Genetically Engineering Technologies (see also "Genetically Altered Mice")
As we have seen, the genomic revolution has opened new and seemingly unlimited possibilities for biomedical research. Reading and understanding the genomic blueprints associated with specific pheno-types, including pathologic or advantageous characteristics, provide the possibility of intervening at the gene level in certain disease conditions. This contrasts with the traditional approach of treating signs of illness and alleviating disease manifestations. Undoubtedly, the sequencing and manipulation of the genome will play a significant role in biomedical research of the future. Using targeted mutagenesis, specific mutations can be introduced and foreign genes can be expressed, resulting in a desired, potentially pathologic phenotype in a wide range of different species. Alternatively, in-depth knowledge of the genome will open unprecedented possibilities for treatment modalities for genetic disorders. These advances in the genetic area of biomedical research will require the expansion and development of repositories and stock centers to supply genetically engineered laboratory animal models available for the scientific research community. Thus, future research will make use of mice, rats, and other rodent models, hence requiring the continued support of programs that improve, oversee, and expand laboratory animal research programs (see "Support of Biomedical Research Directed Towards labaratory Animals, Funding Opportunites"). Maintaining increasingly sensitive and specialized animal strains, which require sophisticated and expensive infrastructures, will form an important part of future biomedical research investigations.
At the present time, the mouse is the only species in which genetic manipulations at the level of gene knockouts have been successfully completed resulting in live animals. This now-widespread technology has, once again, given the murine species a significant advantage in its leading role as laboratory animal of choice. However, other species have been successfully utilized for targeted transgenic manipulations, resulting in the expression of foreign genes in "cloned" offspring. Among the higher vertebrate species, rats, rabbits, pigs, goats, and rhesus monkeys have been successfully used for such research work, although with widely varying in efficiency and cost. Zebrafish and the nematode C. elegans need to be added to this list of model species used for transgene expression. These technologies will be expanded in the future to include other species and also to provide potentially new avenues for biomedical research directions.
The recent explosion of research tools and technologies available to biomedical scientists has created unprecedented opportunities. The capacity to modify the genetic makeup of biologic models and explore gene function provide powerful tools to determine gene function and its modulation by a host of factors. The resulting proliferation of genetically modified research animals, including zebrafish, mice, and other species, has significantly increased the need for centralized repositories for genetically altered animals, with special emphasis on genetic monitoring, phenotyping, and the control of intercurrent infections. Recently established repositories for transgenic and knockout mice and for zebrafish have only begun to address this rapidly increasing need. There are other species, such as Drosophila, that can be maintained only as reproductive colonies. Cryopreservation technologies could significantly reduce the cost and labor of maintaining animals of this type. It is essential that groups work together to develop consistent approaches to housing, health monitoring, and characterization of mutant animals. Harmonization of guidelines for laboratory animal care is thus necessary. Moreover, research has become globalized and requires validation of biologic models used in research. Minimizing or eliminating unwanted duplications of effort will lead to cost-effective approaches and will increase the need to share research resources internationally.
The future of biomedical research will involve existing traditional laboratory animal models, traditional models that will be improved or modified, and nontraditional model species and approaches. One such nontraditional and nonanimal model organism is the small, flowering plant in the mustard family called Arabidopsis thaliana. Arabidopsis is not of agricultural significance, but it has been used and is being further developed for both basic genetic and molecular research in biology. Research utilizing Arabidopsis offers several advantages, including its small genome size of 125 megabases with only five chromosomes, the extensive genetic and physical maps of the genome, and the large number of available mutant lines. Furthermore, Arabidopsis has a short life cycle with a prolific seed production. Since 1965, when the first international Arabidopsis conference was convened, the number of laboratories conducting research on Arabidopsis and the amount of research money spent on Arabidopsis research have significantly increased. Stock centers, databases, and publications related to Arabidopsis have moved this plant to a position where it may become a potential future model organism for studies in cellular and molecular biology that will cover questions well beyond the world of plants.
Nontraditional future approaches supplementing existing laboratory animal models will include the cell culture systems. The recent advances in embryonic stem cell culture technology exemplify one small step towards the limitless expansion that single- or multiple-cell systems could play in advancing biomedical research. The power of computers and their potential to model physiological and pathological situations and conditions, as well as their power to store and analyze data, will allow future biomedical research to move into areas of modeling that will provide opportunities beyond today's imagination.
