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Abundant harvest

Final data comes out of the sugarcane genome, which gave an impulse to projects, companies and scientific careers

Were it to become a movie in the hands of a talented filmmaker, the story of the sugarcane genome would come out something like We All Loved Each Other So Much, a classic by the Italian director Ettore Scola; it is about a group of friends who lived intensely one period of their lives and meet once again, some time later, after having pursued their own paths. The 240 researchers who took part in this pioneering work, which began four years ago, have not yet gathered together at a dinner washed down with, of course, wine, but they would have a reason for celebration with this month’s publication of an article in the scientific magazine, Genome Research. It contains a detailed description of the genetic constitution of sugarcane, a plant that has been cultivated on a large scale in Brazil for a long time. It is known that the first cuttings of this plant arrived in 1532 with the Portuguese colonizer Martim Afonso de Souza.

There it is, in Genome Research: the sugarcane genome is constituted of 33,620 possible genes, of which about 2,000 seem to be associated with the production of sugar. The habitual coldness of the scientific language, obviously, leaves aside the raw material of the hypothetical film the anguish and the joys that sustain this scientific bookkeeping. But only Felipe Rodrigues da Silva, a biologist, and Guilherme Pimentel Telles, a Computing graduate, really know what a torture it was to arrive at these final figures, which in a way put an end to an adventure that started in April 1999. It was then that Paulo Arruda, a professor at the State University of Campinas (Unicamp), accepted the task of coordinating the work of 22 research groups that offered to identify the genes of one of the plants that sustain farming in São Paulo.

Two years ago, initially to determine the number of genes, basic information about any genome, Silva, then studying for a doctorate and 29 years old, and Telles, aged 27, had to figure out something that had not been resolved in any other laboratory in the world: discovering how to eliminate repetitions and to make the best use possible of the information contained in about 300,000 fragments of genes, called ESTs, or Expressed Sequence Tags. The Sugarcane Genome was one of the first plant projects in the world to use this technique for identifying genes. Until they got in step, they worked at least 12 hours a day, over four months, with programs according to which sugarcane would at one moment have 9,000 genes, at another over 100,000, or even an intermediate value, which varied according to the different criteria as to what a gene is. In one of the most emotional moments, they discovered that stretches of the genes were being thrown away that could be put to good use.

Four years afterwards, three more far reaching gains are to be noted from the Sugarcane Genome, a project that was made feasible with finance in the order of US$ 4 million from FAPESP and another US$ 400,000 from the Cooperative of the Producers of Sugar and Alcohol of the State of São Paulo (Copersucar). In first place, the information about the plant fertilized a series of researches, some with promising results, like a potential antibiotic recently discovered by a group from the Federal University of São Carlos (UFSCar). Furthermore, there are 50 projects under way, run by research groups that are doing the so-called data mining the search for information about the metabolism of sugarcane, so as to get, more quickly, varieties that are more productive and resistant to drought or to poor soils. By current techniques for genetic improvement, a new variety consumes ten years of work, from the first tests to approval for use in the field.

Still this month, the sugarcane genes are going public, when they are exposed in a world-wide database on ESTs, as soon as the article in Genome comes out. With 250,000 fragments of genes, sugarcane will be the fifth plant with most sequences described, after wheat, corn, barley and soya. Until now, researchers from other countries could only have access to the clones not to a detailed description of them, kept at the Clone Storage and Distribution Laboratory, in Jaboticabal. There, eight freezers hold 240,000 clones of genes, a result of the sequencing projects already carried out in São Paulo.

Double shift
As a second effect, the project, also called Sucest (standing for Sugar Cane EST) put more yeast into the environment, which gave an impulse to the investments that resulted in the creation of three companies, Allelyx, Scylla and CanaVialis all of them enjoying financial support from Votorantim Ventures, the Votorantim Group’s venture capital fund, and the experience built up following the sequencing of the genome of the Xylella fastidiosa bacterium, the first organism to be studied from this angle in Brazil. Arruda himself divides his time between Unicamp where he lectures at the Biology Institute and researches at the Molecular Biology and Genetic Engineering Center (CBMEG), which was the headquarters for the Sugarcane Genome and Allelyx, today with 50 researchers striving to hold back, for example, Citrus Variegated Chlorosis, or the yellowing disease caused byXylella that is destroying one third of São Paulo’s orange groves.

In May 2002, Telles joined up with João Meidanis, Zanoni Dias and other bioinformaticians the specialists in computing who create or master programs for identifying and analyzing genes and, together, created Scylla, a lean company, with nine members of staff. In a demonstration of how vast is the space to be occupied by bioinformatics in Brazil, Scylla announced last month its first commercial product: a program that detects and analyzes small variations in genes and can be used to identify psychiatric diseases. Another participant in Sugarcane Genome, Eder Antonio Giglioti, is today one of the five partners in CanaVialis, all of them with over 30 years experience in the genetic improvement of sugarcane, now heading up a team of 25 researchers who are going to use genomics and bioinformatics to develop new varieties of sugarcane and to optimize those already existing.

But neither the researches nor the companies would have been possible without the third effect, still more deep-rooted: the qualification of the body of scientists.The Sugarcane Genome drew close together researchers who would otherwise hardly have known each other and consolidated leaderships in 2000, for example, Andrew Simpson, the coordinator of the Xylella Genome, from which Sucest was derived, was probably the best known scientist in Brazil and gave an impulse to the scientific career of the researchers, as can be noted in particular with the three students for a doctorate who worked closest to Arruda: Edson Kemper, André Luiz Vettore and Felipe da Silva.

