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Results over the past decade

How the FAPESP Genome Program has established new paradigms in the Brazilian research environment

The FAPESP Genome Program has yielded long lasting fruit. An initiative launched in 1997, exactly 10 years ago, it obtained its first international acknowledgement by means of the publication of an article on the cover of the journal Nature about the sequencing of the genetic code of the bacterium Xylella fastidiosa, which causes citrus variegated chlorosis,  and attacks orange plantations (v. 406, n. 6.792, 13 July 2000). The article, which described the first complete sequencing of DNA of a plant pathogen, was the work of a São Paulo network of 192 researchers supported by FAPESP. After a full decade, one can state that the pioneering initiative has established new paradigms for Brazilian research. “Up until then, one way of getting together a significant group of researchers of international standards in a strategic area was to send them abroad. But we bet that this could be achieved here in Brazil, by working with a network on a cutting-edge issue,” recalls the physicist José Fernando Perez, FAPESP’s scientific director at the time.

Researchers from several institutions and different disciplines, ranging from biology to medicine and including bioinformatics, which was virtually unknown at the time, worked together in a large virtual network that brought together as many as 60 laboratories to face a shared objective: the genetic sequencing of several organisms. The model challenged the traditional way of setting up partnership arrangements, in which researchers generally turn to others only when they need the latter’s technical expertise to carry their own work forward. What was innovative for the time is now built into Brazilian science. “Today, this type of network project is found in several programs, which no longer depend on the building of a network in order to exist, as was the case in the past,” states the biologist Fernando Reinach, one of the program’s masterminds.

Carlos Henrique de Brito Cruz, FAPESP’s current scientific director and the Foundation’s chairman from 1996 to 2002, highlights the roles of José Fernando Perez and of Fernando Reinach in the program. “They were crucial and doubly opportune when it came to the creation and success of the Xyllela project. Fernando identified the scientific opportunity, sequencing a genome, while Perez identified the ways and means – a virtual institute or network of researchers. The third player has been acknowledged rather less, perhaps because of its institutional nature: the set of institutions in which the project was conducted. These were built by the Brazilian state – especially the São Paulo state effort, because most of the project’s researchers have worked for USP, Unicamp and Unesp – over the course of many decades,” states Brito. He reminds us that the research community in these universities developed thanks to the support of the institutions themselves, which ensured full-time dedication to teaching and research, besides providing the infrastructure, along with the support, based on strict and demanding criteria, of promotional agencies for research, such as CNPq, Capes, Finep and FAPESP. “And, indeed, since the Nature cover in 2000, countless other covers have been achieved by the fine work of São Paulo scientists on other excellent journals,” says the scientific director of FAPESP.

What was also innovative, even though it no longer seems so strange, was placing a set of researchers at the service of a risky undertaking: there was no assurance, as is common in cutting-edge fields, that the FAPESP Genome program would generate significant results. “Risk is part of innovation research, but this was novel in Brazil. The scientific community was used to working on low-risk projects,” recalls José Fernando Perez. Even some of the program’s leaders, says the then scientific director, resented the possibility of spending two years without generating results and publishing papers, and feared the assessment of the promotional agencies. Influential sectors of the scientific community also complained. There were those who argued that the objective of the program (sequencing genomes) was work for computers, not for researchers. “The criticism made no sense, because the accumulation of data has always been essential for the progress of science,” says Perez.

Marie-Anne Van Sluys, a professor at the Biosciences Institute of USP and one of the researchers working on the program, recalls that the researchers joined the effort with an open mind. “It was a very unusual thing. There were several challenges. One of them was how to get more researchers to become conversant with molecular biology. For those who already had experience in this, the target was learning to do an entire genome. Nobody had done this in Brazil and it posed a major challenge for the scientific community,” she recalls. Today, this standard is more widespread. The strategy of bringing together researchers from different disciplines, ranging from the humanities to biology and computer science, in a joint effort around a cutting-edge subject, is now found in the structure of the key FAPESP initiatives, such as Bioen (the FAPESP Bioenergy Research Program), the FAPESP Global Climate Change Research Study, and the Biota FAPESP Program, each of which, in its own way, also incorporates genomic tools in its research targets. “This is a legacy of the Genome Program: to be daring and to create new dynamics. The concepts are the same, but the connections are different, providing us with a different viewpoint, even in regard to scientific policy and our international position,” says Marie-Anne. “Following this paradigm, Bioen, Biota and the Climate Change Program all share scientific competence at an international level. Any research group in these programs is within an international context,” she states.

