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Cover

The new Brazilian product

After being on the cover of Nature, the genome research done in Brazil attracts the attention of the world

The original scientific findings of the research team from Brazil – responsible for the genetic sequencing of the Xylella fastidiosa bacterium – as much as the cultural and political significance for the country of the success of this project, a pioneer in the world, on the genome of a plant pathogen, a microorganism that causes disease in plants – gained new and enlarged international visibility with the issue of Nature that began to circulate on July 13 last.  The scientific article – or paper, as the jargon of research scientists has it – of seven pages about Xylella, with new contributions to genome research, prepared and signed by 116 of the 192 scientists who concluded last January the genetic decoding of this bacterium, made it no less than the cover of issue n° 6792, volume 406 of the magazine, one of the most prestigious and respected scientific publications in the world.

In the 131 years of Nature’s existence, never before has an article produced by a Brazilian research group reached the cover of the magazine. But if that were not enough, the decoding of the genome of the bacteria that causes CVC, Citrus Variegated Chlorosis, or the yellowing disease, by researchers linked to ONSA, the Organization for Nucleotides Sequencing and Analysis (the “virtual” chain of laboratories created by FAPESP in 1997, which has a jaguar as its logo), was commemorated in the editorial of this English publication, and explained in detail, in journalistic language, in its News and Views section.

In the editorial (see the full text in the box), pointed out that the successful sequencing of the plant pathogen “is as much a political achievement as a scientific one”. And  furthermore, that the current concept that only the more industrialized countries have the potential and the qualified people to work in the vanguard of research was proved false by the Brazilian project. In conclusion, the editorial states that the success of the X. fastidiosa project, plus the unusual fact of an agency from the advanced and industrialized world – the US Department of Agriculture – having hired genome research on a variant of Xylella from a developing country “endorses Brazil’s determination to enter the post-genome age hand in hand with scientists from the more prosperous countries”.

In terms of publicity, the effects of this spotlight on the Brazilian project, focused by one of the greatest icons of the international scientific community, took no time to appear. On the very night of Wednesday July 12, after the embargo was lifted on the publication of the weekly material of Nature on the Internet, the online version of the New York Times gave the news that “Genes of plant disease mapped”, and BBC News Online reported “Brazil hails scientific first”. Later, on July 18, the science supplement of the NYT published the story “Agriculture takes its turn in the genome spotlight”.

The BBC material told how the research into the Xylella genome was being hailed as “a triumph for Brazilian science”, and based an interview with the project’s DNA coordinator, Andrew Simpson, showed some of the results that represented new contributions to science and which were kept secret until the publication of the paper by Nature. One of these is that many of X. fastidiosa’s 2900 genes (about a third) are totally new to science, that is, they are genes that have never been described before, while others are analogous to genes found in other organisms. Another fundamental result of the research, highlighted by the BBC, was the identification of genes in X. fastidiosa that codify molecules whose existence has only been described in pathogens of human beings and animals, and whose job to stick them to the cells of their host.  Now what is being unveiled is a clear and important indication of the pathogenic mechanisms of bacteria, whether they affect plants, human beings or other animals.

And then, there was the story published in the online New York Times by the international news agency, Associated Press, highlighting the pioneering nature of the genetic mapping of a pathogen, and putting it as an advance capable of leading to new approaches in the fight against “a bacteriological scourge that causes devastation in orange groves and other plantations”. In continuation, it also said that the work throws light on the way how bacteria infect equally plants and human beings and neutralize their defenses, giving room for the enthusiastic comments of Charles J. Arntzen, president of Cornell University’s Boyce Thompson Institute, on this and other important scientific contributions shown in Nature’s cover article.

On Thursday 13, a new sample of the international repercussion of the cover of the British scientific magazine was to be seen in the pages of Le Figaro.  Under the heading “Les mécanismes de la virulence dévoilés”, the French newspaper published an enthusiastic article, written, shall we say, an eighth above the tone that a good part of the Brazilian press finds recommendable to herald the national conquests outside from the field of sports. There was a summary of the scientific results of the X. fastidiosa project, there was an explanation of how the structure of ONSA was set up to allow the project to be carried out, and there was a presentation of the situation of the CVC disease in Brazil.  Le Figaro found space, of course, to note that the French scientists Joseph Bové and Monique Garnier who identified Xylella as the causal agent of CVC, at the beginning of the 90s.  And to recall that when FAPESP, in 1997, launched the project for the sequencing of X. fastidiosa, Bové offered to supply clones of the bacterium, produced by Inra (National Institute of Agronomic Research) in Bordeaux, at the same time that Frédéric Laigret, a research scientist with the Bordeaux 2 University, was supporting the setting up of a bacteria DNA bank to supply the fragments to be sequenced. But amid all this, what sounded like sweet music to Brazilian ears was the title of the box of the report “Le Brésil parmi les grands”, which begins with the statement that Brazil had risen to the level of the planet’s powers in biology: the United States, Great Britain, France, Japan, Germany” (read the full text on page 14).

