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Scientific production

Brazil’s “hot” articles

Study indicates the themes in which Brazilian science has achieved international visibility

NELSON PROVAZIWhat part of Brazilian research has achieved broad international visibility? A study by Marco Antonio Zago, dean of Research at the University of São Paulo, outlined an answer to this question, by surveying a list of Brazilian articles on the Thomson Reuters database from 2001 to 2005 that achieved more than 200 citations. This is a sign of prestige, as it means that each one of these papers was cited as a reference in at least another 200 articles published subsequently. The list consists of 123 articles, but Zago went into greater depth in this survey and wanted to learn which of them could actually be regarded as a contribution from the country to science in its time. “Many works had only one or two Brazilian authors among a large number of foreigners, and the initiative lay outside the country,” explains Zago. He surveyed a set of 26 papers, in the fields of medicine (7 articles), chemistry (5), physics (5), genomics (2), computer science (2), biochemistry (2), engineering (1), genetics (1) and ecology (1). The study was published in the book Inovações tecnológicas no Brasil – Desempenho, políticas e potencial [Technological innovations in Brazil – Performance, policies and potential], published by Interfarma, the Association of the Pharmaceutical Research Industry.

The highlight of the list is Jairton Dupont, a professor at the Organic Chemistry Department at the Federal University of Rio Grande do Sul (UFRGS) and main author of three out of the 26 “hot” papers in the list. In 1992, Dupont’s group developed new fused salts, which are liquid at room temperature and highly stable; there is a wide range of applications for them in the chemical industry. The contribution includes the production of several ionic liquids, with applications in various fields of science. Two of the three articles were review works published in the journal Chemical Reviews. These two articles analyzed the bibliography on the research themes of Dupont’s group: a type of catalysis reaction in organometallic chemistry, a research area that bridges organic and inorganic chemistry, and the potential of a catalysis precursor, palladacycle, which has various applications, from the development of materials for obtaining liquid crystals to the production of chemotherapy agents to fight tumors. Review articles are usually heavily cited, because they organize the information on a given theme and provide guidance for both students and researchers. “These articles had repercussions because they involved themes that were of growing interest, but also because they provided a critical and solid analysis of the bibliography,” says Dupont.

The third article, published in the Journal of the American Chemical Society,  involves a discovery made by Dupont’s group: the possibility of using metallic nanoparticles in the catalysis of ionic liquids. “The article enabled the development of a new view of matter, by showing that one can apply to a solution analytical techniques previously limited to the solid state,” says Dupont. He draws one’s attention, however, to another study of his, published in 2004, that did not appear on the list in spite of its major repercussion. The article proposed an original model for describing ionic liquids. Turned down by major international periodicals, it was published in the Journal of the Brazilian Chemical Society. “There is prejudice against articles from outside the United States that propose new approaches,” Dupont says. “There are even cases of Nobel laureates having to publish their findings in less renowned journals. It’s important for young researchers to understand that this exists so that they don’t feel constrained when trying to change paradigms.”

The list compiled by Zago has the merit of mapping original contributions of Brazilian science, but the professor himself warns us about the limitations of the survey. It is natural that medical articles should be the majority of the most heavily cited ones, because this is a field that is especially productive in Brazil and the world. The number of citations is influenced by the size of the scientific community involved and by its productivity. In other fields, with smaller academic production, an article already has extraordinary repercussion when it gets 50 or 100 citations. One example mentioned by Zago is dentistry, a field in which Brazil stands out globally, ranking second in the number of articles published and in citations, but does not appear in the list of most cited papers. The limited repercussion of Brazilian research into the social sciences and the humanities is attributed to their dealing with subjects connected to themes of local interest and because they are  published mainly in Portuguese.

NELSON PROVAZIThe fruits of the genome
Two articles on the list are the fruit of the FAPESP Genome Program, an initiative released in 1997, which established a virtual network of 60 laboratories dedicated to sequencing the genome of various organisms. One example is an article published in Nature in May of 2002, which mapped the genes of Xanthomonas citri, which causes citrus canker, and compared the results with the sequencing of the bacteria Xanthomonas campestri. The study was conducted by the same group that sequenced the first pathogen genome, that of Xylella fastidiosa, which causes citrus variegated chlorosis. The article was on the cover of Nature in 2000. “The Xanthomonas study was the continuation of the work on Xylella, but it was much more complex, because it involved two genomes and pathogens that were more complex,” says Fernando Reinach, one of the authors of the article. Some of the 65 researchers that signed the paper left academia and went to do research for private sector institutions. This was the case of the first author, Ana Claudia Rasera da Silva, who now works for DuPont. The article’s performance (565 citations) outdid the Xylella paper, which achieved 529 citations but does not appear on Zago’s list because it was published before 2001. Another contribution of the program to the list of most cited articles was led by Sérgio Verjovski-Almeida, a professor at USP’s Institute of Chemistry. Published in 2003 in Nature Genetics, the article showed the outcome of a research effort that determined the sequences of 92% of the 14 thousand genes of Schistosoma mansoni, the parasite that causes schistosomiasis.

