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Luiz Hildebrando P. da Silva

On the banks of the Madeira river

EDUARDO CESARLuiz Hildebrando Pereira da Silva left Brazil in 1964. At the time, he was a senior professor of Parasitology at the Medical School of the University of São Paulo and was organizing the microorganisms genetics laboratory. He was arrested and fired as a result of Institutional Act no. 1 in October 1964. Having sought exile in France, he joined the team of researchers of the Pasteur Institute and tried to return to Brazil, more precisely to the Ribeirão Preto Medical School, in 1968. One year after joining it he was again fired, this time based on Institutional Act no. 5.

So he returned to France and recovered his position at the Pasteur Institute. He headed the Molecular Biology Department and, in 1979, became the head of the Institute’s Experimental Parasitology Unit, as a result of an invitation extended by Jacques Monod, a Nobel prize-winner.  The objective was to research the molecular biology of malaria parasites in Cayenne (French Guyana),  Madagascar and Senegal (Africa). In 1990, while still in Paris, working together with Erney Camargo, from the USP Parasitology Department, he organized a team to research malaria in Rondônia. Having retired from the Pasteur Institute in 1997, he decided to return to Brazil. “I like doing what I know how to do”, he explains.

He established himself in Porto Velho, Rondônia, a state that, as he explains, does not reject outsiders. There he set up the Cepem Tropical Medicine Center, within the Rondônica Health Bureau, and created the Ipepatro Tropical Pathologies Research Institute with a group of physicians and biologists from that state. The two institutions currently have about one hundred professionals, including physicians, researchers, technicians and postgraduate students, all of whom study diseases that are particularly significant in the Amazon region: malaria, viral illnesses such as hepatitis, and arboviral diseases. He hinted his team was about to take out a patent for a chemical based on drugs developed as a result of biodiversity, though he preferred to keep this a secret. At the age of eighty, while he organizes a health action plan for the region in which the hydroelectric power stations of the Madeira river are to be built, he is also starting to plan his retirement, which should be real this time, and move with his family to a little house “over in the Midi area of France”.

How long have you been in Porto Velho?
We’ve been in Porto Velho for ten years, since 1997. At first, we focused on malaria, but little by little we extended our activities to include other viral diseases such as viral hepatitis and arboviral diseases, which are caused by viruses transmitted by insects and arachnids. Recently we started researching problems related to the chemotherapy of disregarded diseases, such as malaria, leishmaniasis and tuberculosis. We are also trying to identify immunological factors to develop serotherapies for viral diseases and specific emerging diseases.

How big is your team?
There are one hundred of us. We started out with a group of ten. In 2001, we set up a partnership with the Rondônia Federal University, the objective of which was to implement a postgraduate program, which comprised master’s degrees and, later on, doctorates. As a result, we now have a student population being trained. At the same time, we strengthened our ties with the federal, state and local health authorities, and we have included people linked to local public health authorities.

Who provides the funding for the center? 
We have government and private resources. The Ministry of Science and Technology, through CNPq (National Council for Scientific and Technological Development) and Finep (Agency for the Funding of Studies and Projects) has provided us with funds. The Health Monitoring Authorities and the Department of Science and Technology, both of which come under the Ministry of Health, also provided funds. We also obtained funding from the Pan American Health Organization, from the World Health Organization and even from France’s Pasteur Institute. In addition, we get financial support from companies such as electric power utility Furnas. We provide high-quality diagnostic services, which yield returns from the SUS, the Brazilian National Health System. We hope to obtain several patents soon, resulting from our work in chemotherapy; this will be another funding source.

Are these patents related to new treatments?
We are conducting research into chemotherapy and serotherapy with drugs based on plants extracted from Brazilian biodiversity. We have a partnership arrangement with a group from the Rondônia Federal University; this group works with the chemistry of natural products and has obtained several active chemical compounds based on natural products. In the case of serotherapy, we have resorted to a technology developed in Belgium about ten years ago, which uses antibodies from llamas. In Brazil, we have been working with antibodies from alpacas. We have improved the product purifying technology and the definition of strategic metabolic targets of the parasites we want to deal with. At present, genetic engineering has allowed us to prepare and purify molecules of the metabolic paths of the tuberculosis-causing bacteria and of the parasites that cause malaria and leishmaniasis. We use special equipment to expose these molecules to specific purified extracts and fractions obtained from natural products in order to identify the products that adhere to the molecules. This is the basis for the purification of these products, which will allow us to identify their essential components and later on to enable us to conduct biochemical analyses to find out whether they are able to block the parasites’ biological activity. We are trying to detect specific metabolic targets. This is only possible because the malaria parasite is cloned and sequenced and we have already unraveled the genome of the malaria-transmitting mosquito. The same holds true for tuberculosis. International scientific literature has allowed us to identify these molecules, to prepare them through genetic engineering and to look for natural products that are active against them.

