Better Science III. AREAS OF ANIMAL EXPLOITATION AND ADOPTION OF ALTERNATIVES Basic Research The most direct approach to an increased emphasis on alternatives in basic (non-medical) biomedical research is the development of new techniques that are subsequently widely adopted in multiple areas of investigation. For example: Nowhere is this more evident today than with the development and use of in vitro methods to produce monoclonal antibodies (MAbs), which are specific to a single structure, chemical or disease organism. Originally developed as an alternative technique, MAbs quickly became the source of large-scale animal pain and distress (ascites) due to the massive swelling of the animals' abdomens. With the development of new replacement alternatives (several dozen different possibilities), more progressive countries in Europe finally banned the routine use of the ascites method to produce MAbs and required the use of more humane methods. The use of such alternatives is now the mandated first choice approach to MAb production in the United States for anyone receiving funding from the National Institutes of Health. This simple change in perspective, acknowledging that the alternatives were superior to in vivo techniques, will save millions of animal lives. Although still used in some areas of research, polyclonal antibodies (PCA), which attach to multiple research and clinical targets, find their greatest applications in academic and clinical diagnostic kits. PCAs are conventionally produced from the blood of immunized mammals such as rabbits, goats and horses. More than a century ago the possibility of producing such biological compounds via hen's eggs was suggested. This is becoming a more common practice today. Ultimately all antibodies (MAbs and PCA) will be created and produced using recombinant DNA technology, thus completely eliminating the use of animals for such purposes. Development of a completely virtual human computer simulation is still in progress, but some aspects of the concept are available and in use. Several years ago the National Library of Medicine created a set of serial sections of specially prepared male and female human cadavers. Each section was digitized, allowing a complete, anatomically accurate computerized reconstruction of the human body. This in silico alternative is utilized by both academic and corporate institutions for a variety of research and teaching applications including the development of new and/or refinement of existing surgical techniques. The least publicized but most critical aspect of the development of the first artificial heart was not the use of animal models, but rather the use of five brain-dead, artificially maintained human bodies (neomorts) to establish and practice the final surgical techniques and efficacy of implantation of the artificial heart in a human patient. Use of neomorts has widespread possibilities in both academic and applied research such as toxicity testing, but remains a tightly kept secret within the biomedical research community. Applications of in vitro methods are widespread within the basic biomedical research, with some disciplines entirely dependent on them. Nearly 40% of the research program funded by the National Institutes of Health involves some use of in vitro alternatives. Such techniques are not adjuncts but mainstream state-of-the-art scientific methods. With ongoing developments in perfusion techniques, three-dimensional, multiple cell type culture and immortalized cellular (long-term) methods it will be possible to reproduce and/or simulate in vitro all principal human organ systems and responses. Another rapidly advancing area of technique development and application in basic research is noninvasive imaging. Magnetic Resonance Imaging (MRI), Positron Emission Tomography Imaging (PET), Functional Magnetic Resonance Imaging (fMRI) and combinations of these allow very sophisticated, real-time measurements of associations between structure and function in both humans and animals under a wide variety of experimental conditions. Some imaging units are specifically designed for use with small animals. Despite earlier limitations on these techniques, they are now faster and more accurate with resolutions possible down to single cells. These imaging options have had their most extensive applications in the neurosciences, allowing direct, noninvasive studies of neurophysiology that would be impossible to do with nonhuman animals. On a more fundamental level, for decades many of the animals killed in neuroscience experiments died only to identify the specific site of electrode implantation. Such deaths are not necessary. The application or development of new alternatives really is a reflection of the imagination and technical skills of the individual researchers. For example: Computer simulations of cancer cells are now used to test drug targets within them. There are several in vitro models for studying the gastrointestinal system, with the most complex being a multi-culture, in vitro simulation of each portion of the digestive system (FIDO) developed in the Netherlands. Each part of the interconnected model contains cell cultures for that particular organ. A researcher in New Jersey developed a multi-dimensional, bioengineered human skin cell culture for the study of burns and ultraviolet exposure. This in vitro model can reproduce any human skin coloration and tans if exposed to the sun. In vitro models of the brain and more recently the blood-brain barrier have existed in one form or another for more than twenty years, being used for studies of neurotransmitter pathways, electrophysiological characteristics, morphological associations of human diseases (i.e., Alzheimer's, Parkinson's, Huntington's, epilepsy), new drug design, receptor targets and modes of action of new pharmaceuticals. Current in vitro models have reached very high degrees of structural and functional sophistication. The Skin Ethics Laboratories in France have developed ten human in vitro tissue models (cornea, oral, eye, esophageal, lung, vaginal and complex dermal simulations) for use in industry (efficacy and safety testing) and academics (basic research). These models are routinely used by such companies as Pfizer, GlaxoSmithKline, Unilever, Kimberly Clark, Avon and 3M. Multilevel, multi-culture in vitro simulations of different parts of the human lung have been developed at the University of South Carolina for distribution studies of aerosols and eventually respiratory toxicology. Cyprotex has developed a software system that accurately predicts the pharmacokinetics of new drug compounds using a virtual human computer simulation. Although replacement of flawed animal models with more relevant in vitro, computer and clinical methods is the long-term goal of the alternatives approach in basic biomedical research, the majority of every current protocol could benefit immediately from consideration of Reduction and Refinement alternatives. For example: Physical and behavioral enrichment of the animal's environment is finally being taken seriously despite continued objections from researchers and facility personnel. Efforts are underway to identify, characterize and eliminate pain and distress, which always biases the results of studies in which animals are used. A significant number of experiments continue to use or abuse the wrong statistical tests, sample sizes and appropriate design options. Mouse Specific, Inc. has designed an entirely noninvasive system to monitor cardiovascular health and activity. Bioluminescent imaging allows noninvasive measurement of physiologically relevant processes. << Back To Contents | Next Section >>

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