Role of the nonhuman primate for research related to women's health

This overview of the current status of medical problems that affect women is related to current studies on pathophysiology and therapeutic interventions using nonhuman primates to demonstrate the utility of the primate model for the study of disease processes in women. The current medical literature on women's health is compared with the literature on nonhuman primate research. The findings reviewed in the articles of ILAR Journal Volume 45 Issue 2 of 2004 are evaluated in the context of the scope and problems associated with disease entities in women. Nonhuman primate research with known information regarding women's disease is discussed, and the utility of the animal model for the study of human disease is highlighted, based on its significant relevance due to similarities of nonhuman primate and human subjects' physiology, metabolism, and responses to therapeutic interventions. Additional advantages of the animal model include the ability to control the experimental environment and the capacity to perform chronic study procedures. These findings allow us to utilize the nonhuman primate as the most relevant model in the animal world for the study of human disease processes.     

An overview of biohazards associated with nonhuman primates

Because of their close phylogenetic relationship, human and nonhuman primates share susceptibility to many pathogens which do not affect lower animals. This similarity, which makes them invaluable models for studying human infectious diseases, also makes primate animals potentially dangerous to work with. The biohazards inherent in the use of nonhuman primates in biomedical research are zoonoses, injuries, and infectious agents introduced by study protocols. This review addresses the various kinds of parasites, fungi, rickettsiae, spirochetes, and viral agents found naturally occurring, or experimentally induced, in nonhuman primates with reference to measures for preventing spread among the animals or to personnel.     

Advantages and limitations of nonhuman primates as animal models in genetic research on complex diseases

Abstract: The genetic similarity between humans and nonhuman primates makes nonhuman primates uniquely suited as models for genetic research on complex physiological and behavioral phenotypes. By comparison with human subjects, nonhuman primates, like other animal models, have several advantages for these types of studies: 1) constant environmental conditions can be maintained over long periods of time, greatly increasing the power to detect genetic effects; 2) different environmental conditions can be imposed sequentially on individuals to characterize genotype-environment interactions; 3) complex pedigrees that are much more powerful for genetic analysis than typically available human pedigrees can be generated; 4) genetic hypotheses can be tested prospectively by selective matings; and 5) essential invasive and terminal experiments can be conducted. Limitations of genetic research with nonhuman primates include cost and availability. However, the ability to manipulate both genetic and environmental factors in captive primate populations indicates the promise of genetic research with these important animal models for illuminating complex disease processes. The utility of nonhuman primates for biomedical research on human health problems is illustrated by examples concerning the use of baboons in studies of osteoporosis, alcohol metabolism, and lipoproteins.     

Historical perspective of genetic research with nonhuman primates

Genetics became firmly established as a scientific discipline early in the twentieth century, but major genetic research programs that involve nonhuman primates have been initiated only in the last two decades. Considerable activity in this area has been stimulated by the concurrent development of powerful techniques for detecting variability in chromosomes, proteins, and DNA; the establishment of pedigreed breeding colonies; and the recognition that nonhuman primates are ideally suited as models of human disease and social structure. The subdisciplines of cytogenetics, immunogenetics, and biochemical genetics have established a firm basis for biomedical and evolutionary research with nonhuman primates, and they will contribute greatly to future research initiatives. More recently, the advent of molecular genetics has enhanced the opportunities for research; and the exploration of nonhuman primates as potential models for genetically mediated diseases has been richly rewarded.We stand at the threshold of a new and exciting era in genetic research with nonhuman primates. The results of research programs already underway not only will provide more definitive answers about the origin of man, but also will play a critical role in solving the health-related problems of the present and of the future.     

Live rhesus offspring by artificial insemination using fresh sperm and cryopreserved sperm

Artificial insemination (AI) and the cryopreservation of sperm with full reproductive capabilities are vital in the armamentarium of infertility clinics and reproductive laboratories. Notwithstanding the fantastic successes with AI and sperm cryopreservation in numerous species, including humans and cattle, these assisted reproductive technologies are less well developed in other species of importance for biomedical research, such as genetically modified mice and nonhuman primates. To that end, AI at high efficiency in the rhesus macaque (Macaca mullata) and the successful cryopreservation of rhesus sperm is presented here, as are the complexities of this primate model due to differences in reproductive tract anatomy and gamete physiology. Cryopreservation had no effect on the ability of sperm to fertilize oocytes in vitro or in vivo. Post-thaw progressive motility was not affected by cryopreservation; however, acrosome integrity was lower for cryopreserved (74.1%) than for fresh sperm (92.7%). Fertilization rates did not differ when fresh (58.1%; n = 32/55) or cryopreserved sperm (63.8%; n = 23/36) were used for in vitro fertilization. Similarly, pregnancy rates did not differ significantly after AI with fresh (57.1%; n = 8/14) or cryopreserved sperm (62.5%; n = 5/8). Seven live rhesus macaques were born following AI with fresh sperm, and three live offspring and two ongoing pregnancies were obtained when cryopreserved sperm were used. Cryopreservation of rhesus sperm as presented here would allow for the cost-effective storage of lineages of nonhuman primates with known genotypes. These results suggest that either national or international centers could be established as repositories to fill the global needs of sperm for nonhuman primate research and to provide the experimental foundation on which to explore and perfect the preservation of sperm from endangered nonhuman primates.     

