The role of laboratory animals for our research
Diseases such as cancer or immune disorders are influenced by the interaction of different organs and cells. In molecular medicine, we try to understand just these complex interactions in the body and to develop approaches for new treatment methods. Since alternative methods such as cell culture and computer models are still not capable of mimicking the complexity of an entire organism, we resort to laboratory animals, after careful ethical consideration. A designated animal welfare panel and an independent ethics commission monitor this process (see below for details). In most cases, the experimental animals we use are laboratory mice, purpose-bred for research, kept in standardized conditions under the daily care of trained animal caretakers and under veterinary supervision. The best possible living conditions are imperative for high quality scientific results. Additionally, many of our scientists at CeMM – biologists, doctors, chemists, bioinformaticians, veterinarians, animal caretakers, etc. – own pets themselves and have every interest in ensuring that our laboratory animals are exposed to the least distress possible and are treated with the necessary respect.
Authorization of animal experiments
The use of laboratory animals is subject to strict statutory provisions under the Austrian Animal Welfare Act which was re-regulated on an EU level in 2010 by a Directive on the protection of animals used for scientific purposes (2010/63/EU, TVG 2012), s. https://www.ris.bka.gv.at/GeltendeFassung.wxe?Abfrage=Bundesnormen&Gesetzesnummer=20008142.
This Act governs the conditions under which experiments on vertebrates are permitted, how to assess the scientific benefit to be expected compared to the damage inflicted upon the animal, who is permitted to carry out animal experiments, what methods are permitted, etc. In this context, the 3Rs principle plays a central role in the protection of laboratory animals (see next chapter).
Before animal tests can begin, scientists must submit a comprehensive application for a license to conduct animal experiments of often more than 20 pages in length. It requires the provision of detailed scientific justifications with regard to expected knowledge gain, the procedure details of the animal test itself and how the 3Rs principle is to be complied with. The application is assessed by an independent ethics commission of the Medical University of Vienna consisting of scientists and, in particular, veterinarians and biostatisticians. In most cases, the commission suggests changes that improve the animal experiment with regard to the 3Rs principle. Aside from scientific quality, discussions center on options employing alternative methods, the reduction of the number of animals used in experiments and reduced distress.
Only when all these modification requests have been complied with and the application for a license to conduct animal experiments complies with statutory requirements, does the ethics commission forward the application to the Austrian Federal Ministry of Education, Science and Research. There, the application is evaluated by specialists once again. Only after all open questions have been answered and any required amendments have been made, do the scientists receive notification that the animal experiment may proceed. Otherwise the application for a license to conduct animal experiments is rejected.
The 3Rs principle
In the past 50 years, what is known as the 3Rs principle was developed for the protection of laboratory animals in order to ensure compliance with requirements for their humane and ethically justified use. These central 3R principles obligate scientists to
+ use alternative methods whenever possible (Replacement or avoidance)
+ reduce the number of animals being used to the absolute strict minimum (Reduction or minimization)
+ minimize distress and improve the living conditions for the animals used (Refinement or improvement)
These 3 Rs form the basis for all international and national regulations governing the protection of laboratory animals. Our scientists at CeMM comply with these rules and train junior scientists in the 3Rs principle. Moreover, CeMM is one of the world's leading institutes in the development of alternative methods, some of which completely eliminate the need for use of laboratory animals. For example, CeMM scientists pioneered the development of computer-based network medicine with the aid of which large data volumes from cell culture experiments and patients can be linked in order to better understand the illness. Beyond this, new techniques are under development at CeMM that should allow selection of the most promising drug for personalized therapy based on a cancer patient's blood cells.
For further information on the subject of animal testing in Austria, we recommend a current brochure published by the Vienna University of Veterinary Medicine (link: www.vetmeduni.ac.at/fileadmin/v/z/forschung/infobroschuere_tierversuche_06-2016.pdf) and the following video (link: https://www.youtube.com/watch?v=fTLCXZ_3Bn8).
Use of animal testing for medicine
Generally speaking, laboratory animals provide a model for human disease. In this context, our scientists are aware that every model has its limitations. For example, the average life span of a laboratory mouse is only 2-3 percent of that of humans, and genes in mice and humans can be regulated differently. However, mice have the same organs, the same types of cells and nearly all the same genes as humans do and play an important role in the understanding of human disease, alongside alternative methods such as cell culture and computer models. This constitutes the precondition for the development of new target-oriented therapies.
Specific example: immunotherapy for cancer
In recent years, modern immunotherapy has achieved major breakthroughs in cancer therapy in the areas of metastatic melanoma, cancer of the bladder or non-small-cell lung cancer, leading to a paradigm shift in oncology. The roots of this encouraging development reach back to findings in basic immunology in the past 20 years, including the discovery in laboratory mice that chronic infections or cancer can "overwhelm" T cells, thus causing them to lose their activity (Ref 1). T cells constitute one of the most important cell populations of the immune system because they can identify and fight infected or degenerated cells. Subsequently, it was possible to demonstrate in mice that the overpowering of the T cells is attributable, in particular, to inhibitory receptor molecules such as CTLA-4 and PD-1 (Refs 2, 3). In a next step, so-called antibodies were developed that block the inhibitory receptors, thus permitting the T cells to resume their work. This principle was first successfully tested in a mouse model (Refs 4, 5) and later further developed for treatment of cancer patients. With antibodies against CTLA-4 or PD-1 (“immune checkpoint inhibitors”), this immunotherapy has achieved undreamt of success against a variety of previously fatal cancer diseases in recent years (Ref 6, 7). Without animal testing, these achievements of modern cancer therapy would not have been possible.
Unfortunately, it is already clear that these therapies are not effective across all types of cancer. Therefore, more basic research will be needed to develop further innovative therapeutic options.
1) Wherry EJ and Kurachi M. Nat Rev Immunol 2015; 2) Waterhouse P et al. Science 1995; 3) Intlekofer AM and Thompson CB J Leukoc Biol 2013; 4) Leach DR et al. Science 1996; 5) Barber DL et al. Nature 2006; 6) Pardoll DM Nat Rev Canc 2012; 7) Ribas A. N Engl J Med 2015
Additional sources: Babraham Institute, England; Tierversuche-verstehen, Germany; Understanding Animal Research, England; University of Würzburg, Germany, University of Veterinary Medicine Vienna, Austria.