The Bioen case, a program for which Marie-Anne is one of the coordinators, is exemplary. “The research effort involves not only creating new technology for producing energy from biomass, but also studying the social impact of the growth of bioenergy and the development of more efficient engines. We are daring to create new models, with the risk that goes hand in hand with this,” states the professor. Research into bioenergy is one of the chief legacies of the Genome Program. With different sequencing techniques that complement each other, both Marie-Anne and Glaucia Souza, a professor from the Chemistry Institute of USP and also one of the Bioen coordinators, are currently focusing on the study of the variability of sugarcane genes, one of the program’s objectives.

ELLIOT W. KITAJIMA / USPXylella under the microscope: a mobilizing project ELLIOT W. KITAJIMA / USP

Bioen wants to aid the development of sugarcane varieties adapted to Brazil’s range of climates and soils by genetically manipulating the energy metabolism of the plants farmed, thereby creating competitive advantages for Brazilian production. One of the program’s branches is the unfolding of the FAPESP Sucest Program (Sugar Cane EST), better known as the Sugarcane Genome, which mapped fragments of the functional genes of sugarcane, the so-called express sequence tags (ESTs). This project was carried out from 1999 to 2003 by some 204 researchers led by the biologist Paulo Arruda, with financing provided by FAPESP and by Coopersucar, the Cooperative of Sugar and Alcohol Producers of the State of São Paulo. One of the challenges faced by Bioen researchers is identifying the regions of the genome sugarcane responsible for regulating the expression of the genes mapped by Sucest. Learning the physical location of the genes and the dosage of their variations (alleles), besides the environment that they find themselves in, will make it easier to improve the efficiency of using molecular markers to improve crops and transform plants. This knowledge might speed up the development of new varieties, a process that currently takes at least 10 years. The idea is to reduce the number of plants that are evaluated in the field, using molecular marker data to make a prior selection of varieties connected to genes that are of interest.

The Xylella sequencing in 2000 was a landmark, but it is far from diminishing the importance of the FAPESP Genome Program. Marie-Anne Van Sluys highlights the importance of the projects that followed it, such as the Cancer Genome, which led Brazil to rank second globally as concerns the sequencing of the functional genome of human tumors, immediately behind the United States; the complete sequencing of the bacterium Xanthomonas citri, the cause of citrus canker, the most serious orange pathogen; and the Sugarcane Genome. “These four projects form a core,” states Marie-Anne. “They kept the initial effort from dying out, expanding the number of researchers in the network and increasing the degree of complexity. The sequencing of Xanthomonas was far more complex than that of Xylella, making it necessary to learn new technology,” she states. In May 2002, the researchers in this network published a new article in the journal Nature, this time pointing out paths for fighting Xanthomonas citri and presenting the results of the sequencing of Xanthomonas campestri.

The expertise continued to bear fruit, with the sequencing of the genomes of cattle, eucalyptus, coffee, the Xylella that attacks grape vines (a study commissioned by the USA),  leptospira, the bacterium that causes leptospirosis, and  the Schistosoma mansoni worm, which causes schistosomiasis, among others. Companies and cooperatives took part in the effort, as was the case of the Citriculture Defense Fund on the Xylella work, Coopersucar on sugarcane,  the US Department of Agriculture on the Xylella grape, and  the Ludwig Institute on the cancer genome, not to speak of companies such as Suzano, Ripasa, Votorantim and Duraflora, on the eucalyptus genome project, Embrapa, on the coffee genome, and Central Bela Vista, on the cattle genome. All in all, there were US$11.7 million of funds added to the FAPESP Genome Program. The initiative extended beyond state borders and became the model for other major initiatives, such as the national network of the Brazilian Genome Program, created in 2000 by CNPQ, Brazil’s National Council for Scientific and Technological Development. The Brazilian Genome project set up a network of 27 laboratories spread over 18 states, with the task of deciphering the genetic code of the Chromobacterium violaceum bacterium, which is important for biotechnology.

