Many major medical advances of the past century have been achieved, in part, because of translational research conducted in animal models. However, many serious diseases still threaten our well-being: many types of cancer, HIV/AIDS, Alzheimer’s disease, and Parkinson’s disease, to name a few. Finding ways to treat and prevent these and other ailments will involve the use of animals (such as rhesus macaques, a type of monkey, shown in the photograph) to lay the groundwork for clinical studies. The eight NCRR-funded NPRCs are catalyzing such translational research efforts. Closely affiliated with U.S. academic institutions and strategically located across the country, the NPRCs together have more than 27,500 animals representing more than 20 species of nonhuman primates, mostly macaques. (Photo Credit: iStockphoto)
Scientists depend on laboratory animals and other nonhuman models for investigating biological processes, studying the causes of diseases, and testing promising new therapies. Nonhuman animal models also are indispensable for developing effective biodefense strategies and for investigating many other emerging health issues. NCRR supports research and research resources that develop and enhance access to a broad range of nonhuman animal models, including primates, rodents, zebrafish, worms, and cellular models. These programs include a network of eight National Primate Research Centers (NPRCs) with highly specialized facilities that foster the development of animal models such as monkeys and baboons and provide expertise in all aspects of nonhuman primate biology and husbandry. NCRR sponsors initiatives to improve the health and care of laboratory animals and also supports the Animal Facilities Improvement Program, which upgrades animal facilities, improves research animal care, and assists institutions in complying with the regulations and policies related to the use of laboratory animals.
NCRR will provide the intellectual leadership to help guide the development and availability of critical animal models. This includes the need to:
Action Items: In this leadership role, NCRR will:
Mice have been found invaluable by NIH researchers over the years. The mouse is particularly important because it is the only mammalian species in which researchers can delete one gene at a time from the genome. A trans-NIH initiative, the Knockout Mouse Project (KOMP), was conceived in 2003, and this project is aiming to eventually disrupt, or “knock out,” each of the 20,000 or so genes in the mouse genome. The aim is to create 8,500 to 10,000 new lines of knockout mice, tripling the number that existed in 2007. The newly established repository, funded by NCRR, the National Human Genome Research Institute, and the National Institute of Allergy and Infectious Diseases, will make knockout mice available to researchers as live mouse lines, embryonic stem cell clones, frozen embryos, and sperm. Researchers then will be able to study the mice to develop better models of many human diseases. (Photo Credit: iStockphoto)
Preclinical research advances are changing the entire process of discovery of methods of treating human disease; for example, the increasingly common use of microarray analyses generates vast quantities of potentially disease-illuminating data that are useful to many investigators but frequently cryptic to those not associated with the actual data generation. Because of these advances, there is greater urgency for effective integration and application of disparate data sources. The problem is not simply a lack of resources or their archiving, but the lack of our current ability to analyze the data and to share the results across multiple institutions or disciplines. Many of these data are collected and maintained by individual investigators or laboratories that publish only selected results in scientific journals. Negative or nonprocessed data, as well as the processing tools to convert data into analytical formats, need to be made widely available. This approach will prevent unnecessary time being spent on studies that are performed multiple times. Nowhere is this data integration challenge of preclinical research more prominent than in informatics related to animal models.
Action Item: NCRR will lead the development of an informatics system related to animal models to bridge gaps that now exist in the ability to share and use information effectively. The following are a few of the important “knowledge environment” system characteristics:
As the priorities of biomedical research shift from basic molecular and cellular research to translational research, the importance of having veterinarians skilled in translational medicine has increased. The challenge now is to identify, recruit, train, and retain veterinarians who can be principal investigators or other key members of research teams in a variety of initiatives. Through NCRR Institutional Research Training Grants, veterinarians are receiving essential training to prepare them for careers in biomedical research. The photograph shows Rachel Mo Peters, D.V.M., Ph.D., transferring samples to multiwell microtiter plates in a laboratory at Cornell University in New York. She earned her doctorate in comparative biomedical sciences under the university’s training program sponsored by NCRR. (Photo Credit: Alexis Wenski-Roberts)
Since animal models bridge basic science with human medicine, synergies are currently emerging among the CTSAs, RCMIs, and NPRCs. These collaborations are helping to promote a pathway to move discoveries from the bench to the bedside.