On the following Thursday, July 20, an article in the well-regarded English magazine, The Economist, added to the positive assessments of some of the most important organs of the major international press on science carried out in Brazil. “Samba, football and… genomics.  The list of things for which Brazil is renowned has suddenly got longer” was how the article opened, under the title “Fruits of co-operation”. An explanation followed  that, just a few days after publishing the first genome of a plant pathogen, scientists at FAPESP were due to announce, on July 21st, “another success”: the identification of 279,000 human genetic sequences, a number, according to the magazine, second only to the number of sequences identified in the United States and Great Britain. The reference at this point is to the results of FAPESP’s Human Cancer Genome project, which indeed were announced at a press conference in the Palácio dos Bandeirantes (The  State of São Paulo Governmental Palace) on the 21st (the event will be covered in the next issue of Pesquisa FAPESP).

The text of The Economist goes on to give a series of details about FAPESP’s Genome Program and about the Foundation itself, to conclude by saying that “the lesson of all this is that there is no reason why countries such as Brazil cannot compete in leading-edge science if they put their minds to it”. And to wrap it up, considering “the benefits of co-operation and a secure source of financing, and with more than 200 young geneticists trained as a result of the X. fastidiosa project alone”, the article makes a shining prognostic of Brazil’s share in the world scientific production, which, in terms of papers published, jumped from 0.4% to 1.2% of the world total, from 1985 to 1999.

Significant contributions
On the home front, where the attention of the media to projects for genomic research carried out in Brazil has become much greater since the announcement of the conclusion of the sequencing of X. fastidiosa last February, the significance of the Nature cover for this research was told to dozens of millions of Brazilians. On that very Wednesday, radio and TV stations, beginning with Globo TV in its Jornal Nacional (National News), which gave broad coverage to the subject, and, on the Thursday 13th, the main Brazilian newspapers announced, with details, what the British magazine had published. Often the news was put as something like a brilliant goal scored in the field of research in Brazil.  On Wednesday too, the brand new electronic media joined in the coverage of “came out in Nature” line, the inevitable idea for a headline to translate the deed, with a genuinely Brazilian trace of humor, and which ended up actually being used by the magazine, Isto É, on Friday July 14th. On Saturday 15th, Época showed the faces of some of those who were most responsible for the success of the X. fastidiosa project. They were days of such exposure in the media of Brazilian genomics research that the way suddenly seemed open to show science, not only as a privileged space for solving the innumerable problems that affect the individual and society, but also as a field capable of contributing with a fillip to the debilitated national self-esteem.

In fact, a special indication of the fascination exerted by the recognized success of the Brazilian research scientists, in the scientific area most in evidence in the world today, had already been seen on Tuesday July 11th, during the 52nd meeting of the SBPC, the Brazilian Society for the Progress of Science, which gathered in Brasilia some 15,000 people, among senior scientists, young researchers and students still defining their professional paths. There, in an overcrowded auditorium, full of young people, Andrew Simpson was given an impressive ovation, after showing that the X. fastidiosa project, in about two years, had made Brazil jump forward 10 years in its scientific competence.

During his lecture, the researcher showed, for a few seconds, the cover of Nature that was still kept secret, and declared that having an article published by the magazine was the dream of any researcher – he and the other researchers who signed the paper, he stressed, were seeing this dream come true. It was this same declaration that Simpson was to repeat on the following day, in a state of grace, back in São Paulo, at the press conference organized by FAPESP, so that, along with João Setúbal, one of the two coordinators of bio-information technology for the project (the other is João Meidanis), they could explain the scientific findings that would soon be public knowledge all over the world.  Also taking  part in the press conference were the president of FAPESP, Carlos Henrique de Brito Cruz, the foundation’s scientific director, José Fernando Perez, the deputy secretary for Science, Technology and Economic Development of the State of São Paulo, Betty Abramowicz, USP’s pro-rector for research, Hernan Chaimovich, the vice-rector at Unicamp, Fernando Galembeck, and the pro-rector of post graduation and research at Unesp, Fernando Mendes Pereira.

Biology deciphered
The sequence of the genome of X. fastidiosa is the 24th complete genome of a bacterium known by science until now, and is the first of a plant pathogen. Xylella has almost 2.7 million nitrogen pairs or nucleotides in its chromosome (more precisely, 2,679,305), which shows that it is one third bigger than the researchers imagined, when they started  the sequencing in the beginning of 1998.