However, what causes an article to be frequently cited? One common feature is the original contribution of the article, whether in the form of new findings or the interpretation of existing data, as is the case of certain review texts. With 547 citations on the ISI database, an article by Fernando Von Zuben, a professor at the State University of Campinas (Unicamp), and Leandro de Castro, from Mackenzie Presbyterian University, pioneered a proposal in the field of Artificial Immunological Systems, which is characterized by the interest in reproducing the principles and mechanisms of the immune system to solve computer engineering problems. The paper was the first to formalize, computationally, the principle of clonal selection that, in medicine, explains how lymphocites select antigens for destruction. The principle, says Von Zuben, was proposed in the 1950’s and became an immunology landmark. The researcher ascribes the popularity of the article to the functionality of the proposed algorithms and to the quality of the periodical, IEEE Transactions on Evolutionary Computation. “The algorithms satisfactorily fulfill the role of importing into a computer certain skills found in the immune system, such as memory and a stimuli adaptation response,” he states. Another original computer science contribution was made by Paulo Barreto, from the Laboratory of Computer Architecture and Networks (Larc) of the Polytechnic School of USP, together with researchers from the universities of Stanford, in the United States, and of Dublin, in Ireland; Barreto created a practical application for a mathematical concept and presented a set of algorithms geared toward the implementation of encryption systems. The article was published in the book Advances in cryptology – Crypto 2002.

The group of the biologist José Alexandre Felizola Diniz Filho, from the Federal University of Goiás, has developed techniques to avoid statistical errors that arise when one relates ecological data, such as the wealth of biodiversity, with geographic locations. “It was interesting, because the opposite of what normally happens occured in terms of the transfer of science and technology,” says Diniz Filho. “We started to apply the techniques in macroecological data and we relayed this to research groups in the rest of the world.” A professor from the University of California, Brad Hawkins, came to Brazil to learn these techniques in 2002 and encouraged the group to write the paper, which has already been cited more than 200 times. The knowledge resulted in a software program that is distributed freely, called SAM (spatial analysis in macroecology).

Mitochondria and immunity
The originality of an article alone, however, does not ensure extraordinary citation performance, though it can help when the researched theme is receiving a lot of attention and is on the agenda of international scientific journals. Decades of dedication to a subject that is growing in importance in biochemistry explain the almost 400 citations of an article published in the journal FEBS Letters by the group of Anibal Vercesi, a professor from Unicamp and one of the coordinators of the FAPESP Biology area. The paper presents a model of the functioning of mitochondria undergoing oxidative stress. During his post-doctoral studies at John Hopkins University, from 1976 to 1977, Vercesi described results that later became relevant to explain the role of mitochondria in cell death. He showed, together with the US group, that calcium ions constitute signaling for the opening of a pore in the mitochondrial membrane (permeability transition pore) that unleashes the cell death process. In the last few years, he progressed along these lines, going into detail on how this mechanism is activated under stress situations, when the cell suffers the aggression of free radicals. The role of mitochondria in diseases is becoming the target of frequent investigation. Vercesi and two former students of his, Alicia J. Kowaltovski, who is now at the USP Chemistry Institute, and Roger F. Castilho, from Unicamp, wrote the paper. “The article is the result of research conducted in Brazil. But I like to remind my students that this line of research probably wouldn’t exist if I hadn’t done my postdoc in the United States,” he says.

Pioneering and opportunity explain the large number of citations of Brazilian articles published in 2001 in the Journal of Immunology, believes the head of the group in charge of the research, the immunologist Ricardo Gazzinelli, from the Federal University of Minas Gerais and the Oswaldo Cruz Foundation. “The focus of immunology research changed in the late 1990’s, when attention turned toward the receptors of innate immunity,” he says, referring to the initial defense mechanisms against infections, those that promptly attack invaders, and their receptors, which recognize infectious agents. “Our work was the first one dedicated to studying the role of these receptors in infections with protozoa and we became a benchmark reference in this. The area has grown a lot within immunology,” he states. The group of Gazzinelli continues to work on this, focusing on both the protozoan studied in the article, i.e., the Trypanosoma cruzi, which causes Chagas disease, and on the plasmodium, the malaria parasite. However, the group also looks for applications in immunotherapy and in the development of immunological adjuvants used in the formulation of vaccines.

