MIGUEL BOYAYANThe Molecular Cardiology Laboratory analyzes the genes responsible for arterial hypertensionMIGUEL BOYAYAN
The Heart Institute (Incor), of the School of Medicine of the University of São Paulo (USP), is expanding its areas for research. The Genetics and Molecular Cardiology. Immunology and Vascular Biology laboratories have been in operation since the beginning of the year, on the last two floors of Incor’s new building, in a total area of 2,400 square meters. The Bioengineering laboratory will shortly move into an area of 1,800 m2 in the same building. Every year, Incor invests about R$ 15 million on research, without taking into consideration expenditure on infrastructure, which, in the case of the new laboratories, added up to something like R$ 4 million.
“A university hospital cannot just provide medical services. It has an obligation to develop applied research, to the benefit of the patients themselves”, explains the institute’s director, José Antonio Ramires. Since the beginning of the 80’s, the Heart Institute has been carrying out cutting edge research aimed at cardiovascular diseases. In the beginning, the main areas for investigation were those of bioengineering and immunology, because of the needs for perfecting transplant technologies. “Today, there is a wide range of research. Molecular genetics, with its applications in cardiology, is one of our day-to-day tools”, explains Ramires.
For example, its laboratories are carrying out the mapping of the genes responsible for arterial hypertension, developing a vaccine against rheumatic fever, and, in addition, studying the enzyme responsible for vascular stress.Incor attends to 250,000 patients a year, and is considered the largest hospital in Latin America. It carries out an average of 3,800 surgeries and 11,000 catheterizations a year. The original areas occupied by the laboratories became incompatible with the new demands for research, and the project for the construction of a new building, inaugurated in August 2000, was resized so as to allow scientific investigation to be expanded.
The Genetics and Molecular Cardiology Laboratory, for example, left behind a small space in the Hemocenter to occupy the whole of the 10th floor of the new building. According to Incor’s director, the Genetics and Molecular Cardiology Laboratory was planned to meet the needs for the development of therapeutic genetics for the next 15 years. The architectural project was inspired on the model used by laboratories of Harvard University, in Boston: the main researchers’ rooms, management, meeting rooms and workstations are arranged around areas for common use, where the genes sequencers, the bacteriology sector and radioactive material are located, among others, as well as a large research laboratory.
At the entrance to this laboratory, an area baptized as the “hall of ideas” was built, equipped with blackboard and stools with prints that resemble the nitrogenated bases of DNA; it is used by researchers for presentations and debates on their projects. Also provided for is space for the installation of two work modules, with specific laboratories, where researched will be done into viral vectors and genomic expression, and four rooms for human physiology, equipped with a ecocardiograph for observations of the cardiac function. “We can also call on support from a bio-IT group”, adds director José Eduardo Krieger.
The equipment, which is of the latest generation, was purchased with support from FAPESP, the Financier of Studies and Projects (Finep), the National Council for Scientific and Technological Development (CNPq), and a small participation of the pharmaceutical industry. The laboratory’s main focus for research is the mapping of the genes responsible for arterial hypertension. Krieger explains that the goal is to understand the workings of the system that controls the pressure, observing the behavior of the angiotensin converting enzyme (ACE) – which works as a marker for diseases in rats, and seems do the same job in human beings -, its biological importance and its genetic variation in the population (please see Pesquisa FAPESP number 69).
With this expansion in its space for research, the laboratory will intensify the use of genic and cellular therapy for cardiovascular problems; this has already been carried out on animals, and, according to Krieger, it will shortly be tested on human beings. There will also be an expansion in the analyses of candidate genes, identified as being prime suspects in vascular diseases. “With the results of the Genome Project, it is possible to look for variants of the gene and carry our studies on association, and, at the same time, to carry out studies on the behavior of the population”, says Krieger. In partnership with the Federal University of Espírito Santo, the laboratory is beginning studies on candidate genes in a population of 1,600 inhabitants of the city of Vitória.
