Any attempt to assemble a comprehensive or detailed chronological overview of all the contributions to biomedical research that are based on experiments involving laboratory animals would result in either an endless list or a vast volume of medical accomplishments, and would be neither complete nor useful. However, the Foundation for Biomedical Research has compiled a list of Nobel Prize winners from the year 1901 to the present; this includes 67 examples, ranging from determinations of basic biologic mechanisms to studies that have led to the cure and prevention of important infectious diseases. Therefore, this section will start with a brief overview of past contributions of laboratory animals to medical progress and will highlight examples that have significantly influenced human health and reduced suffering.
The use of animals in biomedical research and, in particular, the use of the mouse in such studies dates as far back as the 1600s. During the subsequent centuries, as scientific methods and research practices evolved, laboratory animals have continuously contributed to virtually all aspects of biomedical progress. This fact can be illustrated with history-making contributions from diverse areas of science, as represented in the following list:
Achieved or improved diagnosis of infectious diseases (e.g., rabies, yellow fever) Understanding of susceptibility and resistance to microbial agents leading to antimicrobial agents Knowledge of immune biology and deficiencies (e.g., histocompatibility, severe combined immunodeficiency)
Understanding of transplantation immunology and development of related technologies Development of vaccines (e.g., smallpox, polio)
Development of advanced technologies in heart surgery and other cardiovascular or stroke-related inventions (e.g., open heart surgery) Development of cancer treatments Identification of metabolic dysfunctions Characterization of neurological defects Achievements in space medicine
A few specific examples will underscore that many past accomplishments based on scientific observations or experiments performed on laboratory animals formed the foundation for medical progress, thus leading to some of today's sophisticated health-science technologies.
In 1877, the German scientist Robert Koch built upon observations that were already over a decade old, namely that anthrax could be transmitted from animal to animal. Koch's animal experiments proved that the Bacillus anthracis bacterium caused a particular disease, and that the isolated and purified bacterium from an initial host could cause the same disease in a new, second host. Hence, Koch's postulates were born.2 Koch's observations gained general acceptance and helped lay the foundation for the more-intensive use of laboratory animals, especially for investigations of infectious diseases. Even today, over a century later, Koch's postulates form a cornerstone for infectious-disease biology and research. These simple principles are applied in their original form or in an updated, more molecular version to emerging diseases, such as the Four-Corner-disease in 1993, which is caused by the hantavirus sin nombre, and Kaposi sarcoma, which was etiologically linked to human herpes virus type 8 in 1995.
Without animal research, most of the effective vaccines against infectious microbes or their toxins would not have been developed. Two major milestones were the independent developments of the first vaccines against smallpox and rabies, centuries-old human diseases that resulted in either severe, potentially fatal illness or in 100% mortality, respectively.
In 1798, English physician Edward Jenner conducted experimental vaccination for the prevention of smallpox by inoculating the closely related vaccinia, or cowpox virus.3 Persons inoculated with cowpox virus showed complete resistance to a challenge with the deadly smallpox virus. A century and a half later, Jenner's smallpox vaccine formed the basis for the World Health Organization's 1958 program of global eradication of smallpox. The freeze-dried vaccine, the simple application with the bifurcated needle, and the concept of mass vaccination, combined with surveillance and containment, resulted in the eradication of smallpox in 1979. The subject remains timely, however, given the potential use of this virus in biowarfare and bioterrorism.
In Paris, Louis Pasteur adapted the wild-type, or street rabies, virus to laboratory animals, resulting in a change in viral properties that today would be called attenuated virus strains. Pasteur and his colleagues subsequently developed concepts and experimental approaches that led to the first protective vaccination against rabies. Furthermore, in 1885, Pasteur successfully used the first post-exposure treatment, or passive immunization, against rabies.4 Other excellent examples include the development of vaccines against diphtheria and poliomyelitis, further illustrating the critical role that animal experiments played in the history of immune prophylaxis.5
Much of the knowledge about the structure of immunoglobulins or antibodies — molecules of central importance in immunology and host defense — was derived from extensive investigations into neoplastic plasma cells derived from mouse myelomas. Data on the Y-shaped protein structure and the potential for large-scale production of homologous antibodies were put forth by Kohler and Milstein in 1976.6 The hybridoma technique that these two scientists developed has provided a method of antibody production that is now widely utilized. The basic principle of hybridoma technology relies on the fusion of immortal myeloma cells with antibody-producing spleen cells harvested from a previously immunized mouse against the antigen of interest. Successful hybridoma clones will produce one type of target-specific, or monoclonal, antibody in unlimited quantities. Such monoclonal antibodies have been used for a wide range of applications, including diagnosis of pathogens, identification of physiological cell components, treatments of diseases, and purification of biological materials, to name just a few. Moreover, the production of large quantities of identical immunoglobulins allowed for a better understanding of their molecular structure critical to our understanding of immune-response induction, including the development of a secondary immune response (e.g., antibody class switch). More recently, the traditional production method of monoclonal antibody as mouse ascites is being replaced by alternative in vitro techniques that abolish the need for using live mice.