What is being done concerning serotherapy?
In the case of serotherapy, we are targeting the serious diseases that occur in the Amazon Region that are not being treated properly, such as yellow fever, rabies and tetanus. It is possible to produce the antibodies from the llama species – which are more specific than those of rodents – to recognize the molecular structures of the agents that cause these diseases. The monoclonal antibody of a rodent has a complex molecular structure, while the monoclonal antibody of llamas has a very simple structure which, if manipulated through genetic engineering, can interact with viruses or molecular targets that are strategic for viral de-activation. We injected a de-activated virus into alpacas. Then we isolated the lymphocytes, the cells of the immunity system, which produce specific, single-molecule antibodies. The alpacas produce three kinds of antibodies. Only one of these has a single molecule, unlike the antibodies of other mammals, which contain two pairs of associated molecules. We isolated the variable portion – which recognizes the antigen – of those single-molecule antibodies, and reproduced this variable portion using bacteria and other carriers used in genetic engineering. Thus, we can manufacture the antibody synthetically; this antibody can be mass-produced and then purified.

What stage is the research at?
We are concentrating on yellow fever. We already have efficient antibodies able to recognize the virus. We are also conducting de-activation tests against the rabies virus.

Is there any promising product extracted from the Amazon Region’s biodiversity for leishmaniasis?
We started research into this about two years ago. The study is still very recent and is part of a contract with ten Brazilian laboratories located in the states of Rio Grande do Sul, Rio de Janeiro, Bahia, Ceará, Amazonas and Rondônia. We believe that the scientific activities in our field will include the possibility of applying the findings or of implementing a program that will increase the added value of natural products. Our intention is to enhance the products by exploiting biodiversity. We hope to provide Ipepatro with more visibility by doing so.

How did you manage to schedule these teams to work together? 
The basic initiative of our chemotherapy program came from a group from the Rio Grande do Sul Catholic University, led by Diógenes Santiago Santos and Luiz Augusto Basso; this group has carried out important research on tuberculosis. Diógenes is an old acquaintance and collaborator – we’ve known him since the very beginnings of molecular biology. Older researchers like me have the advantage of knowing everybody – especially highly competent professionals. When Diógenes invited us to join the program, he had already had contact with structural biology professionals such as Mario Palma, from the Paulista State University, Rio Claro campus; Walter Figueiredo, currently teaching at the Catholic University of Rio Grande do Sul; the group led by João Batista Calixto, from the Federal University of Santa Catarina; and Ícaro de Sousa Moreira, from the Federal University of Ceará. Ricardo Ribeiro dos Santos from Fiocruz in Bahia joined us later on. Diógenes was the one who had the idea of proposing that research on malaria and tuberculosis converge. The starting point was the discovery that the tuberculosis bacteria have metabolic paths that are very close and equivalent to those of the malarial parasite. This happens because the malaria protozoa’s genome has a structure that originates from bacteria or single-cell algae. Based on this similarity of the metabolic paths, the theory is that certain products that act against tuberculosis, when properly adapted, should also act against malaria. At present, we are analyzing the effects of isocyanides-derived products on the malarial parasite; isocyanides are the main active drug that works against tuberculosis, and to which the bacteria have developed resistance. Some clues are beginning to appear.

Which drugs are still used to treat malaria?
In Brazil, we’re still using chloroquine, primaquine, quinine, mefloquine, doxycyline, clindamycin or artemisinin. But little by little the malaria parasite is developing resistance to these compounds. Significant progress has been made in the last two years with the introduction of combinations of artemisinin and its derivatives. The most serious kind of malaria in Brazil is caused by the Plasmodium vivax, and not by the Plasmodium falciparum. Here, the vivax malaria has not yet developed significant resistance to cloroquine, which has been used to treat malaria since the forties, when it was synthesized by the Germans. Today, this drug is still used successfully in public health campaigns that target vivax malaria. The control campaign, run in the fifties and sixties by the National Malaria Service, which combined treatment using chloroquine with the use of DDT, an insecticide with residual action to eradicate the malaria transmitting mosquito, led to the eradication of malaria in nearly all of the country, with the exception of the Amazon Region.