In these basic pairs, there are 2,904 genes, protein codifying regions, of which one third are new to science and 47% have their functions precisely described.  This percentage is a little below what other genome research groups have achieved – for example, it came to 54% with Thermotoga marítima, 52.5% with Deinococcus radiodurans, and 53.7% with Neisseria meningiditis. The Brazilian researchers attribute this slightly lower result to the fact that there had never been any other complete sequence of a plant pathogen bacterium genome before Xylella, which in principle would help the job of giving the genes a functional definition. This is to say that it is part of the cost of being a pioneer.

The bacterium multiplies in the glassy-winged sharpshooter, and this vector insect introduces it straight into the vessels that transport the sap of the plants, the so-called xylem. Once installed there, it multiplies, as fastidious as the name suggests, and acts slowly. The symptoms of Citrus Variegated Chlorosis take time to appear, but the final result is vessel obstruction, chlorophyll loss, yellowing, blotches on the leaves, and the premature production of small, hard fruit, which are therefore useless for consumption.  The economic result of this process in Brazil, which produces almost half the concentrated orange juice placed on the international market, are losses estimated at US$ 100 million a year. We must remember that orange cultivation provides an annual income of almost US$ 2 billion a year, and that in São Paulo this business generates 400,000 jobs, both in the direct jobs and the indirect ones.

X. fastidiosa has a refined metabolism. It has adapted to use sugars freely found in the sap of the xylem and to use the glucose from the breakdown of the cellulose, the main component of the walls of the plant cells. The carbohydrates supply energy for all the biosynthetic reactions of this bacterium, which does not have codifying genes of the enzymes needed for the production of sugar from amino acids and other metabolisms.

Another discovery made by the researchers:  67 of X. fastidiosa’s genes are dedicated to withdrawing iron and other metals from the plant’s sap, which they say, contributes towards some of CVC’s typical symptoms.

One more important scientific finding: X. fastidiosa shows two different systems for adhering to the cell. The first one comprises a matrix of extra cellular polysaccharides synthesized and set free by the so-called gum genes, which stick the bacterium onto the cellular wall of the xylem and on other bacteria, and have the effect of clogging up the vessels, blocking the sap, and leading the plant to water stress. It is precisely for this operon or set of genes that synthesizes the xanthan gum that FAPESP asked last year for the patent to be registered in the United States. The other system for adhesion, specified by 26 genes that codify the so-called fimbriate cells, probably serves to stick the bacterium to the sharpshooter’s tract.

The other far-reaching discovery, mentioned above, was the identification of the genes that codify the molecules involved in adhering to the cell, previously only identified in pathogens of human beings and of other animals. They are molecules directly associated with the cellular surface of the bacterium, which account for the adherence to the epithelial tissue of the hosts, whose discovery in X. fastidiosa increases the evidence that the bacteria pathogenic mechanisms – the mechanisms that cause diseases – are the same, whether they infect plants, animals, or human beings.

What the researchers organized through Onsa did is well described in the final conclusions of the paper in Nature. They ascertained “Our complete genetic analysis has determined not only the basic metabolic and replicative characteristics of the bacterium, but also a number of potential pathogenicity mechanisms. Some of these have not previously been postulated to occur in  hytopathogens, providing new insights into the generality of these processes.” The results achieved will now make it possible, says the article, to begin a detailed comparison between animal and plant pathogens. Finally, the new information should provide the basis for an experimental, accelerated and rational investigation into the interactivity between X. fastidiosa and its hosts, which should lead to new findings in the approaches to the control of CVC, the famous yellowing disease.

They are conclusions that, beyond the success, also mark the beginning of a new phase “in which Brazil begins to take part in the setting of a world scientific agenda”, as Brito Cruz, FAPESP’s president, pointed out. “In which our country is already revealing scientific competence on the frontiers of knowledge”, as Perez observed. A phase that the widespread use of vanguard knowledge can now be foreseen, on an equal footing with the most developed countries, stresses Betty Abramowicz, for the production of wealth.