In vitro manipulation of nonhuman primate gametes for embryo production and embryo transfer.

Since nonhuman primates are closely related to humans and share many physical similarities, they are important for use in research areas such as human infectious diseases, reproduction, physiology, endocrinology, metabolism, neurology and longevity. To develop and maintain these animals, we must establish techniques for in vitro manipulation of spermatozoa and eggs. For a decade my research group has been conducting basic research to establish embryo manipulation techniques and to clarify the reproductive phenomena in nonhuman primates. This article summarizes the past research on in vitro manipulation of nonhuman primate gametes, from collection of reproductive cells and in vitro fertilization to the birth of offspring after embryo transfer, as well as the current status of these research areas. The studies summarized here will directly lead to the development of standard techniques for practical and comprehensive use in nonhuman primates.     

Marmoset models commonly used in biomedical research

The common marmoset (Callithrix jacchus) is a small, nonendangered New World primate that is native to Brazil and has been used extensively in biomedical research. Historically the common marmoset has been used in neuroscience, reproductive biology, infectious disease, and behavioral research. Recently, the species has been used increasingly in drug development and safety assessment. Advantages relate to size, cost, husbandry, and biosafety issues as well as unique physiologic differences that may be used in model development. Availability and ease of breeding in captivity suggest that they may represent an alternative species to more traditional nonhuman primates. The marmoset models commonly used in biomedical research are presented, with emphasis on those that may provide an alternative to traditional nonhuman primate species.     

Aspects of common marmoset basic biology and life history important for biomedical research

While common marmosets are increasingly used as alternative primate models in biomedical research, their life history, specialized behavior and unique physiology are not well known. This paper describes important marmoset attributes that are particularly relevant for biomedical research, including reproduction, neurobiology, immunology, endocrine signaling, obesity and aging, in addition to fetal and postnatal development. While common marmosets exhibit characteristic anthropoid primate traits, they clearly differ from Old World primates and humans in a variety of functions, including reproduction, endocrine signaling and immunology. These differences, however, permit the use of common marmosets in unconventional research strategies targeted on human pathology.     

A genetic linkage map of the vervet monkey (Chlorocebus aethiops sabaeus)

The spectacular progress in genomics increasingly highlights the importance of comparative biology in biomedical research. In particular, nonhuman primates, as model systems, provide a crucial intermediate between humans and mice. The close similarities between humans and other primates are stimulating primate studies in virtually every area of biomedical research, including development, anatomy, physiology, immunology, and behavior. The vervet monkey (Chlorocebus aethiops sabaeus) is an important model for studying human diseases and complex traits, especially behavior. We have developed a vervet genetic linkage map to enable mapping complex traits in this model organism and facilitate comparative genomic analysis between vervet and other primates. Here we report construction of an initial genetic map built with about 360 human orthologous short tandem repeats (STRs) that were genotyped in 434 members of an extended vervet pedigree. The map includes 226 markers mapped in a unique order with a resolution of 9.8 Kosambi centimorgans (cM) in the vervet monkey genome, and with a total length (including all 360 markers) of 2726 cM. At least one complex and 11 simple rearrangements in marker order distinguish vervet chromosomes from human homologs. While inversions and insertions can explain a similar number of changes in marker order between vervet and rhesus homologs, mostly inversions are observed when vervet chromosome organization is compared to that in human and chimpanzee. Our results support the notion that large inversions played a less prominent role in the evolution within the group of the Old World monkeys compared to the human and chimpanzee lineages. Electronic supplementary material The online version of this article (doi: ) contains supplementary material, which is available to authorized users.     

Generation of transgenic monkeys with human inherited genetic disease

Modeling human diseases using nonhuman primates including chimpanzee, rhesus, cynomolgus, marmoset and squirrel monkeys has been reported in the past decades. Due to the high similarity between nonhuman primates and humans, including genome constitution, cognitive behavioral functions, anatomical structure, metabolic, reproductive, and brain functions; nonhuman primates have played an important role in understanding physiological functions of the human body, clarifying the underlying mechanism of human diseases, and the development of novel treatments for human diseases. However, nonhuman primate research has been restricted to cognitive, behavioral, biochemical and pharmacological approaches of human diseases due to the limitation of gene transfer technology in nonhuman primates. The recent advancement in transgenic technology that has led to the generation of the first transgenic monkey in 2001 and a transgenic monkey model of Huntington’s disease (HD) in 2008 has changed that focus. The creation of transgenic HD monkeys that replicate key pathological features of human HD patients further suggests the crucial role of nonhuman primates in the future development of biomedicine. These successes have opened the door to genetic manipulation in nonhuman primates and a new era in modeling human inherited genetic disorders. We focused on the procedures in creating transgenic Huntington’s disease monkeys, but our work can be applied to transgenesis in other nonhuman primate species.     

