the last decade.

It is based on this existing platform that the company Alellyx is working with the possibility of shortly launching a DNA test capable of carrying out a precocious diagnosis of the most recent threat to the orange trees of the States of São Paulo and Minas Gerais, the so-called citric sudden death. As one of its first practical challenges, Alellyx has taken on the effort to help fight this pest. Since the problem is diagnosed at a late stage in the orange trees, the losses have been enormous. Once the tree begins to show signs that it probably has this disease, probably caused by a virus, it can die in a matter of weeks.

With a lot of luck the producer might be able to harvest one more crop. If the formation of Alellyx was considered the beginning of the end of the problem ? because the objective of the genomic project was exactly to establish qualified human resources so as to crank up the molecular biotechnology industry in the country ?, a victory in practical terms will mean more than dividends for the shareholders: it could serve as an example so that new investors bet on the future results in biotechnology.

As well as this, it should demonstrate that to carry out science on the frontier of knowledge, with the objective of directing the solutions to relevant economic problems, is a goal to be sought after through new scientific projects in the country. “Without a doubt, the investment in Alellyx had as its objective the harvesting of future results that the genomic researchers could very well generate”, João Setubal, a bioinformatics expert at the Computer Institute of the State University of Campinas (Unicamp), says. One of the pioneers in bioinformatics in the country, Setubal had been part of the founding team of Alellyx, but after some nine months at the company decided to leave and return to dedicating himself exclusively to the academic world.

“I continue believing that private initiative is one of the various pathways for research into biotechnology. Mine was simply a personal decision. I decided that I didn?t want to cut myself off from the university. The demand on my time by Alellyx prevented me from being able to remain in both places”, the researcher from Unicamp explained, who at the side of João Meidanis, also a bioinformatics expert, played a determining role in the success obtained through theXylella fastidiosa project.

Transgenic plants

“The massive investment in research in the agricultural biotechnology area and the recent setting up of companies as a result of the optimistic prospects over the last twenty years, has demonstrated this areas? potential in Brazil”, comments Marcio de Castro Silva Filho, a researcher at the Luiz de Queiroz College of Agriculture (Esalq) of USP, who is working with transgenic sugarcane projects. “This process of large scale investments is irreversible”, explains Silva Filho, who this year is going through a sabbatical period in Melbourne, Australia. Besides the fifty years of the double helix, the year 2003 also has another historic date for biotechnology. In 1983 the publication of the first scientific study on the laboratory production of a transgenic plant took place.

The study, carried out in the United States, managed to create a type of tobacco leaf resistant to pesticides used at that time. It was simply the writing of one more chapter in vegetable improvement. In spite of the debate about transgenics still taking place during the twenty first century, so long after Gregor Mendel?s, in 1865, launch of the basis for modern genetics, human beings are attempting to produce improved species from the economic point of view. More productive and resistant.”The contribution of genomics and of the post genome era, is still in its initial phase in such a way that it is worth using the image of the iceberg”, Silva Filho says.

“What one sees today does not reflect that which is hidden below.” In the first phase of this genomic era, the sequencing of entire organisms produced in reality an exceptional quantity of information. Every day researchers throughout the world send in close to fifty million genetic sequences or even genes to international gene banks such as the Genebank, into which the discoveries were deposited. Therefore per month there are 1.5 billion new sequences of plants and animals. Based on these numbers one can have an idea of how many genes of economic interest are being the object of study for possible direct application, in the form of transgenic plants, through the incorporation of new characteristics, or even for a project on new medicines for human use, which are getting started as the result of the DNA sequencing already identified.

For Silva Filho, Brazil can be considered to be a model not only for the developing countries. “It is an example even for the Northern Hemisphere nations”, says. In the study of the sugarcane genome, to which Silva Filho?s laboratory team are dedicating themselves, some potential applications can already be perceived. “We have already identified gene promoters that are active when the plant is attacked by insects”, the researcher says. “These promoters will be used to direct the expression of the genes with insecticide properties.”

The use of microsatellites in the genetic improvement programs of plants is another application derived from the studies on the transgenic sugarcane. Conceptually, microsatellites are small sequences of DNA repeated along the genome of an organism. They are important because, when correctly identified, they can help in the programs of genetic improvement. Since they are generally located close to the genes that control characteristics of interest to the researchers, the microsatellites help the researchers to select the study material. In the crossing of plants, these sequences follow together with the characteristics of interest that the researchers are studying.

One cannot deny the advances and the imminent applications of genomics, although it also must be made clear that there are obstacles confronting biotechnology and even of basic research in the agro-industrial sector. Because of the debate over transgenics, the research in this sector is moving at a jeopardized pace. Furthermore, the polemic issue about the right of access to research data, obtained both by public institutions and private enterprise, has not as yet been resolved. However, genomic research throughout the world is suffering from a mistake originating in the publicity put out by agribusiness companies involved in biotechnology research. “In the beginning, a lot of publicity was directed in a distorted or ill-intentioned manner”, Silva Filho explains. “They promised to solve all problems with the new technologies.”

The consequences of error

In the vision of the researcher from Esalq, the companies themselves in this segment underestimated public perception on the issue, in the manner in which they believed that popular acceptance of transgenic plants would be unconditional, as a result of these propagated benefits. “This was a mistake and until today the companies are paying for it. A vacuum was created between the new technology and popular approval.” Even at that, according to a recent report put out by the International Service for the Acquisition of Agri-Biotech Applications (ISAAA), a non-profit institution located in the town of Cornell in the United States, the products coming from transgenic plants are spreading throughout the world. Independently from the error in the calculations of the companies in the biotechnology and farming sector, genomics, because of the scientific effort initiated in the state of Sao Paulo and afterwards spread throughout Brazil, is already a reality.

More than this: the knowledge generated and the form by which it has been obtained, have become international reference points. Various studies that are being carried out in diverse states can be found in an advanced phase. For example, one can note a tendency for consolidated research whether it is in the state of Bahia, in the study of the genome of the fungusCrinipellis perniciosa (that causes witches? broom, an illness that devastates the cacao plantations in the south of that state), or in Rio de Janeiro, with the bacteriumGluconacetobacter diazotrophicus (a microorganism that fixes nitrogen in plants such as sugarcane and coffee).

The objective craved by those idealists of theXylella genome project has been attained: new groups are being formed and business is also taking an interest in this area. Returning to the image of the iceberg, one is reminded that researchers throughout the world now have an idea of how vast their work promises to be and how it may well take time to be concluded. It was exactly the notion of time that seems to have been missing from some companies that decided to place all of their bets on genomics.

This is the case of the American company Celera Genomics, which carried out the sequencing of the human genome parallel to that done by a consortium of public institutions. In this manner, it embarked on the idea that the block of ice insinuated by the iceberg would be quickly understood and would render immediate profits. Reality was somewhat different. “I don?t know if Celera got it wrong”, João Meidanis, a bioinformatics expert from Unicamp who is also working with the company named Scylla, observed. Celera has still not made any money selling information about the human genome and today is a company practically the same as any other in the pharmaceutical industry. But according to Meidanis one thing is certain: if it had not been for the pressure exerted by Celera, it is unlikely that the public consortium would have already concluded the sequencing of the human genome.