Funding from external sources is the lifeline for most biomedical research scientists. In the USA, the National Institutes of Health (NIH), composed of 27 institutes and centers, is the primary federal agency for conducting and supporting medical research. One of these centers, the National Center for Research Resources (NCRR) provides financial support and resources to clinical or translational scientists working to understand human disease. Through the Division of Comparative Medicine, the NCRR funds projects focused on the development and use of model organisms to understand, diagnose, prevent and treat disease. Here, officials within the NCRR’s Division of Comparative Medicine discuss some of the funding opportunities and resources available to researchers who use model organisms, and their perspectives on the future of model organism research.
Both basic and clinical biomedical scientists design trials to explore the pathways that lead to illness and to search for new ways to treat human disease. Their long-term goal is to improve human health and reduce suffering. Frequently, these scientists use disease models in their research, especially to test specific hypotheses or to explore unintended reactions. Today, scientists who plan to use a disease model have a multitude of possibilities available but, especially for the novice research scientist, selecting the most appropriate model can be both confusing and intimidating. The range of available models is extensive indeed, ranging from computer models to single cells and simple organisms such as worms, to higher vertebrate species such as mice and monkeys. Unfortunately, there is no comprehensive resource of the available disease models that also lists these models’ applications and their histories of both successful and failed uses. Efforts are under way to address the absence of such a resource, but until it is created, scientists have to make do with the resources that are currently available.
Currently, scientists can benefit by consulting the NIH’s web site (www.nih.gov/science/models/) on ‘Model Organisms for Biomedical Research’ and, for more specific information, by looking at the web site of the Division of Comparative Medicine (DCM)/National Center for Research Resources (NCRR) (www.ncrr.nih.gov/comparative_medicine/). The disease model resources listed at these sites can provide outstanding information for scientists who need advice regarding the availability, characterization, maintenance, or cost of these models. In addition, investigators can obtain general or specific guidance regarding disease models in research investigations. The following paragraphs provide a short overview of some of the available disease model resources, explain how to make contact with experts and obtain information, give some advice with respect to contacting funding agency staff, and offer some final thoughts on future directions.
NCRR, one of the 27 institutes/centers of the National Institutes of Health (NIH), supports research to create and develop crucial resources, models and technologies. NCRR’s mission is to provide clinical and translational scientists with the tools and training to understand, detect and prevent a wide range of diseases.
Within NCRR, the DCM supports the biomedical research community through grants that fund research resources and projects designed to create, characterize, preserve and distribute a broad array of high-quality animal and animal-related models. Research in comparative medicine has evolved to include many models – both mammalian and non-mammalian – as well as a wide range of research resources and resource centers, such as those for genetically altered human adult and animal embryonic stem (ES) cells, zebrafish mutants and transgenic swine models. The largest portion of DCM’s budget supports research center grants that provide support for special colonies of laboratory animal models, as well as other resources such as cultures and genetic stocks that serve the biomedical research community (Fig. 1). The Division’s funding also supports research projects, resource-related research and investigator-initiated research to develop, characterize or preserve a wide range of specific animal models and biological materials to study human disease. In addition, DCM supports career-enhancing training programs for young scientists, or their mentors. These programs are intended to enhance the research careers of individuals with a veterinary background or interest in animal models, at both the doctoral and predoctoral levels, thereby providing broad-based education that will help them become independent research scientists.
Distribution of DCM fiscal year 2008 budget.
An overview of existing disease model resources
Mammalian model resources
Rodents
Rodents represent the most frequently used species in biomedical research, as they share much in common with humans with respect to genetics, development, physiology, behavior and disease. These well-characterized animal models are essential to many important biomedical discoveries related to human health. To ensure that such resources are accessible to the biomedical research community, DCM/NCRR supports programs that engage in ongoing, peer-reviewed, health-related research to establish special animal colonies and genetic stocks. Additionally, continuous research activities by core scientists at these resource sites generate new knowledge, enhancing the overall value of these resources to the biomedical research community. Key NCRR-supported rodent resource centers and programs include the Mutant Mouse Regional Resources Centers (MMRRC), the Mouse Models Resources at the Jackson Laboratory (in Bar Harbor, Maine), the Knockout Mouse Project (KOMP) repository, and the Rat Resource and Research Center.
The MMRRC consists of three mouse facilities and an information-coordinating center, functioning as a single multisite repository for mouse lines to serve the biomedical research community. The MMRRCs accept, cryopreserve, maintain and distribute mutant mouse strains for use in biomedical research. The centers archive transgenics, knockouts and other kinds of induced mutant mouse lines, at no cost to the donors. After specific-pathogen-free rederivation and cryopreservation, they also distribute mice for a fee to requesting investigators for noncommercial, academic research purposes (www.mmrrc.org/). NIH-supported resources at the Jackson Laboratory serve a very similar purpose (http://jaxmice.jax.org/research/index.html).
