Pesquisa FAPESP 2013

Pesquisa FAPESP 2013 _ edition 1

2013 _ Edition 1 www.revistapesquisa.fapesp.br

Scientific Production

BRIC scientific communities are becoming increasingly similar to those in developed countries Depression

Crises can accelerate aging Royal Society

Brazilian researchers find 350-year-old alchemy powder

Journey to the center of the Earth Physicists investigate the behavior of minerals in the Earth’s deep interior

2013 _ edition 1 www.revistapesquisa.fapesp.br

14 COVER Physicists detail the structures and transformations of the minerals found deep inside the planet Cover illustration Drüm

interview 6 Eduardo Moacyr Krieger A physiologist created a leading Brazilian team at InCor to perform integrated research on blood pressure

Sections 4 Letter from the editor 66 Art

SCIENTIFIC AND TECHNOLOGICAL POLICY 20 Scientific Production

Studies show that the structure of BRIC scientific communities is increasingly similar to that found in developed countries

24 Investment

State expenditure on research and development reveals the gap between São Paulo and other Brazilian states

28 Recognition

International awards, such as the one granted to Fernando Henrique Cardoso, enhance the reputation of the Brazilian scientific community

SCIENCE 32 Mental Diseases

Episodes of depression and euphoria cause chemical imbalances that may damage cells and accelerate aging

42 Muscular Dystrophy When combined, stem cells and growth factors reduce the symptoms of this disease in mice

TECHNOLOGY 44 Business Research Vale celebrates its 70th anniversary by investing in long-term projects that focus on mining and sustainable development

50 Global warming

Emissions of the most hazardous greenhouse gas by sugarcane plantations are lower than previously estimated

53 New materials

Brazilians discover a new family of materials that conduct electricity without losing energy.

HUMANITIES 54 History of Science Brazilian researchers discover alchemy powder in an archive at the Royal Society, the seat of the scientific revolution

62 Foreign Relations The idea that Brazil might sit on the Security Council, which analysts considered a “whim,” was introduced by the United States

PESQUISA FAPESP| 3

Letter from the Editor SÃO PAULO RESEARCH FOUNDATION

Celso Lafer President Eduardo Moacyr Krieger Vice-President Board of trustees Alejandro Szanto de Toledo, Celso Lafer, Eduardo Moacyr Krieger, Fernando Ferreira Costa, Horácio Lafer Piva, Herman Jacobus Cornelis Voorwald, João Grandino Rodas, Maria José Soares Mendes Giannini, José de Souza Martins, Luiz Gonzaga Belluzzo, Suely Vilela Sampaio, Yoshiaki Nakano

Heading toward the endless unknown

Executive board José Arana Varela President director Carlos Henrique de Brito Cruz Scientific director Joaquim J. de Camargo Engler Administrative director

issn 1519-8774

Editorial board Carlos Henrique de Brito Cruz (President), Caio Túlio Costa, Eugênio Bucci, Fernando Reinach, José Eduardo Krieger, Luiz Davidovich, Marcelo Knobel, Marcelo Leite, Maria Hermínia Tavares de Almeida, Marisa Lajolo, Maurício Tuffani, Mônica Teixeira Scientific committee Luiz Henrique Lopes dos Santos (President), Adolpho José Melfi, Carlos Eduardo Negrão, Douglas Eduardo Zampieri, Eduardo Cesar Leão Marques, Francisco Antônio Bezerra Coutinho, João Furtado, Joaquim J. de Camargo Engler, José Arana Varela, José Roberto de França Arruda, José Roberto Postali Parra, Luis Augusto Barbosa Cortez, Marcelo Knobel, Marie-Anne Van Sluys, Mário José Abdalla Saad, Paula Montero, Roberto Marcondes Cesar Júnior, Sérgio Luiz Monteiro Salles Filho, Sérgio Robles Reis Queiroz, Wagner do Amaral, Walter Colli Scientific coordinator Luiz Henrique Lopes dos Santos Editor in chief Mariluce Moura Managing editor Neldson Marcolin Executive editors Carlos Haag (Humanities), Fabrício Marques (Policy), Marcos de Oliveira (Technology), Ricardo Zorzetto (Science), Maria Guimarães (On-line) Special editors Carlos Fioravanti, Marcos Pivetta Editorial assistant Dinorah Ereno Translator Deborah Neale Reviewer Nature Publishing Group Art editor Laura Daviña Art Ana Paula Campos, Maria Cecília Felli Photographers Eduardo Cesar, Léo Ramos Eletronic media Fabricio Marques (Coordinator) Contributors Drüm, Eduardo Sancinetti, Igor Zolnerkevic, Mayumi Okuyama, Pedro Hamdan, Yuri Vasconcelos Printer IBEP Gráfica

The reprinting of texts and photos, in whole or in part, is prohibited without prior authorization

Pesquisa Fapesp Rua Joaquim Antunes, nº 727, 10º andar São Paulo, SP – CEP 05415-012 Fapesp Rua Pio XI, nº 1.500 – Alto da Lapa São Paulo, SP – CEP 05468-901

DEPARTMENT FOR ECONOMIC DEVELOPMENT, SCIENCE AND TECHNOLOGY SÃO PAULO STATE GOVERNMENT

4 | january 2013

Mariluce Moura Editor in Chief

“I dared not look into the bottomless pit I was diving into, perhaps forever. There was still time to give up.”

T

he fine cover story of this Pesquisa FAPESP issue gave me an irrepressible wish to reread the Jules Verne 1864 classic Journey to the Center of the Earth due to a very basic association. This issue addresses studies that may not accomplish the dream of actually descending into the remotest depths of the Earth (only partially achieved by the audacious Professor Otto Lidenbrock in the French novel) but that probe these depths indefatigably (though, of course, with less risk) by resorting to tools more appropriate for the twenty-first century, such as computer simulations, that are far removed from the rugged adventures of the 1800s. Based on the virtual probing of the interior of our planet, the people responsible for these studies—primarily physicists, rather than geologists—have discovered new information about the structure and transformation of minerals formed thousands of kilometers below the surface of the Earth. They have also strengthened the hypothesis about the existence of a volume of water greater than an ocean that is spread “over the thick mass of rock under our feet,” as explained by our special editor, Carlos Fioravanti, beginning on page 14.

The reference to this mass of water within the Earth, with the word ocean (so suggestive of vastness) used as a sensitive measure of volume, may have been what impelled me toward Verne. That huge fictional underground sea on the way to the core of the planet emerged from my memory peopled by formidable prehistoric animals engaged in terrifying fights, shaken by cataclysms, cut by dizzying abysses. Facing this

sea and its astonishing events, now rather pale in my recollection, were three adventurers created by the famous writer: Lidenbrock, his nephew Axel (the narrator), and Hans, the brave and silent Icelandic guide. I had to sharpen these images; to determine how the contemporary Pesquisa FAPESP article had removed them from their remote mental refuges, I thirstily returned to the book.

First, I encountered Verne’s clear love of science. I had failed to grasp his illuminist nature, broadly speaking, at the age of 10 or 11 years.

“Well, I have learnt, Axel, that science can always be improved upon, and that each theory is soon replaced by another more recent one,” warns Lidenbrock, talking to his nephew and disciple. These lessons in the abyss shed light upon the scientific method: “Science, my son, is full of errors; but errors that one should learn about, because, little by little, they lead to the truth.” Statements about the nature of scientific knowledge are interspersed with explanations about geological, cosmological and biological theories that, at the time, lacked technological and technical solutions. Nevertheless, everything is so well blended and woven into the powerful structure of Jules Verne’s narrative, so embedded in the tension-rich adventure toward the center of the Earth, so mixed with the fantastic inventions of the author’s imagination, that one can intelligently absorb all this so that it becomes an experience of pure pleasure. I was thinking about this as I was finishing the book, and I suddenly recalled an old and marvelous feeling, one that Verne’s works

triggered in me long ago: the feeling that one can do, redo, transform, create, and venture forth into the unknown and discover worlds.

I did not yet know the name of the basic tool that Verne identified for this power of being.

Page 54 presents the exciting results of a scientific study in the field of the history of science that Pesquisa FAPESP brings to its readers in the cover feature this month. It is exciting because of the description of the adventures that led to finding a powder that suggests a material link between alchemy and chemistry at the venerable Royal Society in England, which excites the human imagination and provides the inclination to unravel (or, at least, to follow) the story of how the mysteries were solved.

This story becomes more interesting when one learns that the substance, after lying forgotten for approximately 350 years in a closed envelope among other documents at the institution’s archives, was found by two Brazilian researchers. Nothing is more understandable than enthusiastically supporting our “team.”

The duo has been dedicated for several years to examining certain periods of the history of science to understand how the construction of scientific knowledge is fuelled by affluence of various sorts, even if, to our contemporary eyes, it seems radically anti-scientific. The authors take important steps in their reconstruction of the history of contemporary science. It is worthwhile to read the fine article by our humanities editor, Carlos Haag, which includes in the survey of the subject a dip, in loco, into the documents kept in London. n PESQUISA FAPESP | 5

interview eduardo moacyr krieger

The master of high blood pressure The physiologist who created Brazil’s leading team at InCor to conduct integrated research on blood pressure Mariluce Moura and Ricardo Zorzetto Published in July 2012

W

hen Eduardo Moacyr Krieger, a native of the State of Rio Grande do Sul, received his medical degree in the city of Porto Alegre in 1953, one of his main objectives was to become a cardiologist and work at the Medical School. However, under the decisive influence of two prominent Argentineans (physiologist Bernardo Houssay, recipient of the Nobel Prize in Physiology or Medicine in 1947, and Eduardo Braun Menendéz, who discovered angiotensin in 1940), Krieger decided to change his career goals. As a result, Brazilians have a strong reason to be thankful to these two Argentinean mentors: the fields of cardiovascular physiology and, more specifically, the field of blood pressure research have benefitted the most from Krieger’s work. Professor Krieger, now 84 years old, contributed enormously to the understanding of the mechanisms that control blood pressure. In addition, in the 1950s, he organized a prominent research group at the Medical School of the University of São Paulo (USP) in Ribeirão Preto. In 1985, he created Brazil’s most highly respected integrated team for research on blood pressure, which 6 | january 2013

was based at the Heart Institute (InCor) of USP’s Hospital das Clínicas teaching hospital in São Paulo.

Krieger, who is one of nine children of a retailer of German descent who had settled in the town of Cerro Largo near the border of the State of Rio Grande do Sul and Argentina, was the only one of the nine to receive higher education. In addition to working as a professor and a researcher, he was actively involved in the politics of the academic community.

One of his outstanding achievements was his 14-year term as chairman of the Brazilian Academy of Sciences (ABC).

During this time, he worked tirelessly to improve the position of Brazil’s scientific community and its scientific endeavors on the international stage.

Professor Krieger has two children, the well-known scientists José Eduardo Krieger and Marta Helena Krieger, and three grandchildren. He and his wife Lorena have been married for 55 years.

He has also has been the vice-chairman of FAPESP since 2010. Currently, he is concluding one additional thematic project developed under his coordination and is preparing to take on a new challenge, that of organizing the discipline of translational medicine and the related

department at InCor. Below are excerpts from the interview he granted to Pesquisa FAPESP. Let’s start by talking about the line of research that you have dedicated most of your attention to: the mechanisms that regulate blood pressure. How your interest in this area first aroused?

Actually, my interest was aroused when I began my scientific career. I had just graduated from the Medical School in Porto Alegre and met a group of Argentine physiologists led by Professor Bernardo Houssay, the 1947 Nobel laureate in Physiology or Medicine. His disciples included Eduardo Braun Menéndez, who had discovered angiotensin in 1940. Angiotensin is one of the substances that regulate blood pressure. At this time, I wanted to follow an academic career path. In 1954, this group came to Porto Alegre under a program organized by the Coordination for the Improvement of Higher Level Personnel (CAPES). The members of the group took turns coming to Porto Alegre, where they would stay for one month at a time. Bernardo Houssay himself spent some months in Porto Alegre. At that time, I was interested in cardiology, so I worked with Braun Me-

néndez. Then, I went to Buenos Aires, where I stayed for seven or eight months, working on the renin-angiotensin system.

léo ramos

At whose laboratory?

In Buenos Aires, I worked in Professor Bernardo Houssay’s lab, who had had been out of the university community for nearly 10 years. Because the group had protested against the military dictatorship, it had been expelled from the Medical School in 1943. Houssay, a patriot, always said that science did not have a mother country but that a researcher always did. Although Houssay was a Nobel laureate, he refused to leave Argentina, where he worked under very poor conditions. His workspace consisted of a house that belonged to the very wealthy family of Braun Menéndez, where each room had been turned into a lab. The house was on Costa Rica Street in a distant neighborhood [Palermo]. The people from the medical school no longer knew Bernardo Houssay, but prominent researchers from all over the world would come to his lab every week. It was a fantastic environment. There was a small house next to the big one that was accessed via a gate in the garden, and this smaller house was the site of Louis Leloir’s biochemistry lab. Leloir won the 1970 Nobel Prize for Biochemistry, and this was an environment populated by current and future Nobel Prize laureates.

I joined it thinking that I would only go through an internship and then return to Brazil to specialize in cardiology, but this environment stirred my interest in basic research. As a result, I went to the United States to conclude my scientific training at the University of Georgia, in the southern US. Bernardo Houssay suggested that I go there because that was where the best cardiovascular physiologists were working at the time. I had gotten a grant from the Rockefeller Foundation, which had suggested that I go to a university on the East Coast or the West Coast. However, Houssay suggested that “the University of Georgia might not be the best university, but it has the top cardiovascular researcher.”

And who was he?

William Hamilton. He and Raymond Ahlquist, who was also at the University of Georgia, had discovered the alpha and beta adrenoreceptors, and I learned PESQUISA FAPESP | 7

all about these receptors from the people who had discovered them. This was good; I stayed for a little over a year and took part in a fantastic cardiovascular physiology and pharmacology training program. While I was in the United States, I received an invitation to go to Ribeirão Preto. The university in Ribeirão Preto was getting organized and looking for prominent professionals from abroad; it wanted to hire someone who had been part of Bernardo Houssay’s group. The university found Miguel Covian, who was from Argentina. He came to Ribeirão Preto and invited me to organize a cardiovascular group. I made my decision in the United States, and rather than returning to Porto Alegre, I moved to Ribeirão Preto. I knew nothing about the university except that it was part of USP and that it was a good reference center. I also knew that the university was heavily funded by the Rockefeller Foundation, which meant that the faculty could focus on scientific work. I arrived in Ribeirão Preto in 1957. The first group of undergraduates had entered the university in 1952 and graduated in 1957. Thus, I came into a prominent, captivating environment at USP’s second medical school that was completely focused on research.

Basic research?

There was clinical research as well. Ribeirão Preto was a pioneer and exclusively dedicated to the field of clinical studies in Brazil. I started researching pressure regulation during hypothermia until equipment from the United States arrived. For these experiments, I studied reflexes to analyze how the nervous system and the regulation of pressure functioned at increasingly lower temperatures. I also had to stimulate the system using various forms of reflex, central or peripheral stimulation. This was very interesting, and during this research on reflexes, a field I was familiar with, I discovered that the nerve that controls and provides information on arterial pressure in rats, which receives information from what we refer to as baroreceptors or pressor receptors, was isolated from the cervical region. As this discovery of the isolated nerve was novel, I decided to conduct a systematic study of the pathway controlling the rat’s pressor receptors. As a result, I was able to demonstrate total denervation of the 8 | january 2013

system, a model that is still in use today.

This component of my research has been cited most frequently, approximately 600 times. The study was published in 1964 in Circulation Research, a leading journal.

Interestingly, this important research stemmed from a casual observation, one that I was not looking to make. However, after I had come across this nerve, I decided to conduct the systematic study, which resulted in several papers involving how traffic in these nerves takes place and what their blood pressure regulation characteristics are in rats.

Do you remember the day you discovered this?

I do. It was in the late 1950s or early 1960s.

We didn´t yet have any students enrolled in postgraduate programs (postgraduate students came to the university from 1970 onwards), but a group from Buenos Aires would come to Ribeirão Preto during vacations, and each lab would show the group what it was working on. While doing some demonstrations for the group, I noticed that when I stimulated the central part of the vagus nerve, the pressure would sometimes go up but other times would go down. I found that rather strange, and one day I told the group during my demonstration that I would try to find out whether my hypothesis was correct, i.e., whether the curare I was giving the animal was causing response inversion.

So, I administered the curare, stimulated the vagus nerve, and nothing happened. I decided to use a stronger magnifying glass and noticed that it was not only one nerve but actually two nerves that were involved.

I also noticed that there was a small nerve – the sympathetic nerve – next to the larger nerve, which could be easily isolated when it was stimulated in the center.

In most species, the smaller nerve is not separate from the larger nerve, but this was not the case in rats. So, I stimulated both nerves and found that one showed a drop in pressure while the other showed an increase in pressure. These results suggested that, in rats, one could isolate the sympathetic nerve from the vagus nerve and that the sympathetic nerve had aortic pressor receptor fibers. This was astonishing!

Your conclusion was: “I had just discovered something that nobody was aware of.”

I conducted a systematic study and published several papers on traffic in these nerves; two or three of these papers described the possibilities of working with rat pressoreceptors. Then, I wrote a well-known paper on the denervation of the pressoreceptors. I got really excited because one of the most important aspects of my work was to discover how the nervous system adapts to hypertension, and the pressoreceptor is continuously a part of this process; at each heartbeat, the pressoreceptor is discharged because the pressure increases, distends the vessel and excites the receptors. Moreover, the pressoreceptors are the main source of information that enables the maintenance of blood pressure at normal levels. As pressure increases and the discharge increases, the inhibition of the sympathetic nerve causes the pressure to go down. Likewise, exciting the pressor receptors stimulates the vagus nerve to reduce the heart rate and cardiac output, which results in normal blood pressure levels. It is widely known that chronic hypertension does not provoke bradycardia, which shows that this reflex has adapted. Thus, I decided to study how this nerve functions under high blood pressure conditions.

It had been shown that when acute hypertension occurs, these nerves adapt after a given period of time, which is why a person with high blood pressure does not experience a reduction in heart rate. However, this situation can occur if the pressure goes up suddenly, due to the reflex. In other words, the reflex adapts itself chronically.

You referred to bradycardia.

Yes, a slow resting heart rate – one of the leading indicators of how the pressoreceptor is functioning. When you increase the stimulus, this produces bradycardia and vasodilation because it changes the sympathetic nerve. This is the main reflex and is adapted in hypertension, which was common knowledge. However, the challenge was finding out how this occurs.

Studies had been conducted with dogs in which adaptation began four or five days after the arterial blood pressure had increased. In the case of the rat – a model in which pressure can be better controlled – one of my early studies focused on the adaptation sequence of pressor receptors in hypertension. I triggered sudden

hypertension by compressing the aorta coarctation. I maintained the pressure at a high level and showed that a slight adaptation, approximately 30%, had occurred after six hours, whereas after 48 hours, most of the animals had adapted.

What is adaptation? Adaptation is the movement of the stimulation threshold and the functioning range of the pressor receptors. I showed that full adaptation takes 48 hours, although in some animals, it may take more or less time. On average, nine out of every ten animals had become fully adapted within 48 hours. I conducted many studies on this topic to show how, when pressure returns to normal, the adaptation becomes normal as well.

I also built kidney hypertension models, which is something I had done a long time ago with Braun Menéndez, by placing a clip on the renal artery to keep the rat’s arterial pressure chronically high and the pressoreceptor adapted. I would also suddenly revert the hypertension by removing the clip and check how much time this would take, and I observed that six hours were necessary for the reversion. By doing so, I was trying to understand how the main reflex control mechanism works during increases and decreases in blood pressure. For example, does the mechanism adapt itself and how? Later, I found that the mechanism adapts itself and its functioning range increases in response to hypertension levels, although the sensitivity changes. Specifically, the mechanism becomes less sensitive, and I was the first to publish this finding in the literature. We were able to test the sensitivity of the mechanism by acutely varying the pressure and observing how the discharge of the pressor receptor located on the artery wall behaves.

As this pressoreceptor sends information to the central nervous system, it was possible to compare the discharge curve of a normal animal to that of an animal with high blood pressure, and the latter curve was shown to be a sloping one.

hed many papers showing this reversion, and I published other papers showing that hypotension, which is very rare in clinical terms, also goes through this adaptation in approximately 48 hours and that the reversion is quite fast. Sensitivity is another issue, and this topic has regained clinical importance. For example, a patient with hypertension for any reason, where the main regulation mechanism is adapted yet shows decreased sensitivity, has a less efficient pressure control mechanism. Blood pressure changes from one moment to the next; when an individual is sleeping, sitting, getting up, or running, the pressure goes up or down according to the physiological circumstances. If the regulating system is less efficient, the fluctuations are sharper, and this happens be-

blished showing that stimulating the baroreceptor in resistant hypertension is a possible therapeutic measure.

What is the role of the kidney in regulating arterial blood pressure?

There is no doubt that primary hypertension is due to several factors, such as the imbalance between pressor and depressor mechanisms. The sympathetic nerve, which controls the calibration of the vessels and cardiac output, was the first pressor mechanism studied by researchers. This research was followed by studies on the renin-angiotensin system. Renin was discovered in the late nineteenth century, but angiotensin, the factor that increases blood pressure, was discovered by Braun Menéndez and by [Irvine] Page from the United States. These discoveries focused attention on the mechanism of the renin-angiotensin-aldosterone system.

