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No advances without them

Experiments with animals are still being conducted, contrary to what activist claim

miguel boyayanNine out of every ten experiments make use of rodents, which are cheap to maintain and easy to handlemiguel boyayan

The City Council of Rio de Janeiro passed a bill between Christmas and New Year’s. If this law goes into effect, it will obstruct a significant portion of the scientific research projects conducted in this city by institutions such as the Oswaldo Cruz Foundation (Fiocruz), the federal and state universities of Rio de Janeiro and Inca, the National Cancer Institute. The bill of law, submitted by TV actor and city councilman Claudio Cavalcanti, makes it illegal to use animals in scientific experiments in Rio. “A human being who tortures creatures unable to defend themselves, beings that scream and cry in pain – whether the human being is a scientist or a psychopath – is the scum of the earth,” justified Cavalcanti, a well-known animal-rights activist, when explaining his proposed bill.

The academic community reacted. The strategy was determined in the first week of January, at a meeting between the Rio de Janeiro state secretary of science and technology, Alexandre Cardoso, and researchers from several institutions. The federal congressmen representing the State of Rio de Janeiro will be requested to help approve a bill that has been analyzed by Congress for the last 12 years, and that establishes the rules for the careful use of animals in experiments. The city law would become ineffective if the federal law submitted to Congress were to be approved. Concurrently, the researchers also decided to disobey and disregard the city law. “We will continue working with laboratory animals, whose protocols were approved by the ethics committees, and with animals from the research institutions,” says Marcelo Morales, president of SBB, the Brazilian Biophysics Society and a professor at the UFRJ, the Federal University of Rio de Janeiro; he is one of the leaders of the scientific community’s protesters.

The interruption of lab tests would promptly lead to nationwide problems, such as the lack of vaccines, including the yellow fever vaccine. Quality control of vaccines manufactured in Rio by Fiocruz is done on lab animals. The inoculation of mice attests to the quality of the antigens before they are applied on people. Without being able to use lab mice, the distribution of vaccines such as the ones for hepatitis B, rabies, meningitis and tuberculosis (BCG) would have to be suspended due to safety issues. “It is also crucial to clarify to the population that if these experiments are forbidden in our city, all of our recent efforts to develop vaccines against dengue fever, Aids, malaria and leishmaniasis would be thrown out the window,” says Renato Cordeiro, a researcher at the Physiology and Pharmacodynamics Department at Fiocruz. Marcelo Morales lists other losses. “Research based on stem cells in the fields of cardiology, neurology, lung and kidney diseases, led by UFRJ researchers, and on anti-cancer therapies, conducted by Inca, would have to be put on hold,” he states.

The controversy in Rio de Janeiro is worrying researchers from all over the country because it is not an isolated case. In November, city councilmen from Florianopolis also prohibited the use of animals for teaching and research purposes. In 2005, the São Paulo State Assembly approved a law which puts limits on rodeos and slaughterhouses, and prohibits the use of animals in pain-causing research. This law still needs to be regulated and its constitutionality is being challenged at the Federal Supreme Court. “The pressure is getting stronger and we are unable to explain to the population what is at stake,” says João Bosco Pesquero, a professor of biophysics at Unifesp, the Federal University of São Paulo, and general director of Cedeme, the university’s Center for Development of Medical and Biological Experimental Models. “People are against using animals in research, but they don’t realize that this is fundamental for the development of the medication they purchase at drugstores and that it has enabled progress that has led to increased human life expectancy,” points out Pesquero.

Walter Colli, a professor at the Chemistry Institute of USP, wrote an article in October 2006, together with Maria Júlia Manso Alves, published in Ciência Hoje (Science Today). In the article, the professor writes that scientists need to publicize science and scientific methods more clearly, in order not to lose the support of public opinion for an activity that is essential for progress. “Until recently, scientists were seen as benefactors of humanity. However, scientists are now often seen as cold, calculating professionals devoid of feelings. Groups that have this opinion are mistaken, as no scientist deliberately derives pleasure from mistreating animals,” wrote Colli.