But we still hear that malaria has also become resistant to chloroquine in several parts of the world…
The resistance of falciparum malaria to chloroquine was first detected in Colombia, in Asia and in Brazil in the sixties. The resistance spread throughout the world, including Africa. This is why a new treatment, based on quinine in combination with a tetracycline-type antibiotic, was begun in Brazil ten years ago. This treatment had produced good results, but several cases reporting resistance to this combination began to surface in the last couple of years. Coincidentally, this happened at a time when artemisinin was synthesized. Nowadays, we are using an analogous version of quinine, known as lumefantrine, in combination with artemisinin. The brand name of the medicine is Coartem; we have had good results in the case of falciparum malaria. The Ministry of Health assessed the sensitivity in the entire endemic region and so far has not found any resistance to Coartem.

What is the biggest concern, given that resistance to the drugs is not the main problem of malaria in Brazil? Access to the medication? 
Malaria is concentrated in the Amazon Region, in places that have hardly any access to healthcare services. One of the problems is population dispersion, especially in rural areas, where there are no public healthcare services available. Migration is the second problem. The population in the Amazon Region moves around a lot. In the last 40 years, due to all the highways built in those years, people in the region have moved en masse and many of them settled on the fringes of cities. Manaus has the highest incidence of malaria in Brazil because of this migration; many people have invaded the lands around the cities and towns – these regions are extremely unsanitary, with stagnant water, and it is highly unlikely that anything will ever be done to turn them into a healthier environment. This leaves the population highly exposed to the malaria carrying mosquito.

How does migration influence the spread of malaria?
External migration from malaria-free regions moves people who have never been exposed to malaria to a region where the disease is endemic. This is what worries us the most about the Santo Antônio and Jirau hydroelectric power plants on the Madeira River. The problem is not the local population that will be affected by the construction of these dams or the reservoir. This population is small: fewer than ten thousand people. They have always been exposed to malaria, but have become immune to the disease. The migrant population, however, is rising fast. The companies estimate that twenty thousand direct jobs will be generated by the dam construction work alone. If we factor in these workers’ families, then we’re talking about sixty thousand people. The workers will not be recruited only from the local population, and migration has already increased. Of course the power plants’ employees are not the biggest population at risk, as they will be able to rely on help from the construction companies; they will be housed in complexes and will have access to medical care, as our labor laws require. The problem is the secondary migrating population drawn by the demand for services that range from food to prostitution. This is the group at risk, as these people will not have access to the same level of medical care enjoyed by company employees. This secondary group will have to rely on local public health services, which are precarious and can barely deal with the current needs.

What is your opinion on the construction of these new power plants?
The hydroelectric power plants on the Madeira River will expand the supply of electric power. In addition, agreements with Bolivia and Paraguay will enable river travel from Belém to Manaus in the future. All the industrial and agribusiness products from Brazil’s central region and from bordering countries will travel along this waterway. The prospect of building highways from Porto Velho, across Peru and all the way to the Pacific, means it will become easier to transport the products made in inner regions of Latin America to the Asian market. So this isn’t only an issue of hydroelectric power plants. This involves a number of aspects that are important for the region’s development. At the beginning of this year, I gave a lecture at the Pasteur Institute on “How to travel from Belém to Buenos Aires without sailing on the Atlantic Ocean and without catching malaria”.

So what is the secret of preventing someone from getting malaria?
To prevent people from catching malaria in the future, we have to implement sanitary and preventive measures along the valley of the Madeira River, especially in the regions surrounding Porto Velho. The social and economic impact of the power plants and the prospects they will open up justify dealing with the technical and scientific issues related to healthcare very carefully, especially because scientific and technical knowledge has made huge progress since the beginning of the last century, which witnessed the tragic construction of the Madeira-Mamoré railway. We have the means to create exemplary work in terms of healthcare services, capable of blocking the outbreak of an epidemic, and to improve the healthcare services provided to the rural population living along the basin of the Madeira River.

What are the project’s repercussions?
There has been a lot of negative repercussion about technical issues. The project is indirectly promoting increased deforestation in the states of Mato Grosso and Rondônia. This is aggravated by the current mania that everything has to focus on ethanol and biofuel, and by the rise in soy and beef prices on the international markets; all of this encourages deforestation. This control of the consumption and export of primary products in the underdeveloped regions of the country is a major problem. Public opinion is putting a lot of pressure on capitalism in the states of São Paulo, Rio de Janeiro and Minas Gerais concerning ecological balance and environmental protection. But in the Amazon Region, many business and economic activities are still in the hands of predators. In terms of healthcare, the major issue is the health of the rural population. My mentor, Samuel Pessoa,  already referred to these issues back in the forties and fifties: “Why is malaria rampant in the Amazon Region?” And he himself answered this question: “Because there is no organized service that provides healthcare to the region’s rural population.” The two power plants are expected to bring in investments of R$ 20 billion to the region. It will be possible to carry out sanitation works and implement a basic healthcare structure for the rural population. This is the obligation of the Federal Government and of the companies that will build the plants which in turn will increase their profitability. After the start-up of the power plants, Porto Velho, the state capital alone, will be paid royalties of US$ 60 million. This amount can be used as collateral for loans of up to US$ 600 million for sanitation.