* Authors: A. J. Simpson, F. C. Reinach, P. Arruda, F. A. Abreu, M. Acencio, L. M. C. Alves, J. E. Araya, G. S. Baia, C. S. Baptista, M. H. Barros, E. D. Bonaccorsi, S. Bordin, J. M. Bové, M. R. S. Briones, M. R. P. Bueno, A. A. Camargo, L. E. A. Camargo, D. M. Carraro, H. Carrer, N. B. Colauto, C. Colombo, F. F. Costa, C. M. Costa-Neto, L. L. Coutinho, M. Cristofani, E. Dias-Neto, C. Docena, H. El-Dorry, A. P. Facincani, A. J. S. Ferreira, V. C. A. Ferreira, J. A. Ferro, J. S. Fraga, S. C. França, M. C. Franco, M. Frohme, L. R. Furlan, M. Garnier, G. H. Goldman, S. L. Gomes, A. Gruber, P. L. Ho, J. D. Hoheisel, M. L. Junqueira, E. L. Kemper, J. P. Kitajima, J. E. Krieger, E. E. Kuramae, F. Laigret,  M. R. Lambais, L. C. C. Leite, E. G. M. Lemos, S. A. Lopes, C. R. Lopes, J. A. Machado, M. A. Machado, A. M. B. N. Madeira, H. M. Madeira, C. L. Marino, M. V. Marques, E. A. L. Martins, E. M. F. Martins, A. Y Matsukuma, C. F. M. Menck, E. C. Miracca, C. Y. Miyaki, C. B. Monteiro-Vitorello, D. H. Moon, M. A. Nagai, A. L. T. O. Nascimento, L. E. S. Netto, A. Nhani Jr, F. G. Nobrega, L. R. Nunes, M. A. Oliveira, M. C. de Oliveira, R. C. de Oliveira, D. A. Palmieri, A. Paris, B. R. Peixoto, G. A. G. Pereira, H. A. Pereira Jr, J. B. Pesquero, R. B. Quaggio, P. G. Roberto, V. Rodrigues, A. J. de M. Rosa, V. E. de Rosa Jr, R. G. de Sá, R. V. Santelli, H. E. Sawasaki, A. C. R. da Silva, A. M. da Silva, F. R. da Silva, W. A. Silva, J. F. da Silveira, M. L. Z. Silvestri, W. J. Siqueira, A. A. de Souza, A. P. de Souza, M. F. Terenzi, D. Truffi, S. M. Tsai, M. H. Tsuhako, H. Vallada, M. A. Van Sluys, S. Vejovski-Almeida, A. L. Vettore, M. A. Zago, M. Zatz, J. Meidanis & J. C. Setubal  

Brazil amongst the great (from the french newspaper Le Figaro)

With the sequencing of the Xylella fastidiosa bacterium, Brazil rises to the level of the biological powers of the planet: the United States, the United Kingdom, France, Japan and Germany.  The venture arose, three years ago, at FAPESP, the State of São Paulo Research Foundation. Anxious to develop molecular biology, this institution, which manages the state taxes intended for science, therefore launched a sort of Keynesian plan for growth in the sphere of science. FAPESP supplied each one of the thirty laboratories that answered the invitation a sequencer with a unit price around 700,000 francs. These efforts have been rewarded. Better still, the United States has just put in an order for the Brazilians to sequence a variant of X. fastidiosa that is infesting vineyards there. And that perfectly well could threaten Europe, and France, one day. It causes no surprise that this great country has been invited, along with China, India and Mexico, to take part in the meeting of the G8 research ministers at the end of June, in Bordeaux.

Genome sequencing for all (from Nature magazine)
The successful sequencing of a plant pathogen by Brazilian researchers is a political as well as a scientific achievement

There is a common misconception that only advanced industrialized nations have the wherewithal and skilled human resources needed to achieve cutting-edge science. This misconception is fanned by the number of researchers from developing countries who find it necessary to obtain their research training abroad — and frequently decide not to return, citing a lack of scientific opportunity. But it is given the lie by a paper published in this issue which describes the result of a project carried out by a consortium of research centres in the state of São Paulo in Brazil to sequence the bacterium Xylella fastidiosa. This bacterium causes a disease that affects citrus fruit and other important crops, resulting in many millions of dollars of damage each year.

As the first public sequence of a free-living plant pathogen, the paper represents a significant scientific milestone. But it also sends a clear political signal, namely both the  desire and ability of countries such as Brazil to play in the big league. The sequencing project was deliberately chosen by the project’s main funding agency, FAPESP, to play a catalytic role in helping research teams equip themselves for the challenge of the post-genome era. It was also intended to send a signal to Brazil’s young scientists that they do not need to leave the country to engage in world-class science. In both respects, it appears to have succeeded.

Of course, sequencing the genome of the bacterium is only the first step towards controlling the damage that it causes. The next is to apply functional genomics to understand how the bacterium’s genes operate, opening up routes to possible intervention in limiting its spread by insects. Eventually, knowledge of the genome could provide the information required to breed resistant varieties of the affected crops. This raises a separate set of challenges — to persuade the Brazilian public that transgenic plants can play an important economic role, and at the same time to take firm steps to avoid untoward social and environmental consequences.

On the technical side, much of this lies some way in the future. But the success of the X. fastidiosa project has already attracted significant expressions of interest for similar  projects from other parts of the farming community — one proposal high on the list is for the same sequencing centres to turn their attention to chicken expressed sequence tags (ESTs). It has also given rise to the welcome and relatively unusual phenomenon of an agency in the advanced industrialized world — in this case the US Department of Agriculture, worried about the impact of a variety of X. fastidiosa on citrus* crops in California — contracting research from a developing country. Both achievements endorse Brazil’s determination to enter the post-genome age hand-in-hand with scientists in richer countries.

*In fact, the variant of X. fastidiosa affects the vines of California