The heated battle going on in Brazil sounds familiar to countries like the United States and England, where vocal activists usually hold protests at universities and have even physically attacked researchers involved in experiments. In our country, the guarantee that animals are treated ethically stems from restrictive laws, which in general forbid the futile use of these models and demands transparency from the scientists. British laws regarding this issue have been in effect since 1876. International experience has inspired Brazilian researchers to advocate that the bill submitted in 1995 by former congressman Dr. Sérgio Arouca (1941-2003) be passed. The so-called Arouca Bill, for example, establishes that lab animals will only be used if there is no other way of testing the hypothesis under study and that the use of models will be monitored by specific ethics committees created for this purpose by each institution. The entire system would be coordinated by a national committee, comprised of scientists and representatives from ministries. The committee would be responsible for establishing rules related to the ethical use of animals and to ensure compliance with the law.

It is important to highlight that the approval of this law would have very little impact on the routine of the country’s main universities, which in the last ten years have already adapted to the provisions of the Arouca bill. However, this approval would ensure the implementation of the rules by research institutes located in poorer regions, which sometimes cannot afford to properly maintain their lab facilities. In the opinion of Marcelo Morales, president of SBB, the creation of a legal framework is essential and the lack of this framework generates uncertainty, hindering research. “Even when conducting experiments with protocols approved by the UFRJ ethics committee, Leopoldo de Meis, one of Brazil’s most highly regarded scientists, for example, was accused of mistreating animals and was summoned to testify at the police station,” he said. De Meis, a professor at the Medical Biochemistry Institute of UFRJ, was accused, in December 2006, of torturing animals by exposing them to a temperature of 4ºC; the accusation was based on a photograph of his lab, taken by an activist using a cell phone camera. At the police station, the scientist explained that most of the world’s rabbits live in this temperature normally and was released from the police station.

miguel boyayanThe cosmetic industry’s sacrifice of rabbits provided activists with argumentsmiguel boyayan

No smoking
The anti-animal testing activists usually wield an articulate list of arguments, which has won over the hearts and minds of politicians and voters. The main arguments state that the animals are victims of mistreatment and torture. “I state that lab animals live in conditions with nutrition, maintenance and comfort that are better than those of many Brazilians, because it is essential that the animals used in scientific experiments be healthy,” says Luiz Eugênio Mello, a professor of physiology at Unifesp and president of Fesbe, the Federation of Experimental Biology Societies. The rules followed by the animal research lab at Unifesp, which supplies the animals that Luiz Eugênio uses in his research studies on the physiology of epilepsy, state such details as the maximum time (12 hours) that an animal can go without food before it undergoes surgery and the adoption of a ventilation system that changes the air 15 to 20 times per hour in the environment that houses the animals. It is forbidden to smoke on the premises.

As for torture, Luiz Eugênio says that the ethics in research committees implemented since the nineties at all universities and research centers already conduct ethical monitoring of the animals, which includes requirements regarding the use of anesthetics and pain killers and painless euthanasia after use. Agencies such as FAPESP and CNPq also have a number of requirements on the use of animals in research studies. “It stands to reason that if I am testing a medical drug for pain or anxiety, I will not be able to evaluate its efficacy without submitting the animal to pain or a stressful situation. But the type of situation the animal is submitted to is always controlled and quantified; otherwise, it is impossible to measure the result of the experiment,” says Luiz Eugênio.

Another current argument voiced by animal rights activists is that the use of animals has become obsolete, given the availability of alternatives for the experiments. “It is a fact that there are alternatives, but not all of them are valid or can be used. As the alternatives are developed and validated, researchers will be the first to use them. The important issue for the researcher is the validity of the result, whether the result is produced with animals or alternative techniques,” says Marcel Frajblat, a professor Univale, the University of Vale do Itajaí in the city of Itajaí, State of Santa Catarina, and president of Cobea, the Brazilian College of Animal Experimentation. “In the case of medical drugs, they have to be tested on at least three animal species before they are marketed. There are no alternatives, other than animals, to test medication before it is tested in pre-clinical trials on human beings,” says Frajblat. Milton de Arruda Martins, full professor of clinical medicine at FMUSP, gives examples: “Anti-HIV drugs and anti-cancer drugs have to be very powerful and animal experiments have been crucial to evaluate the beneficial effects and the side effects.” Likewise, says Martins, the development of vaccines requires, at some point, that the antigen be applied on a live organism to verify its capacity of producing antibodies. “We have two options: test them on animals or apply them directly on human beings. There is no third option and society needs to know this,” he states.