Angiotensin stimulates the adrenal gland to produce aldosterone, which provokes salt retention, and these mechanisms are well known.

Depressor mechanisms involve the kinins, such as bradykinin, which was discovered in 1948 by Maurício Oscar da Rocha e Silva from São Paulo’s Biological Institute. Enormous progress was made when Robert F. Furchgott, also a Nobel laureate, discovered twenty years ago that the endothelium, rather than merely protecting the vessels and preventing coagulation, is also a factory of hypertension and hypotension components. It was further discovered that nitric oxide (NO) acts on hypotension and exerts a tonic action. Each system previously believed to have a pressor or a depressor action was in fact shown to have both pressor and antipressor elements. Therefore, the pressure regulation mechanisms became very complex. So what causes high blood pressure? Based on existing data, we first know that the arterial blood pressure control system is very closely linked to genetics, as the synthesis of the pressor and depressor mechanisms is performed according to specific genes.

Therefore, the genetic load may facilitate

Houssay always said that science did not have a native country but the scientist does; this is why he never wanted to leave Argentina

Was that the article from 1970?

No. The 1970 article demonstrated the sequence of the adaptation. Later, I publis-

cause individuals with high blood pressure have a less sensitive pressoreceptor and their blood pressure levels can therefore fluctuate significantly. So what does this mean? It has already been proven that the level and variability of blood pressure can seriously damage the vessels. In the last few years, practitioners reinitiated an effort that hadn’t worked very well in the past; specifically, they have stimulated the pressoreceptor to change the sympathetic nerve and reduce the arterial blood pressure. Technological improvements have made it possible to implant electrodes in the patient’s carotid, and it seems that these electrodes do not damage the vessel significantly and can stimulate the site. Several papers have already been pu-

PESQUISA FAPESP | 9

the production of pressor substances or may produce less hypotension-inducing substances. As a result of an individual’s genetic load, there is either the tendency to have high blood pressure or not.

However, it is not enough to have a genetic predisposition; the environment also continuously affects the regulation of arterial blood pressure.

When you say the environment...

This includes salt, lack of exercise, obesity, stress, and, more recently, inflammation.

All of these elements have an impact, in one way or another, on the regulation system.

Therefore, if an individual has a very good regulation system, nothing will cause an impact on blood pressure; however, if an individual has a very poor regulation system, he or she will have high blood pressure regardless of salt intake or exercise. This combined effect of the genetic load and the environment represents the current dogma for primary arterial hypertension. It is currently very difficult to analyze the genetic component, but in the future, we aim to address each individual’s genetic load.

When this becomes possible, individuals will likely receive marriage counseling in relation to their hypertension genetic status.

manner. This is when the clinical part of my research began. I continued doing my experimental research because this was what I knew how to do and I had obtained international recognition for my efforts, but I also wanted to do clinical research. In Ribeirão Preto, I had worked in the Physiology Department with lab animals, but, in São Paulo, I had the opportunity to develop a line of research with patients. I studied pressure regulation during sleep and exercise and wanted to understand the influence of reflexes on arterial blood pressure by investigating the pressoreceptor and the chemoreceptor, the cardiopulmonary system. We developed a technique to register the sympathetic nerve, and therefore the functioning of the nervous sys-

gases. When a person stops breathing, the gases change, the chemoreceptors are stimulated and the pressure goes way up. After a while, the effects of these spurts have permanent consequences.

Does sleep apnea alter the blood pressure?

It is very common for apnea to be associated with hypertension. However, an individual’s blood pressure tends to fall when the apnea is addressed.

To continue, this interaction...

This is where the clinical part comes in.

We have worked with clinicians, cardiologists, and pneumologists, as well as the physical education professionals who are part of the group headed by Carlos Eduardo Negrão, who was a member of our group and had worked on experiments with lab animals and then with human beings. Negrão is now pursuing an independent line of research. In regard to nursing, I started working on projects involving nurses who had had issues with patients’ compliance with treatment.

This was followed by work on molecular biology, which was included in a very interesting way. My son graduated from Ribeirão Preto in 1984 and then went to the United States to join the doctoral program on classic Guytonian physiology. Guyton was one of the world’s foremost physiologists. My son concluded his doctoral program in early 1990, when molecular biology was beginning to play a major role in hypertension studies.

He concluded his doctorate and went to Harvard and then to Stanford to study the molecular biology of hypertension.

He joined our group after he returned to Brazil. Our first research work together was to mate rats with high blood pressure to normal rats. After the rats mated twice, their grandchildren displayed different blood pressure conditions. The goal of these experiments was to study these grandchildren; if they demonstrated high blood pressure, it means that they had inherited a predisposition from the grandfather with high blood pressu-

A person with a poor regulatory system can refrain from eating salt and exercise and will still have high blood pressure

You had already been working in the field of physiology, regulation mechanisms, etc. when many advances were made in the field of genetics in recent years.

To what extent did these advances help your experiments?

For 28 years in Ribeirão Preto, my numerous postgraduate students and myself worked on lines of research that were mostly linked to the nervous system and to the regulatory mechanisms of arterial blood pressure. I subsequently came to São Paulo and continued working on this line of research.

When did you come to São Paulo?

I retired from Ribeirão Preto in 1985 and came to São Paulo at the age of 56 because I had been invited to research hypertension at InCor in an integrated 10 | january 2013

tem, using a needle placed in the peroneal nerve. We were able to observe the basal activity of the sympathetic nerve and how it behaves under different circumstances. In short, we set up an extensive line of research and also studied the role of pressoreceptors in the sleep mechanism, based on the sleep research of one of our collaborators, Geraldo Lorenzo, from InCor. One of the important research topics concerning hypertension at InCor is pressure regulation during sleep. Apnea is closely linked to arterial blood pressure, and the oxygen level increases along with the carbon level during apnea, which stimulates the chemoreceptors located in the carotid that are sensitive to the tension from

re. In addition, we studied the rats’ genomes to detect differences in relation to the rats with normal blood pressure.

So this is when you identified some chromosome regions...

That was our first collaborative effort.

We found five regions linked to hypertension. The projects that I submitted to FAPESP in the last ten years have always been integrated, with thematic projects comprising both experimental and clinical aspects. This is the type of work that I have done in recent years. Now, I am moving into another field, and I have organized a team of professionals from the fields of physiology, clinical medicine, molecular biology, physical education, nursing, psychology and nutrition who are all focused on studying hypertension.

So this research group is at the forefront of research work on hypertension.

Undoubtedly. Our group is quite distinct. One of the first members to leave the group went to Milan to study the monitoring of arterial blood pressure. Another member went to Paris to study the elastic properties of vessels and how they change under hypertension. Another member went to Charleston to study metabolism in relation to hypertension. Then, one more left to study neurogenetics, and the last member left to study sleep apnea at Johns Hopkins. This group from InCor is at the forefront because it integrates knowledge from world-renowned institutions.

loped in partnership with Brazilian labs.

Maria José Campagnole dos Santos is another full professor, Maria José and Robson worked with me in Ribeirão Preto, and then there’s Kleber Franchini, in Campinas, who was my doctoral student.

Franchini developed a molecule and is now trying to do something innovative with the Brazilian pharmaceutical industry. The group in Ribeirão Preto has two or three full professors, and Lisete Michelini, who leads cardiovascular physiology at USP’s Biomedical Sciences Institute, worked with me in Ribeirão Preto.

You have written more than 200 scientific articles. Which was the article that contributed the most to knowledge on hypertension?

to solve them. As a result, I told him that I wanted to observe the behavior of the location where the pressoreceptors are found in acute hypertension. The literature refers to the Strain Gauge [a device used to measure the stress of an object], which was a Silastic elastomer with mercury on one of the tips of the Wheatstone bridge [an electrical circuit used to measure electrical resistance]. The Silastic was typically placed in the heart, or elsewhere, and has been widely used in medicine.

However, this was impossible to do with the rat’s small aorta because the mercury would be damaged. However, José Venâncio found a way, and he prepared a saturated copper nitrate solution that worked beautifully. We placed the Silastic in this liquid, which is a conductor and has some stability, for two or three days, which gave us enough time to carry out the experiments.

Venâncio developed this solution together with Lisete, who was enrolled in the postgraduate program at the time. We were able to do several major studies showing how the aorta’s caliber functions in hypertension. We also compared the adaptation time to the time it took the vessel to change, and we observed that the vessel adapts itself. During the first six hours, the vessel resists the increase in pressure, but subsequently, the pressoreceptors undergo a slight adjustment. The full adaptation takes 48 hours and varies from one rat to another and takes place when the aorta distends.

The aorta reaches a new threshold and starts working normally, so to speak. That was how it worked previously, when the receptor was there; now it works with a dilated caliber, and the receptor is stimulated in a similar but not identical manner because the sizes are different and the sensitivity is reduced.

We found five chromosome regions linked to hypertension in our first research study on molecular biology

And you, as the founder of the group, must feel very proud of this.

Yes, I am. In Brazil, I trained 32 or 33 PhDs, 10 of whom have become full professors. We have really good people working in our group. There is also a physiology group in the city of Belo Horizonte that is one of the world’s foremost groups in this field. This group is studying angiotensin 1-7, which is different because it’s the “good” angiotensin. Headed by Robson Augusto dos Santos, this group patented compounds with the potential to become drugs, which are being deve-

I would say it’s the series of articles in which I explained how pressoreceptors function, regarding the adaptation sequence of these receptors in hypertension and hypotension and their sensitivity. Lisete Michelini and I studied their adaptation mechanism and showed that this adaptation sequence is the same as that which occurs during the dilation of the aorta in the case of hypertension. We associated this adaptation with the changes that take place in the vessels. By the way, I had an outstanding colleague at the Physiology Department in Ribeirão Preto, José Venâncio de Pereira Leite, who was extremely knowledgeable about science and was also very cultured. We would tell him about our problems, and he would try

When the aorta is enlarged because it has adapted itself to the process, doesn’t the blood flow more slowly? Doesn’t the circulatory system slow down?

No, because hypertension occurs at the level of the arterioles, which is where the resistance increases. The aorta suffers the consequences of having to increase PESQUISA FAPESP | 11

the pressure to overcome this resistance. The aorta adapts itself because of its elasticity, and it stores a portion of the systolic volume. The heart beats, and, if the artery were stiff, the blood would flow directly to the capillaries and no blood would flow during diastole, which would result in fainting. The artery system is very interesting because the arterioles are highly resistant; they resemble tightly shut water faucets. So when the heart expels the blood, it has a higher possibility of distending the large arteries to accumulate the blood rather than to let it flow. As a result, the arteries accumulate blood. When the heart stops expelling the blood and goes into diastole, which lasts twice as long as systole, the large arteries release the blood that they had accumulated. In the capillary vessels, where the exchange occurs, the flow is continuous as a result of this fantastic but very dangerous mechanism, as any changes in the arterioles can induce hypertension. This is a fantastic mechanism that nature created, and the system would be very precarious if this mechanism didn’t exist. A high-resistance elastic chamber is necessary for oxygen to reach brain cells that constantly require new blood.

mal treatment. However, there are no extensive studies on this in Brazil. We will evaluate patients who first undergo standard treatment with controlled, optimum doses, and then we will monitor the pressure to discover the percentage of resistant individuals. Then, we will randomize the resistant patients to determine the best medication for them, potentially one that will act on the central nervous system or the renin-angiotensin-aldosterone system.

This is translational medicine, which involves two aspects. The first aspect translates research results into clinical applications, whereas the second aspect transforms clinical findings into public health measures. This project will be concluded in a little over a year, and we

My most important research studies describe the action of pressoreceptors on hypertension

You are about to resign from your position as coordinator of the group at InCor. What are you planning to do?

I have two tasks to conclude.

One is a thematic project that should take another year or so. Specifically, we are trying to obtain biomarkers to assess patients’ therapeutic evolution and to see whether a patient responds or not to a given treatment. The other project, which is conducted under the Ministry of Health and the CNPq, is related to resistant hypertension. Specifically, 26 research centers and universities are participating in this project, which is designed to enumerate the percentage of the Brazilian population that is resistant to hypertension treatment.

Is there any hypothesis?

Yes. In developed countries, 20 to 30% of patients continue to have high blood pressure even when they receive opti12 | january 2013

have already recruited one thousand of the two thousand patients we need to conduct the project.

The concept of translational medicine was developed approximately 10 years ago...

The theme is new, but the idea of translational research is not that new, as it goes back to the 1940s. Silicon Valley was established in partnership with Stanford University during the war because of the need for military technology, which illustrates the speed at which knowledge moves from universities to the private sector. This was the beginning of a virtuous cycle, which resulted from the fast pace at which knowledge

was translated into application. However, medicine took a long time to accomplish this translation, and translational medicine became part of the medical field only 12 years ago. First, the Institute of Medicine of the US National Academy of Sciences began to discuss why clinical investigation did not advance at the same pace as basic, first-rate biomedical research. The NIH [National Institutes of Health] was concerned about this issue, and the matter moved forward when Elias Zerhouni became the president of the NIH. He prepared the so-called road map of the NIH that included three major areas: strategic topics that needed to be studied; multidisciplinary teams; and the re-engineering of clinical investigation or translational medicine. Zerhouni felt that an effort had to be made for clinical investigation to benefit public health.

A program was created to fund translational medicine centers at universities, and this program began in 2007 and 2008 with the participation of 10 or 12 universities; currently, 40 or 50 universities have benefitted from this program. The NIH intends to fund the management of university research projects, with the goal of establishing a center of integration at the university, especially in the field of health, to foster basic knowledge through interaction with other fields of study (physics, chemistry, information technology, etc.). In addition, the NIH hopes that clinical trials can be quickly translated into clinical practice and public health. I recently visited the University of Pennsylvania, which has an amazing translational medicine center.

So you decided to organize something similar in Brazil?

Yes, I have thought about this. InCor was created to be a translational center; it was based on the concept that clinical knowledge must be translated from the bench to the bedside. In addition, I decided that the time had come to introduce a field of study called ‘translational cardiology’. My objective was to help researchers conduct projects and

introduce innovations, one of the elements that permeate this field of medicine. A symposium on innovation was held at InCor, at which I spoke about the “Lei do Bem,” the federal and state laws that address innovation. I stressed the importance of setting up technological innovation departments at research and university centers. I am also helping the director to make the Medical School’s activities more international.

Tell us about your experience at the Brazilian Academy of Sciences.

I was part of the Academy for fourteen years. I became its chairman in 1993, and, in 1997 or 1998, the Academy was invited to join a federation of academies, namely, the Inter-Academy Panel/ IAP, which has nearly one hundred members. We had a meeting in Tokyo in 2000 at which the IAP’s by-laws were approved. I was elected chairman to represent developing countries, and my term lasted from 2000 to 2003. I also represented the ABC at the Interacademy Council, which is comprised of thirteen academies. These two organizations enabled the ABC to gain international exposure. I became acquainted with scientific politics, how the academies help each other, and the global issues that academies and researchers should be concerned about. It is important to emphasize that my term as president of the ABC coincided with the opportunity to participate in the national political world. José Israel Vargas had been appointed Minister of Science and Technology when he was vice president of the ABC, and he promoted the academy, which gained nationwide exposure. The SBPC was the dominant entity, but we were able to balance the game, and currently both entities are considered equally important, as they understand and help each other.

biochemistry that the time had come for the basic fields of biomedicine to create a national journal in English, as this field had grown considerably and many papers had already been written. We were contacted by the physiologist Alberto Carvalho da Silva and by the people from the CNPq concerning the hematologist Michel Jean, who had created the indexed Revista Brasileira de Pesquisas Metrobiológicas. They wanted us to become involved in the journal, but we wanted to promote a journal in English.

The solution was to change the name, and Michel told me the following: “I’ll pass the journal on to you to do whatever you see fit.” The CNPq supported the idea, and so that’s what we did. To make the journal feasible, we set up the

InCor was based on the idea that knowledge must be translated from the bench to the bedside

You helped to create the Brazilian Journal of Medical and Biological Research.

I was the chairman of the Brazilian Society of Physiology, and we had discussed with professionals from the field of

Brazilian Association for Science Dissemination (ABDC), which comprised the same societies that would subsequently (four or five years later) become part of the Federation of Experimental Biology Societies/Fesbe. We created an association that would act as the owner and publisher of the journal. I became chairman of the association and the editor of the journal, together with Sérgio Henrique Ferreira. I was also a member of FAPESP’s magazine committee.

I worked with librarian Rosali Duarte, who came from the Revista de Genética.

We realized that we had requests for journals, but we didn’t know what this meant. So, we prepared the first paper to be published in Brazil concerning the

qualification of journals. Thus, one of our papers contained the first classification of journals, but we had to do that to decide what the next step would be.

What was your most important achievement among all the accomplishments that you achieved in scientific politics?

My term as ABC chairman was my outstanding achievement, as this enabled Brazilian science to gain national and international recognition. Another achievement was the academy’s recognition as an advisory entity to the federal government. I am still a member of the National Science and Technology Council, which reports to the President, and I always insist that the council must function more efficiently. The foundation of FESBE was important as well, as was the creation of the Brazilian Society of Hypertension. I have always been a member of different associations because I have always worked in labs; I am a professor, a scientist and an activist. When we established the IAP, Bruce Alberts, who had been the chairman of the American Academy for 12 years, wrote an article that I really enjoyed reading. His thesis was that academies should become more activist.

A scientist’s social obligation is to make sure that science results in benefits for society, and my current effort is to view medicine with a focus on prevention, as prevention entails education.

Does your relationship with translational medicine reflect this concern?

It is the focus. We are scheduling an international conference on medical education to be held at the medical school.

We cannot train a physician who is knowledgeable about all fields of medicine but has no idea of primary care.

Medical students must learn how to prevent and cure diseases. We do not have enough financial resources to provide technologically sophisticated treatment, so we have to put disease prevention in the spotlight because this is much cheaper and has greater repercussions. This will enable people to enjoy good health for longer periods of time. n PESQUISA FAPESP | 13

cover

Opening up the

Earth Physicists detail the structures and transformations of minerals in regions deep inside the planet Carlos Fioravanti

illustrations drßm

Published in August 2012

G

oing to the Moon, which is almost 400,000 kilometers away, or sending satellites to explore other planets may seem harder than investigating the Earth’s interior. Earth is only 12,000 km in diameter, but boreholes have only reached 12 km deep, hardly penetrating the crust, the outer layer of the Earth just beneath the surface. Because scientists cannot directly examine the interior of the planet, they are using computer simulations to understand how minerals behave and transform in the deepest layers of the Earth, where pressures and temperatures are much higher than those on the surface. Computations have identified minerals formed thousands of kilometers below the surface, and there may be a volume of water larger than an ocean dispersed in the thick mass of rocks under our feet.

Brazilian physicist Renata Wentzcovitch, a professor at the University of Minnesota in the United States, is responsible for fundamental discoveries about the interior of the planet. Since 1990, she has been developing analytical and computational methods to model deep-Earth structure and processes, especially in the lower mantle, the largest layer of the Earth. The lower mantle is a 2,200 km thick layer and much less understood than the other layers of the mantle (see infographics below on the layers of the Earth’s interior). In 1993, she shed light on the atomic structure of perovskite at high pressures. Perovskite is the most abundant mineral in the lower mantle (~75% vol) and its properties are essentially responsible for the properties of this large layer still not well understood.

In 2004, Wentzcovitch and her team identified post-perovskite, a mineral that results from the transformation of perovskite under pressures thousands of times greater than those on the surface. Their results helped explain the speed of seismic waves throughout the

deepest part of the mantle. Seismic wave speeds depend on the density and elastic properties of rocks they travel through and three dimensional velocity maps are widely-used for investigating the nature of Earth’s interior. New studies

by Wentzcovitch and her team have now indicated that post-perovskite tends to break down into elementary oxides, such as magnesium oxide and silicon oxide when pressure and temperature increase way beyond those reached in the Earth’s interior, as those found in the interior of giant planets Jupiter, Saturn, Uranus, and Neptune.

“We have powerful computational tools for discovering the mineralogical make up of planetary interiors”, she says. According to Wentzcovitch, the techniques she pioneered can forecast the behavior of complex crystalline structures, such as those of silicate perovskite with 20 atoms per unit cell.

“The crystalline structure of minerals change with depth in the Earth’s mantle but its chemical composition seems to be uniform, except perhaps in the deepest regions of the mantle above the core mantle boundary.”

This kind of research helps us to understand how minerals deep in the Earth become denser and harder. Pressure and temperature increase with depth, so we expect the greatest density in the Earth’s center. Research has shown the Earth’s core is a layered mass of iron, the outer part being liquid while the inner is solid.

Temperatures in the core are close to 6,000°C and density there is almost 13 grams per cubic centimeter, twice greater than the density of iron on the surface.

Without resorting to fiction, physicists, geophysicists, and geochemists are opening up the planet and expanding our knowledge about the compacted, rocky region below 600 km. Laboratory experiments have helped us understand the upper layers, the upper mantle, down to 410 km depth, and the transition zone, from 410 km to ~ 660 km. However, much less is known about the Earth be-

low the transition region. Scientists are now making extensive use of computer simulations of rock properties, seismic wave propagation, and geodynamic flow in the Earth in addition to laboratory experiments and geological surveys to understand Earth’s interior structure and processes and perhaps one day predict surface processes such as earthquakes and tsunamis.