Jigsaw puzzle
There are visible legacies in other areas. José Fernando Perez tells us that he recently attended a congress of a scientific society in the field of bioinformatics. “There were more than 600 participants. But this field in Brazil was almost non-existent before 1997,” says Perez. The area was essential for putting in order the jigsaw puzzle that studying a genome generates and was one of the key question marks regarding the program’s success. “International advisors warned us that we’d have a bottleneck at this point. We then decided to get two young scientists on board, João Setúbal and João Meidanis, both from the Computer Science Institute at the State University of Campinas (Unicamp). They had been simulating genomes and had published a book on the subject, though they had never worked with any real genomes.” Another key name in the program was Andrew Simpson, a geneticist from the Ludwig Institute of Cancer Research. “With his scientific leadership, he rounded off the program’s rough edges and enabled it to move ahead,” he states.

Result of sequencing genetic material

One of the results that illustrate the magnitude of the program’s importance was the establishment of biotechnology enterprises inspired by this project. In 2002, Votorantim Novos Negócios set up Alellyx (Xylella written back to front), bringing together a group of researchers that had been involved, in the late 1990’s, with the Xyllela fastidiosa sequencing. It turned into an applied research company centered on the creation, based on molecular genetics, of products and technologies to improve agriculture. In 2003, Votorantim created CanaVialis, which became the world’s largest sugarcane improvement enterprise. The Votorantim Novos Negócios investment in the creation of the two firms was some US$40 million. In December 2008, the two companies were sold for US$290 million to Monsanto, to become the global platform for research into sugarcane seeds of the multinational. According to José Fernando Perez, the dividends of genome research are concentrated, as one might expect, in the sectors of the economy that made the best use of the knowledge, as was the case with sugarcane. “The Xylella sequencing could have led to the development of a type of pest resistant, genetically modified orange, but there is still a lot of resistance to genetically modified foods and producers weren’t interested in it,” he states. However, this does not bother him. “The last thing we did in this program was to choose the bacterium to be sequenced, which would be the driver of the project. The objectives, which were far broader, were achieved,” he states.

Back to Nature
Ten years after the cover article on the sequencing of Xylella fastidiosa, an editorial in the very same journal, Nature, (v. 466, n. 7.304, 15 July 2010) recalled the Brazilian achievement and the other developments that resulted from this effort, such as the sequencing of the functional genome of sugarcane and the contribution to the international Human Cancer Genome program, besides the creation of two agricultural biotechnology enterprises, Alellyx Applied Genomics and CanaVialis.

“FAPESP invested an amount equal to US$12 million, most of which went toward sequencers, computers and reagents, whereas the group brought together and trained researchers from several fields to develop a broad and lasting set of skills and know how,” stated the journal.

According to Nature, Brazilian biotechnology has matured so much that its scientists have become international players. “And FAPESP continues to promote great ideas,” says the journal, referring to the Foundation’s investments in several fields of research into bioenergy and in the training and globalization of São Paulo researchers. “This acknowledgement in the Nature editorial is extremely important for FAPESP. By highlighting the achievements, the editorial also underscores the activities currently under way. It is with immense satisfaction that we see FAPESP contribute, once again, to good global visibility for science developed in Brazil,” said Carlos Henrique de Brito Cruz, FAPESP’s current scientific director and the Foundation’s chairman in 2000.

The sequencing of Xylella, says Nature, shows the benefits of thinking big: the researchers undertook a major project, performed it with precision and published it in English in a respected scientific journal. “The results were publicized by the main media worldwide and Perez believes that this unique – and unexpected – achievement also helped to change the relation between Brazilian science and Brazilian media. Xylella helped to change Brazil’s perception of itself, of its capabilities and its place in the world of science,” says the journal.