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clinical testing

With the computer’s assistance

Brazilian and foreign researchers discuss ways to reduce animal testing

Microchip developed at the Wyss Institute at Harvard simulates the functioning of the human lung

Wyss InstituteMicrochip developed at the Wyss Institute at Harvard simulates the functioning of the human lungWyss Institute

The search for alternatives to the use of animals in clinical trials and product testing has intensified in the last decade. One of the best examples of this is the Tox 21 Program (21st Century Toxicology), created jointly by two U.S. federal agencies: the National Institutes of Health (NIH) and the Environmental Protection Agency (EPA). Launched in 2008, Tox 21 uses mathematical and computer models in conjunction with genomics and robotics to study the structure and toxicity of a broad array of chemical compounds. The program’s goal is to understand the ways in which toxins affect organisms and to create methods that can be used to predict whether a potential pharmaceutical should be subject to clinical testing. By ruling out molecules that are dangerous to health in this way, animal testing of compounds previously classified as toxic can be avoided. In a two-year period, more than 10,000 substances were studied. The results are available in virtual form.

“The success of the program’s next phases will depend on stronger collaboration involving pharmaceutical companies,” says Raymond Tice, of the National Institute of Environmental Health Science in the United States, one of the institutions involved in Tox 21. Tice participated in the workshop Challenges and Perspectives in Research on Alternatives to Animal Testing, held at FAPESP in March 2015. Tice believes that the animal testing paradigm does not account for advances that would make the process safer and more precise.

In the workshop, Eduardo Pagani, drug development manager at the Brazilian Biosciences National Laboratory (LNBio), showed how computer models can compare the structure of a candidate molecule with that of other molecules that have already been tested and determine whether or not it is worth developing. The LNBio, which is working in this area, is looking for partnerships; in this case, it wants to work with groups that have mastered the technology known as organs-on-a-chip. This is a technique being studied in the United States and Germany that uses cells to grow human tissue to which microchips have been added and which can therefore mimic the function of live human organs. “We want to work in the area of tissue mimicry,” Pagani says.

Researchers who participated in the workshop brought new perspectives on the use of animal models in research. These models demonstrate similarities with human beings only 60% of the time, according to Thomas Hartung at the Center for Alternatives to Animal Testing at Johns Hopkins University Hospital in the United States. Hartung cited the example of aspirin, which although it has been proven safe for humans would be rejected in animal testing because it leads to fetal deformities in some cases. “We are trying to show Brazilian researchers the importance of using alternative models and their limitations, along with the need for a sensible experimental plan,” says Lorena Gaspar Cordeiro, a professor at the Ribeirão Preto School of Pharmaceutical Sciences at the University of São Paulo (USP), one of the event’s organizers.

Some methods presented in the workshop are looking for alternatives to the use of mammals, such as the zebrafish, known in Brazil as the peixe paulistinha, and larva of the insect Galleria mellonella (see Pesquisa FAPESP Issue No. 220). “About 75% of the 26,000 genes of the zebrafish are similar to human genes,” says geneticist Cláudia Maurer-Morelli, of the University of Campinas (Unicamp). The larva has immunological mechanisms similar to those of mammals. “The larva’s cuticle acts like skin. When it is injected with a toxic substance, it reacts and turns darker,” explains Maria José Giannini, a professor at the Araraquara School of Pharmaceutical Sciences at São Paulo State University (Unesp). “Brazil wants to travel the same path as countries like the United States and those in Europe,” says Giannini, who coordinated the workshop.