Submerged oceans

New facts are emerging that are calling into question the image of the interior of the planet as a sequence of regular, onion-like layers. In 2003, detailed global surveys began to show irregularities in the thickness of the crust. It varies between 20 and 68 km, leaving the thinner regions more subject to earthquakes and the thicker ones to collapse.

“We began to see the interaction of the crust and the region of the mantle closer to the surface,” commented geophysicist Walter Mooney of the United States Geological Survey (USGS) at the “Frontiers in Earth Science” meeting that was held in June at the University of São Paulo (USP). Geophysicists are reexamining the possible consequences of two phenomena that occur within the crust. The first is the diving of tectonic plates (movable and rigid pieces of the lithosphere, the surface layer that includes the outermost region of the mantle) into deeper regions of the mantle, increasing the risk of earth tremors in the regions where they occur. The data confirm the conclusions of a recent study coordinated

by Marcelo Assumpção, a professor at the Institute of Astronomy, Geophysics and Atmospheric Sciences (IAG) at USP. Assumpção, in collaboration with researchers from the University of Brasília, found that earth tremors in Brazil occur most frequently in regions where the crust and the lithosphere are thinner and, therefore, more fragile.

The entry of water into the lithosphere, below the crust, is another phenomenon being detailed. This phenomePESQUISA PESQUISA FAPESP FAPESP 198 | 15

non is intriguing: water cannot be stored in the lower crust because the pressure caused by the layers of rock and the temperature (almost 205°C) would cause the water to quickly evaporate. In fact, what is present in the Earth’s interior is not exactly water but the components of the water molecule—hydrogen and oxygen—linked to the crystalline structure of minerals in the form of H2O or OH. Mooney and his team detected an intense aquatic intromission in regions of the Andes, where the crust is as much as 65 km thick, but they were unable to explain why. Speaking to colleagues from various countries at USP, Mooney asked, “Where is this water stored? What is the volume of the water? Perhaps,” he noted, “the water comes from tectonic plates that sink or separate.” The specialists have determined that the lithosphere without water is geologically older, whereas the hydrated lithosphere is more recent, indicating that hydration may contribute to the formation or transformation of the outer layers or even of the deeper mantle, closer to the core.

Water molecules are important because, “even in minute proportions, such as 0.1%, they can change the viscosity of materials and therefore the view of the circulation of matter and energy in the interior of the Earth,” comments physicist João Francisco Justo Filho, a professor at USP’s Polytechnic School who has been working with Renata Wentzcovitch since 2007. “A great amount of water may be hidden in the lower mantle in minerals,” says geochemist Francis Albarède, from the Lyon École Normale Superieure, in France. “Perhaps the equivalent of a whole ocean,” he adds. Or “perhaps several oceans” ponders Wentzcovitch.

Using computational methods, she began to examine the possibilities of two atoms of hydrogen substituting for the magnesium linked to oxygen and forming units of H2O. “The more we looked, the more we found defects in the crystalline structures, where the hydrogen could enter,” she says. The problem is that it is not known how much hydrogen may be stored in the mantle.

Lower down, the uncertainties increase, given the impossibility of accurately measuring what happens at depths of 6,000 km. Little is known about the composition of the Earth’s core, which is so dense as to concentrate 16 | january 2013

The interior of the Earth may house a volume of water equivalent to several oceans that is present in the form of H2O molecules and OH ions dispersed in the midst of the mass of rocks 30% of the planet’s mass in two regions: one external, which is molten, and the other internal, which is solid and where the temperature may exceed 6,000°C. A team from University College London used the same conceptual approach as the group from Minnesota, density functional theory, to estimate the intensity of the heat flow that comes from the boundary region between the core and the mantle, based on the amount of iron, oxygen, sulfur and silicon as suggested by the speed of the seismic waves that cross the core and by the flow of heat from the lower mantle. The results, published in May in Nature, indicate that the heat flow that emanates from the core must be two or three times greater than previously estimated. Where this energy goes, no one can yet say.

Mineral decomposition

Many ongoing studies are concentrating on the mantle, a thick, solid, slightly flexible layer that deforms very slowly, like pitch. Only rarely, when magma emerges from volcanoes, bringing material from the mantle, are studies carried out indirectly, by monitoring the speed of the seismic waves, because it is difficult to directly study what happens in

the mantle. The Japanese want to beat the current 12 km drilling record and reach the mantle by using a ship with a drill similar to an oil drill. The mission, announced in July in New Scientist, will not be easy: the material for the drill bits to be used for drilling through the crust and reaching the mantle has to resist pressures 2,000 times greater than on the surface, as well as temperatures close to 900°C, a task similar to the plan to extract oil from the pre-salt layer off the coast of São Paulo.

“I cook rocks to understand how they were formed,” says geologist Guilherme Mallmann, a researcher from the Institute of Geosciences at USP, who has adopted another method for getting to know the interior of the planet better. He submits the chemical components that constitute the minerals to high pressures and temperatures in the laboratory. Furnaces and presses like the ones he uses, however, only allow him to reproduce phenomena that take place up to 150 km down, the region of the upper mantle in which the magma that sometimes emerges via volcanoes is formed. The pressure conditions at a greater depth in the Earth’s interior may also be achieved experimentally, according to Mallmann, but it is far more difficult. Because pressure is the result of the force on an area, the volume of material analyzed would have to be greatly reduced to achieve these extremely high pressures. “Producing greater pressures is often unfeasible.”

Perovskite, named in honor of Russian mineralogist Lev Perovski, is formed in environments under high pressures and temperatures, which in the lower mantle may vary from 23 to 135 gigapascals (1 gigapascal is approximately 10,000 times greater than the pressure on the Earth’s surface) and 2,000°C to 4,000°C, respectively. Wentzcovitch presented the crystalline structure of this mineral (a silicate of magnesium and iron) in 1993 in Physical Review Letters using green and yellow rhombuses reminiscent of the Brazilian flag. The reason was simple: “I miss the country,” says the researcher, who lives in the twin cities of Minneapolis-Saint Paul, which have 2.5 million inhabitants and are close to the border with Canada, where the temperatures in winter can remain at - 20°C for weeks at a time.

A press under our feet Minerals in the interior of the planet lose their elasticity and become denser as the pressure and temperature increase Crust

Crust

Depth 0 in km

Upper mantle

0

Approximate temperatures

re ssu Pre a p in C

600ºC

20

Transition zone

Upper mantle

1.300ºC

40 1.000

60 80

Lower mantle

Transition zone

100 2.000

D” region 3.000

3.500ºC

200

Outer core 4.000

Lower mantle

5.000

Outer core

300

Inner core

6.500ºC 6.000

Inner core

6.371

360

When the Earth shakes

Perovskite in transformation

Earthquakes generate two types of waves, P and S. P-waves cross the entire Earth, whereas S-waves die when they reach the outer core. The path of the wave depends on the properties of the materials it crosses

High pressures and temperatures modify the most abundant minerals in the lower mantle

P-waves S-waves

Epicenter

Pa

w av e

s

Magnesium

S

nd

P

an

d

e av Sw s

Oxygen (points of the octahedron)

Solid inner core

2

Molten outer core

closest to the core of giant planets in the Solar System

it ho ut Pw av es

W

re

ct re di ut e s ho av w P-

Mantle

Perovskite is transformed into post-perovskite in the Earth’s interior and eventually decomposes into simple oxides in the regions

105º

Shadow zone of P-waves

ct

Shadow zone of P-waves

it

Silicon (center of the octahedron)

0º

di

1

W

INFOGRAPHICS drüM images 1 Andrew Silver / USGS 2 Renata Wentzcovitch SOURCE University of york

D” region

14

Crust Without direct S-waves

PESQUISA FAPESP | 17

In collaboration with physicists from Italy and Brazil, Wentzcovitch found that the iron atoms of a mineral called ferropericlase, the second most abundant mineral in the lower mantle, lose one of their magnetism, thus explaining a phenomenon that has been observed in the laboratory. In 2007, João Justo worked in Minnesota with Wentzcovitch and developed a series of equations that establish the change in elastic properties and seismic speeds during the loss of magnetism in ferropericlase.

“The size of the iron atom decreases when it loses the magnetic moment, and this is what makes the ferropericlase denser. Furthermore, minerals with iron soften during the slow densification process, as has already been observed in the laboratory, but has not yet been explained,” says Justo. This is a surprising phenomenon because the material normally becomes harder as it becomes denser.

The results that he and Wentzcovitch obtained were published in 2009 in the journal PNAS. Their results explained the loss of magnetism under pressures and temperatures equivalent to those in the lower mantle, which James Badro, from the Universities of Paris 6 and 7, had detected in the laboratory and reported in Science in 2003 and 2004. Experimental verification of this phenomenon, one of the great discoveries of geophysics in the last few years, indicated that the proportion of non-magnetic iron may increase with depth. What is more, the deeper layers of the lower mantle may be even denser than the shallower layers.

The journey

As a child, Renata Wentzcovitch enjoyed the math tests that her grandfather, Adolfo Foffano, used to give her every day when they were together during her end-of-year vacations in Sumaré, in the State of São Paulo. She studied physics at the University of São Paulo and then began studying at the University of California at Berkeley in the United States in 1983, on the recommendation of José Roberto Leite and Cylon Gonçalves da Silva.

Wentzcovitch’s journey included a stay in Cambridge, in the UK, and London from 1990 until 1992 after she had broadened the applicability of her material simulation techniques. Her new 18 | january 2013

Views of the Earth Athanasius Kircher 1665

Hans Kramer 1902

Under very high pressures, iron atoms lose one of their remarkable characteristics, their magnetism, and become more compact

techniques were so general that they served to study the atomic movement and transformations of crystalline structures at high pressures and temperatures. To do this, she used so-called firstprinciples calculations, based on the density functional theory, whose essence is simple: the total energy of a group of electrons in their state of equilibrium depends on the total electron density.

Her hard work eventually paid off. “In less than a month, using my techniques, I’d solved the structure of magnesium silicate at high pressure, which researchers at Cambridge had been working on for two years,” she says. Solving a structure, she explains, “means identifying the position of equilibrium and the degrees of freedom of a crystalline structure with a certain symmetry that minimize the internal energy.” Until then, it was only possible to easily determine structures such as that of diamond, which is formed by two atoms at the base and has a de-

gree of freedom that is reflected in the distance between the carbon atoms. The structure of perovskite has 20 silicon, magnesium and oxygen atoms and 10 degrees of freedom. “It is much more complex than the structure of semiconductors, and that’s why its behavior at high pressures was unknown until then,” she says.

In the beginning, one of her problems was that she was unable to check her theoretical forecasts experimentally. However, in 2003, while working with researchers from the Tokyo Institute of Technology, Wentzcovitch and her team from Minnesota analyzed the spectrum of X-rays, which differed greatly from what was expected at very high pressures. They concluded that a phase transformation had occurred (or a change in the crystalline structure) to an unknown structure. “At first I didn’t believe it,” she says, “because perovskite seemed so stable!” The following year,

Bruce Bolt 1973

Adam Dziewonski 1990

mantle in the laboratory. They showed, by means of X-ray analyses, that partially molten rocks, when submitted to high temperatures and pressures, may move toward the surface of the Earth, giving rise to volcanic islands, such as those of Hawaii.

A more real Earth

an article in Science presented the new crystalline structure, christened postperovskite. Today, post-perovskite is recognized as the most abundant material in the region of the mantle known as D”, which is in contact with the outermost layer of the Earth’s core. “Postperovskite explains many geophysical characteristics of this region of the Earth,” observed Mallmann, from USP. Post-perovskite has a layered structure, through which seismic waves travel at speeds that depend on their initial direction. This work reinforced the conclusion of other studies that had indicated that this mineral could be formed at different depths in the lower mantle.

In a report published in Science on March 24, 2004, physicist Surendra Saxena, from the International University of Florida, challenged the conclusions and said that he still believed that perovskite decomposes only in those regions of the mantle closest to the core, and he reiterated that the theory was still not perfect.

Subsequent studies on the propagation of seismic waves, however, seem to confirm the presence of post-perovskite in region D”. “We’ve been very lucky,” Wentzcovitch commented. “The results of the computational calculations of speeds in post-perovskite are surprising because they reproduce many seismological observations of D” inexplicable until then.

It can’t be mere coincidence.”

It was also in 2004, when this work began to circulate, that Wentzcovitch received funding of US$ 3 million from

the National Science Foundation of the United States to assemble the Virtual Laboratory of Planetary and Earth Materials (VLab) at the Supercomputing Institute of the University of Minnesota. The VLab brought together chemists, physicists, computational scientists, geophysicists and mathematicians who, motivated by the possible existence of post-perovskite on other planets, began to look at the probable transformations that minerals could undergo at even higher pressures and temperatures inside the giant planets in the solar system (Jupiter, Saturn, Uranus and Neptune), which have masses at least 10 times greater than that of the Earth.

The results of her group, like those detailed in Science in 2006, presenting the probable transformations of magnesium silicate in the giant planets closest to Earth, indicated that these calculation techniques might be useful for studying the evolution of planets. “The behavior patterns of minerals on different planets cannot be just a coincidence,” she commented to an audience that listened attentively to her during the seminar at USP. Simulations of the behavior of materials at great depths and experimental studies, principally when they coincide, help clarify phenomena in the interior of the Earth. In July, French researchers announced that they had managed to re-create the environmental conditions at the limit of the outer core and lower

The new information about the interior of the planet is being used in the work of Brazilian research groups in basic geophysics at São Paulo, Rio de Janeiro, Rio Grande do Norte and the Federal District who are focusing on examining the Earth on a large scale. More broadly, this information is useful to the applied geophysics teams that are working with oil, mining and underground water in Bahia, Pará, Rio, São Paulo, Rio Grande do Norte, the Federal District and Rio Grande do Sul. Taken together, the results help construct a more solid picture of the Earth, which has been represented in many ways over the past few centuries. Knowledge of the structure of the Earth’s interior has greatly advanced since 1912, when German geophysicist Alfred Wegener concluded that the Earth is likely formed of rigid plates that move, and our understanding is moving increasingly farther away from the poetic images of Journey to the Center of the Earth, the magnificent work by French writer Jules Verne, published in 1864. “Today, we know that the center of the Earth, unlike the version described by Jules Verne,” Justo guarantees, “is absolutely mysterious and certainly uninhabitable.”

“But that’s no reason for our planet to be any less fascinating,” says Assumpção. n

The Project Simulation and modeling of minerals at high pressures no. 09/14082-3 Modality Thematic Project Coordinator João Francisco Justo Filho – USP Investment R$ 184,378.73

Scientific articles Wentzcovitch, R.M. et al. Ab initio molecular dynamics with variable cell shape: Application to MgSiO3. Physical Review Letters. v. 70, p. 3.94750. 1993.

Tsuchiya, T. et al. Phase transition in MgSiO3 perovskite in the earth’s lower mantle. Earth and Planetary Science Letters. v. 224, n. 3-4, p. 241.

2004.

Wentzcovitch, R.M. et al. Anomalous compressibility of ferropericlase throughout the iron spin crossover. PNAS. v. 106, p. 8.447-52. 2009.

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S&T Policy Scientific production y

Delicate balance Studies show that the structure of BRIC scientific communities increasingly resembles the structure of scientific disciplines in developed countries Fabrício Marques Published in August 2012

The evolution of the profile of disciplines in various countries The graph shows the fields of knowledge to which the 10 disciplines of greatest weight in each country belong, relative to the world, and the evolution of this profile between 1991 and 2009

%

1991 2009

Earth sciences; Environmental sciences and Energy

Mathematics, Physics, Chemistry, Engineering

Agriculture

Life sciences

100 90 80 70 60 50 40 30 20 10

SOURCE A comparison of disciplinary structures in science between the G7 and the BRIC countries, 2012

Ind ia

Ch ina

Ru ssi a

Bra zil

Jap an

Ca na da

Ita ly

Fra nc e

Ge rm an y

U Kin nited gd om

US A

0

H

ow can science and technology systems in emerging nations, such as Brazil, Russia, India and China (BRIC), be compared with those in developed countries, which have a more consolidated scientific community? A study conducted by a group of researchers from China and published on the web site of the journal Scientometrics shows that despite notable differences between the scientific structures of the so-called BRIC countries and the group of the world’s richest countries, the G7, the divide between the two blocs is decreasing. The work, whose main author is Li Ying Yang, from the National Library of the Chinese Academy of Sciences, analyzed how the scientific communities in these countries are distributed into disciplines and major fields of knowledge, using the scientific papers published by these communities as a parameter. Although scientific production from rich countries has a certain homogeneity and reflects an equilibrium among the various areas of knowledge, with life sciences leading, the BRIC countries have a more heterogeneous structure and lack a common identity, with physics, chemistry, mathematics and engineering as the dominant disciplines. The exception is Brazil, with a profile closer to that of the industrialized countries. However, this concentration has decreased over the past 20 years, with the BRIC countries becoming increasingly more balanced.

The index of inequality The Gini coefficient analyzes differences in performance among disciplines in each country. The lower the number, the greater the equilibrium among them; the higher the number, the greater the polarization 1991

2000

2009

0,647 0,517 0,388 0,258 0,129

Bra zil

Ind ia

Ru ssi a

Ch ina

Jap an

US A Un ite dK ing do m

0

SOURCE A comparison of disciplinary structures in science between the G7 and the BRIC countries, 2012

According to Yang, the decision to seek a balance between the disciplines or invest heavily in strategic areas is always complex and corresponds to the particular needs of each nation.

“The disciplinary structures of each country are influenced by cultural factors, political history and their geography. They are also affected by scientific and technological development,” the researcher observed. “Experience shows, however, that an asymmetric structure can harm sustained development in science and technology,” wrote Yang, referring to the importance of maintaining a scientific community interested in all fields of knowledge and prepared to face future scientific and technological challenges wherever they appear.

The Chinese group developed a methodology for comparing the structure of disciplines in science in the BRIC bloc and the G7. The papers published on Thomson Reuters’ Web of Science database in 1991, 2000 and 2009 furnished the raw material for the analysis. These papers were classified according to the list of more than 170 disciplines in the Journal Citation Reports, which is used to assess scientific journals. It should be made clear that the methodology uses just the number of papers and not the number of citations and/or impact factors. Its concern, therefore, is quantity, not quality. Likewise, it ignores the weight of international collaborations. Each paper is credited to just one country, the country of the corresponding author (the person responsible for submitting the work for publication).

Two parameters were used to develop an index for the analysis. First, the percentage of the number of papers from a country in each discipline relative to the total number of papers from the same country was determined. In addition, the percentage of papers in each discipline in the world relative to the total number of papers published worldwide was calculated. The ratio between these two parameters was used to define a standardized indicator, the Activity Index (AI), which measured the weight of each discipline in the country relative to the world and helped the researchers compare the disciplinary structures of the countries.

The paper contains interesting graphs, such as those that illustrate the opening of this report. In one of the graphs, the disciplines were regrouped into four major areas of knowledge: life sciences; agrarian sciences; earth, environment and energy sciences; and mathematics, physics, chemistry and pESQUISA FAPESP z 21

Different discipline profiles In the distribution of scientific articles by discipline, the United States and England have equivalent profiles, which differ, however, from the other countries in Europe, or the bloc formed by Argentina, Mexico and Brazil 26

Papers (%)

24 USA England

22 20

F

18 16 14 12 10 8 6 4 2 0

18

Papers (%)

16

Argentina Brazil Mexico

14 12 10 8 6 4 2 0

Papers (%) France Italy Spain Germany Belgium Austria Switzerland

Cli nic al me d Bio Ch icine em log ist ya ry nd bio Phys ics ch e En mist gin ry S Ne Bo ocia eeri l sc ng Mo uro tan y ie sc lec ula ienc and z nces ea rb o iol nd olog o Ps yc gy a beha y hia n v try d ge ior n /P syc etics En ho vir on Geos logy me cie n n t M / E ces Ec on ate ria colo om gy l s ics an scien db c Co us e M mp in uta athe ess ma tio na t l s ics Im cien mu ce Sp Ph ac nolo arm es gy ac olo Mi cien ce cro gy s Ag and biolo ric t ult oxic gy olo ura gy Mu l sc ltid ien ce isc s ipl ina ry

32 30 28 26 24 22 20 18 16 14 12 10 8 6 4 2 0

engineering. The 10 most prominent disciplines in each country, those that had the highest Activity Index, were evaluated. Although its disciplinary structure is considered to be balanced, the United States had just a single color graph – all 10 disciplines with the greatest weight were from the life sciences, such as medicine and biology. In China and India, however, the 10 disciplines belonged to the fields of mathematics, physics, chemistry and engineering. Brazil had seven disciplines in life sciences, one in mathematics, physics, chemistry and engineering, and two in agrarian sciences.

SOURCE Normalized country profiles (CPI) Revisiting country research profiles: learning about the scientific cultures – 2012

22 z january 2013

inally, the Gini coefficient for each country was calculated from the distribution of the weight of the disciplines, as measured by the AI. The Gini coefficient is used to measure inequality. If it is lower than 0.3, the authors consider that the discipline structure is balanced. If it exceeds 0.4, they consider that the structure is asymmetric and polarized. The evolution of the Gini coefficient between 1991 and 2009 was able to show clearly how each country is changing.