Color and ancestry
Some of the papers on the list also call attention due to repercussion among the lay public as well. An article published in 2003 in the journal PNAS points out how inappropriate the concept of race is from the biological point of view; it shows that in Brazil, the correlation between color and genomic ancestry is very weak. “In other words, it showed that at the level of the individual it is virtually impossible to infer the genomic ancestry of a Brazilian from his or her color or vice-versa,” says its author, the geneticist Sérgio Danilo Pena, a professor at the Federal University of Minas Gerais who is responsible for a series of studies on the genetic composition of the Brazilian population. According to him, the research received a lot of repercussion because it addressed a topic that is of general interest. “However, the citations have more to do with scientific aspects and with the novel aspects of our findings,” he says.

There is a group of articles that evidences the contribution of Brazil’s medical research to the development of therapies and drugs. Two articles published in 2001 in the journal Circulation, by the cardiologist José Eduardo Sousa, of the Dante Pazzanese Institute of Cardiology, presented the first results of a clinical study, conducted on 30 Brazilian patients. These results made a significant impact on the treatment of people with atherosclerosis, an inflammatory disease in which plaques  form within the blood vessels. The papers talked about the high level of efficacy of a procedure that is now common: the application of rapamycin, a drug, on stents, the prostheses that keep damaged coronaries open. “The articles, which showed for the first time the evolution of patients immediately after the procedure and one year later, indicated that rapamycin, when released over the course of the first 30 days, could avoid in most cases the formation of scar tissue where the stent had been placed. This tissue often causes the artery to become blocked again,” says Sousa, a pioneer in Brazil in the use of angioplasty, which consists of squashing the plaque with a balloon, and in the use of stents.

The development and trial of a vaccine against the four most prevalent types of the human papillomavirus (HPV), which vaccine is now commercially available, also resulted in a heavily cited article, whose main author is the physician and researcher Luisa Villa, the director of the Brazilian branch of the Ludwig Institute for Cancer Research. “It was the first demonstration of the vaccine with the four types, which attested to its immunogenicity and efficacy in humans, and it had a huge impact,” she says. In 90% of the cases, the vaccine prevented the onset of genital warts and in 86% of the cases, it avoided the onset of infections (see Pesquisa FAPESP nº 157). Published in May of 2005 in the journal Oncology, the study was sponsored by Merck, the pharmaceutical company and creator of the vaccine. The study involved researchers from countries such as the United States and Norway. However, the first four authors are Brazilian scientists, from institutions such as the Brazilian Institute for Control of Cancer, the A. C. Camargo Hospital and Unicamp, under the leadership of Luisa Villa. “Merck believed that the participation of the Brazilian researchers and patients played a major role in the clinical trial,” she states. According to her, the work was important in order to speed up the use of the vaccine in Brazil.

NELSON PROVAZIAn epidemiological study that linked the development of type 2 diabetes with the presence of a set of inflammation markers, even at modest levels, became one of the most cited articles of the group of researcher Bruce Duncan, from the Federal University of Rio Grande do Sul. Published in the journal Diabetes, the study resorted to a US database that monitored 15 thousand people for several years in search of the causes of atherosclerosis, its sequels and risk factors. “Our study was only possible thanks to the collaboration that my wife and I have maintained with American researchers for the last two decades,” states Duncan, who is married and has a scientific partnership agreeement with the epidemiologist Maria Inês Schmidt, winner of the Conrado Wessel Prize in the Medicine category in 2003. To conduct the study in question, the stocked samples of plasma of 1,152 Americans were analyzed, split into two groups: one with diabetes and the other without. The UFRGS group is responsible for a set of studies, using this same database, according to which diabetes has metabolic origins in common with atherosclerosis. Inflammatory processes, even mild ones, predict and probably cause not only atherosclerosis, but also obesity, diabetes, hypertension, low good cholesterol and high triglycerides, comments Duncan. “We observed that there is no inflammation marker that is more important than another. The sum of them all is what underscores the inflammatory process, without necessarily indicating where the cause lies,” states Duncan.

Nanotechnology emerges
In a study published in 2007, Rogério Meneghini and Abel Packer, the coordinators of the electronic library SciELO Brasil, examined in depth the Brazilian publications from 1994 to 2003, a period before that which Zago’s article covered. They concluded that there were 11 fields of knowledge in which Brazilian science  achieved international standing –  research into genomics, chemical catalysis, cardiology and mitochondria already featured in this survey (see Pesquisa FAPESP nº 132). The list of the 26 most often cited articles suggests an emerging theme among Brazilian groups that have gained notoriety: nanoscience. There are four articles connected to the subject. One of them is the aforementioned review paper of Jairton Dupont. Another, whose main author is Gerardo Goya, who back then was a professor at the Physics Institute of USP and who is currently at the University of Zaragoza, in Spain, presents a study about the behavior of nanoparticles of magnetic iron oxide; it was published in 2003 in Journal of Applied Physics. “The study evaluated the magnetic properties of   magnetite iron oxide with different particle sizes, ranging from 10 nanometers to larger particles,” explains Thelma Berquó, the co-author of the article, who is now at the University of Minnesota, United States. At the time of the publication, she had a post-doctoral grant from FAPESP. “The impact is due to the fact that nobody had ever done this before and to the multidisciplinary interest in the subject, which can be applied in medicine, materials science and geosciences, among others,” she states.