Granted that the argument of the obsolescence of the animal models is based on suppositions that make sense. In fact, certain uses have been abandoned, some for ethical reasons and, yes, options have arisen that allow animal testing to be eliminated in many kinds of experiments. But new scientific advances, with new questions and challenges that they impose on researchers, lead to new animal testing models arising every day – and there are no reasons to believe that this will change.

Genetic knock-out
Regina P. Markus, a professor at the Physiology Department of USP’s Biosciences Institute and president of SBFTE, the Brazilian Society of Experimental Pharmacology and Therapeutics, provides an example of obsolete use. She recalls that a technique to diagnose pregnancy developed in the thirties: the urine of a woman was applied to female rats and an evaluation was made of whether the uterus had dilated, an effect of the female hormone storm that follows fertilization. “It is obvious that nowadays it does not make any sense to conduct a pregnancy test like this, but the use of this technique led to the discovery of the current pregnancy diagnosis method.” In the eighties and nineties, experiments on animals partially gave way to molecular biology. “The study of genes and proteins through cell models was so widely disseminated that physiological studies involving animal testing lost their importance,” wrote Bianco, associate professor of medicine at Harvard, in his column on the Pesquisa FAPESP website.

A noteworthy event, however, happened in the last few years. The possibility of creating strains of animals through the inactivation or induction of one or more genes created a new impulse for animal testing, as highlighted by Bianco. U.S. geneticists Mario Capecchi and Oliver Smithies and Britain’s Martin J. Evans were granted the Nobel Prize for Medicine and Physiology in 2006 for their creation of a technology, named genetic knockout, which turns off certain genes and monitors the effects of this action, thereby leading to a portrait of the development of the disease. So far, more than ten thousand rat genes were “knocked out” and many other genes are expected to go through this process in the near future. The result is that more than 500 models of human illnesses, including cardiovascular problems, neurodegenerative diseases, diabetes and cancer, were addressed. “The evolution of the knowledge on genomes tremendously increased the use of mice as a research tool,” says José Eduardo Krieger, associate professor of the Clinical Medicine Department of FMUSP and a researcher at the Heart Institute (Instituto do Coração) in São Paulo.

luiz francisco poli de figueiredoSuture training on plastic rats: if an alternative is available, animals are not usedluiz francisco poli de figueiredo

Rational soul
The first known reports on the use of animal testing go back more than 2 thousand years ago, when Hippocrates (450 B.C.) conducted studies that related sick human organs to those of animals for teaching purposes. Investigations using animal models gained a new impetus in the 16th century. In 1638, William Harvey published a book in which he explained experimental studies on the physiology of blood circulation in 80 different species. French Philosopher René Descartes (1596-1650) ratified the experiments when he stated that human beings had a rational soul, whereas animals did not. Britain’s Jeremy Bentham (1748-1832) was one of the first scientists to present a counterpoint to Cartesian reasoning, when he questioned the ethics of imposing suffering on animals. “It is likely that the ideas of Bentham were the basis for the first measures related to animal protection in the 19th century,” wrote Marcia Raymundo and José Roberto Goldim, researchers at the Clínicas Hospital in Porto Alegre, who wrote the article “Ética da pesquisa em modelos animais” (Research ethics in animal models).

The advent of the first animal protection societies in the 19th century mobilized scientists. In 1865, Doctor Claude Bernard vehemently justified the use of animals in his book on the introduction to studies in experimental medicine. “Do we have the right to conduct experiments and vivisection on animals? I believe we have this right, totally and absolutely. It would be strange if we were to accept the use of animals for domestic services, for food, and forbid their use for instruction in one of the most useful sciences for humanity. The science of life can be established only through experiments and we can save live beings from death only after sacrificing others,” wrote Bernard.