The BRIC countries are in the process of reducing concentration and seeking equilibrium. Brazil, for example, had a coefficient of 0.568 in 1991, an indication of a polarized structure, but this index decreased to 0.389 in 2009, an indication of equilibrium. A similar trend was found for India, a decrease from 0.471 to 0.360, and for China, a decrease from 0.568 to 0.395. Russia was the great exception. The Gini coefficient has remained at approximately 0.64 since 1991. Investment in disciplines in the fields of mathematics, physics, chemistry and engineering, which dates to the Cold War era, is still prevalent. The United States increased its Gini coefficient slightly, from 0.182 in 1991 to 0.229 in 2009. In France, inequality decreased – the coefficient changed from 0.297 to 0.158. “The developed world is standing still, while we’re changing,” says Hernan Chaimovich, vice president of the Brazilian Academy of Sciences, a retired professor of the Chemistry Institute of the University of São Paulo and an adviser to FAPESP’s Scientific Department.

If the equilibrium trend among these areas of knowledge is encouraging, the data motivate a discussion of the desirability of particular varieties of fine tuning among the disciplines, although a model that proves successful for one country is not necessarily suitable for another nation. “In the United States, there’s fierce debate about the disciplines’ relative loss of space over the last few years in the field of engineering, including a drop in the number of undergraduate students, but it’s impossible to say that this discussion applies to other countries,” says Rogério Meneghini, scientific coordinator of the SciELO electronic library. In the case of Brazil,

a lack of engineers is already being identified as an obstacle to sustained economic growth (see Pesquisa FAPESP 149). According to Meneghini, unlike the other BRIC nations, Brazil has a tradition in life science disciplines. “This goes back to the start of the 20th century, with great scientists such as Carlos Chagas and Oswaldo Cruz, who were heavily influenced by research that was being done in Europe. But China, India and Russia did not come under this influence,” he says.

He mentions the example of genetics studies in the former Soviet Union, which were stifled for a substantial part of the past century due to the influence in the country of the Ukrainian biologist Trofim Lysenko (1898-1976), who would have nothing to do with Mendelian genetics.

For Hernan Chaimovich, the debate about this fine-tuning in Brazil is relevant but still secondary. “The number of scientists in the country is still small when compared with the average number in developed countries.

We need to increase the number of scientists in all areas,” he says. The fundamental question, according to Chaimovich, is that the quality of According to Brazilian research is not increasing Hernan in the same proportion as scientific production. “Quantity and qualChaimovich, the ity need to grow together. We have to create strategies that favor this,” key issue is that says the professor, who cites as an example FAPESP’s strategy for enthe quality of couraging the internationalization Brazilian research of Brazilian science by funding research projects in collaboration with has not grown as institutions from other countries.

Although developed countries fast as scientific have a more consolidated structure, it is a mistake to imagine that production they form a monolith. Another study published online in the same journal, Scientometrics, in March and authored by Peter Schulz and Edmilson Manganote, professors from the Gleb Wataghin Physics Institute at the State University of Campinas (UNICAMP), shows that the so-called “Western model,” in which there is a predominance of medical and biomedical research, has in fact a series of nuances. The United States and United Kingdom, in fact, have a very similar pattern, with medicine representing one-quarter of their scientific production, but the distribution is different in countries in continental Europe, with a slightly greater share in physics and chemistry and with medicine varying between 18% (Spain) and 30% (Austria). “The Western model is clearly divided into two sub-groups,” says Peter Schulz.

T

he researchers from UNICAMP based their analysis on the profiles of countries, as published by Science Watch, from Thomson Reuters, which ranked the accumulated scientific production of each country (including citations) for approximately 10 years in the 22 main fields of knowledge. Based on these data, the Brazilians proposed a new indicator, the country profile index (CPI), also with the objective of comparing the disciplinary structure of countries. “The article by the Chinese uses a more sophisticated methodology. In our case, we initially used open data, because we were thinking of creating an analysis tool aimed at an audience that is not very specialized in scientometrics, but that would be an important agent in decision-making in the scientific territory,” explains Schulz. The CPI also shows the heterogeneity of the profile of the BRIC countries and indicates that the profile of publications in Brazil is similar to that of Argentina and Mexico, with a predominance of clinical medicine, chemistry, physics, botany and zoology, and with the agrarian sciences occupying a greater space than the world average (4% of the total Brazilian production). South Korea, Taiwan and Japan form another clearly defined bloc, with a prominent role for engineering (see graphs). “Disciplinary structure can be correlated with the economic development strategies in each country, as we briefly indicated in the case of the Asian tigers and the BRIC countries,” says Schulz.

Both the Chinese and the Brazilian studies suggest a change in the profile of disciplines in Brazil, bringing it ever closer to the Western model.

Manganote from UNICAMP warns about a bias in these data, the recent inclusion of several Brazilian scientific publications on the Web of Science database. There were just 26 Brazilian journals on this database in 2006. Today, there are more than 100. “The spectrum of indexed Brazilian publications on the WoS database expanded after 2007. But this group certainly doesn’t yet correspond to the Brazilian reality. Some areas, like the agrarian sciences, business and economics, are probably still concealed by the incompleteness of the basis used,” he says, referring to Brazilian production that is still not indexed internationally.

Another important bias, say the researchers from UNICAMP, concerns the low weight of human and social sciences in the disciplinary structure in various countries, including European countries. This is a result of the reality that scientific production in these areas is not represented in journals indexed on Web of Science but in regional publications and in books. “In our paper, we discuss how the WoS database doesn’t provide an entirely true picture of the disciplinary structure of a country,” says Peter Schulz. n

pESQUISA FAPESP z 23

investment y

One country, two models State expenditures on research and development reveal the gap between São Paulo and the other Brazilian states Fabrício Marques

B

razilian states have made increasing investments in research and development (R&D) in recent years. However, São Paulo continues to make more substantial investments of this type, consistently spending significant sums on R&D in its three state universities. In contrast, the other states have university systems that are less developed and are sustained by modest investments. A survey published by the Ministry of Science, Technology and Innovation (MSTI) that assesses R&D in Brazil based on national science and technology indicators reveals this gap. This data compilation compared the states’ expenditures on R&D by their respective higher education institutions. Of the R$ 4.5 billion invested in this area by the Brazilian states in 2010, almost R$ 3.9 billion, or 86% of the total, was provided

by São Paulo. “São Paulo is a state that invests a lot in science and technology relative to the rest of the country,” observes Marco Antonio Zago, the Dean of Research at the University of São Paulo (USP). “This is the result of a state policy that started a long time ago and not the strategy of one governor,” he adds. Rio de Janeiro ranks second after São Paulo, with state expenditure of approximately R$ 208 million on R&D by higher 24 z january 2013

education institutions in 2010. Paraná (R$ 183 million), Bahia (R$ 68 million), and Santa Catarina (R$ 46.9 million) are ranked third, fourth, and fifth, respectively.

A total of 9.57% of the state tax on goods and services (ICMS) collected in São Paulo is used to maintain the state’s three universities. These funds are distributed proportionally to the size of the institutions. Thus, 2.344% are distributed to Paulista State University (Unesp), 2.195% to the State University of Campinas (Unicamp) and 5.029% to USP. “These funds, which are managed autonomously, guarantee a very strong base for the state universities, providing quality laboratories, teachers who work full time for the universities, and research technicians,” says Zago.

However, Zago has one reservation: “Although money is distributed according to the size of the institution and not in a competitive way, FAPESP funds, invested in research projects and scholarships, fulfill this purpose. Researchers have to submit their projects and they’re assessed. And it’s only quality projects that are considered,” says the Dean. In 2010, FAPESP disbursed R$ 780 million in research projects, awarding just over R$ 100 million more than was disbursed in 2009.

According to the MCTI indicators, USP (the

illustrations pedro hamdan infographics ana paula campos

Published in September 2012

State investment in R&D Estimated 2010 expenditure on research and development (R&D) conducted by state institutions of higher education Southeast

1

4,1 millions

By region (in R$) North

11,5 millions

Northeast

149 millions

Midwest

12,7 millions South

230 millions

2

By state (in millions R$) SP

3.885

3

RJ

In the state of São Paulo (in R$)

208

Pr

183

uSP

2,2 billions

MT

AM

go

8,5

6,6

PA

MA

unicamP

ce

1

4,8 3,7 42,6

1,4

billion

rn

5,6

pb

uneSP

13,1

655

millions

pe

15,7

famerp*

7,7

ba

68,4

millions

mg

ms

10,2

2,8 sc

46,9

*School of Medicine of São José do Rio Preto

The contribution of São Paulo Brazil

Evolution of R&D spending by state higher education institutions (in billions R$)

4,5 billions

3,6 3,0

1,5 1,4 2000

1,7 1,6

2001

1,9 1,8

2002

2,0

São Paulo 3,8 billions

3,1

3,1

2008

2009

2,6 1,8

1,9 1,6

2003

3,7

2004

1,9 1,7

2005

2,0 1,7

2006

2007

2010

Source National Science and Technology Indicators/MCTI

pESQUISA FAPESP z 25

highest ranked Latin American university in the international rankings) received almost half of the funds invested in R&D within the state’s university systems. In 2010, this percentage amounted to R$ 2.2 billion in funding. Unicamp received R$ 1 billion, and Unesp received R$ 655 million. The School of Medicine in São José do Rio Preto also appears in the MCTI table, with R$ 7.7 million invested in 2010. The MCTI data reflect spending on postgraduate study, which is the most research-oriented university activity. The MCTI calculates the ratio of the funds used by the institution in question to the number of teachers involved in postgraduate work. The funds allocated to technicians, facility maintenance and pensions are omitted from the Ministry’s calculations because these are not considered to be R&D expenditures. According to the Organization for Economic Cooperation and Development (OECD), the term R&D “refers to the creative work carried out systematically with the objective of increasing the stock of knowledge and using it to develop new applications.” R&D expenditure is the funding invested in science and technology to support basic and applied research, which thereby helps to provide countries with the skills that they require for innovation.

Continuity

The Dean of Research at Unesp, Maria José Giannini, observes that one of the advantages of the São Paulo model is its continuity and dependability. “Obviously, there are many highly competent researchers in federal universities, but it’s common for their work to suffer the impact of research funding restrictions. In state universities, we have ample conditions for encouraging researchers to present projects and look for funds because FAPESP always favors those who have merit,” she says. According to data from Unesp, in the last four years, the number of regular and thematic projects approved by the FAPESP was twice the number approved in the previous fouryear period. The Studies and Projects Funding Agency (Finep) increased the funding it awarded by 230% during this four-year period.

Ronaldo Pilli, the Dean of Research at Unicamp, emphasizes that São Paulo’s state universities have played an important role in providing individuals with funding that would help to ensure the development of the country. “It comes as no surprise that the numbers show a predominance of investments in São Paulo. But an increase in corporate participation in the R&D sector would be welcome, because we have a human resource base to offer,” he says.

Even so, São Paulo is a unique case: a Brazilian state in which the R&D investment by com26 z january 2013

International overview Total expenditure on R&D relative to GDP – Brazil, São Paulo State and selected countries – 2010 or most recent year Israel South Korea United States Germany Total OECD United Kingdom China São Paulo Spain Brazil South Africa Argentina

0

0,5

Source OECD, MCTI, FAPESP Indicators

1

1,5

2

2,5

3

3,5

4

4,5 % GDP

panies exceeds the public investment (the former comprises 62% of the total according to the report Various states Science, Technology & Innovation have expanded Indicators in the State of São Paulo, which was published in 2011 by their FAPESP). Likewise, the state-level public expenditure on R&D in investment in São Paulo, which amounted to R$ 3.7 billion in 2008, exceeds that of science and the federal government in the state technology in (which totaled R$ 2 billion during that same year). This breakdown is the recent past very different from that of Brazil as a whole, where the federal investments in R&D account for most of the funding (see the table on the opposite page).

Regarding Unicamp, Pilli highlights the role of FAPESP, which is responsible for 40% of the research funds received by the university. “We increased fund-raising for research from R$ 220 million in 2007 to R$ 350 million in 2011. The funds from the Foundation grew from R$ 80 million in 2007 to R$ 131 million last year. In the same year, CNPq funding fell and those from Capes grew from R$ 52 million to R$ 61 million,” he notes.

Although the R&D investment in São Paulo may appear most impressive, several other states have recently expanded their investments in science and technology. In 2008, Rio de Janeiro increased the share of taxes that is earmarked for the State Research Funding Agency (Faperj) to 2%. “With this, and also thanks to the increase in state tax collection, Faperj’s budget jumped from R$ 100 million to R$ 300 million,” says the

way. And Faperj invests a substantial part of its resources in federal university projects. We’ve only got one public bid notice, directed at equipping laboratories, which is only open to state universities,” says the secretary. He notes that the Rio state university system has been shaped by its history. “Rio de Janeiro was the country’s capital for 200 years and various universities were created by the federal government. Other research institutions with a great tradition also arose in Rio, like the Oswaldo Cruz Foundation. In São Paulo, on the other hand, growth of the research system deIn the state of São Paulo, pended on the effort of the corporate R&D investment exceeds state and as it grew economically, state universipublic investment in this area ties became consolidated,” he explains.

The development trajectory of the universiteaching faculty at Uerj – approximately 1,800 ties in Minas Gerais was similar to that of the – is similar to that of Unicamp, although the universities in Rio. In 2010, the state invested number of graduate students (2,800) is a tenth R$ 10.2 million in R&D at two institutions: the of that of Campinas University. “With the in- State University of Minas Gerais (Uemg) and crease in state tax collection, there has been an the State University of Montes Claros (Unimoneffort to recover the capacity of state universi- tes). This amount, though modest, was more ties,” explains Leite. than triple the R$ 2.9 million that was invested in 2007. The State Secretary of Science, Technology and Higher Education of Minas Gerais, Federal universities Most of the public universities in Rio de Janeiro Narcio Rodrigues, explains that this increase is are federal. These include the Federal University the result of the government’s 2007 decision to of Rio de Janeiro (UFRJ), the Fluminense Federal enforce the legal rule requiring that 1% of the University (UFF), the Federal Rural University of taxes collected in the state be invested in science Rio de Janeiro (UFRRJ) and the Federal Univer- via the Research Funding Agency of Minas Gerais sity of the State of Rio (Unirio). “But the federal (Fapemig). Rodrigues explains, “Our strategy has and state universities operate in an articulated been to guarantee that there’s no going back on complying with this norm and to leverage the funds by partnering with the federal government and private initiative, which contribute Federal and state R&D expenditure equivalent amounts.” He notes that there are only two state universities because in the past, Breakdown of government R&D expenditure in the state of São Paulo, the task of promoting the Minas Gerais univerin Brazil, and in Brazil excluding the state of São Paulo – in % sity system fell to the federal government. “Our 100 n Federal system has 14 higher education institutions, 12 n State of which are federal, but we function as an ar80 ticulated system,” he says. The largest of these institutions is the Federal University of Minas Gerais (UFMG). “Our universities work heavily 60 in regional development. Unimontes, which is the main state institution, is pretty active in the 40 poorest region in Minas Gerais. This regionalized system is important for the development 20 of the state, but of course, the ideal thing would be to mix it with the current system in São Pau0 lo, where the state government took over the São Paulo Brazil Brazil excluding mission of promoting higher education and has São Paulo consolidated institutions that have nationwide influence,” says Rodrigues. n State Secretary of Science and Technology, Luiz Edmundo Costa Leite. According to the MCTI survey, R&D funding by the Rio government for its two universities, the Norte Fluminense State University (Uenf ) and the State University of Rio de Janeiro (Uerj), was R$ 208 million in 2010, more than double the R$ 100 million that was made available in 2005. Uerj was better funded in 2010, having received two thirds of the amount that was spent during that year. The number of

Source Science, Technology and Innovation Indicators in São Paulo, 2010

pESQUISA FAPESP z 27

Recognition y

Intellectual references International awards, such as the one granted to Fernando Henrique Cardoso, enhance the reputation of Brazil’s scientific community Fabrício Marques Published in August 2012

O

n July 10, the U.S. Library of Congress awarded the John W. Kluge Prize to sociologist Fernando Henrique Cardoso, 81, former president of Brazil. The US$ 1 million award recognizes the work of scholars in fields that are not included in the Nobel Prize categories, including history, philosophy, political science, psychology, anthropology, and philosophy. “I am deeply moved by how unexpected this honor was. I am the first Brazilian – and the first Latin American – to receive the Kluge Prize. This is a true privilege,” Cardoso said in his acceptance speech. “There was a time, not so long ago, when such an honor would have been difficult to imagine. I spent a portion of my academic career studying the relationship between the wealthy core of countries in Western Europe and North America and what was then known as the ‘periphery’ – countries such as Brazil that were distant, economically and geographically. This division between rich and poor seemed immutable,” he said.

Professor Emeritus of the University of São Paulo (USP), Fernando Henrique Cardoso was president of Brazil from 1995 to 2002. He was previously a senator (1983 to 1992), Minister of Foreign Relations (1992) and Minister of Finance (1993 to 1994). Historian James H. Billington, U.S. Librarian of Congress since 1987, highlighted the importance of the Brazilian sociologist’s work. “Former President Cardoso is an example of the modern researcher who combines deep knowledge and empirical evidence,” he said. “His basic aspiration is to seek the truth about society and to keep an open mind to re-

28 z january 2013

photos 1 library of congress 2 and 3 wikimedia commons

1

Fernando Henrique Cardoso is congratulated by historian James Billington on receiving the John Kluge Award in Washington, D.C. On the side and below, the U.S. Library of Congress, which grants the US$ 1 million award

3

2

pESQUISA FAPESP z 29

state his conclusions when new evidence arises.” The Library of Congress’ Kluge Center manages the Kluge Prize. An endowment from businessman John Kluge (1914-2010) established the center with the objective of “fostering an enriching relaPhysicist José tionship between the world Goldemberg of ideas and the world of action, between scholars and received the political leaders.”

Ac c o rd i n g t o a n a n Blue Planet nouncement made by the Library of Congress, FernanPrize, do Henrique Cardoso was considered the nominated for the award for his contributions as a sociNobel Prize for ologist and an intellectual, which provided the foundaenvironmental tion for his political leadership. “His academic analysis science of the government’s social structures, the economy and racial relationships in Brazil established the intellectual basis for scribed a far more complex and dynamic his leadership as president. During his world,” Cardoso said. “Starting with the presidency, he transformed Brazil from economic analysis of Argentine econoa military dictatorship into a vibrant, mist Raúl Prebisch and other thinkers more inclusive democracy with strong from the Economic Commission for Latin economic growth,” the announcement America (ECLA), we realized that the pesaid. The Library of Congress empha- riphery was far from being homogeneous sized the “enormous intellectual ener- and static. We focused on the historical gy” of Brazil’s former president, who au- formation of the social classes and the thored or co-authored more than 23 aca- state as well as on the different relationdemic books and 116 scientific articles. ships with the world market.” According “He became internationally renowned to the former president, these differences for the innovative analysis, developed paved the way for alternative forms of together with Chile’s Enzo Faletto, of economic and social development. “In the best alternatives for development,” other words, the poor countries were not the Library’s announcement said. The condemned to permanent backwardness book he wrote with Faletto, Dependên- but challenged to find suitable ways to cia e Desenvolvimento na América Latina overcome structural barriers. This seems [Dependency and Development in Latin evident today but was considered heretiAmerica], was published in 1969. cal at the time. We were among the first people to talk about the globalization of domestic markets,” he said in his speech.

“Heretical at the time” Cardoso and Faletto emphasized the Since the Kluge Prize was first awardrole of domestic factors in explaining ed in 2003, laureates have included U.S. the structural processes of dependency. historian Jaroslav Pelikan (1923-2006), Their objective was to demonstrate how French philosopher Paul Ricoeur (1913different forms of networking between 2005) and Polish philosopher Kolakowsnational economies and the international ki (1927-2009). Renowned scholars from system indicate distinct forms of inte- Brazil’s academic and research commugration with the hegemonic elements of nities have recently received other intercapitalism. “Working with my colleague national awards in recognition of their Enzo Faletto, we wrote a book that de- achievements. For example, physicist Jo30 z january 2013

sé Goldemberg received the Blue Planet Prize from Japan’s Asahi Glass Foundation in 2008. Blue Planet Prize laureates receive 50 million yen (equivalent to R$ 800,000) for “outstanding contributions to the formulation and implementation of diverse policies associated with improvements in the use and conservation of energy.” The award made special mention of a concept Goldenberg devised that eliminated the need for poor countries to follow the technological paradigms for development previously used by wealthy countries.

Created in 1992 and regarded as equivalent to the Nobel Prize in the field of environmental studies, the Blue Planet Prize has rewarded contributions by researchers such as Great Britain’s James Lovelock, whose Gaia hypothesis posits that the Earth is a huge living organism.

The most recent recipients, including Thomas Lovejoy, the biologist who introduced the word “biodiversity” to the scientific community, were announced at the Rio+20 Summit.

In 2006, architect and urban planner Paulo Mendes da Rocha, 82, was the second Brazilian to receive the Pritzker Prize, the world’s foremost architecture award.

“His signature architectural projects in concrete, as well as his intelligent and re-

photos Miguel Boyayan

In 2006, architect Paulo Mendes da Rocha received the Pritzker Prize, the most important prize for architecture markably direct methods of construction have resulted in powerful buildings of international renown,” the Pritzker Prize’s panel of judges said. The architecture of Paulo Mendes da Rocha is an example of the thinking that characterizes the São Paulo state style of Brazilian architecture.