During almost the whole of the project, they took care of strategic tasks like the control over the project’s finances, they collected samples of sugarcane tissue in the field (from the root to the flower, gathered both in the interior of São Paulo and from the plantations in the state of Alagoas), they made the clones of sequences of the genome, they took care of the distribution of research material to the 22 laboratories in the project, and they interpreted on the computers the results that came back. In four years, they managed 9,375 plates with 900,000 clones, which made up the so-called libraries of cDNA, the acronym for the coding deoxyribonucleic acid that is complementary to the plant’s original DNA.

Perhaps the three did not relish the excessive work, the weekends at the laboratory, and being reprimanded by their girlfriends for once again putting off going to the movies for having to work until late. But one by one, Arruda’s quasi-children in the purely scientific sense, of course left the CBMEG, pursued their own paths, and are today well placed in research institutions or in companies. Better still, applying what they have learnt. “Sugarcane Genome was a concrete example that teamwork works, brings results, and encourages everyone to do more and more”, says Kemper, an agronomist-engineer recognized for his almost limitless dedication. If, for example, the data from the sugarcane sequencing laboratories arrived at the end of the afternoon, when the support technicians had already gone away, he would see no reason for waiting until the following day and, without any hesitation, he himself would do the work, advancing through the night until the task was finished.

The first to leave, in August 2000, Kemper today works at the headquarters of Monsanto, in Saint Louis, a city in the United States planted between the Mississippi and Missouri rivers. At the age of 34, Paulo Arruda’s former pupil for a doctorate is managing the Genetic Purity Laboratory, which in the moments of more intense work houses up to 35 researchers and technicians, heedful that transgenic corn and soybeans should comply with the quality requirements defined by the American government and by the company itself. The plant most similar to sugarcane that one sees over there is sorghum, a tiny member of the grass family, no more than a meter in height, used as feed for cattle.

“We lived together through an era of effervescence, there was no vanity or obstacles, and we would talk like equals with the most experienced researchers”, recollects Vettore, the second to leave CBMEG. A first-class planner of the costs and the routine of work, Vettore swapped Campinas for the São Paulo capital in July 2001. Today, as a coordinator of the cancer genetics laboratory at the Ludwig Cancer Research Institute, he is trying to identify molecular markers for tumors.

Three months afterwards, when the conclusions of the work with sugarcane were now well advanced, it was Silva’s turn to bid farewell to Paulo Arruda and to Adilson Leite, his former supervisor and one of the coordinators of CBMEG, who died of lung cancer in February 2003. Silva spent eight months at an Embrapa unit in Rio, and since July has been working at another unit in Brasilia, the National Research Center for Genetic Resources and Biotechnology (Cenargen), where he is working on the genomes of coffee and the banana, with computer programs that are a bit more cordial than those he had to face years back.

“The respect with which the other researchers treat me today has no price”, comments Silva, who had participated in 11 scientific articles by when he finished his doctorate. The balance of strengths, to his mind, was essential for the group to survive in the same room in which they worked together and to overcome the differences in the style of work he, for example, is dispersive and noisy (he has been in a rock band since the age of 12), while Vettore won a name for being ultra-organized and methodical.

The very history of sugarcane would emerge as the discoveries about its genome built up, to be announced in 2001, in a special issue of Genetics Molecular Biology and summarized in an article in Genome Research, signed by 57 Brazilians. The researchers concluded that sugarcane keeps at least 70% of similarity with another group of plants, the dicotyledons, like beans and soya (sugarcane is a monocotyledon) between 50 and 70 million years ago, before separating, there was one single species, with characteristics of the two groups. The comparison between genomes also reveals that 71% of the sugarcane’s genes are also to be found in Arabidopsis thaliana, a plant model used in genetics that does not reach 10 centimeters in height, and 80% of the sugarcane genes show corresponding ones in rice.

This information is important for signposting how to make sugarcane productive or more resistant to drought. In practice, it means, for example, intensifying the activity of at least part of the 2,000 genes tied up with the production of sugar in the sugarcane hybrid cultivated today in Brazil, the result of crossbreeding carried out in the course of five centuries between the two species, Saccharum spontaneum, more effective in the production of sugar, and S. officinarum, more resistant to diseases. The researchers have known for a long time that they are dealing with a complex plant, the cells of which carry up to 12 copies of each gene.

If on the one hand these peculiarities make the work more difficult, on the other, they make the achievements more gratifying “The work with the sugarcane genome facilitated the development of more simple tools for comparing genomes, that allow any biologist to draw very good conclusions for any living organism”, comments Carlos Menck, a geneticist from the Biomedical Sciences Institute at the University of São Paulo (USP). Menck, Michel Vincentz, from the CBMEG, and a group of 10 researchers from Sucest, are finalizing an article in which they compared genes from sugarcane and from Arabidopsis and present some that had not yet been identified.

The work has put the scientists on another level. For this reason, the film with the routes covered by the scientists that revealed the essence of sugarcane could not fail to reconstruct the scene in which João Meidanis went into CBMEG in 1995, anxious to achieve a small genetic sequence. Three thousand base pairs would be enough. With them, he intended to develop the programs that were to be essential, a few years afterwards, in studying Xylella, sugarcane, and other organisms now sequenced. The desired raw material, which in those days would take six months before being delivered, comes out today in a couple of minutes, time to have a cup of coffee or, better still, some chilled sugarcane juice.

The Project
Sugarcane Genome; Modality Research project in the ambit of the FAPESP Special Genome Program; Coordinator Paulo Arruda – Unicamp; Investment US$ 4,484,090.619