KOMP is a trans-NIH initiative with the goal of generating a public resource of mouse ES cells containing a null mutation in every protein-coding gene in the mouse genome. The KOMP repository was established to archive and distribute the 8500–10,000 KOMP vectors and ES cell clones, and to ensure the preservation, protection and availability of these resources and any associated services for the scientific community (www.komp.org/).
The Rat Resource and Research Center distributes high-quality, well-characterized inbred, hybrid and mutant rat strains to investigators. This center selects and imports rat strains and stocks that are important to biomedical research; rederives rats to a pathogen-free state; cryopreserves gametes and embryos; and performs genotyping and infectious disease monitoring to assure the quality of the rats. The resource distributes rats to scientists as live animals, cryopreserved germplasm or tissues (www.nrrrc.missouri.edu/).
Resources of other specialized rodent models species, e.g. gnotobiotic mice and perimyscus, are available to scientists; more information can be found at the DCM web site listed above.
Nonhuman primates (NHPs)
The close molecular, immunological, reproductive and neurological relationships of nonhuman primates (NHPs) to humans make them essential surrogates for humans in biomedical studies that require an integrated understanding of a whole individual. They enable discoveries that apply directly to studies on human health and help scientists test treatments for conditions such as obesity, infectious disease (e.g. malaria, AIDS) or drug addiction. DCM’s NHP program funds animals, facilities, technologies and materials that support this research. Additionally, DCM is responsible for the National Institutes of Health Chimpanzee Management Program.
The major goal of the NHP resource program is to facilitate the use of NHPs as models of human health and disease for basic, translational and clinical biomedical research. Through funding to eight National Primate Research Centers (NPRCs), scientists gain access to resources that provide animals, appropriate facilities and exceptional expertise in all aspects of NHP biology and husbandry. Together, the NPRCs have more than 28,000 animals representing more than 20 species of NHP, with the majority being macaques. The centers also provide thousands of NHP blood and tissue specimens to investigators at research institutions worldwide. The centers’ specialized resources are intended to support investigators who receive their primary research project funding from the NIH, but are also used by investigators who are funded by other federal, state and local agencies, and by research foundations and the private sector. The multidisciplinary environment at each NPRC stimulates innovative collaborations on studies of major human diseases (www.ncrr.nih.gov/comparative_medicine/resource_directory/primates.asp).
In addition to NPRCs, the DCM supports several other NHP resource centers and research resource facilities that provide natural environments for specially bred NHP colonies. These resources, including baboons, vervet and squirrel monkeys, among others, advance multidisciplinary research of human social behavior, geriatrics, reproductive biology, genetics, spontaneous diseases, vaccine development, hypertension, AIDS, cancer and more. Research emphasis at some of these centers is to establish and maintain a specific-pathogen-free rhesus macaque supply and breeding colony program in order to produce high quality, genetically characterized animals for use in AIDS-related research by grantees (www.ncrr.nih.gov/comparative_medicine/resource_directory/primates.asp).
Under NIH’s Chimpanzee Management Program, a few chimpanzee colonies are maintained by research institutions in the USA. Like all other animal model research and resource centers, these facilities are required to meet stringent federal requirements for laboratory animal care, and to use and provide a favorable environment for the chimpanzees. The Chimpanzee Management Program supports long-term, cost-effective housing and maintenance at NCRR-supported facilities for chimpanzees. NCRR provides programmatic oversight of the facilities and ensures they comply with the Animal Welfare Act and with specific policies concerning laboratory animal care and use.
California NPRC, University of California, Davis, CA
New England NPRC, Harvard University, Southborough, MA
Oregon NPRC, The Oregon Health Sciences University, Beaverton, OR
Southwest NPRC, Southwest Foundation for Biomedical Research, San Antonio, TX
Tulane NPRC, Tulane University, Covington, LA
Washington NPRC, University of Washington, Seattle, WA
Wisconsin NPRC, University of Wisconsin, Madison, WI
Yerkes NPRC, Emory University, Atlanta, GA
Other mammalian resources
Additional mammalian resources provide models for biomedical research investigations that aid in understanding, detecting, treating and preventing a wide range of human diseases. These disease model resources include a national swine research and resource center, and a referral center for animal models of human genetic disease.
Swine are the optimal model species for investigating a number of human diseases, such as atherosclerosis, diabetes and obesity. Specifically, swine share anatomic and physiologic characteristics with humans that make them ideal models for research on such human diseases. The NCRR-supported National Swine Research and Resource Center (Columbia, Missouri) serves as a repository and distribution center for valuable swine models. Established in 2003, the center also serves as a central resource for reagents and for the creation of new genetically modified swine, and provides information and training related to the use of swine models in biomedical research (www.nsrrc.missouri.edu/).