The school’s primary proponent was João Batista Vilanova Artigas, and it is associated with the University of São Paulo’s Architecture and Urbanism College (FAU), where Mendes da Rocha taught. The São Paulo school of architecture focuses on fostering “raw, clean, clear and socially responsible” architecture.

In the opinion of sociologist Simon Schwartzman, a scholar who studies the Brazilian scientific community and works as a researcher at the Institute for Studies on Labor and Society (IETS), the international recognition granted to such prominent Brazilians as Fernando Henrique Cardoso, Goldemberg and Mendes da Rocha is significant for Brazilian science. “In addition to the prestige and national pride resulting from such awards, they help to enhance the reputation that Brazil has competent people who work or worked at high level institutions. This has enabled them to participate on an equal basis in the exchange of knowledge and to host international students

and scholars,” said Schwartzman, who emphasizes the academic background of the three researchers. “They were professors at the University of São Paulo, considered the best university in Latin America, and one of the few Latin American universities to be ranked in international rankings of academic excellence,” he said. “But we’re still missing a Nobel Prize laureate.”

National pride

There are examples of laureates who have inspired future generations after being granted scientific and academic awards, said science historian and USP Professor Shozo Motoyama. One of these was theoretical physicist Hideki Yukawa, Japan’s first Nobel Prize winner for physics in 1949. “The prize raised the self-esteem of a country that had been devastated by war and encouraged young Japanese students to dedicate themselves to a scientific career, which produced excellent results,” Motoyama said.

Another example is Denmark’s Niels Bohr, the 1922 Nobel laureate in physics. “The prize was a source of pride for tiny Denmark. Niels Bohr founded the Institute for Theoretical Physics at the University of Copenhagen, a venue not only for talented young Danish physi-

cists but also for physicists from all over the world who went there to conduct their research,” Motoyama added.

“I think these awards mean a lot to Brazilian society, a nation with no scientific tradition. In a globalized, networking world, the search for an identity—whether an individual one or a national, community, religious, or any other identity—entails the creation of references, also referred to as myths, that leverage a nation’s culture,” Motoyama said.

José Goldemberg claimed that many prominent Brazilian scientists possessed the credentials to be Nobel Prize laureates, such as Carlos Chagas (1878-1934), who discovered the protozoa that causes Chagas disease, and Maurício da Rocha e Silva (1910-1983), who discovered bradykinin, a chemical used to treat high blood pressure.

“The Nobel Prize selection is unfair in relation to contributions from the peripheral countries,” Goldemberg said.

“Jorge Amado was a much more important writer than many laureates of the Nobel Prize for Literature.” Goldemberg noted that the Nobel Prize was created in the early twentieth century and was based on the structure of disciplines at that time, recognizing achievements in physics, chemistry, medicine and physiology. “In fact, the Nobel Peace Prize and the Nobel Prize for Economics were not contemplated in the will left by Alfred Nobel, who died in 1896; they were created after Nobel’s death,” he said.

The Blue Planet Prize that Goldemberg received is akin to a Nobel Prize for ecology, a field that scientists did not acknowledge in 1901. “This is a renowned award, and I was quite upset because not much was said in Brazil about the fact that I was granted it. The award granted to Fernando Henrique Cardoso, which he really deserved, restored my pride because many of us have made significant contributions. The former president is an example of an intellectual who contributed greatly towards solving the problems of society,” Goldemberg said. n pESQUISA FAPESP z 31

science Mental Diseases y

Storms of the body and soul Crises of depression and euphoria cause chemical imbalances that may damage cells and accelerate aging of the body Ricardo Zorzetto

Illustrations EDUARDO SANCINETTI

Published in July 2012

S

ince 2009, psychiatrist Rodrigo Bressan and other researchers from the Federal University of São Paulo (Unifesp) have been monitoring a group of teenagers with a high risk of developing serious mental diseases, such as bipolar disorder and schizophrenia. These scientists would like to discover the appropriate moment to act before disease manifests itself and thus try to prevent these disease symptoms from becoming established. At the same time, they are trying to teach the teenagers and their families how to address stressful situations, which may trigger crises.

Bressan and psychiatrists Elisa Brietzke and Ary Araripe Neto are tirelessly working to determine whether anti-inflammatory, antioxidant or neurotrophic compounds might protect brain cells and possibly reduce the risk of developing these mental diseases.

The strategy for protecting the brain with these and other compounds is based on the hypothesis that neurons and other brain cells suffer gradual damage from the initial onset of The idea that a disease episode, and bipolar disorder some researchers even suspect that the damage and depression may begin before these events are observed. Reworsen with cent studies indicate that in these disturbances the every attack may brain produces harmful indicate the need levels of certain compounds that upset the for early diagnosis functioning of cells and may cause irreparable and intervention damage if they are left to persist, leading to a deterioration of the capacity to reason, plan and learn and even to permanent changes in mood. Further- body. These crises are like chemical storms that more, as the concentration of these substances unsettle the equilibrium of the brain microenviincreases, there is also a drop in the level of nat- ronment and release compounds that are carried urally produced neuroprotective compounds. via the blood throughout the body, occasionally One of the researchers who helped to develop leading to a degree of intoxication almost as sethis hypothesis is the psychiatrist Flávio Kapcz- rious as that in individuals with a generalized inski, a professor from the Federal University of infection (sepsis). Repeated over years or even Rio Grande do Sul (UFRGS) and coordinator of decades, these toxic avalanches, precipitated by the National Institute of Science and Technol- outbreaks of depression or mania, produce slow ogy in Transactional Medicine. He is convinced and progressive wear in the brain and the entire that the dramatic evolution of serious cases of body, thereby reducing the capacity for recovery bipolar disorder and depression is the conse- and accelerating the aging process. quence of physiological alterations caused by Kapczinski began to prepare this theoretical the recurring crises. model based on experiments carried out by his Kapczinski believes that the crises that from team and by other groups that aimed to explain time to time plague the mind also intoxicate the how and why depression and bipolar disorder, 34 z january 2013

once established and not appropriately treated, follow a pattern of progressive deterioration that may culminate in early death due to cardiovascular problems and even cancer. According to the model, other diseases that apparently have nothing to do with what is happening in the brain might evolve as a result of these organic imbalances generated by severe episodes of depression and mania.

Initially presented in 2008 in Neuroscience and Behavioral Reviews, this hypothesis has gained international recognition. In the last year, Kapczinski’s studies have been cited approximately one thousand times in other works. Australian psychiatrist Michael Berk, from the University of Melbourne, has been keeping track of this research and, with Kapczinski, has called this new model “neuroprogression.”

“We know that these disorders are progressive, and this theoretical proposal explains why,” says Berk. According to him, the interpretation that these diseases become worse with each additional attack may have a major impact on treatment because it indicates the need for diagnosis and early intervention and because it suggests that neuroprotective therapies may alleviate these negative effects.

“The idea has been launched,” says Kapczinski. “Now, one can work to try to confirm or refute it.” He knows that the model is bold and that it is necessary to gather more evidence to show that it represents the evolution of depression and bipolar disorder in an appropriate way.

“We have enough work for the next two decades,” says the researcher from UFRGS. concePT AND REALITY

Poisoned body The graph below shows the average levels of toxic compounds in the blood that, in bouts of mania or depression, are increased in healthy or treated people and lower in people with sepsis

Toxicity index

Source Kapczinski et al. /Molecular Psychiatry 2010

2.0

1.0

0.0

-1.0

Healthy

Treated

Mania

Depression

Sepsis

According to some specialists, the concept of neuroprogression explains the clinical symptoms well, but one can question whether these biological alterations do in fact occur, as the evidence in support of this theory remains at an early stage.

Brain images of patients indicate that there is a general reduction in the volume of some brain areas. But, most of the time, these images have been taken of the brains of patients of different ages who have suffered different quantities of mania and depression attacks. More consistent proof would require monitoring patients for several years and regularly examining them to assess the evolution of the problem.

Although it is far from being proven, this proposal is opening the way for a search for more specific and efficient therapies and for the development of strategies that enable the early identification of people at risk for developing these problems, as the team from Unifesp has been doing.

If this model is correct, it might help us to understand how a disease that first presents relapESQUISA FAPESP z 35

tively benign clinical symptoms can, in just a few years, lead to deterioration in the capacity to reason, plan and learn, as well as a permanent alteration in mood. Furthermore, these symptoms often escalate and prevent patients from leading a normal life, as Kapczinski and other doctors have frequently observed.

“This is one of the multiple progression mechanisms of the disease,” says American psychiatrist Robert Post, an international authority on bipolar disturbance. “The clearest evidence [of what may be going on] is that the number of preceding episodes of depression or mania is related to the degree of cognitive dysfunction,” says Post, with whom Kapczinski has been collaborating since 2008.

In an article published in May of this year in the Journal of Psychiatric Research, Post, Kapczinski and Jaclyn Fleming analyzed almost 200 pieces of work and found evidence that as cognitive dysfunction increases, changes in some regions of the brain intensify and treatment loses its efficiency as the number of crises and the duration of the disease increase. In the paper, the researchers recognize that it is impossible to know if these transformations are the cause or the consequence of the disease, although from a clinical point of view, they suggest that it would be prudent to start treatment as early as possible and maintain it for a longer period.

“According to this view, an attack of mania or depression can be looked at as being similar to a heart attack,” says Elisa Brietzke, a former PhD student of Kapczinski. “All are acute events, but they result of alterations that were present in the

organism long before.” Given this interpretation, adds Araripe, “the objective of the treatment ceases to be merely the remission of the symptoms and becomes one of avoiding a relapse and helping to maintain functional capacity.”

DaMAGE TO CELLS

The model of the progression of mental diseases proposed by Kapczinski and his collaborators repWith the resents an advance in relation to repetition of previous models. The most widely accepted theoretical proposal concrises, cognitive siders mental disturbances to be the result of the interaction between dysfunction the social, economic, psychological and cultural conditions in which the increases, brain individual lives (the environmenalterations tal factors) and their propensity to develop the problem, which is deintensify and termined by their genetic characteristics. treatment loses This older approach was constructed a decade ago by psycholits efficacy ogists Avshalom Caspi and Terrie Moffit, researchers at King’s College, London, from the results of studies in which they monitored 1,037 children from the age of 3 to 26 years. In this work, they observed that certain alterations in the genes responsible for the production of chemical messages in the brain (neurotransmitters) increased the risk of an individual developing antisocial behavior or depression.

Vicious cycle From the tenth mania or depression crisis, the bouts occur even in the absence of stress-provoking factors

stress IN THE ENVIRONMENT 1

4 5 6 7 8 9 10 2 3

Pathological reorganization

RESPONSE TO TREATMENT Patients with multiple episodes had the worst response to treatment, especially to lithium

mania oR depressION CRISIS

CELL DAMAGE

Improvements in mood symptoms

10

Valproate Lithium

8

Placebo

6 4 2 Number of episodes

0 0

36 z january 2013

2

4

6

8

10

12

14

16

As the disease progresses, the bouts of mania and depression may gain autonomy and become independent of the factors that triggered them

In addition to the influence of genes and environment, Kapczinski and his collaborators included a third element in the model: damage to cells in the brain and other organs caused by attacks of the psychiatric illness itself. These attacks generally begin as the response to a stressful event that may be intense and brief, such as an armed hold-up, or less dramatic but longerlasting, like that experienced by someone who constantly works under pressure. Repeated many times, the episodes of mania or depression may end up undermining the capacity of the body to address new stressful events. “Our hypothesis is that the disease ‘feeds’ itself,” says Kapczinski.

This proposal seems to provide a better explanation for the worsening of psychiatric disturbances, such as depression and bipolar disorder, when they are marked by successive crises. In these illnesses, the influence of environmental factors on the genetic propensity is fundamental for triggering the initial episodes of mania or depression. However, these factors become less important as the disease advances and the attacks become increasingly frequent and longlasting (in some cases, even when medication is being used) and the intervals between them become shorter. Over time, generally from the tenth crisis on, the attacks gain autonomy and may become independent of the stressful conditions that previously triggered them (see the infographics on the next page).

CHEMICAL STORM

It has long been known that in every modest or intense episode of stress, caused by a real or imagined danger, the organism reacts by releasing the

hormone cortisol. Produced by glands situated above the kidneys and released into the blood stream in small amounts and for a short time, cortisol increases the heartbeat, raises blood pressure and speeds up energy production. In short, it prepares the body to flee or confront dangerous situations. However, in high doses and for extended periods, as occurs before crises, cortisol begins to damage organs, including the brain (see Pesquisa FAPESP 129).

Recently, researchers from the National Institute of Mental Health of the United States observed that in brain cells, especially neurons, high levels of cortisol damage the mitochondria, compartments in which the sugars from food are converted into energy. Damage to the mitochondria is certainly a problem, as they produce 85% of the energy that the cells consume to stay alive.

Acting in an indirect manner, excess cortisol causes pores to form in the walls of the mitochondria, from which toxic compounds seep out, damaging lipids and proteins and altering the structure of the DNA within the nucleus of the cell.

Moreover, this transformation activates mechanisms of apoptosis, or programmed cell death.

Using a technique that allows for an evaluation of thousands of proteins produced by the organism at a certain moment, Brazilian biologist Daniel Martins-de-Souza, a researcher at the Max Planck Institute for Psychiatry in Germany, also obtained evidence that the functioning of these organelles is altered in psychiatric diseases. Especially in depression, he found differences in the final phase of energy production, so-called oxidative phosphorylation or cell respiration, which occurs in the mitochondria.

The consequences of damage to the mitochondria are not restricted to cells, as the compounds they release reach the blood stream and activate defense system proteins that trigger inflammation, such as interleukin-6 (IL-6), interleukin-10 (IL-10) and tumor necrosis factor-alpha (TNFalpha). When these factors reach the brain, they activate other biochemical reactions that cause additional neuronal death. According to Kapczinski, this process feeds cellular destruction, which is reinforced by another typical phenomenon of bipolar disturbance: the over-production of the neurotransmitter dopamine, which also activates apoptosis.

It was by measuring the levels of these compounds in the blood that Kapczinski’s group identified a phenomenon to which little attention had previously been paid: the attacks cause systemic toxicity. According to Kapczinski, during the pESQUISA FAPESP z 37

episodes of mania and depression, the levels of compounds associated with inflammation were much higher in the blood of individuals with bipolar disorder; in some cases, these levels were similar to those detected in patients admitted to the intensive care unit with generalized infection (sepsis).

In rodents, it has already been shown that the toxicity that is observed in the blood corresponds to alterations in brain cells. However, this is yet to be proven in humans. “The best way to prove the toxic effects of these episodes would be an intervention to avoid the effects, followed by an evaluation of whether this intervention was capable of preventing the neurobiological alterations,” says Post.

Most of the cells seem to survive this chemical storm even though they are damaged. Images evaluating brain function and microscopic examinations of postmortem brain tissue indicate that in mania or crises of depression, some regions lose 10% to 20% more neurons than under normal circumstances. According to psychiatrists and neurologists, this level of loss is insufficient to classify mood disturbances as neurodegenerative diseases. Both in bipolar disturbance as well as in depression, the biggest problem is that the neurons that survive do not remain whole; they 38 z january 2013

apparently lose the projections called neurites, which connect them to other neurons.

Many brain researchers believe that it is the loss of neuronal connectivity that compromises the functioning of the brain regions most affected in mood disorders. The fact that these changes are subtle may explain why 100 years ago the German neuropathologist Alois Alzheimer, who first described the neuronal damage typical of the disease that bears his name, found no important alterations in the brains of people with depression (fostering the popular sentiment at the time that neuropathology embodied the death of psychiatrists). “Despite being subtle, these transformations are sufficient to cause a pathological reorganization of the brain,” says Kapczinski.

The automatic transformations of the brain observed in illnesses affecting mood first became obvious approximately 10 years ago, when Grazyna Rajkowska and her group at the University of Mississippi found a reduction in the volume of the prefrontal cortex in patients with depression.

The volume reduction in this area as well as in the region of the ventricles has been confirmed by imaging examinations in cases of bipolar disorder. Located in the front part of the brain, the prefrontal cortex is responsible for reasoning, decision-making and behavior control. This morphological alteration provides an explanation for why, with the advance of the disease, those who have bipolar disorder progressively lose their capacity to plan and learn. These people also become more impulsive and susceptible to emotions because there is a simultaneous increase in the volume of the amygdala, which coordinates the response to fear and negative emotions.

HYPOTHESIS IN FORMATION

In 1997, when he returned from completing his PhD in England and from an internship in Canada, Kapczinski began to collect evidence that a chemical storm installs itself in individuals who suffer from bipolar disorder. At the time, the group he led in the Laboratory of Molecular Psychiatry at UFRGS had noted that individuals with bipolar disorder, in addition to the psychological and cognitive alterations generally observed by psychiatrists, also had high levels of compounds in the blood indicative of brain cell damage and low levels of neuroprotective factors. “The molecules we study function like biomarkers [indicators of biological alterations] that allow us to distinguish if the disease is at an initial or advanced stage,” says Kapczinski.

Identifying the stage of the disease is important for providing appropriate treatment, and Kapczinski thought his new hypothesis may help to improve the use of medication. There is evidence to suggest that controlling the disease immedi-

ately after the first episodes of depression or euphoria can preserve the recovery capacity of the patient and prevent psychological and cognitive degradation. Medications – mood stabilizers, antidepressants, antipsychotics and anticonvulsives, used alone or in combination – are generally effective in 80% of all cases of bipolar disorder and depression and have been proven to produce a neuroprotective effect, especially lithium, a cheap and efficient mood stabilizer that was once used to combat stress, gout and kidney stones.

Still, psychiatrists do not always manage to precisely administer the correct medication and dose at the first attempt. A recent North American study of 4,035 patients with bipolar disorder, undertaken by researchers at the Mount Sinai Medical School, found that in 40% of these patients, especially those with more serious depressive clinical symptoms, the illness was only brought under control when they took three or more medicines.

Kapczinski believes that these illnesses generally reach a much more difficult stage to control after the tenth crisis, which usually occurs approximately 10 years after the first manifestation of the disease. For this reason, psychiatrists believe that starting medication as early as possible is fundamental. It had With every crisis, already been observed that lithithe brain cells um, one of the most widely used medicines for treating bipolar may suffer disturbance, loses its effectiveness after the tenth attack (see damage and lose graph on page 44).

Furthermore, individuals with some of their mental disturbances normally connections to wait to see a psychiatrist until long after the first signs of the other cells disease appear, and years may pass until a specialist makes the correct diagnosis and prescribes suitable medication. In the case of bipolar disturbance, the period between the first manifestation of the problem and the start of treatment varies between 5 and 10 years, which is enough time for complications to arise at work, in family life and in relationships with friends, causing these patients to feel as if their lives are ‘falling apart.’

THE PARTS AND THE WHOLE

When he was analyzing variations in the levels of these biomarkers in the blood, Kapczin-

ski felt the need to seek a more comprehensive explanation that would allow him to associate the clinical signs of the disease with the physiological and anatomical alterations that could be detected in the brains of individuals suffering from mental disorders. Through this type of analysis, he sought to more effectively evaluate bipolar disorders, which affect approximately 1% of the population (but it is calculated that as many as 8% may have less serious forms), and another more common mood disorder – major or unipolar depression – which almost 15% of adults develop during their lifetime.

Kaczynski realized that he was not satisfied with what he had at hand when he received an invitation to present his group’s results at an international symposium in the Barcelona Hospital Clinic in Spain in mid-2006. “We were missing the theoretical ‘glue’ showing how the data fit together,” says Kapczinski.

He and his team had collected blood samples from people with bipolar disturbance during the periods in which they were experiencing extreme mood states, which can vary from intense sadness and low self-esteem to great vitality and energy, far beyond anything considered to be normal. Using a battery of tests, psychiatrist Angelo Miralha da Cunha, then at UFRGS, observed a phenompESQUISA FAPESP z 39

enon that was new to both depressive crises as well as manic episodes. He found that the levels of brain-derived neurotrophic factor (BDNF), with its neuroprotective action, were at least 25% lower in bipolar patients compared to individuals who did not experience the disorder or who kept it under control with the help of medication.

At the same time, Ana Cristina Andreazza and Elisa Brietzke, who were part of Kapczinski’s team, detected higher rates of proteins indicative of inflammation, as well as higher levels of free radicals, highly reactive molecules with the potential to damage cells during periods of mood change. These data suggested that the blood may provide clues as to what was happening in the brain. However, at that time, it was impossible to know with any degree of certainty what those alterations meant or why they occurred.

THEORETICAL ‘GLUE’

Kapczinski found the theoretical ‘glue’ he was looking for in the studies of American neuroscientist Bruce McEwen. In 2000, McEwen put forward the hypothesis that stressful situations 40 z january 2013

oblige the organism to make adjustments to recover the stability it has lost. McEwen called this adaptation allostasis, a change that is necessary to re-establish equilibrium (homeostasis). He went on to suggest that, over time, there would be a price to pay for this adaptation, as it caused wear indicate that there is a general reduction in the volume of some brain areas the organism.

The theoretical proposals of psychiatrist Robert Post completed this idea. In the 1980s, Post had suggested that the clinical signs of bipolar disturbance would become more intense with each crisis as a consequence of the greater sensitivity of the brain circuits affected in previous episodes.

The phenomenon, called ‘kindling’, had been discovered 20 years earlier by Graham Goddard, an English neuroscientist who studied epilepsy.