The Physics Department of the Federal University of Minas Gerais (UFMG) has two articles on the list, both connected with the characterization of carbon nanotubes using a technique called Raman spectroscopy, developed by two researchers from this institution, professors Marcos Pimenta and Ado Jorio. “This technique became one of the most powerful ones available for characterizing these materials,” says Ado Jorio, the main author of one of the articles, published in 2003, in New Journal of Physics, and co-author of the second, published in 2004 in Physical Review Letters. Jorio says that an interest in carbon nanotubes brings together physicists, chemists, materials scientists and biologists, among others. “They have thermal, optical, electronic and mechanical properties that are unique in nature,” she explains.

Some ten articles on the list are review works, whose impact is not connected to discoveries, but to the scientific depth of the authors who set out to conduct a broad review of the literature. Bernardo Leo Wajchenberg, a professor from the School of Medicine at USP, is the author of a fairly often cited article   in the journal Endocrinology Reviews concerning the relation between visceral fat and metabolic syndrome, a set of factors that heighten the risk of developing diabetes and coronary diseases. Norma de Oliveira Santos, a professor at the Institute of Microbiology at the Federal University of Rio de Janeiro, received attention from an article on the global distribution of the serotypes of rotavirus and the implications of this for implementing a vaccine. This was published in 2005 in Reviews in Medical Virology.

An important piece of data is that the authors are from universities in various parts of Brazil, indicating decentralization of academic excellence. A review article on electroluminescent polymers, published in 2003 in the journal Progress in Polymer Science, has amassed 372 citations. It was written by Lena Akcelrud, head of the Paulo Scarpa Laboratory of Polymers of the Federal University of Paraná (UFPR), which has synthesized more than 50 light-emitting polymers. Electroluminescence in plastics was discovered in 1990. The article has achieved 500 references. “It took me two years to finish it, but we set the foundations for comparisons among several systems,” he says.

New molecules
A group from the Federal University of Santa Maria (UFSM), for example, produced a heavily cited review article on the toxicology and the pharmacology of organic compounds containing selenium and tellurium atoms. The paper, published in 2004 in the journal Chemical Reviews, had a significant impact because it involved an emerging theme. “These are new molecules, with potential for the development of new drugs,” says Cristina Wayne Nogueira, a professor at the Department of Chemistry of the Center of Exact and Natural Sciences of UFSM, who wrote an article together with two other professors from the institution while doing her post-doctorate at Iowa State University in the United States. The invitation to write the article was due to the qualifications of the group, which is a pioneer in this line. “We had an advantage, which was the possibility of conducting experiments on laboratory animals, such as rats, as there are limitations in other countries that make researching this field harder,” says Cristina. As for the Russian physicist Viktor Dodonov, a professor at the University of Brasília, he says that he was only able to write his “hot paper”, an analysis of 75 years of publications about non-classical states in quantum optics, because at the time he was working for UFSCar (the Federal University of São Carlos) and had access to the library of the Institute of Physics at USP at the São Carlos campus. “The article was only possible thanks to the quality and availability of the institute’s library,” says Dodonov, who exchanged Russia for Brazil in 1996.

Henrique Hippert, a professor of statistics at the Federal University of Juiz de Fora, says that the impact of a review article written with another two authors in 2001 was due, first, to the rising interest in the theme of forecasting energy consumption. The text, published by the journal IEEE Transactions on Power Systems, brought all the information together in a technique called artificial neural network. “There was a lot of interest among researchers to find out what had already been published. Two or three other reviews appeared at the time, but they were less comprehensive,” he says.

Periodicals value good review articles, as they ensure an audience and help to expand the impact factor of the publications, which consists of the mean number of citations. Two papers on the list were published in the journal Memórias do Instituto Oswaldo Cruz (IOC) and resulted from the publication’s strategy of investing in good review articles in order to raise its impact factor. “As I was the journal’s editor, I wrote the first article of the series,” says José Rodrigues Coura, author of a review, published in 2002, on the still scarce methods for treating the victims of Chagas’ disease. “Interest in the article is due to the invariably renewed wish to look for new drugs,” states Coura, head of IOC Laboratory of Parasitic Diseases. Professor Zago’s list also includes a review article on the impact of the methods for controlling Chagas’ disease in Latin America, published in Memórias do IOC,  and written by the tropical medicine expert João Carlos Pinto Dias, from Fiocruz, and two other authors.