The Referral Center for Animal Models of Human Genetic Disease identifies and characterizes new and existing large-animal models of complex human disease and makes them available for research. The disease models are identified by defects in homologous gene loci that have similar molecular and clinical phenotypes to those in the corresponding human diseases. The center also provides the clinical, pathological and molecular genetic studies required to discover novel disease models and establish their homology with human disorders. Verified models are made available to other investigators as collaborations in the form of DNA, cells, frozen semen, and/or breeding stock (www.ncrr.nih.gov/comparative_medicine/resource_directory/genetic_analysis.asp).
Resources for other specialized model species, e.g. sheep, horses, are available to scientists; more information can be found at the web sites listed above.
Nonmammalian model resources
Progress in biomedical research is continuing in parallel with the sustained development of new disease model systems and unrelenting efforts to develop tools related to existing model systems that make those models more useful, or more widely applicable. Some biological characteristics may be revealed more readily in less complex, more tractable species because of structural simplicity, especially at the genetic or cellular levels. Nonmammalian models, such as fish, worms, squid and fruit flies continue to make cost-effective and invaluable contributions to studies of gene function, protein interactions and disease processes. More extensive screening, mutagenesis and transgenesis studies can be carried out in these organisms than in mammals because the cost of keeping non-mammalian vertebrates is far lower than keeping mice and other mammalian species. DCM ensures the availability of several resources that provide a diverse array of nonmammalian models for researchers to exploit the full potential of novel, or developing, model systems for comparative and functional studies, and to gain better understanding of human genetics, disease mechanisms and health.
The National Resource for Zebrafish is housed at the University of Oregon, Eugene. The resource’s mission is to provide a central repository for wild-type and mutant strains of zebrafish, and for materials and information about zebrafish research. The resource accepts strains of wild-type fish and lines carrying mutations and transgenes from the research community, and maintains and distributes them upon request (http://zebrafish.org/zirc/home/guide.php). Pathology services are provided for diseased fish.
The Bloomington Drosophila Stock Center (University of Indiana, Bloomington) collects, maintains and distributes genetically defined strains of Drosophila melanogaster, the fruit fly, with significant research value. Drosophila is one of the foremost model organisms for investigations into many fundamental problems in biology, owing to the high degree of conservation of many proteins, and cellular and developmental pathways, between insects and vertebrates combined with an extensive set of well-developed genetic tools. The resource’s collection consists of over 23,300 different stocks that carry more than 31,100 unique genetic components. Mutant alleles of over 7600 genes account for 41% of these unique components. Insertions of transgene constructs (engineered transposable elements) make up 49% of unique components, and chromosome aberrations account for the remaining 10%. Up-to-date stock lists are available for searching, browsing or downloading/copying (http://flystocks.bio.indiana.edu/). Further, for researchers who are new to the field, stock center scientists are available to answer questions about center stocks, use of the database, or general queries about Drosophila genetics.
The Caenorhabditis Genetics Center (CGC) resource acquires, maintains and distributes genetic lines and information about stocks of the small free-living nematode Caenorhabditis elegans, for use by investigators initiating or continuing research on this genetic model organism. C. elegans has also been used to model aspects of embryogenesis, morphogenesis, development, nerve function, behavior and a number of age-associated neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington diseases. The CGC’s collection of more than 4000 strains includes one allele of each mapped gene, all available chromosome rearrangements and selected multiple-mutant stocks for genetic mapping. In addition, the CGC has stocks of nematode species that are closely related to C. elegans. Information about CGC stocks can be obtained from the CGC web site (www.cbs.umn.edu/CGC/).
Resources for other specialized models of nonmammalian species, e.g. squid, Xiphophorus and Aplysia, are available to scientists; more information can be found at the DCM web sites listed above.
Genetic, biological and information resources
The NCRR supports a variety of sources for genetic analysis services, biological materials such as cultures and reagents, and online information about model organisms. This program supports research resources to facilitate and broaden the utility of animal models, and to provide biomedical researchers with access to an array of important biological materials, such as cell lines and genetic materials.
The goal of the NIH’s NHP reagent resource is to facilitate the optimal use of NHP models in biomedical research by identifying, developing, characterizing and producing reagents for monitoring or modulating immune responses. The resource provides antibodies for in vivo administration and in vitro diagnostics in NHPs. It also maintains a database of commercial reagents that cross-react with 12 different NHP species and provides NHP recombinant proteins, reference reagents and cell lines. The resource is continuing research on the in vivo effectiveness of mouse/human, mouse/rhesus, fully human, and fully rhesus recombinant monoclonal antibodies directed against cell targets. The goal is to develop reagents for administration to NHPs that provide the optimal efficiency and duration of effect (http://nhpreagents.bidmc.harvard.edu/NHP/default.aspx).