During tests with rodents, Goddard found that low-intensity electrical stimuli, initially incapable of causing the animals any harm, began to trigger epileptic crises after they were repeated a few times, indicating increased brain sensitivity.

“Starting with these experiments, other authors began working on the idea that the brain learned to

Medication controls 80% of the cases of bipolar disturbance and depression, but patients often delay seeking treatment and doctors are not always successful in their first treatment attempt

become sick in other situations, especially in bipolar disorder,” says neurophysiologist Luiz Eugenio Mello, from Unifesp. “According to this idea, modifications in the central nervous system, possibly at the level of the synapses [connections between brain cells], could transform a brain that was not very sick into one that was very sick,” he explains.

Upon analyzing his data in light of the concept of allostasis and sensitization (later brought together in the concept of neuroprogression), Kapczinski found the link between what his group had observed and the alterations in the volume of certain brain areas that foreign teams had detected. This unification of concepts may also explain the origin of the clinical signs that are characteristic of these diseases and, furthermore, why people with bipolar disorder and depression have been shown to die 25 to 30 years earlier than people without psychiatric disorders.

Moreover, a greater proportion of people with bipolar disorder and depression develop cancer and cardiovascular problems.

Influenced by neuroscientist Iván Izquierdo, Kapczinski did something that is rather uncom-

mon in field of psychiatric research in Brazil: he formulated a theory to explain the development and consequences of psychiatric diseases. Like any attempt to reproduce reality from sparse data that can be identified and measured, the theoretical model conceived by the group from UFRGS is still being improved. Since its initial presentation in Barcelona, Kapczinski and his collaborators in Brazil, Australia, the United States and Spain have been working to improve this theoretical proposal and to verify that they are on the right track.

Kapczinski himself is testing his hypothesis by evaluating on mice the neuroprotective effect of a modified version of the antidepressant tianeptine, developed at UFRGS. He is also planning to examine chemical and cellular alterations in brain samples taken from patients with psychiatric diseases, which are kept in brain banks like the one psychiatrists Beny Lafer and Helena Brentani are currently organizing at the University of Sao Paulo Medical School. In another line of work, Lafer has recently started a clinical trial with supplements of the amino acid creatine, which are likely to improve the functioning of the mitochondria and may also increase cell protection.

Ana Cristina Andreazza, currently a researcher at the University of Toronto, is investigating the effects of malfunctioning mitochondria in brain cells. Her research suggests that an adequate diet rich in antioxidants may also help protect the brain.

“The hypothesis of neuroprogression represents an important model for explaining the progression of these diseases,” comments Lafer, who is collaborating with the group from UFRGS. “There are other hypotheses based on genetics, which deal with the interactions between genes, the environment and inflammation, but no consensus has been reached.” n

The Projects 1 Postmortem stereological analysis of the main regions of the brain in individuals with affective bipolar disorder no. 09/51482-0; 2 Prevention of schizophrenia and bipolar disorder from neuroscience to the community: a multiphase, multimodal and translational platform for investigation and intervention no. 11/50740-5. Modality 1 Regular Research Funding; 2 Thematic Grant/Pronex. Coordinators 1 Beny Lafer – USP; 2 Rodrigo Affonseca Bressan – Unifesp. Investment 1 R$ 130,249.30; 2 R$ 2,378,201.50

Scientific articles 1 KAPCZINSKI, F. et al. Allostatic load in bipolar disorder: Implications for pathophysiology and treatment.

Neuroscience and Behavioral Reviews. v. 32, p. 675-92.

2008.

2 BERK, M. et al. Pathways underlying neuroprogression in bipolar disorder: Focus on inflammation, oxidative stress and neurotrophic factors. Neuroscience and Behavioral Reviews. v. 35, p. 804-17. 2011. pESQUISA FAPESP z 41

muscular DYSTROPHY y

Joint treatment The combined use of stem cells and a growth factor reduces disease symptoms in mice

Marcos Pivetta Published in July 2012

P

eriodic injections of a type of adult human stem cell in combination with daily doses of a growth factor may be a promising alternative in the treatment of progressive muscular dystrophies. Researchers from the Human Genome Research Center (HGRC) at the University of São Paulo (USP) have obtained encouraging results using this approach in muscle cells from patients with Duchenne muscular dystrophy and in mice with a congenital form of muscular dystrophy. The joint therapy used mesenchymal stem cells (MSCs) obtained from the umbilical cords of newborn infants along with doses of insulin-like growth factor 1 (IGF-1). In human tissue cultures, this therapeutic scheme increased the expression of dystrophin, a protein that is essential for maintaining the integrity of muscles. In rodents, the experimental treatment protocol reduced muscle inflammation and fibrosis, which led to an improvement in the animals’ clinical condition. The results of the work were published on June 4 in the online version of the scientific journal Stem Cell Reviews and Reports.

The stem-cells-plus-IGF-1 double treatment did not generate new, healthy muscles, as was expected. However, it appears to have created more favorable conditions for preserving the functionality of the already-existing musculature.

Therefore, this approach could be a means of avoiding or reducing the degeneration caused by dystrophies in general. The joint therapy has an additional advantage: “Mesenchymal stem cells have immunosuppressive properties,” explains

42 z january 2013

Mayana Zatz, coordinator of the team that conducted the study at the USP center, one of the Research, Innovation and Dissemination Centers (RIDC’s), which are financed by FAPESP. “With these cells, we reduced the risk of the injected material being rejected,” says Zatz. The immune systems of the mice in the experiment, for example, did not need to be “switched off” before the animals received the human stem cell injections.

Normally, when the donor and the recipient of tissues or cells are not the same individual, it is necessary to temporarily destroy the immune defenses of the recipient, which is always a risky procedure that leaves the patient vulnerable to external infections. If this procedure is not performed, however, the donor material will be perceived by the recipient’s defenses as a potentially dangerous agent, and the implant will be fatally rejected. By using mesenchymal stem cells, rejection can apparently be avoided without the need to overrule the patient’s immune system.

This benefit occurs even in extreme cases, such as the experiment performed at USP, in which the recipient (mouse) and the donor (human) were members of different species.

There are indications that both components of the candidate joint therapy against dystrophy may be beneficial to muscles. Mesenchymal stem cells are largely undifferentiated and possess the capacity to generate many types of tissue, including bone, cartilage, fat cells that support blood formation and fibrous connective tissue.

It is also suspected that MSCs may have a role in

technology Business Research y

Mining expansion Vale celebrates its 70th anniversary by investing in long-term projects with a focus on mining and sustainable development Dinorah Ereno Published in August 2012

I

n seventy years, Vale has grown from a small mining company in the town of Itabira, in the State of Minas Gerais, to the world’s leading global iron ore producer and the world’s second largest producer of nickel. With business operations in 38 countries on five continents, the company is also involved in the logistics business, including railways, port terminals, cabotage, energy, and fertilizers. The company’s outstanding success is based on enormous investments in state-of-the-art technology and in research and innovation. The immediate needs of clients are supported by three research and development centers, including two centers in Brazil and one center in Canada. Other long-term research projects in several areas are conducted at the Vale Technological Institute (ITV), which was founded in 2009.

The initial conversations about the creation of a non-profit institute began in 2007. However, the project only gained momentum at the end of 2008, when neurophysiologist Luiz Eugênio Mello was hired as the executive director of ITV. At that time, Mello was the dean of undergradu44 z agosto DE 2012

ate studies at the Federal University of São Paulo (Unifesp). “Last year, Vale invested US$ 1.7 billion in R&D. Of this amount, nearly R$ 23 million went to ITV,” states Mello, who is also a former assistant coordinator of FAPESP’s Scientific Director’s Office. In 2011, at US$ 22.8 billion, the mining company’s net profit was 32% higher than it had been in 2010.

Since it was founded, ITV has entered into 97 R&D agreements and has established partnerships with 36 national and international institutions, including Embrapa, the Massachusetts Institute of Technology (MIT) and Switzerland’s Federal Polytechnic School of Lausanne. The institute also has partnerships with FAPESP and with the research foundations of the states of Minas Gerais and Pará. These entities have provided ITV with funds of R$ 120 million, which have been allocated to research projects in the fields of mining, energy, and ecoefficiency.

Two research units with different research objectives – sustainable development in Belem, in the State of Pará, and mining in Ouro Preto, in the State of Minas Gerais –conduct research

IMAGES mariane secco infographics ICS laura daviña SOURCE HUMAN GENOME research center OF THE University of São Paulo (USP)

A possible therapy against dystrophy Once per week

Pump with a daily dose

IGF-1

MESENCHYMAL STEM CELLS

A therapy that combines the use of human mesenchymal stem cells (MSCs) obtained from the umbilical cords of newborn infants and insulin-like growth factor 1 (IGF-1) was tested on sick mice for two months

Untreated

The rodents displayed clinical symptoms that were considered a model of congenital dystrophy. They had weak muscles and reduced life expectancies due to a dysfunction caused by a genetic mutation

With IGF-1

the muscle regeneration process. Among other functions, IGF-1 is involved in the development and growth of muscles.

Therefore, it was logical to assess the possible effects of a therapeutic scheme using these two factors.

For 60 days, the researchers evaluated the in vivo effects of different treatment protocols on 46 mice with clinical symptoms similar to those of congenital muscular dystrophy. Due to a mutation in the lamina-associated polypeptide 2 alpha gene, the animals had a deficiency in the production of the merosin protein, a dysfunction that causes muscle weakness and reduces life expectancy. “They drag their back legs and have considerably reduced muscle strength,” states Mariane Secco, the biologist chiefly responsible for the human and animal experiments.

The rodents were divided into four groups: the first was not treated and functioned as a control group; the sec-

GROWTH FACTOR

The combination of stem cells and growth factor did not generate new muscles, but it did reduce the levels of inflammation and fibrosis in the existing muscles. The animals treated with either MSCs or IGF-1 alone improved only slightly

The MSC injections were administered weekly. A small, subcutaneous pump implanted in the rodents supplied a daily dose of IGF-1.

At the end of the experiment, there was a significant clinical improvement in the animals that had undergone the joint treatment

With MSCs

MUSCLE FIBERS: The combined therapy reduced inflammation and connective tissue (white points)

IGF-1 + MSCs

ond received only stem cell injections; the third received only doses of growth factor; and the fourth received the combined therapy. The stem cells were injected into the rodents once per week.

A small, subcutaneous pump supplied a dose of two milligrams of IGF-1 per kilogram of the animal’s body weight every day. At the end of the study, a biopsy was performed on the muscle tissue, and a significant improvement was found in the animals that received the joint therapy.

Given the positive results, Zatz, Secco and their collaborators initially suspected that the IGF-1 had stimulated the MSCs to become muscle cells. However, this transformation was not detected in any of the four groups of mice. Instead, the improvement was caused by decreased levels of inflammation and muscle fibrosis, which in turn may have led to increased skeletal muscle strength in

Healthy muscle

the sick animals. Apparently, the growth factor boosts the effects of the stem cells and vice versa. “We believe that it is unnecessary for the stem cells injected into the muscle cells to differentiate in order to produce a clinical benefit,” says Zatz.

The combined treatment will be tested on dogs with dystrophy to determine whether the positive results are also manifested in these animals. n

The Project Human Genome Research Center no. 1998/14254-2 Modality Research, Innovation and Dissemination Centers (RIDC’s) Coordinator Mayana Zatz – IB-USP Investment R$ 34,412,866.53

Scientific article SECCO, M. et al. Systemic delivery of human mesenchymal stromal cells combined with igf-1 enhances muscle functional recovery in LAMA2dy/2j dystrophic mice. Stem Cells Reviews and Reports. Published online on June 4, 2012. pESQUISA FAPESP z 43

marcio nunes

From left to right, Regina Bronstein, Sandoval Carneiro, Roberto Dal’Agnol, Cláudia Diniz, Luiz Eugênio Mello, José Oswaldo Siqueira and Hugo Resende, all of whom are affiliated with the Vale Technological Institute

studies in the fields of climate change, water management, sustainability in the mining industry, biodiversity, energy, and environmental monitoring technology. These fields were defined as priorities at workshops that were organized by Vale in 2010 and attended by researchers from several institutions who are experts in their respective fields of study.

The ITV Sustainable Development unit is headed by Luiz Carlos de Lima Silveira, a physician and neuroscientist who assumed the position of scientific director of the unit in 2010.

Currently, 33 researchers from a variety of fields are conducting research on six different topics: biodiversity, including soil microbiology and plant biotechnology; climate change; water management; bioenergy and photosynthesis; sustainable mining; and environmental monitoring. Two other fields – sustainable architecture and urban planning in the Amazon region and sustainomics, which is defined as the science of sustainable development – are also being researched.

Silveira, who created the postgraduate program in neuroscience and cell biology at the Federal UnipESQUISA FAPESP z 45

1

versity of Pará (Ufpa), defines his current work as a continuation of his academic experience: “I gained administrative experience during my career as a researcher and implemented two research groups: one focusing on the basic sciences and the other, on the neuroscience of tropical medicine.” Silveira explains. “These credentials enabled me to take on my current job.” Silveira has a medical degree from Ufpa, as well as a master’s degree and a doctorate in biophysics from the University of Rio do Janeiro (UFRJ). He did his postdoctoral work in neuroscience at Oxford University, England.

Taquari Mine in the State of Sergipe: exploiting potassium

An urban phenomenon

In Silveira’s opinion, the creation of a research group in Brazil requires a number of skills, especially when the focus is the Amazon region, which has many regional disparities and must be integrated with the other regions in the country.

At ITV in Belém, more than 10 research projects are being conducted in collaboration with local institutions, such as Ufpa and Embrapa Amazônia Oriental, and international institutions, such as Belgium’s Flanders Biotechnology Institute and Israel’s Weizmann Institute of Science.

The choice of Belém as one of the physical locations of the research network was strategic; the city is the capital of the State of Pará, where Vale has a large iron ore mining operation in the Carajás mountain range. Belém has two million inhabitants. The mines in Carajás alone account for 36% of the iron ore that is currently produced

by Vale. In 2011, Vale’s iron ore production totaled 322.6 million tons. According to Silveira, “Belém is a big city that lies geographically and temporally on the frontier between the Amazon Region and the Atlantic Ocean; the region’s 46 z january 2013

36% of the iron ore produced by Vale is in Carajás in the State of Pará

enormous biodiversity has to be studied.” Two research projects are at an advanced stage. One is the Urbis project, which focuses on urban planning and is dedicated to the urban development in the western part of the Amazon region. The other project focuses on the climate-related effects of Vale’s mining operations.

The Urbis project is coordinated by Ana Cláudia Cardoso and space engineer Antonio Miguel Monteiro, who is employed by the National Institute for Space Research (Inpe). “Our plan is to work on a multidisciplinary vision of the urban phenomenon of Pará,” states Cardoso, who has a degree in architecture and urban planning from Ufpa, a master’s degree in urban planning from the University of Brasília (UnB) and a doctorate in architecture from Oxford Brookes University in England. The researchers want to understand how major economic activities such as mining, animal husbandry, and timber exploitation are influencing not only the capital city but also the medium-sized and small towns in forest conversion areas and the villages along highways and river banks. The project participants include economists, urban planners and ecologists from institutions such as the Federal University of Minas Gerais (UFMG), the State University of Campinas (Unicamp), and the Getúlio Vargas Foundation. The participants will use specific tools to analyze occupation levels in the state.

According to Cardoso, “Migration rates in some municipal regions of Pará are four times higher than in other regions of Brazil because of the investment dynamics of Vale and the influence of farming and cattle ranching.”

The research team working on climate change is comprised of a physicist and two meteorolo-

gists. It is coordinated by Luiz Gylvan Meira Filho, the former president of the Brazilian Space Agency. Luís Antônio Lacerda Aímola has been a member of the team since he left Israel to move to Belém. In Israel, Luís Antônio worked as a researcher in the field of climate change and modeling. He has a degree in physics from Unicamp and a doctorate in environmental sciences from the University of São Paulo (USP); he did his postdoctoral work at the Weizmann Institute. “I was attracted by the company’s innovative vision, which led it to create a center of excellence in research focused on the field of sustainable development, and by the possibility of conducting long-term research projects,” explains Aímola.

Climate events

Since May of 2011, he has been working on a project that seeks to connect the possible physical changes in the tropical region’s rainfall regime due to global warming with the economic elements of climate models. “If significant changes occur, they can change the dynamics of the Amazon Forest,” he states. Because mining depends on rainfall regimes, mining operations can be jeopardized by extreme climate events. “I am working on the physical as-

photos 1 and2 Vale 3 Agencia Vale 4 Salviano Machado/ Vale

2

pects of climate, as well as on possible future climatic effects on the economies of tropical regions,” Aímola explains. One of the meteorologists on the team is studying the effects of climate change on Vale’s operations in the eastern Amazon region.

The other meteorologist is constructing a climate model for the Amazon region.

ITV Mineração is in the process of being established in the city of Ouro Preto in Minas Gerais.

The priority fields are infrastructure, metallurgy, mineral processing and exploitation, prospectAgriculture begins ing and geology, and wawith mining. The raw ter resources. One of the projects is coordinated by materials that are agronomic engineer José Oswaldo Siqueira, who extracted from is also a retired professor from the Federal Univerrocks are used to sity of Lavras (Ufla). He produce fertilizers was hired by ITV one year ago to work on technology for manufacturing fertilizers. “Agriculture starts with mining,” Siqueira explains. The raw materials extracted from the rocks are used to produce fertilizers. “Our biggest challenge,” he says, “is to bring the requirements of agriculture and food production to a On the side and below, computer mining company.” Siqueira has a degree from the images show the School of Agriculture of Lavras (which is curnew iron ore rently known as Ufla) as well as a master’s degree processing and a doctorate from the University of Florida. projects in Carajás. On the He did his postdoctoral work at the University right, the same of Michigan. Siqueira argues that because of this mine’s current connection between agriculture and mining, it is processing area is displayed

3

4

pESQUISA FAPESP z 47

Salviano Machado/Vale

necessary to seek new technological processes that can increase the efficiency of the extraction of raw materials and thus make it possible to obtain high-quality, environmentally friendly products.

“Most of the technology used to make fertilizers nowadays was developed between 1950 and 1970,” Siqueira explains. This stagnation has been caused by a lack of interest on the part of developed nations, by farm policies and by the historically low price of fertilizer. However, the situation has changed in the last five years. Brazil must now increase the technological competence of the entire production chain.

The Mining Frontier

“This is a strategic issue, because the country imports approximately two-thirds of the fertilizers it consumes,” states Siqueira. Phosphate, for example, is essential for agricultural production, but the worldwide reserves of this mineral are extremely limited. Vale produces fertilizers such as phosphate and potassium, but its aim is to become a major producer of raw materials for fertilizers on a global scale. Toward this end, the company has invested heavily in Brazil and in Africa, Peru, Argentina and Canada, acquiring mines and companies. In addition to developing fertilizer production technology, ITV Mineração is working on eleven other research areas, one of which is the mining frontier of the ocean floor.

This research is being conducted in partnership with Ufla, USP, and universities such as Australia’s Queensland University of Technology.

After working for 25 years at Embraer, aeronautics engineer Hugo Resende accepted the

Iron ore storage area at Carajás

invitation extended to him in October of 2011, when he was asked to organize a department that would focus on an incubator for technology start-ups linked to the ITV. “The challenge is to identify new, technology-based business start-up opportunities based on research studies conducted not only at ITV but also at Vale’s other research centers,” explains. Resende, who has a degree from the Aeronautics Technology Institute (ITA) as well as a master’s degree and a doctorate from Stanford University. At Embraer, Resende worked on aircraft development and aeronautical software. Prior to becoming the chief scientist responsible for the company’s partnerships with universities and for identifying projects of interest to the company, he worked as a technological development manager.

Resende accepted Vale’s invitation because he envisioned it as a new challenge. “Identifying

Institutions at which the company’s researchers studied Luiz Eugênio Mello Physician, executive director of ITV

Unifesp Undergraduate degree, master’s degree and doctorate University of California postdoctoral work

Luiz Carlos de Lima Silveira Physician, scientific director of ITV Sustainable Development

Ufpa Undergraduate degree UFRJ Master’s degree and doctorate University of Oxford Postdoctoral work

Luís Antônio Lacerda Aímola Physicist, researcher at ITV Sustainable Development

Unicamp Undergraduate degree USP Doctorate Weizmann Institute of Science, Israel Postdoctoral work

José Oswaldo Siqueira Agronomy engineer, researcher at ITV Mining

Ufla Undergraduate degree University of Florida Master’s degree and doctorate University of Michigan Postdoctoral work

Ana Cláudia Cardoso Architect, researcher at ITV Sustainable Development

Ufpa Undergraduate degree UnB Master’s degree Oxford Brookes University Doctorate

Stephen Potter Mine engineer, director of Integrated Planning and Technological Development

Royal School of Mines, London Undergraduate degree and master’s degree

Hugo Resende Aeronautical engineer, manager of business start-up incubator

ITA Undergraduate degree Stanford University Master’s degree and doctorate

Rogério Carneiro Metallurgical engineer, general manager of the CTF

UFMG Undergraduate degree and master’s degree

48 z january 2013

vale

opportunities and transforming them into business was a missing element in my professional experience,” says Resende, who also held several positions on the executive board of the National Association of R&D at Innovative Companies (Anpei) and was the president of this association in 2006. The start-up incubator is expected to become operational in 2013. This activity is being integrated into the MIT model, which was chosen as a point of reference for the process that created ITV. According to Mello, “MIT’s focus is to transfer technology to companies and to train entrepreneurs.”

