Replacement, reduction, refinement
The horrible pictures of laboratory animals, mutilated, genetically manipulated, dissected and forced into experimental gadgets, have shocked time and again – but eventually they also have made a difference. For years now, researchers more and more consider alternative or less cruel methods for animal experiments. All efforts are based on the so-called 3R-principle which was published in 1959 originally as "The Principles of Humane Experimental Technique" by Russell and Burch. Those three "R"s stand for replacement, reduction and refinement.
The footrace between the hare and the hedgehog
In most European countries, the legislation regarding control of animal testings orientates itself by those directives. As an additional inducement for research, incentives are provided on a European as well as a national level for years to push the development of replacement methods according to 3R. And remarkable results were achieved. But the reduction on one side is destroyed by a rapid development in medical research on the other side. Without an acknowledgement of the 3R-principle, the situation would be even desolate as suggested by the Swiss toxicological computer tests.
Toxicological tests on the computer
There are numerous foundations in Switzerland, among others by the federal state and the pharmaceutical industry promoting the study and distribution of alternatives to animal testings. Biographics Laboratory 3R in Basel benefits of these as well. The non-profit organization was founded in 1990 by Professor Dr. Angelo Vedani – among others lecturer at the Basel University – with the target to utilize computer technologies for the reduction and replacement of animal tests in biomedical research. Over the last few years, the scientists working with Vedani concentrate on the development of software capable of making toxicological tests for pharmaceutical substances and chemicals on the computer – a field where obviously the majority of the straining tests are made worldwide.
Computer-aided drug discovery
The centerpiece of the Basel development is a special software reconstructing quantitative structure-activity relationships (QSAR) mathematically. The single modules are based on the technology of computer-aided drug discovery (CADD). The target of the researchers: The reduction respectively complete replacement of animal testings in toxicological tests as well as in pharmaceutical research. The name of the entire system: "VirtualToxLab". According to Vedani, it is available to universities, hospitals, validation centers and registration authorities since recently as a so-called "peer test" free of charge. Beginning 2008, the pharmaceutical industry will be able to benefit from it as well – but for money. "The "VirtualToxLab" is running on our own Unix-computer network. The authorized user can enter his substances via the internet and receives as a result the toxic potential, i.e. he just needs a computer with internet access," Vedani explains the technical requirements. And how does the system work? "The software calculates how strong an active agent will bind to one or several receptors responsible for the transfer of a toxic effect (e. g. estrogen- or dioxin receptor). If a bond is strong, side effects will occur in all probability".
In silico toxicology remains to be just a drop in the ocean
CADD itself is not a new invention. Today computer-aided development of drugs is mainly used in the pharmaceutical industry particularly for optimization of the "major effect" of an active ingredient. New in "VirtualToxLab": The software recognizes side effects and toxicity of potential ingredients and environmental chemicals. Up to now, toxicity tests could only be made on animals, explains Vedani. The technology, also called "In silico Toxicology", is to be another step to get closer to a replacement for animal testings. However, and the experts agree on this, we are far yet from the final target, the human organism is too complex to be translated into Bits and Bytes in its entirety.
Safe identification in toxicological tests
So is the computer impotent? Vedani: The "VirtualToxLab" can reduce the number of animal testings per pharmaceutical entering the market. Nobody will consider a substance as a pharmaceutical when a high toxic potential has been predicted. That means, such an active agent will neither be manufactured chemically nor tested on animals. But if the pharmaceutical industry will develop and market faster due to more efficient procedures, the total number of animal testings will hardly decrease. You can hardly blame the alternative methods for that, though. It is like with the catalyst. It is good indeed and it also reduces the escaping pollutants, but if people drive double as much as before, the environment is not exactly benefiting from it. Today we are able to detect substances with a high risk potential for sure in silico which means we do not need to test those compounds on animals any more.
Increase of animal experiments in the EU
Vedani's estimations are confirmed from other sides. The fifth EU statistics on animal testings just recently published and relating to 2005 shows an increase of 12 percent compared to 2002. Although, the figures are misleading since they include the test animals of the ten new EU states. According to a press release the German interested grouping "Ärzte gegen Tierversuche e. V." (physicians against animal testing), the figures broken down to the old EU states result in a total of 3.1 percent compared to 2002. If you differentiate according to fields, the majority of the animal tests are made in medical pure research and, among others, in biotechnology.
A chip instead of 100 lab mice
Since 2001, the Research Center Jülich, as the project agency, decides about the allocation of the BMBF funds for "Replacement for Animal Testings" in biotechnology. Dr. Manfred Hansper, jointly responsible for the project, ascertained an increase of animal testings in the field of functional genomics as well. Here especially transgene mice play an important role in the analysis of specific gene functions. For Hansper, the number of animal testings is not only an ethic, but also an economic problem. Because the in-vivo method is expensive and shaky. This is why we need more projects like the one of the Max-Planck-Institute in the field of molecular genetics. The researchers are working on an in-vitro method for transfection taking place on a glass chip under robot control. Just one chip will save up to 100 lab animals. Overall it looks better in product control, says Hansper, for example in the batch control of vaccines.