Social interaction in nonhuman primates: an underlying theme for primate research.

Social living is assumed to be a critical feature of nonhuman primate existence inasmuch as most primate species live in social groups in nature. Recent USDA legislation emphasizes the importance of social contact in promoting psychological well-being and recommends that laboratory primates be housed with companions when consistent with research protocols. Our goals were to examine the link between social housing and psychological well-being and to explore the idea that research may be compromised when primates are studied in environments that vary too greatly from their natural ecological setting (individual cage housing versus group housing). Three general points emerge from these examinations. First, providing companionship may be a very potent way in which to promote psychological well-being in nonhuman primates; however, social living is not synonymous with well-being. The extent to which social housing promotes psychological well-being can vary across species and among individual members of the same species (for example, high- and low-ranking monkeys). Secondly, housing conditions can affect research outcomes in that group-housed animals may differ from individually housed animals in response to some manipulation. Social interaction may be a significant variable in regulating the biobehavioral responses of nonhuman primates to experimental manipulations. Finally, a larger number of socially housed subjects than individually housed subjects may be necessary for some biomedical research projects to yield adequate data analysis. Thus, social living has significant benefits and some potential costs not only for the animals themselves, but for the research enterprise.     

Markers of cartilage and bone matrix metabolism differ between the sera of macaque and squirrel monkeys

BACKGROUND: Nonhuman primates develop the characteristic lesions of osteoarthritis, making them attractive biomedical models for the study of environmental factors, such as diet, which may influence the progress of the condition. METHODS AND MATERIALS: We used ELISA assays of potential markers of osteoarthritis which were developed for use in humans to see if we could determined the presence of immunoreactivity in two nonhuman primate genera - Macaca (macaque monkeys) and Saimiri (squirrel monkeys). RESULTS: Inter-generic differences were significant for most markers. Three markers (bone alkaline phosphatase, hyaluronin and YKL-40) were outside the human range and two markers (laminin and C2C) did not yield useful results because they were off-scale high. CONCLUSION: Our results indicate that most of the ELISA assays designed for use with human serum can be used in nonhuman primates. The highly significant differences we observed between the sera of Macaca and Saimiri, suggest that further examination is warranted.     

灵长类比较基因组学的研究进展

随着人类和黑猩猩全基因组测序工作宣布完成,以及其他灵长类基因组测序工作的逐步开展,目前已经积累了大量的灵长类基因组数据,一个崭新的研究领域——灵长类比较基因组学应运而生。该文主要通过对人类和其他非人灵长类系统关系和基因组结构的比较,从系统进化、基因组结构和基因表达调控等方面评述该领域的研究进展,阐述人类、黑猩猩与其他非人灵长类之间的主要生物学差异,揭示人类进化的生物学机制。     

Use of primates in research: a global overview

We assessed the use of nonhuman primates and nonhuman primate biological material in research by reviewing studies published in 2001 in peer-reviewed journals. The number and species of primates used, the origin of the animals, the type of study, the area of research of the investigation, and the location at which the research was performed were tabulated. Additionally, factors related to the animals that may have affected the outcome of the experiments were recorded. A total of 2,937 articles involving 4,411 studies that employed nonhuman primates or nonhuman primate biological material were identified and analyzed. More than 41,000 animals were represented in the studies published in 2001. In the 14% of studies for which re-use could be determined, 69% involved animals that had been used in previous experiments. Published studies most commonly used nonhuman primates or nonhuman primate biological material from the species Chlorocebus aethiops (19%), Macaca mulatta (18%), M. fascicularis (9%), and Papio spp. (6%). Of these studies, 54% were classified as in vitro studies, 14% as noninvasive, 30% as chronic, and 1% were considered acute. Nonhuman primates were primarily used in research areas in which they appear to be the most appropriate models for humans. The most common areas of research were microbiology (including HIV/AIDS (26%)), neuroscience (19%), and biochemistry/chemistry (12%). Most (84%) of the primate research published in 2001 was conducted in North America, Europe, and Japan. The animals and conditions under which they were housed and used were rarely described. Although it is estimated that nonhuman primates account for an extremely small fraction of all animals used in research, their special status makes it important to report the many husbandry and environmental factors that influence the research results generated. This analysis has identified that editors rarely require authors to provide comprehensive information concerning the subjects (e.g., their origin), treatment conditions, and experimental procedures utilized in the studies they publish. The present analysis addresses the use of primates for research, including the effects of a shortage of suitable nonhuman primate subjects in many research areas.     