Immediate Response

Three large laboratories are responsible for addressing technological needs that require immediate responses. The Mineral Development Center (CDM) and the Ferrous Technology Center (CTF) are located in Minas Gerais. The third laboratory, which is dedicated to nickel and base metal technology, is located in Canada. Founded in 1965, the CDM is considered to have made the company’s first technological advancement by developing its own technology for processing minerals with low iron ore content. The company developed this technology in the 1960s, which enabled Vale to extend the life of its mines. The CTF, which was created in 2007, conducts research on the entire iron ore chain from mining to steel. “Our work focuses on the steel industry,” explains metallurgical engineer Rogério Carneiro, who is the general manager of the CTF and has an undergraduate degree and a master’s degree from UFMG. “Several laboratories and mathematical models that simulate steel manufacturing processes enable us to develop solutions for our clients,” states Carneiro, who has worked for Vale since 2001. Before joining Vale, he worked for 17 years at a Brazilian steel company, coordinating research on iron ore, sintering, and blast furnaces.

Of the CTF lab’s 120 employees and contractors, 30 are researchers with master’s or doctoral degrees, including metallurgical engineers, mining engineers, and geologists. Using these labs and models, one can test items ranging from different processing routes to the behavior of the iron ore in steel mills. According to Carneiro, “CTF has equipment that simulates a steel mill.”

The innovative technologies that are used to produce iron ore distinguish Vale from other companies and have helped to secure the company’s outstanding position within the international community. One example of such innovative technologies is the transportation of iron ore using bulldozers and mobile stone crushers rather than trucks. This mode of transportation is being used as part of a project for Carajás known as S11D. The bulldozers and stone crushers will

Experiments at the Mineral Development Center in Minas Gerais

extract the iron ore and transport it to the processing unit. “The processing of iron ore, based on its own natural humidity, with no added water, is another technology that will minimize environmental impact,” explains mining engineer Stephen Potter, director of Integrated Planning and Technological Development at Vale. Potter has an undergraduate degree and a master’s degree from London’s Royal School of Mines.

“Besides reducing water consumption, this technology will allow us to recover the mined ore at the mine,” states Potter, an Englishman who has worked in the mining industry for 20 years and has been with Vale since 2009. The finer particles that are eliminated in the conventional process will be mixed into the end product. In addition, it will no longer be necessary to discard the waste from the process into a dam specifically built for this objective. “The fact that no loaded trucks will be moving around the mine will lower the impact on the environment,” explains Porter.

Vale has recently been granted the preliminary environmental license necessary to implement the project. n pESQUISA FAPESP z 49

Global warming y

Cleaner sugarcane fields Emissions of the most hazardous greenhouse gas from sugarcane plantations are lower than previously estimated Yuri Vasconcelos

D

irect emissions of greenhouse gases from sugarcane plantations are much lower than estimates previously reported in the international scientific literature. This finding is reported in the journal Global Change Biology Bioenergy and is the result of a field study on sugarcane plantations conducted by a group of scientists from different national universities and research centers. The focus of the study was the emission of nitrous oxide (N2O), which is considered to be the most hazardous greenhouse gas, being nearly 300 times more harmful to the environment than carbon dioxide (CO2). In addition, nitrous acid persists for a prolonged time in the atmosphere.

Nitrogen-based fertilizers used by farmers to stimulate the growth of sugarcane are the primary source of nitrous acid in sugarcane fields.

The results of the field study are important because, if nitrous oxide emissions become excessively high, the environmental benefits of sugarcane ethanol would be questionable. Brazil is the world’s largest sugarcane grower, with an annual production of 596 million tons.

“We established the objective of our research work because of an article by Dutch scientist Paul Crutzen published in 2008. Crutzen won the Nobel Prize for Chemistry in 2005. In his article, Crutzen states that nitrous oxide emission factors in crops that produce biofuels were higher than 3% and could go as high as 5%, directly affecting the planet’s climate as a result,” says agronomy engineer Janaína Braga do Carmo, coordinator of the research study and a professor in the Department of Environmental Sciences at the Federal University of São Carlos (UFSCar) in Sorocaba, São Paulo State. Another prognosis, 50 z january 2013

announced by specialists from the Intergovernmental Panel on Climate Change (IPCC), stated that the emission factor was lower, more specifically, approximately 1%.

“Ours was the first study based on field studies rather than on mathematical models or indirect estimates. Our study showed that nitrous oxide emissions in sugarcane fields in São Paulo State were much closer to the estimates of the IPCC; in other words, the level was much lower than the one stated by Crutzen,” says Janaína. She notes that the study conducted by the Nobel Prize laureate did not refer solely to the ethanol produced in Brazil. That study involved a view of the global production of this biofuel, including ethanol produced from corn and other crops. The emission factor is a measure that expresses the amount of nitrogen released into the atmosphere in the form of nitrous oxide as a proportion of the amount of nitrogen added to the soil in the form of nitrogenbased fertilizer. Nitrous oxide is released into the air by microorganisms in the soil through two processes: nitrification and denitrification.

The research study revealed that the emission factor in sugarcane fields fertilized only with nitrogen fertilizers totaled 0.68%. In other words, out of every 100 kilograms of nitrogen used to fertilize crops, 680 grams was transformed into nitrous oxide and “leaked” into the atmosphere.

The percentage increases to 3% in areas where vinasse is also used as a fertilizer and where a huge volume of sugarcane waste accumulates in the soil after the sugarcane has been harvested.

Vinasse, a residue from sugar and ethanol production, is widely used as a fertilizer in sugarcane fields because of its high potassium content.

The sugarcane waste forms a protective layer

Photo léo ramos infographics ana paula campos

Published in September 2012

Up and down Emission factors and consumption of carbon and other greenhouse gases in sugarcane crops

Emission Factors

Consumption factors

Respiration Release of CO2 and consumption

CO2

O2

Photosynthesis With absorption of carbon

of oxygen (O2) by leaves

CO2

dioxide (CO2) by leaves

Leaves

Soil respiration

CO2

Roots and microorganisms release

Absorption of methane

carbon (CO2)

DENITRIFICATION Is the transformation process of

N2O

NO2

Bacteria consume and oxidize methane to obtain energy (carbon)

nitrogen fertilizer (NO3-nitrate) into

during the decomposition of

nitrous oxide (N2O)

organic matter

Roots Microorganisms

CH4

Less impact on the atmosphere Emission-related differences between estimates and field studies

Since 2008 Nitrogen fertilization

5% to 3% Paul Crutzen’s estimate

1%

In 2012 Fertilization with vinasse

3% Field study results

Nitrogen fertilization

0,68% Field study result

Estimate of specialists from the IPCC Source Janaina do Carmo/UFSCar

that reduces soil erosion and water loss.

“Our study shows that we have to develop stewardship methods to reduce the emissions associated with using vinasse and sugarcane waste,” says Janaína.

Treatment-related differences

The research study coordinated by Janaína is part of the FAPESP Bioenergy Research Program (Bioen), which also involves researchers from the University of Maryland in the United States, the Agronomy Institute (IAC), the Center of Sugarcane Technology (CTC), the Nuclear Energy in Agriculture Center of the University of São Paulo (Cena/USP), Embrapa Meio Ambiente, the Federal Rural University of Pernambuco (UFRPE) and the Paulista Technology Agency.

The researchers quantified greenhouse gas emissions in eight sugarcane plantation treatments, each of which utilized a different fertilization method.

In the municipal region of Jaú, which is located 300 kilometers from the capital city, the experiments were conducted on plant cane crops. For these crops, the soil is prepared to open the furrows in which the stands will be placed. At this point, the farmer normally adds 60 kilograms of nitrogen, in the form of urea, per hectare. In the region of Piracicaba, 165 kilometers from São Paulo, the focus was on ratoon cane, the phase that comes after the sugarcane has been cut for the first 52 z january 2013

time. At this point, no soil preparation is necessary, and 100 to 150 kilograms of nitrogen fertilizer, usually ammonium sulfate or ammonium nitrate, is used per hectare. In Jaú, the crops were fertilized with urea, vinasse, filter cake—a residue of the sugarcane industry composed of crushed bagasse and mud—or a combination of the three. In Piracicaba, the researchers studied the effect of sugarcane waste on the soil. The four soil treatments used in this municipal region included different quantities of waste: 0, 7, 14 and 21 tons per hectare. The level of emissions was examined for each treatment, both with and without vinasse.

“Our calculations indicate that the highest percentage (3.03%) of the N2O emission factor in all the experiments and treatments was observed in the plant cane crop (Piracicaba) treated with vinasse and with the highest quantity of sugarcane waste on the surface of the soil – 21 tons per hectare,” the research study specified. “In the case of the plant cane crop, treatment with vinasse plus synthetic fertilizer showed the highest emission factor (2.65%). Without the vinasse, the percentage dropped to 1.1%.”

The lowest emission factor, 0.68%, was observed in the experiment that involved the ratoon cane crop, where treatment did not include sugarcane residues, vinasse or filter cake and the crop was fertilized only with nitrogen fertilizer. “Our

field study showed that nitrous oxide emissions are insignificant with this kind of treatment. If the estimates predicted in the literature had been correct, the environmental damage caused by the nitrous oxide wouldn’t have been offset by the consumption of carbon caused by photosynthesis and by the sugarcane’s high energy efficiency,” said Janaína. In addition to evaluating the N2O emission factor, the researchers also calculated the total emissions of the three main greenhouse gases: nitrous oxide, carbon dioxide and methane. To compare the effect of these emissions in the various experiments and treatments, the researchers converted the emissions of these three gases into CO2 equivalents, which is the measure used to compare emissions of various greenhouse gases and is based on the global warming potential of each gas. The global warming potential of nitrous oxide, for example, is 296 times greater than that of carbon dioxide. The CO2 equivalent of a given emission source is therefore the result of multiplying the number of tons emitted by the greenhouse gases (GEE).

In both plant cane and ratoon cane, the highest CO2 equivalents were associated with the use of vinasse. In the case of plant cane, the critical emission levels of CO2 equivalents (1,380 kilograms per hectare per year) were achieved when urea, filter cake, and vinasse were used.

In the case of ratoon cane, the worst scenario occurred when vinasse was used together with 21 tons of waste per hectare. In this situation, 3,000 kilograms of CO2 equivalents per hectare per year were generated. n

Projects 1. N2O, CO2 and CH4 emissions from agro-biofuel production in São Paulo State, Brazil – no.

2008/55989-9; 2. Nitrogen nutrition of sugarcane with fertilizers or diazotrophic bacteria – no.

2008/56147-1. Modality 1. Young Investigator Award for the FAPESP Bioenergy Research Program (Bioen); 2. Bioen Thematic Grants. Coordinators 1. Janaina Braga do Carmo – UFSCar; 2. Heitor Cantarella – IAC. Investment 1. R$ 237,330.83 and US$ 67,054.00 (FAPESP); 2. R$ 957,280.37 and US$ 75,853.15 (FAPESP)

Scientific article CARMO, J.B. et al. Infield greenhouse gas emissions from sugarcane soils in Brazil: effects from synthetic and organic fertilizer application and crop trash accumulation. Global Change Biology Bioenergy. On-line, 26 Jul. 2012.

New materials y

The value of impurities Brazilians discover a new family of materials that conduct electricity without losing energy Igor Zolnerkevic Published in September 2012

M

aterials engineers Antonio Jefferson Machado and Carlos Alberto Moreira dos Santos of the Lorena School of Engineering of the University of São Paulo (USP) radically transformed the electrical properties of a metallic compound. They did so by inserting atoms of lighter chemical elements such as boron, carbon, and nitrogen between the atoms that form the crystalline network of the compound.

Using this technique, which is referred to as interstitial doping, they have created approximately 30 new superconductive electrical materials since 2003.

The most promising discovery involving these superconductors was announced in June of this year in an article published in the Journal of Applied Physics. Here, the researchers from Lorena, in partnership with materials engineer Ausdinir Bortolozo of the Federal University of Itajubá and physicists Renato Jardim of USP and Flávio Gandra of the State University of Campinas, describe what happens when carbon atoms are added during the manufacturing process of a well-known metal compound, Nb5Ge3, which is a combination of niobium and germanium. This compound, which emerged in 1977, has not been of significant interest to materials science because it becomes a superconductor at a temperature that is considered to be too low for practical applications— less than -272 degrees Celsius (°C). “The electrical behavior of the doped material changed completely,” says Machado, who has already successfully doped Nb5Ge3 with six other chemical elements.

The carbon-doped material is a superconductor at a temperature of -258°C, the

Transformed molecules Brazilian superconductor: This compound based on germanium (red) and niobium (blue) conducts electricity without resistance when doped with carbon atoms (black)

•

Germanium

•

niobium

•

carbon

highest temperature ever achieved by the Brazilian engineers. This temperature is of industrial interest. Although it is extremely low, it is 11 degrees above the boiling point of liquid helium (-269.15°C), which is normally used to cool superconductor metals in their technological applications, for instance, in equipment used for magnetic resonance imaging.

NO RESISTANCE

In a superconductor material, the electrical resistance disappears below a certain temperature, meaning an electric current can travel through the material without losing energy in the form of heat. In 1911, superconductivity was observed for the first time by Dutch physicist Heike Onnes. A number of superconducting materials—most of them metallic—have been discovered since then.

These materials become superconducting at extremely low temperatures, a few degrees above absolute zero (-273°C).

Although relatively high, the temperature achieved by the Brazilians is far

from the world record, which is held by another class of materials based on copper oxides. This class of materials, with superconducting temperatures above -196°C, was first synthesized in 1987.

However, the fact that these materials are ceramic makes them heterogeneous and brittle, which hinders large-scale production. Therefore, researchers are engaged in an ongoing search for a superconducting material that can function at higher temperatures and is malleable and homogeneous like metals.

According to physicist Zachary Fisk of the University of California at Irvine, the discovery made by the Brazilian engineers has opened up the possibility of using interstitial doping to create highly desired high-temperature superconducting metal alloys. “This is an exciting development,” he says. n Scientific article BORTOLOZO, A. D. et al. Interstitial doping induced superconductivity at 15.3K in Nb5Ge3 compound. Journal of Applied Physics. 2012. pESQUISA FAPESP z 53

history

The original letter sent by Boutens to Oldenburg, showing the small closed envelope

History of science y

An inconvenient pinch of magic Brazilian researchers discover alchemical powder in an archive at the Royal Society, the seat of the scientific revolution Carlos Haag, from Londres Published in september 2012

Photos: Joanna Hopkins/Royal Society

I

t is not easy to rattle the British, which explains the reaction of Keith Moore, director of archives at the Royal Society, when he was questioned about the importance of the findings of researchers Ana Maria Goldfarb and Márcia Ferraz, from the Simão Mathias Center of the Pontifical Catholic University of São Paulo (Cesima PUC-SP). Raising his eyebrows, Moore cautiously replied, “It was right under our noses, but nobody found it for 350 years.”

He was referring to a pinch of yellowish powder with a pungent odor, wrapped in a small envelope attached to a letter from 1675 that was addressed to the first secretary of the Royal Society, Henri Oldenburg (1515-1677), who came from Antwerp. The letter had been sent by an apothecary and alchemist named Augustin Boutens.

Although it attracted no attention, it is a valuable and concrete sample of alkahest, the famous universal solvent that was the target of searches by generations of alchemists and natural philosophers, such as Robert Boyle and Isaac Newton.

In 2010, the duo revealed the only complete recipe for alkahest, from 1661, in a thematic proj-

ect that was supported by FAPESP (“The secret agenda of chemistry,” Pesquisa FAPESP 184).

They have now found what they say is “the first real sample of the compound Ludus, an alkahest, which we have been hearing about since the seventeenth century.” What is this powder?

The Royal Society wants the sample to be analyzed by one of its fellows, such as Martyn Poliakoff (see interview on page 25), vice-president of the institution. “Despite our personal curiosity, as researchers of science history, we have no intention of going to a laboratory to try to find out what this powder is in today’s terms,” says Márcia. “What’s important is the discovery of further strong evidence that a substantial portion of the ancient sciences, such as alchemy, persisted after the appearance of a new view of science (and even played a part in the formation of it), remaining on the agenda of the figures who promoted the scientific revolution from which modern chemistry originated. There’s a little-known story that says that this passage was gentler and more coherent and only ended in the nineteenth century,” says Ana. pESQUISA FAPESP z 55

Various waves competed during the rise of modern science, the result of a slow passage that only ended in the nineteenth century

Lavoisier Seen as the apex of new science, he was the result of a long process and many visions, which resulted in the modern standard laboratory

Eighteenth century

Isaac Newton As an exponent of reason, he was a natural philosopher who brought together rationality and hermetic beliefs in a way that few others did

Sixteenth and seventeenth centuries

Robert Boyle A hermeticist who converted to being a mechanist, he created greater distance in the division between the two views

In common Anti-Aristotelians; experimentation with and observation of nature; science and religion supporting each Hermeticists A heterogeneous group

other; practical knowledge

of philosophers of nature,

Mechanists

along with alchemists and

Division between the

neo-Platonists, whose

inanimate world and

view of the world included

live matter

magic and charms

Antiquity

56 z january 2013

Aristotelianism

Above all, the story confirms the researchers’ belief that investigating the history of science means rolling up one’s sleeves and facing the dust of centuries that has accumulated on original documents in an attempt to breathe life into them. To Moore’s surprise, the document passed through the hands of historian Marie Boas, who was responsible in the 1960s for cataloguing the correspondence of Oldenburg, for fifteen years the “the jack of all trades“ of the Royal Society. When she came across the small envelope, Marie merely noted “a sample of what appears to be pyrite, attached to the text.”

“Marie’s work is impeccable, but thinking like many did at the time, she ignored the possible alchemical interests of the ‘new scientists,’ and so she ended up not investigating the hermetic character of Oldenburg’s letters, which sometimes included ‘cleaning up’ the past and unrecommended interventions,” Ana explains. “This finding expands the view that chemical philosophy did not die with the triumph of the mechanical and corpuscular view. Knowing that they were still after materials like Ludus and alkahest proves this and adds further important names to the list of those who undertook these searches, even some who thought they had been converted to rationalism and, even more, to the mechanicality of the seventeenth century,” explains Pyio Rattansi, professor emeritus at University College London. He revealed the importance of hermeticism and the Bible in the scientific works of Newton, who had previously been seen as the ‘patron saint’ of modern science.

“Besides him, other ‘men of reason’ had ‘hidden agendas’ that discreetly included alchemical processes,” says Ana. This revision of the history of science only came to light when, despite the “siren song” of technology, researchers saw the limitations of digital catalogues and began delving directly into the “closed bottoms” of the archive, much to the initial incredulity of the British. “It was clear to us that it was necessary to understand the thinking of the men of science of that time. There was a type of duality toward any new facts. On one hand, there was the need to keep them secret because many were veritable state secrets, especially when dealing with laboratory materials or processes. On the

Photo reproduction

The paradox of the slow evolution

other hand, there was a maxim (which is, incidentally, still upheld) of new science that advocated knowledge [being] prepared by many and within the grasp of everybody,” says Ana. “Many people have itchy palms and want to get their hands on this knowledge, and who knows what they will do to have it published,” wrote Newton to Oldenburg in 1676. The “intricate adventures” required of researchers to find the recipe for alkahest were the result of this view.

Henri Oldenburg: secretary of the Royal Society, centralized all information for the institution and was one of the pioneers of scientific standards

‘A

fter the initial document discoveries, we considered everything relating to alkahest in the Royal Society clear and visible,” says Márcia.

This was true until they found the mysterious letter from Boutens to Oldenburg. “Years have gone by since I sent a good quantity of Ludus helmontiano to you, from which I produced the sulfurous material I enclose below. I trust in your wisdom to understand what effects it produces.” The reference to the clay-like mineral attracted the attention of Ana and Márcia. After all, Ludus was the basis of a recipe for liquour alkahest produced by the Belgian doctor Van Helmont (1579-1644), who dedicated his life to studying the obscure works of Paracelsus to produce what would be the “remedy for all diseases.” Capable of dissolving any substance without leaving a residue (because the substance would be reduced to its primary constituents), alkahest could be the source of powerful remedies, especially against the “ills of the stone,” renal lithiasis (i.e., kidney stones), the incurable cause of many deaths until the nineteenth century.

“According to Van Helmont, it was possible, for example, to create medicine to fight urinary calculus by dissolving Ludus in alkahest, not so much because of the mineral but because of the capacity of alkahest to transform it into the source of a cure. Everything was the result of millenary thinking: the solvent was a gift from God when the world was approaching its end,” explains historian Paulo Porto, a professor from the Institute of Chemistry at the University of São Paulo (USP). Ludus functioned like the plastic capsule that today forms the shell of a pill, allowing for the gradual diffusion of medication into the organism. The dilemma for alchemists was to guarantee that alkahest dissolved gradu-

7

The researchers felt the digital catalogues had some limitations and delved into the secret archives, despite the initial incredulity of the English

ally and did not kill patients in the attempt to cure them. “Since the 1640s, the main objective of English science had been to prolong the life of people, and alkahest prepared with Ludus helmontiano was the medicine indicated for this,” says Paulo. For many of his contemporaries, King Charles II created the Royal Society to bring together the greatest minds of the age to produce “the great remedy.”