Immunology
Created in 1985, the Immunology Laboratory used to share its space with the Tropical Medicine Laboratory, until it was transferred to the 9th floor of Incor’s new building, to occupy an area of 850 square meters. From the outset, its activities have been linked to the study of histocompatibility for kidney, bone marrow, liver and heart transplants. “Today, we are a laboratory that is a point of reference for the state of São Paulo”, says director Jorge Kalil. More recently, it incorporated into its line of research investigations into cardiac immunological diseases, such as Chagas’s disease and rheumatic fever, the latter responsible for operations to replace heart valves, very common in Brazil.
Rheumatic fever is an auto-immune disease, resulting from a streptococcus infection in the throat that has repercussions on the heart. To fight it, the laboratory is working on the development of a synthetic vaccine against rheumatic fever, since a vaccine produced from the bacterium could unleash the disease, Kalil adds. Studies will be started in the next few months to develop immunology for arteriosclerosis. In all its research lines, the laboratory makes use of molecular biology techniques, and proteomics in its studies of peptides and proteins.
Along with clinical and allergy institutes of the Federal University of Bahia (UFBA), the institute is part of the Institute of Investigation into Immunology, one of the Millennium Institutes selected by the Ministry of Science and Technology (MCT), that will be receiving funds in the order of R$ 4.5 million for financing research over the next three years. Kalil explainsthat the objective is to take the knowledge accumulated at the laboratory benches to be applied in medicine, addressing not just the treatment of infectious diseases, but also allergies that affect one third of the Brazilian population.
One of the proposals from the Institute of Immunology is to develop allergenic preparations with improved standardization, so as to create products with less collateral effect and greater efficiency. Kalil recalls that there have been promising results in animals and human beings with the use of peptides in specific immunology, a DNA vaccine, CpG oligonucleotides and vaccines with microbacterial antigens, which leads one to believe that, in future, it will be possible to prevent or to cure atopic diseases, though the immune response.
“Once again, we will be joining our capacity with that of the Butantan Institute, with which we have already developed the Anti CD3 vaccine, with the Federal University of Minas Gerais (UFMG), which is working with the DNA vaccine, and with the University of Brasilia (UnB), in the study of monoclonal antibodies”, Kalil reports.
Vascular Biology
The Vascular Biology Laboratory, which is run by Protásio Lemos da Luz and Francisco Rafael Martins Laurindo, uses an area of roughly 170 m2, next door to the Immunology Laboratory. “Protásio started research work in the experimental division of the Physiology Laboratory, studying ischemia of the myocardium in animals”, says Laurindo, who was his supervisor at the time. Today, Protásio runs the Clinical Arteriosclerosis Group, and shares with Laurindo the coordination of research into Vascular Biology, which has molecular physiology as its main focus.
One of the projects developed by the laboratory is a thematic project, financed by FAPESP, which has the objective of studying the oxidized NADPH enzyme, which is responsible for vascular stress. The project is being done in partnership with Hugo Monteiro, from the Hemocenter. The expansion of the area of the laboratory will also make it possible to broaden the lines of research.
One of the proposals is to go ahead with the analysis of the role of the superoxide dismutase enzyme – in vascular lesions. This is a protective enzyme that becomes deficient after the vascular lesion, but which recomposes itself when there is a response in the animal organism. “We are now assessing polymorphism in the gene of the NADPH in human beings, to check whether there are similar alterations or not, and if it related or not to a greater occurrence of heart attacks”, Laurindo explains.
In his assessment, the expansion of the area of the laboratory and in its research lines is a result of the good interaction between Incor and the development agencies, above all FAPESP. “We wouldn’t be able to carry out these changes on our own”, he comments. “The major part of the laboratory equipment was purchased with funds from FAPESP and Finep, and all the furniture was bought with funds from the Foundation’s Technical Reserve”, were examples he gave.
Bioengineering
Incor is doing a new evaluation of other traditional research areas, such as bioengineering, explains Ramires. The laboratory will be transferred to the new installations, equipped to carry out studies with ceramics, electronics, tissue culture and molecular biology.
The return from the investments lies in perfecting the way of treating the disease and in the benefit that this brings to the patients. “The improvement in the knowledge of the disease and of the processes for treating it also contributes for other centers to adopt the same procedure. This is where a teaching hospital is important”.
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