Support of Biomedical Research Directed Towards Laboratory Animals, Funding Opportunities
Continued strong support from both federal and private sources is necessary to ensure the steady growth and progress of our ability to decipher the secrets of biology. Funding from many agencies targets research aimed at basic biomedical questions, specific disease modalities, or their model systems. Research applications with broader focus, including shared research tools or applications, specific laboratory animals, animal colonies or their infrastructure support, are supported through the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH).
The Division of Comparative Medicine at NCRR, as its name suggests, has the goal and responsibility of developing and supporting an array of mammalian and nonmammalian models to both underpin and facilitate biomedical research. In addition to traditional research grants, the division awards competitive grants aimed at the development of specialized research tools, centralized animal colonies, research training for veterinarians, and career-development programs for individuals across the educational spectrum. The variety of NCRR-supported biorepositories is quite broad, ranging from micro-organisms through invertebrates, to higher vertebrates, including nonhuman primates. One of the major challenges presented to these resources is to remain responsive in a timely manner to the ever-changing needs of investigators and to not become a rate-limiting barrier for research.
Animal-based research is increasingly dependent on technologies that are continuously being developed, e.g., MRI, ultrasound, and arrays. Such tools and equipment are important in basic science as well as clinical settings, and lead to improved diagnostic and therapeutic outcomes.
One of the means to increase and improve in the present and future is bioinformatics. The power of computer-based research technologies, data analysis, and data transmission is not only significant in its growth, but also in its future potential. However, this comes with significant costs and needs for coordination and standardization of approaches used to preserve and manipulate a wide variety of data.
SUMMARY - IMPLICATIONS FOR LABORATORY ANIMAL MEDICINE (TRAINING, RESEARCH, CAREER DEVELOPMENT)
With the advances of modern technologies in medical research, new ways of thinking in terms of combating diseases have emerged. Today, many investigations can be conducted in vitro, or outside the living animal body, especially since the advancement of technologies in cell culture and molecular biology techniques allows performing assays in test tubes, thereby mimicking metabolic reactions in an isolated setting. Many biomedical subspecialists, including anatomists, biochemists, geneticists, immunologists, microbiologists, pharmacologists, and physiologists, perform in vitro experiments to understand how cells and their subcellular components function, how cells and their membranes and receptors react to other cells or chemicals, or what external factors affect their metabolism and growth rate. Scientists need to understand how these pieces fit together into the big picture; that is, how the entire animal body functions as a whole. For these reasons, laboratory animals, as they have in the past, will continue to be an essential component of biomedical research and to contribute vitally to continued exponential growth in biomedical progress.
To ensure this continued and successful progress in animal-based biomedical research, training of broadly based scientists is growing increasingly important. There are numerous demands for individuals with research backgrounds in such areas as organismic biology, including laboratory animal medicine and comparative pathology. Individuals trained in emerging technologies, including bioinformatics and biotechnology transfer, will also become increasingly important. At this time, there is a significant need for such individuals, and this need will only increase. Challenges in this area include the duration and cost of extended research training. The impediments that these factors impose to interested and qualified candidates must be lowered through mechanisms of debt forgiveness, integration of research training with professional educations, and provision of quality mentoring of candidates by established investigators early in their educational careers.
The rapidly proliferating volumes of biomedical data place increasing demands on databases and associated technologies. Harmonized approaches will be necessary to reduce costs and to increase exchange of information among widely divergent groups. Much of these data is in a format that can be readily exchanged electronically; this provides advantages in terms of ease of sharing, but possible hazards related to data alteration or corruption. Individuals trained in biological sciences must increasingly become familiar with the bioinformatics tools and their application for data management, ranging from data visualization to modeling and validation of experiments.
There is a need for increased synergy on national and international levels. This can be done through sharing biomaterials internationally and by scientific collaborations over state-of-the-art networks in cyberspace, supplemented with access to Web-based databases that provide carefully recorded information about genetic models. As research becomes more complex, research teams become a necessity to provide the wide-ranging expertise required in this setting. The coming decade has great promise for biomedical research of all types. It also will pose significant challenges and demands on the biomedical research community, upon which individuals with expertise in veterinary and comparative biomedical science can have a major impact.
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