Because of this goal, the letter aroused the suspicion of the researchers. “How to understand, regarding this ‘great remedy,’ which had been sought for years, that there were no records in the minutes of the Royal Society about the arrival of a sample of one of its components? Everything indicated that we were looking at a ‘secret’ that was valuable to the fellows of the institution,” says Márcia. It was necessary to understand the relationship between Oldenburg and Boutens. The first clue was a letter from September 1667 written by Boyle immediately after the secretary had left prison, where he had been jailed because of his “excessive” contact with people abroad. It was soon discovered that intense correspondence was part of his work. Oldenburg exchanged correspondence with anyone who might have known, or who knew someone who had known, some pESQUISA FAPESP z 57

T

1

1 Brazilian researchers sitting in a research room at the Royal Society 2 Interior of the institution’s archives 3 Decree establishing the Royal Society, with an effigy of King Charles II

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secret about the “Art.” The various spies he spread throughout Europe informed him of any experiments.

The first thing he did after leaving prison was to write the letter to Boyle.

“You mention a box that I believe was addressed to me. It’s Ludus from Antwerp. Feel free to open it and, after, send it to me with your opinion as to whether it is genuine Ludus.” Several subsequent letters, with the same tone of humble supplication, were not sufficient for Boyle to honor his request, and Oldenburg never laid hands on the 58 z january 2013

precious box. The archives gradually revealed the links between the secretary and Boutens, the alchemist from Antwerp. In November 1667, Oldenburg wrote to the alchemist, “I learned from a friend in Paris [certainly one of his spies] about your great predisposition to curiosity and your special inclination towards the solid philosophy that is based on the observation and experiments we are trying to establish here in the Royal Society. I was also informed of your untiring attempts to discover the secrets of nature by the good path of chemistry.”

he epistolary seduction goes further. “I’d like you to know that the English admire chemical operations carried out by men of good sense who are free from the common prejudices imposed worldwide by the some people who intend to talk dogmatically without any preliminary critical experimentation, as the excellent Mr. Boyle found it necessary to do in his Sceptical chymist (1661),” he continues. “We know that there is Ludus helmontiano in abundance in your region: I would earnestly ask you to send it to us in London by sea.” In December, the reply arrived from Boutens: “I’m going to send more than 70 kg of Ludus with a description of the method I use to make the remedy.”

The payment from the impoverished Royal Society was made in books that were much sought after by alchemists.

The letter was enthusiastically received by the members of the Royal Society, as was another letter written by Boutens some months later, describing the places Ludus could be found. This correspondence, however, was not continued, and only in June 1675 did another letter from Boutens appear: the one attached to the sample of the “extremely secret powder.”

Oldenburg, however, did not reply to the letter. Initially, the researchers attributed this atypical attitude of the secretary to excessive work. However, they discovered another reason. Francis Mercurius, son of Van Helmont, was in England during the same period and clearly had knowledge of his father’s many secrets; he even brought samples of his materials with him. Junior, as he was known, quickly grew close to the great English academics. Through Henri More, he became the mentor of Lady Anne Conway, a victim of terrible migraines that Harvey was unable to cure. In addition to More and Ralph Cudworth, Anne’s circle included leaders of the Platonists from Cambridge and an experienced laboratory man, Ezekiel Foxtrot, a friend and collaborator of Newton. “What united them was a concern about the radical skepticism of the period, which they tried to combat with ‘rational’ acceptance of Biblical prophecies mixed with millenary views.

To justify the new skeptical scientific universe, they assumed the ideal that they lived in times like those described in the books of Daniel and Revelation,”

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For Rattansi, the findings mean that the intellectual origins of sixteenth- and seventeenth-century science must be revised observes Rattansi. Daniel believed that knowledge would increase as mankind approached its end. This was the daily reality of the seventeenth century and is present in the dialogue of Junior and Lady Conway. The two ultimately converted to the Quaker sect; Quakers were notorious millenarians and supporters of these ideas.

Junior took to England samples of his father’s secret materials, among which were pieces of the precious Ludus. One of these pieces was given to Foxtrot, who passed it on to Newton, who gave it to

the naturalist John Woodward. “Newton gave me a piece of material brought from Germany by the young Helmont as being the true Ludus from his father, which in my view is in no way different from what is found here in England,” the disbeliever noted. Newton’s interest in alkahest and other alkahest-like materials was profound, and this interest is now apparent. What of the box sent to Oldenburg years before? “Boyle took it and handed it to Locke, one of his favorite men in the laboratory, for him to analyze,” says Ana.

“Such revelations expand the spectrum of the complex link of the English circle with nascent science and the debates that were going on, such as those between the empiricists and rationalists, begin to lose sense,” affirms Rattansi.

According to the professor, the findings oblige us to revise the intellectual origins of the sixteenth and seventeenth centuries. “Aristotelian science was discredited as being sterile. There was then a split between ‘mechanistic philosophy,’ based on Galileo and Descartes, and heterogeneous groups of ‘nature philosophers,’ especially the neo-Platonists and hermeticists. The differences between the groups was not very strong: they were anti-Aristotelian; they advocated observation, experimentation and experience, to the detriment of abstract thinking; they preached that science and religion supported each other; both dreamed about improving and spreading knowlpESQUISA FAPESP z 59

1 Façade of the Royal Society in London 2 Second-floor hall, with the door to the library 3 The institution’s seal, with its motto Nullius in verba: one cannot trust words alone but experiments

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edge about nature for practical purposes,” the professor noted.

However, although one group believed that behind all of the changes in nature was the mechanism of matter in movement, others saw these changes as a game of secret sympathies and antipathies acting at a distance. “For the mechanists, there was a division between the inanimate world of matter and that of the soul and intelligence. The hermeticists, on the other hand, believed that everything had life and understanding. In short, the beliefs were divided between those who had a magical and enchanted cosmic view, which was full of prodigious happenings, and the mechanists, who chose to view the world as being sober and disenchanted, being mainly concerned with the daily course of nature,” explains Rattansi.

Shortly before the Glorious Revolution, hermetic science took over in England because it contained the ideal of a new natural philosophy as part of a great reformist project. This explains the initial harmony between the powerful currents of revolution and the hermeticists; the Puritans were partly responsible for disseminating this enchanted and reforming view. In times of war, famine and poverty, any current that preached the realization of ways to improve daily life, agriculture, education and health for all had great popular appeal. Therefore, some groups began to preach extensive reform, such as 60 z january 2013

2

Samuel Hartlib and his Invisible College, supported by the maxims of a Czech, Jan Comenius. Comenius was invited to England, where he wrote extensively about education, employing ideas that combined alchemy and natural philosophy.

Among his proposals was the creation of universities in every city. Even Boyle and others who founded the Royal Society and who sympathized with the cause of Comenius began to fear for order and stability in this climate of sectarianism.

England began to be invaded, this time by the new and “sober” doctrines of Descartes and de Gassendi. This invasion included a notable number of con-

versions to mechanistic science, which began to be appreciated as the most appropriate type of science, a synthesis between theology and natural philosophy. If the Universe was like a machine, this doctrine pointed to its creator. “In seventeenth-century England, it was usual for the study of natural philosophy to harmonize with the mystic and theological view of the world; hence, the worship of Newton. But not just of him, as we now know, but of prisca sapientia, knowledge of the classics that he and others believed to be truths revealed by God to the first inhabitants of the Earth,” says Rattansi.

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The archives of the Royal Society are a salutary reminder of the many currents that brought about the scientific revolution of the seventeenth century Thus, the professor suggests, the researchers’ findings reinforce this revisionist perspective of the scientific revolution because even after the acceptance of mechanistic explanations, the problems that attracted the attention of rationalist figures such as Newton and Boyle were the same ones that concerned the hermeticists: transmutation and the alkahest; the action of the powder of sympathy; the influence of constellations on men; and the use of magisterial formulas for medicinal purposes. “What we find in the archives of the Royal Society are salutary reminders of the many currents that competed in the scientific revolution of the seventeenth century.

These are reminders about the extent to which the creators of modern science, like Newton, still used the hermetic tradition along with natural philosophy,” observes Rattansi.

“Medical problems have always driven interests, and the doctors were always an extensive community. The people who looked at a wider context, such as Isaac Newton, always existed in smaller numbers, even in the seventeenth, eighteenth and nineteenth centuries.

For example, in 1820, there were just 100 people on that island to carry out research. Science was not seen as something that could solve the problems of technology or medicine because there was no investment in human capital for working in these areas,” remembers historian Frank James, the chairman of the Royal Institution.

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n James’ analysis, “It’s clear that Newton’s work on the force of gravity is associated with his experiences with alchemy, precisely because these concepts were not considered in the philosophic thinking of that period. This is why other authors have a problem with Newton’s ideas, given that they do not necessarily acknowledge that the origins of his postulates are legitimate. Only Newton knew of the validity of his studies because much was based on his work as an alchemist.” Rattansi agrees: “Newton only made his discoveries when he made use of all manner of knowledge, which allowed him to see what the ‘rational’ thinkers were unable to see.”

Historian Michael Hunter, from Birkbeck College, London, sees “exaggeration and inconsistency in these statements.

Some individual members may even have dabbled in alchemy or in a search for miraculous cures, but they left this aside when they joined the Royal Society, which outlawed looking for magic to the detriment of the study of natural philosophy, of which the institution was the biggest propagator, publicly,” says Hunter.

“One must keep in mind that the Royal Society functioned as a corporate entity and played a fundamental role in establishing the boundaries of what was or was not science,” he observes. According to Hunter, in the Philosophical Transactions’ articles, when alchemy was talked about at all, it was addressed tangentially.

This was a point of honor for their editor, Henri Oldenburg, who rejected “magic.” “We rarely find laboratory investigations linked to alchemy, particularly because the intellectual audience of the time rejected supernatural things, and

entering this field would mean tarnishing the reputation of anyone who did it” says Hunter. It is worth remembering, however, that the researchers found a document, written by Oldenburg, listing “the experiments carried out at the Royal Society during the stewardship of Sir Murray,” among which was alkahest.

Nevertheless, the most important point in this story, which today might go unnoticed, is the standardization of ways of thinking and operating in the laboratory. “In a world in which alchemy worked with secret theories and prescriptions, each group of academics had different ways of thinking and working with the subject. The work of the Royal Society and Oldenburg, therefore, can be seen as a way of bringing together these disparate groups and establishing standards of work in the laboratory that could be repeated, as modern science preaches,” says Ana. This issue is present in the correspondence of the secretary with the Venetian hermeticist doctor, Francesco Travagino.

Oldenburg discovered that his Italian friend had changed common mercury into pure silver, and he wanted the recipe.

When Travagino sent it, he bemoaned that he had been incapable of repeating the deed. Oldenburg’s reply reveals just how anxious people of the time were to find a modern path for laboratory science. For Oldenburg, one of the greatest difficulties in any procedure was knowing the origin of the material, which was one of the rare parameters. “Just like Boyle, Oldenburg thought about clearly defined standards so that the experiment could be reproduced and universally accepted,” observes Márcia. The letters reveal that the first secretary of the Royal Society perhaps had been more than an “intelligencer,” exchanging ideas with great figures such as Boyle. As an immigrant who was always viewed with mistrust and aware of his position as secretary, Oldenburg preferred to share his ideas and laboratory experiences with other members of the society. In doing so, he obtained an official position and a better salary.

We move on, then, to a new mystery about the possible swallowing of hermetic preparations by notable figures of the time, with dramatic outcomes. The researchers are investigating history to tell it with documents. n pESQUISA FAPESP z 61

Foreign Relations y

Dance of the wheelchairs at the United Nations The idea of Brazil on the Security Council, seen as a “whim” by analysts, came from the United States Carlos Haag

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he star of the meeting, Rui Barbosa, confessed his disappointment with the course of events at the Conference of The Hague in 1907, “but its invisible results went far because they showed the strong nations how necessary the weak were in preparing peoples’ rights.” This concept of dominance in asymmetrical power relations through ideal forms of diplomatic interactions in which the egalitarian statute is essential persists in Brazilian diplomatic discourse. This is especially true in the country’s candidacy for a permanent seat on the United Nations Security Council. For many analysts, this aspiration is a misperception of Brazil’s true international stature, a desire for status that, if achieved, would result in a high financial and military burden.

These critics even claim that the Executive’s recent action in this sense is an “obsession.”

History reveals, however, that the pretension of being the “sixth member” of the Council is not the result of a distorted view but has formed part of the agenda of the United Nations Organization (UNO) since its creation. “In the 1944 Dumbarton Oaks Conference that brought together the allied powers, proposals were approved for the creation of a new international organiza62 z January 2013

tion charged with maintaining future peace, by force if necessary. Brazil, which was absent from the meeting, was the only country considered to hold a sixth permanent chair on the future Security Council,” says diplomat Eugênio Garcia, full professor at the Rio Branco Institute and author of O sexto membro permanente: o Brasil e a criação da ONU [The sixth permanent member: Brazil and the creation of the UN] (Contraponto). The suggestion came from President Roosevelt, who instructed his delegation to work for Brazil’s candidacy. Being part of the body that held real power in the UN and was responsible for global security was a consummate dream, a privilege of the so-called four police forces: the United States, Great Britain, the Soviet Union and China. France would subsequently join these countries to form the P-5 group.

“I reported to the president that we had raised the question of a permanent place for Brazil on the Security Council, which the Soviet and British groups opposed, and that to press for it at this juncture would not be advisable. The president finally agreed not to include Brazil in the initial draft, but that a general clause should be included in the proposal in such a way as to leave a door open so that working with Stalin and the

British prime minister, he might touch on the subject again in the future, before the organization started functioning,” wrote the American Under-Secretary of State, Edward Stettinius, in his personal diary in August 1944. Days later, he added, “I delivered to the president the memorandum about Brazil, which recommended that we do not press for a permanent place for Brazil. In principle, he did not like it, but later agreed. The president declared that this was important because in the future he might want to propose a place for an Islamic country and Brazil was a hidden trump card for subsequent use.”

The mission of the group, which was placed above a general assembly of “smaller” countries, was to share the “security” role between various regions, thus relieving the United Sates of the burden of having to intervene militarily worldwide. “The Brazilian government was not consulted and only found out about the proposal in October 1944, when the draft of the Charter that had been approved in the secret meeting was disclosed. The initiative had not come to maturity in American decision-making circles, but, just as he included China in the group despite the resistance of other allies, Roosevelt thought that the suggestion would succeed,” observes Garcia. An

un

Published in July 2012

Bertha Lutz signs on behalf of Brazil in San Francisco Conference

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internal memorandum from September 1944 reported to the Department of State a conversation with the Brazilian representative in Washington: “The ambassador explained the difficulties arising from the complete ignorance in which they were being kept with regard to the Dumbarton Oaks negotiations. He said that President Vargas was very embarrassed to have to admit that they only knew what had come out in the press and that even the Argentinean government was as well informed as they were.”

RIO BRANCO

The immediate resistance of Great Britain and the Soviet Union was linked to Brazilian pro-Americanism, which had been explicit since the time of Rio Branco. The members of the Council used to say that Brazil would be a “double vote” for the United States. Even the American delegation advised Roosevelt against Brazil’s admission to the Council because the United States would be “responsible” for Brazil’s performance. It was therefore agreed that Washington’s support would be limited to the candidacy of Brazil to a temporary place on the body, which occurred in 1946.

“However, the arguments were very selective. It was said that military power was a condition for a seat, but at the time, China only controlled a fraction of its own territory. The American imposition was strategic, to strengthen the Asian ally in the struggle against Japan,”

The United States changed its mind and was only prepared to defend Brazil’s position as a non-permanent member

according to Eugênio Garcia. Great Britain, which opposed Brazil, set aside its restrictions on new members to give a seat to Gaullist France. In Catete, Roosevelt’s attempt was greeted with enthusiasm and was seen as a reward for being the only South American country to send troops to Europe.

It was also a chance to settle accounts with the great powers after the disastrous episode of the League of Nations in 1926, when the administration of Arthur Bernardes bet everything on the “natural candidacy” of Brazil to be a permanent member of that body. Passed over for Germany, the country withdrew from the in-

stitution. A seat would lead to a return of Brazilian multilateralism with a universal scope. Vargas, who personally directed Brazil’s foreign policy (to the detriment of the Foreign Office of his friend, Oswaldo Aranha), had faith in his personal friendship with Roosevelt and bet on a bilateral conversation to bargain for his place on the Council. Later, resigned to a provisional seat, Vargas’ diplomacy remained focused on the Council. “Brazil chose this option because it saw that the main game would be played out there.

That Vargas made this decision is noteworthy. Despite his focus on economic development, he had given up going after a role for Brazil in the international security sphere,” says Garcia.

The “special” relationship with Washington meant that Brazil maintained its weak ties with its neighbors, who reacted by “turning their backs” in mistrust, especially Argentina. “Vargas, however, wavered between being aligned with the United States and guarding against the deterioration in relations with the Argentineans,” says Garcia. After all, between 1944 and 1945, with the end of the conflict, Brazil was no longer a strategic partner, and the United States began to distance itself slowly from its “loyal friend.” Roosevelt’s death in 1945 finally buried the era of “special” bilateral relations. The São Francisco Conference was convened in that year to formalize the proposal of Dumbarton Oaks with the “45 smaller countries.”

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photos un

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1 Dumbarton Oaks conference, in 1944, where the UN was “invented” 2 Dutra (center) looks at the UN building project, in 1947

PRESSURE

Several countries were pressured to establish relations with the Soviet Union as a condition for participating in the conference and in response to complaints from Stalin. Brazil was the first to be “worked on” by the Americans. Since 1917, the country had not had diplomatic ties with the Russians. Vargas reluctantly found himself constrained into reaching an agreement with Moscow.

The friendship lasted a very short time; in 1947, President Dutra, caught in the crossfire of the Cold War, broke off relations with the USSR. However, the pressure of 1945 had already set the tone for the encounter, which was merely to ratify the decisions of the “Police Forces,” including the veto power of the Security Council. The conference served to maintain the essence of the Charter “by force”; either they maintained the prerogatives of the permanent members, or, it warned, there would be no organization at all.

Faced with the threat of the conference being a total failure, Brazil, which from the beginning had opposed granting the veto, retreated and accepted the terms. Before giving in, the Brazilian delegation proposed a review of the Charter in five years with the “Velloso amendment,” named after the foreign minister who had substituted for Aranha. The five-year review mechanism would be the responsibility of the General Assembly, which would have constituent powers to change the Charter by a two-thirds majority vote without a veto. That was also defeated. The only notable outcome was the participation of Bertha Lutz, the least conservative choice

by Vargas for the delegation, who strongly argued for the rights of women.

“Brazil bet on American intercession as a shortcut to its objective, but the strategy failed because the United States no longer saw the country as strategically vital. When the Brazilian government was extremely anxious to gain recognition for its loyalty to harvest the fruits of

the special relationship it believed it had with the United States, the latter abandoned the country. It was the beginning of the disenchantment,” observes Garcia.

If the country had gained a seat in 1945, it would have been through American intervention, as in the case with China, or, going back further, in the same way that Brazil had entered the Council of the League of Nations in 1919 on the suggestion of President Wilson. What was left were concessions, such as a temporary seat (already occupied approximately a dozen times), the participation of Oscar Niemeyer in the team that designed the UN headquarters building in New York, and Aranha’s invitation to preside over the prickly 1947 session of the General Assembly that ratified the partitioning of Palestine. The strong still did not recognize the necessary role of the weak in preparing the rights of the people.

In 1989, then-President José Sarney gave a speech in front of the General Assembly that once again touched on the subject of the Council seat. In 1994, during the Itamar Franco administration, Brazil officially re-launched its candidacy for a permanent place and acted in favor of reform of the Council. During the Lula administration, reform and the Council seat became the main topics of his foreign policy, and in 2003, in his first speech at the UN, the president openly defended the project. This was the same attitude adopted in 2011 by President Dilma Rousseff, who insisted on arguing for Brazilian candidacy.

For Eugênio Garcia, Brazil’s chances today are greater. He warns, however, “The permanent chair does not mean that Brazil has been transformed into a ‘world power’ from one day to the next but that the Council has opened up to developing countries by accepting them as permanent members via election in the General Assembly.” According to Garcia, the body, which is extremely important, does not reflect reality in its composition. “It needs to be more representative to be more legitimate and effective,” he observes. Garcia believes that the country is prepared for this function.

“If in 1945 President Roosevelt thought Brazil could be a council member, when the country was very much less than it is currently, why can’t Brazil today be the sixth permanent member? This needs to be thought about,” he says. n pESQUISA FAPESP z 65

Art

Nanotechnology and art Published in July 2012

What appears to be moving strips of woven fabric is actually a pile of iron oxide nanoparticles. This is a photo of a type n semiconductor, which is used to capture photons (light particles) for transformation into electric energy.

Photos of nanoparticles are acquired with an extremely high-resolution electron microscope and are subsequently colored by researchers or technicians. “The habit of painting photos of nanometric formations has given rise to nanoart, for which there is now guaranteed room in gallery exhibitions worldwide,� says Elson Longo, coordinator of the Interdisciplinary Laboratory of Electrochemistry and Ceramics (Liec) at Universidade Estadual Paulista (Unesp), Araraquara campus. The photo, named Spirals, was exhibited at a show in New York in 2011.

Photo taken and colored by Rorivaldo Camargo and submitted by Elson Longo, both from Liec/Unesp

66 | January 2013