Progress and challenges in therapies for AIDS in nonhuman primate models

Efforts to develop animal models for human immunodeficiency virus type-1 (HIV-1) vaccine testing have focused on lentivirus infection of nonhuman primates. A long-term goal of this primate research is to utilize the models to understand the mechanisms of pathogenesis leading to AIDS. Because the time to disease is compressed relative to HIV infection in humans, therapeutic strategies and compounds can be tested in nonhuman primate models in a shorter time frame and under more controlled conditions than are possible in many clinical studies. Recent interventive studies in primates using antiviral drugs or passive immune globulin (IgG) have demonstrated that multiple log reductions in plasma virus can be achieved and sustained, with accompanying health benefits. Information gained about timing and dosage may be of utility in designing clinical studies. The development of reliable and predictable animal models for effective therapies and vaccines against AIDS remains a critical priority for primate research.     

The African Green Monkey model for cutaneous and visceral leishmaniasis

Non-human primates are valuable models for biomedical research because of their similarities to human anatomy, immunology and physiology. Leishmaniasis, a disease caused by protozoan parasites, has a worldwide distribution and results in high morbidity and mortality. Availability of a non-human primate model of leishmaniasis would facilitate the study of different aspects of this disease and would accelerate the development of vaccines and new drugs. In this article, some interesting features of the vervet monkey (African Green monkey) model of human cutaneous and visceral leishmaniasis are discussed.     

The Implications of Primate Behavioral Flexibility for Sustainable Human–Primate Coexistence in Anthropogenic Habitats

People are an inescapable aspect of most environments inhabited by nonhuman primates today. Consequently, interest has grown in how primates adjust their behavior to live in anthropogenic habitats. However, our understanding of primate behavioral flexibility and the degree to which it will enable primates to survive alongside people in the long term remains limited. This Special Issue brings together a collection of papers that extend our knowledge of this subject. In this introduction, we first review the literature to identify past and present trends in research and then introduce the contributions to this Special Issue. Our literature review confirms that publications on primate behavior in anthropogenic habitats, including interactions with people, increased markedly since the 2000s. Publications concern a diversity of primates but include only 17% of currently recognized species, with certain primates overrepresented in studies, e.g., chimpanzees and macaques. Primates exhibit behavioral flexibility in anthropogenic habitats in various ways, most commonly documented as dietary adjustments, i.e., incorporation of human foods including agricultural crops and provisioned items, and as differences in activity, ranging, grouping patterns, and social organization, associated with changing anthropogenic factors. Publications are more likely to include information on negative rather than positive or neutral interactions between humans and primates. The contributions to this Special Issue include both empirical research and reviews that examine various aspects of the human–primate interface. Collectively, they show that primate behavior in shared landscapes does not always conflict with human interests, and demonstrate the value of examining behavior from a cost–benefit perspective without making prior assumptions concerning the nature of interactions. Careful interdisciplinary research has the potential to greatly improve our understanding of the complexities of human–primate interactions, and is crucial for identifying appropriate mechanisms to enable sustainable human–primate coexistence in the 21st century and beyond.     

Nonhuman primate infections after organ transplantation

Nonhuman primates, primarily rhesus macaques (Macaca mulatta), cynomolgus macaques (Macaca fascicularis), and baboons (Papio spp.), have been used extensively in research models of solid organ transplantation, mainly because the nonhuman primate (NHP) immune system closely resembles that of the human. Nonhuman primates are also frequently the model of choice for preclinical testing of new immunosuppressive strategies. But the management of post-transplant nonhuman primates is complex, because it often involves multiple immunosuppressive agents, many of which are new and have unknown effects. Additionally, the resulting immunosuppression carries a risk of infectious complications, which are challenging to diagnose. Last, because of the natural tendency of animals to hide signs of weakness, infectious complications may not be obvious until the animal becomes severely ill. For these reasons the diagnosis of infectious complications is difficult among post-transplant NHPs. Because most nonhuman primate studies in organ transplantation are quite small, there are only a few published reports concerning infections after transplantation in nonhuman primates. Based on our survey of these reports, the incidence of infection in NHP transplant models is 14%. The majority of reports suggest that many of these infections are due to reactivation of viruses endemic to the primate species, such as cytomegalovirus (CMV), polyomavirus, and Epstein-Barr virus (EBV)-related infections. In this review, we address the epidemiology, pathogenesis, role of prophylaxis, clinical presentation, and treatment of infectious complications after solid organ transplantation in nonhuman primates.