In the evaluation of Luiz Eugênio Mello, from Fesbe, advocating animal rights gained prominence in the 18th century with the advent of the concept of the “good savage,” coined by Jean-Jacques Rousseau, in reference to the superior qualities of individuals, in his opinion, who lived in a natural state. “The feeling that man corrupts nature appeared during the Industrial Revolution and never ceased to exist,” he says. “It led to the advocacy of animal rights, to the discourse of environmental activists and, more recently, to opposition to transgenic animals. As a utopia, it is undoubtedly nice, and provides wonderful scripts for Walt Disney studios. But the real world is very different. Many people like to eat meat. Scientific research, which has increased humanity’s life expectancy and made medical drugs and treatments feasible, was entirely based on animal experiments,” he says. “It is utopian to ignore that we depend on eating vegetables and animals to survive. For man to exist, something else has to cease to exist. This is a rule of nature,” states Luiz Eugênio. Marcel Frajblat, president of Cobea, raises the basic issue: society, including the city councilmen of Rio and Florianópolis, have an incorrect perception of how science is produced, associating the use of animals in research studies to mistreatment and failing to realize the benefits of this practice on peoples’ daily lives. “Many of the anti-animal testing activists think much more about themselves and the animals than about the people who need drugs and therapies developed with the help of animal testing,” states Frajblat.

Beneficiaries
The anti-vivisection movement was given a shot of adrenalin in seventies, with a book written by Australia’s Peter Singer, a professor at Princeton University in the United States. Among other accusations, the book shockingly revealed the cosmetic toxicity tests conducted on rabbits’ eyes. Singer is one of the people who coined the word “specism,” a type of discrimination that assumes that the interests of an individual are of lesser importance due to the mere fact of belonging to a specific species. In this respect, strangely enough, there is some room for convergence. The idea that drugs, treatment and surgical techniques should be first tested on animals to then be tested on human beings is undoubtedly based on the notion of human superiority. However, scientists reject the idea that there are winners and losers. “Experiments on animals helped develop treatment, drugs and procedures for the veterinary sciences and nowadays animals also benefit directly from all of this,” says Luiz Francisco Poli de Figueiredo, full professor of surgical techniques at the Medical School of USP.

Sacrificing lab animals is not an issue that has been totally resolved among researchers. Geneticist Mayana Zatz, dean of research studies at USP, advocates the use of animals in scientific experiments. “Without them, all the research into stem cells would have become unfeasible. We cannot apply the results on humans without first testing them exhaustively on animals,” she states. Mayana, however, prefers to delegate this to her assistants who are given guidance when animals have to be sacrificed. “I look from a distance. I don’t like to kill animals, and I don’t like to eat meat. But just because I have a problem working with lab animals doesn’t mean I don’t think they are absolutely necessary for research,” she states. Professor Regina P. Markus, from the Biosciences Institute of USP, is used to dealing with this kind of problem. “I have never seen any difficulties in animals being used by medical students. They know very clearly that this is justifiable, that this means advances in terms of therapies or surgeries. The same does not hold true in the case of biology students. It is common to see this attitude among students who want to follow a career that has a conservationist bias and find it difficult to work with animals. I have witnessed situations in the lab where I had to sacrifice the animals myself because no student volunteered to do this job,” she says. Regina says it is important, in these situations, to refrain from being judgmental. “This is a very personal issue, and one that must be respected. The important thing is to maintain the consensus that the use of animals is crucial for research,” the professor points out.

It must be stated, in favor of animal rights activists, that their activism played a role in the creation of a set of ethical procedures for experiments. An event that took place in 1988 illustrates this influence. At that time, the then mayor of São Paulo, Jânio Quadros, forbade the city’s Zoonoses Center from supplying stray dogs to experimental labs at universities and research institutions. Jânio gave in to the appeals of his wife, Eloá, who loved dogs and believed that stray dogs would have a cruel destiny in the hands of researchers. The researchers reacted very strongly to this and the mayor finally gave in. The years went by and what had been viewed as being essential in the eighties became damning according to current ethical criteria. Many of those stray dogs were being used in classroom experiments during which future surgeons practised their surgical skills, for example. “At present, the use of animals to demonstrate techniques in the classroom has dropped and has been gradually replaced by other techniques. The pressure from animal rights entities and from many students has changed this habit,” says Mirian Ghiraldini Franco, a professor at Unifesp and coordinator of Cedeme. The fact that strays were unhealthy, and might contaminate researchers and students, also helped to eradicate this custom at São Paulo’s institutions. “Nowadays, research is conducted only on healthy animals. International journals no longer publish articles on experiments with unhealthy animals,” says Mirian.