The Adult Mesenchymal Stem Cell Resource provides well-characterized human adult, rat and mouse stem cells to academic researchers upon request. The adult stem cells are the plastic adherent cells from bone marrow, referred to as mesenchymal stem cells or marrow stromal cells (MSCs). The focus of the resource involves preparing a continuous supply of quality-tested human, rat and mouse MSCs, and distributing them on request to other investigators for research. The resource also prepares MSCs from human bone marrow aspirates sent by investigators, and develops improved methods of isolating and characterizing human MSCs (www.som.tulane.edu/gene_therapy/distribute.shtml).
The Viper Resource Center, located in the Natural Toxins Research Center, Texas, provides the research community with reliable sources of venom and other snake products. The center has a serpentarium that houses more than 450 venomous snakes, representing 29 species, with the goal to eventually include all North American species of venomous snake. The venom from individual snakes is collected, lyophilized and entered into the database. The snakes are cataloged on the Internet database, along with their geographical location data, their venom’s hemorrhagic and proteolytic activities, and high-performance liquid chromatography and electrophoretic titration profiles. The center also provides snake venom, glands, blood and organs (www.ntrc.tamuk.edu/index2.htm).
DCM supports the mission of the Institute for Laboratory Animal Research (ILAR) to develop guidelines and disseminate information on the scientific, technological and ethical use of animals and related biological resources in research, testing and education. ILAR serves as an informational resource to the biomedical community by promoting high-quality humane care of animals and the appropriate use of animals and alternatives. ILAR functions within the mission of the National Academies as an advisor to the federal government, the biomedical research community and the public (http://dels.nas.edu/ilar_n/ilarhome/index.shtml). In addition to supporting the general mission of ILAR, DCM supports the ILAR journal, which provides the scientific research community with a unique repository of high-quality, timely, peer-reviewed information on new developments in biomedical research that involve the use of laboratory animals (http://dels.nas.edu/ilar_n/ilarjournal/journal.shtml).
Funding opportunities for disease models
Scientists are always looking for additional support to fund their studies. The NIH’s guide (http://grants.nih.gov/grants/oer.htm) for funding opportunity announcements provides information about new or existing program announcements and new requests for applications. However, other funding sources, both federal (e.g. Department of Defense, Department of Agriculture, Food and Drug Administration, Centers for Disease Control and Prevention) and nonfederal (e.g. Morris Foundation, American College of Laboratory Animal Medicine), provide potential opportunities that should be explored. Furthermore, some of the largest resource centers, including the National Primate Research Centers and the Clinical Translational Science Awards (CTSA), provide scientists with opportunities to compete for pilot funding [see the individual NPRC (www.ncrr.nih.gov/comparative_medicine/resource_directory/primates.asp) or CTSA web sites (www.ctsaweb.org/) for more details].
One example of such a funding opportunity supported by NCRR is the ongoing announcement PA-07-336, Development of Animal Models and Related Biological Materials for Research (http://grants.nih.gov/grants/guide/pa-files/PA-07-336.html). Applications are accepted under the R21 mechanism. Prior to submitting an NIH application, scientists are strongly encouraged to contact NCRR’s (or the appropriate NIH institute’s) program staff. After carefully reviewing the announcement, the researcher should always contact the NIH program scientist listed in the document. A brief discussion, by e-mail or phone, will clarify whether the investigating scientist’s idea and plan are in alignment with the funding announcement. This approach can avoid a significant amount of wasted time, and sometimes help an application to focus on the intended target.
Final thoughts on future directions for disease models
One major emphasis of today’s biomedical research is translational research, which ultimately enables research scientists to provide new treatments more efficiently to patients. Animal models play an integral part in translational research. Trained scientists who are knowledgeable in the selection and use of appropriate animal models have been, and will continue to, play a key role in translational research investigations. Veterinary scientists, among others, can take on this role as leaders, collaborators or partners. Consistent with this emphasis on using animal models in biomedical research is the ‘one medicine/one health’ concept supported by both the American Medical Association (AMA) and the American Veterinary Medical Association (AVMA); this concept makes it clear that scientists, physicians and veterinarians, and policy makers are combining their efforts towards a better understanding of disease control and prevention (Enserink, 2007; Kahn et al., 2008). Multidisciplinary and interdisciplinary teams of research scientists are breaking new ground in combining their skills, knowledge and expertise to engage in partnerships that take full advantage of existing resources. The scientist of the future needs to be knowledgeable about existing and expanding opportunities, flexible enough to adapt to new methods, techniques and collaborators, and willing to face new challenges.