Is it possible to control these diseases through sanitation alone?
Sanitation is one of the basic control factors. It is also necessary to improve the basic healthcare structure. The works will facilitate river transportation and it will be possible to navigate from Porto Velho to the south of the state, to the frontier of Bolivia and the State of Mato Grosso. I’m not saying that we have to have medical care units every hundred meters; the idea is to distribute the SUS services, through community healthcare professionals, family care and advanced science and technology centers. We know how to do this very efficiently.

Have the risks of the disease to the population been assessed?
In relation to the risk of an epidemic, first we assessed the prevalence of asymptomatic malaria in the population that will be affected by the construction of the dam for the Santo Antônio plant. We conducted a demographic survey to update the IBGE data; the survey showed that the related total population comes to three thousand people. We analyzed a sample of 1,500 residents and prepared an assessment of the prevalence of malaria. This would have been impossible if we had been using outdated techniques. It would have taken 1,500 work hours for specialized microscopy technicians to do the survey in the past. Nowadays, we conduct this survey by means of a technique known as PCR, which works in real time and analyzes one hundred reactions per day. If the technician has been well trained, you can assess one half of the population in two weeks.

What is the percentage of asymptomatic malaria?
In some regions, we found a prevalence of 50% among adults. When construction began on the Madeira-Mamoré railroad, the region had already been populated by the “seringueiros”, the rubber tappers, who were a source of malaria and who were probably responsible for the initial transmission which resulted in a huge epidemic that caused thousands of deaths. To our knowledge, there are no existing non-human reservoirs of falciparum malaria.  There may be something of this kind in the case of vivax malaria, but we’re still investigating. The asymptomatic population is a reservoir: this population transmits the parasite to the mosquito. The risks increase through disorganized human occupation, which provokes major, never-ending environmental degradation: it creates swampy areas, destroys the native forest and blocks swamped areas. The result is that the malaria carrier proliferates. The surface water has to be cleaned up and the asymptomatic population has to be treated. But this population has to be diagnosed first. And diagnosis cannot rely on microscopes anymore – more advanced technology has to be used for this purpose.

Is the parasite eliminated and the transmission of the disease avoided if the asymptomatic population is treated?
Falciparum malaria does not have a liver reservoir; vivax malaria is more complicated. In fact, we’re doing some research on this: in the case of vivax malaria, we want to find out whether there are any dormant parasites in the liver, which exit from it three months later. In addition to treating the asymptomatic population, on-going surveillance is essential. Every person who has had vivax malaria has to pay constant attention to the risk of facing a recurrence of the parasite. The strategy is to intervene massively in the beginning; this has to be followed by a high-level, permanent surveillance system. We forwarded a proposal to the Ministry of Health and to the Ministry of Science and Technology to partner them in implementing this strategy. The situation cannot remain solely within the scope of the Health bureaus of the city of Porto Velho or of the state of Rondônia. The strategy must be coordinated by the Ministry of Health, as this is an issue of nationwide interest; the local and state bureaus and the construction companies have to be part of this. The start-up of the Santo Antônio plant is scheduled for 2012. So the next few years will probably be very dynamic.

Has the region to be affected by the power plants been assessed yet?
We conducted an overall analysis of the Madeira River valley; the region encompasses 250 kilometers. We have completed an initial analysis of the impact of the first dam; we have also set up a technical assistance agreement with Fiocruz and the local university. The idea is to organize a reference healthcare center in the area under the direct impact of the works and smaller such units for healthcare services and surveillance in the other areas. This healthcare center will be a model. The healthcare professionals will provide treatment for other diseases besides malaria. It will offer basic healthcare assistance, infant and mother care, and prevention of water-borne diseases and of sexually transmitted diseases, not to mention teen-age pregnancies, which are a major problem.