TIM KELLYMario Capecchi and the modified rat: its technology won the Nobel Prize in 2007TIM KELLY

Anti-flight drains
The need to raise quality animals for research has transformed animal research laboratories. The new Centro de Bioterismo (the Live Beings Center) of the USP Medical School of (FMUSP), an investment of R$ 5 million, was inaugurated in 2002. The building was adapted to the standards of the International Council for Laboratory Animal Science/Iclas and of the Association for Assessment and Accreditation of Laboratory Animal Care International/Aaalac, two organizations that regulate this kind of center. Anti-flight drains, paints resistant to cleaning products, steel doors with pneumatic locks, and air conditioning systems – among other materials – were developed in partnership with construction material manufacturers. “It was necessary to invest in big facilities for raising animals, facilities that are expensive to maintain, in order to produce animals more suitable for research, with less genetic variability, raised under controlled environmental and sanitary conditions,” says Roger Chammas, associate professor and director of the FMUSP Live Beings Center.

The rationale related to animal use follows the model proposed in 1959 by zoologist William Russell and microbiologist Rex Burch, who established the three Rs for animal research: Replace, Reduce and Refine, whereby use is allowed but has to be reduced to a minimum and replaced, whenever possible, by other techniques. Last year, the Unifesp lab animal raising facility, which supplies two thousand rats and five thousand mice a month, took a major step toward rationalization. The facility began to charge for the lab animals – the prices range from R$ 5 to R$ 50 (transgenic mice are more expensive). This measure led to a 50% drop in demand, indicating that their use, until then, had been exaggerated. At the USP Medical School, dogs were abolished from experiments and student training in surgical techniques, for example, is done on animals used in important research projects that would have been discarded. These lab animals are always given anesthetics and pain killers. The learning of suture techniques and graft implants, formerly conducted on live dogs, is now performed on dead dogs – and even on cattle tongues purchased at butcher shops. The creation of new student training techniques, such as a simulator for laparoscopic surgeries, which involve the use of a computer screen, helped reduce the use of animals at FMUSP. The simulator submits medical students to real situations, and the students practice on plastic rats and mannequins, on which it is possible to reproduce some real situations. “These resources replace animals efficiently in the initial phase of the training, and they also prepare the students and professionals much better for proper clinical practice,” says Luiz Francisco Poli de Figueiredo, full professor of surgical techniques at the USP Medical School.

Apes
The rationale follows economic requirements. Currently, nine out of ten experiments involve rats and guinea pigs, which are much easier to handle and cheaper to maintain, while the use of cats and dogs has diminished. The zebra fish is increasingly being used as well, as it reproduces very quickly and many of its genes are similar to those of humans. “The use of zebra fish is still in the early stages, but the model is quite promising. The zebra fish is a transparent vertebrate that can be easily observed, is prolific in terms of embryo production and has very low maintenance costs,” says researcher José Xavier Neto, coordinator of the FMUSP’s Multiusers Center of Transgenic Animals and a researcher at the InCor heart hospital.

The use of apes, which has always been controversial because of their similarity with humans, is still controversial and difficult. Nevertheless, monkeys are still considered essential for research into vaccines such as the anti-Aids vaccine, because of the similarities with the human body; in addition, monkeys are becoming increasingly necessary for neuroscience research. “I have never had any problems in getting permission to use monkeys in the United States and I think that the decision of the Rio de Janeiro City Council is absurd, it is a huge step backwards and just plain silly,” says Miguel Nicolelis, a Brazilian professor at Duke University and the author of pioneering studies involving the communication between monkey brains and robotic prostheses.

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