Action Item: NCRR will enable research scientists working at CTSA-, RCMI-, and NCRR-supported Animal Resource Centers to engage in productive, mutually beneficial collaborative research relationships that take full advantage of the knowledge and infrastructures of both the clinical and animal resource entities. These new partnerships will aim to utilize animal or biological materials for preclinical investigations leading to cutting-edge translational science programs. In addition to utilizing the specific models, the partnerships also may facilitate sharing of research cores, such as pathology, informatics, or statistics, thus helping to increase resource utilization and cost-effectiveness among the CTSA, RCMI, and NPRC grantees, as well as with other animal resources. Focus will be placed on collaborations that involve sharing of knowledge, expertise, or labor costs associated with researchers working together to accomplish a common mission.
Veterinarians play a critical and unique role in government, academia, and industrial organizations engaged in biomedical research. In particular, the One Medicine–One Health concept offers opportunities to encourage partnerships between human and veterinary medicine. There are considerable challenges in identifying, recruiting, training, and retaining veterinarians who can fill these research roles. With biomedical research priorities shifting from basic molecular and cellular research to translational research, the importance of animal models and, therefore, veterinarians skilled in comparative medicine has increased.
Action Item: NCRR will address the growing need for research-trained veterinarians by sponsoring career development programs that attract and train graduate veterinarians in such specialties as primate clinical medicine, laboratory animal medicine, and rodent pathology.
The NCRR-funded Sea Urchin Genome Resource at the California Institute of Technology provided critical reagents and informatics support for sequencing the genome of the purple sea urchin, Strongylocentrotus purpuratus. The sequencing was performed at the Baylor Human Genome Sequencing Center, funded by the National Human Genome Research Institute. The sea urchin genome, which consists of about 23,300 genes, is closer on the evolutionary scale to the genome of humans than to other invertebrate animal models that are often used by developmental scientists. Equipped with knowledge of the sequence and analysis of the 814 million DNA bases that make up this marine animal’s genome, researchers will be able to perform functional studies in a simple animal model that shares a common ancestor with vertebrates. (Photo Credit: Laura Francis, National Oceanic and Atmospheric Administration)
Primate centers need support to upgrade and expand the space they have, enabling them to move research forward and have the flexibility they need to provide more models targeted toward specific diseases, such as AIDS, avian influenza, and obesity. The same holds true for other research animal centers and resources. Appropriately designed facilities are needed to support research using these animal models. Adequate resources also are required to train clinical veterinarians to properly manage and care for these valuable research animal models, given their specialized veterinary care needs.
Action Items: NCRR will continue its effort to:
The ability to produce transgenic, knockout, and mutant lines of many animal species has provided biomedical researchers with many models for the study of human diseases. However, the requirements to maintain these strains as live animals can overwhelm the capacity of even the largest animal model resource center. Although cryopreservation of gametes and embryos is a proven method for the long-term maintenance of laboratory animals, there are wide differences in the success with which various forms of germplasm can be cryopreserved in various species. With researchers producing thousands of new strains, NCRR needs to critically assess the status of the cryopreservation of germplasm and embryos for cost-effective management of breeding colonies in NCRR animal resource centers.
Action Items: NCRR will:
NCRR will, in collaboration with other NIH ICs, develop a priority list of needed validated animal models. Validation criteria should be defined and should include, at a minimum, the characteristics of the animal that make it useful as a model for the study of human disease and descriptions of mechanism-of-action studies that indicate whether the endpoint for the model is reached through the same pathway as for the human condition.
Action Item: NCRR will hold a workshop in partnership with grantees, other NIH ICs, or the pharmaceutical industry to determine:
Historically, research in neuroscience and neurodegenerative diseases has been translational in nature, essentially a dance between research in nonhuman primates and that in humans. Research using nonhuman primates serves as a basis for clinical research, and clinical research provides additional questions to explore in nonhuman primates. One technology that has arisen from work in nonhuman primates is infrared eye tracking, which allows researchers to determine, with much precision, how and where an animal looks at a stimulus. This technology has been translated to the clinic, and trials are under way to test its ability to predict who will develop mild cognitive impairment (MCI) and, of those with MCI, who will develop Alzheimer’s disease. Other studies focus on the use of eye tracking to rehabilitate patients with brain injury or cognitive impairment. Moreover, the NCRR-funded NPRCs hold the promise of developing models for neurodegenerative diseases. (Courtesy of Stuart M. Zola, Ph.D., Yerkes National Primate Research Center. Photo Credit: Getty Images, Inc.)