Another application of our expanded understanding of the immune system is in the field of tissue transplantation, which was significantly advanced by experimental findings in mice. At the Jackson Laboratory, scientists performed pioneering work by restoring to health a mouse with a blood disorder after performing a bone marrow transplant.7 Furthermore, working at the same institution, George Snell discovered genetic factors recognized by the immune system that determine the possibilities of transplanting tissue from one individual to another. This pioneering work on the concept of the H antigen and the major histocompatibility complex later resulted in the shared 1980 Nobel Prize in Physiology and Medicine.
Specific Examples from the Past — Nonhuman Primates
As noted previously, the eradication of poliomyelitis from the human population was dependent upon the development of an effective vaccine. Critical to this was the use of nonhuman primates, specifically, rhesus macaques, to study the pathogenesis of the disease and to test the efficacy of candidate vaccines. They have more recently continued to be of use, although in greatly reduced numbers, in ongoing testing of the candidate AIDS vaccines currently produced.
Several types of viral hepatitis are of major importance as human health problems worldwide. Again, nonhuman primates have been and continue to be essential in development of control methods for these conditions. Chimpanzees, susceptible to hepatitis B virus, were of critical importance in development of an effective vaccine against this agent. This vaccine is widely used and has helped to bring this disease under control. As close human relatives, chimpanzees are also susceptible to other human hepatitis viruses. One of the most important of these, hepatitis C virus, is a major cause of acute disease and, more importantly, of chronic liver failure. It is present on all continents and is responsible for extensive suffering and economic damage. Efforts are now underway to determine the pathogenesis of this disease in chimpanzees and to develop control methods, including an effective vaccine.
As close human relatives, nonhuman primates have been important in neurobiological studies in a wide range of fields, including perception, behavior, and basic neurologic studies. Many of these experiments have been of relatively long duration and require training of animals in controlled experiments, which can help to pinpoint the effects of specific treatments on various parts of the complex primate brain. Nonhuman primates are of special value in determining the addictive potential of specific compounds and in dissecting the mechanisms of such addictions.
Specific Examples from the Past — Nontraditional Species
Several unlikely species have been and continue to be of significance in biological and medical studies. The armadillo, native to the southern United States, is one of few species susceptible to the mycobac-terium that causes human leprosy. Thus, the animals can serve as sources of this agent and also can be used in the attempts to identify the pathogenetic mechanisms that it employs and to assess potential therapies.
The chinchilla, a South American rodent raised for its pelt and used in the fur industry, has a large and accessible acoustic system, which has been exploited to study basic mechanisms of hearing and to assess the effects of factors that are toxic or otherwise detrimental to hearing.
Ferrets, now common as pets, are also of importance in the study of influenza, which continues to be a major threat to the human population. The development of efficacious vaccines is dependent upon a susceptible host; the ferret acts as such a host.
Over the past decade, the use of cats and dogs in biomedical research has significantly diminished for a variety of reasons. First and foremost is the changing focus of much research to basic biologic questions that are best investigated in the rodent model. However, there is also continuing and increasing public concern about the use of dogs and cats in research. The general public — primarily urban — views these animals as members of the family; thus, there is opposition to their use by certain vocal groups. It is of interest to note that such opposition to the use of these animals in research is not new; in fact, Congressional hearings in 1900 on the subject of vivisection were a forum in which founders of the Johns Hopkins University School of Medicine were active participants.
Public concern has also focused on the use of nonhuman primates for research studies (see "Specific Examples from the Past - Nonhuman Primates"). Cultural differences contribute to these concerns for certain species, as reflected by the intensity and vocalization of objections to animal-based research in Europe and the United States as compared to other regions.
It is worthy of note that dogs and cats (and their owners) have benefited greatly from research done to improve human health. Numerous therapeutic technologies and drugs used to treat conditions of all types were developed for human medicine, but are of critical importance in the veterinary arena, which itself does not have the financial resources to support such research.
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