Is it possible to protect these people?
This problem can be dealt with. There were two major accidents in the history of Rondônia. The first one occurred during the construction of the Madeira-Mamoré railway in the early twentieth century. It is estimated that twenty thousand people died for every railroad sleeper laid. At that time, badly prepared and impure quinine was the only drug available for malaria treatment; it was very toxic and was used as a prophylactic agent. Quinine is terrible for prophylaxis because it remains for a very short period of time in the bloodstream. And it is extremely toxic for people with red globule deficiency, such as for ethnically African people. Many workers who built the railway came from Barbados and the Antilles and were of African descent. One must highlight that although many deaths were ascribed to malaria, some of them may have been the result of infectious diseases such as yellow fever or viral hemorrhages, among others. The other accident in the history of Rondônia happened in the sixties, during the gold rush. Things are different nowadays. We have conducted a detailed analysis of those regions that will undergo a major impact from the dams and found that the level of asymptomatic reservoirs of malaria is extremely high. In some places, 50% of the adults are asymptomatic carriers: they have the parasite but have not developed the disease.

How were you able to conduct this survey?
We had funds from the Ministry of Health and from the Ministry of Science and Technology to conduct an in-depth analysis of the health situation related to malaria, to the reservoirs of sexually transmitted diseases, and to arboviral diseases. Furnas provided some funding, which included means of transportation.

Does treating people with asymptomatic malaria bring any results?
We have very little experience. In a specific community, we only treated reservoirs of falciparum malaria. We evidenced that there was a reduction in the transmission of falciparum malaria. But in the case of a combined infection, caused by both Plasmodium falciparum and Plasmodium vivax, the vivax breaks out again when the falciparum malaria is treated. We’re repeating this experiment, which involves treating both forms of malaria at the same time. In places with a lot of population mobility, such as the banks of the Madeira River, the floating population brings in different parasites and the treatment of the local asymptomatic population has virtually no effect. There are no miraculous measures. It is also necessary to deal with the problem of decontaminating surface waters, to control the carrier – in other words, a properly targeted insecticide – and maintain epidemiological surveillance of the symptomatic forms, as well as treating these symptoms at early stages. Our project proposes  a real effort to increase surveillance, to avoid having the disease get out of hand. This is public health. We’re not creating anything new, other than a more efficient parasitological diagnosis using molecular methodology. This can be done in specific regions and it is possible, with funds provided by the construction companies, to disseminate this strategy through efficient epidemiologic diagnosis networks throughout large regions, without having to increase the number of diagnostic units by one hundred or one thousand. The secret is to centralize and create networks. The surveillance network is more complex and involves people who work in contact with the population.

Why did you leave the banks of the Seine for the banks of the Madeira?
I like doing what I know how to do. I worked on malaria at the Pasteur Institute for 18 years, with the prospect held at the time that an efficient vaccine would be developed. With the Pasteur structure, we had the competitiveness required for this. I had a lot of contact with Dakar and Madagascar in Africa, and I became interested in disease control by using the available means rather than vaccines, in control through public health. I returned to Brazil with a lot of experience in malaria and wanted to work in the Amazon Region. Rondônia was the best place to do this, because the population was less resistant to the arrival of outsiders like me. The locals in the States of Amazonas and Pará believe that they have to solve their own problems. They feel they don’t need anyone from the State of São Paulo. It’s different in Rondônia: everyone’s an outsider there. I was just one of many. Nobody resisted my presence. Rondônia has 40% of the malaria cases in Brazil but 10% of the population of the Amazon Region. The situation was very serious and that is where I found the right circumstances for my work. I started studying the science of epidemiology under Samuel Pessoa. We worked in the State of Paraíba in the fifties with schistosomiasis and later on with Chagas disease. I’ve always been interested in field work, in having direct contact with the victims of parasitical diseases, with people who have no access to scientific progress and to new techniques that help control these diseases. It is a challenge for me to set up a lab on the wild frontier, in a region with a high incidence of the disease, and to find out whether it is possible to create a structure in which modern science and technology might have a positive impact on the environment. The impact today is small. It will be useful in the future, but not in the short term.

Do you ever think about retiring?
I don’t know if I will stay here much longer. I’ll stay another two or three years. Then I want to rest. But I’ll always be around to help. I have a little house in the Midi, in France. I might be more useful in France than here. I spent two weeks in Paris fifteen days ago and found it was easier to speak to federal government authorities and to Brazilian ministers from Paris than from Porto Velho. All I have to do is tell the secretaries that “this is Dr. Luiz Hildebrando, calling from Paris” for the government authorities to take the call. Things have become much easier with Skype. I spent fifteen days calling Brazil from France, solving problems.