William R. Morton, VMD
The task of summarizing this workshop has been very difficult; however, I have had the help of a number of individuals, particularly Drs. Abee and Klein. Together we have culled several relevant points, which I will describe.
In opening the session, Dr. VandeBerg established two important points about nonhuman primates: the number used in research is decreasing; and they have become less and less accessible over the last several years. That combination of factors can and will have an impact on our ability to do biomedical research on human health problems. We need to work diligently to communicate the value of human health research to the people in the areas or countries of origin and resource providers here. In addition, as a spin-off, animal health improvements and progress are often the result of our human health research efforts. We can avoid future shortfalls of nonhuman primate resources by making a long-term investment now in the resources and the infrastructure needed to provide them for biomedical research. We have heard that theme repeatedly throughout the last 2 1/2 days.
There is a need for a continuing and increased investment in infrastructure for nonhuman primate-based research. As Dr. Hearn emphasized in the keynote address, this is a unique time in science, when the
Director, Washington National Primate Research Center, Seattle, WA
basic sciences, the applied sciences, and human health problems are coming together at an unusually rapid rate. We hope that the efforts we and others in the research field are making will translate rapidly into human health applications. Some of the current research efforts with nonhuman primates, particularly in the field of AIDS, offer great potential in the development of antivirals and, hopefully, effective vaccines. In the future, some of the strategic biotechnology areas of research that will loom larger are AIDS, stem cell research, gene therapy, aging, and learning and behavior. These fields may require the use of nonhuman primates to assure progress in human medicine.
However, to achieve the necessary balance between environmental needs, conservation needs, and the provision of resources, we need alternatives to the use of the rhesus monkey (Macaca mulatta). Dr. VandeBerg urged NCRR (National Center for Research Resources), ILAR (Institute for Laboratory Animal Research), and other such agencies to take a combined leadership role in providing the resources to allow us to move ahead in a thoughtful way in the use of the nonhuman primate. He outlined prospective actions and recommended that we build on the resources to fund the national primate centers and other nonhuman primate facilities to conduct state-of-the-art research. He described coalitions between institutions such as the National Academy of Sciences (specifically ILAR), NIH (National Institutes of Health), USDA (US Department of Agriculture), and private industry that would result in the development of even better international collaborations. There must be a mutual outreach between the national and the international efforts to provide not only what we need, but also what they need. We must work toward conservational funding as well as resource sharing.
Several speakers expressed increasing concern in regard to bioterrorism and the research surrounding that concern, including vaccine development. Vaccines for use throughout the world are the ultimate and tremendously valuable product of these efforts.
Our international guests, who have come from virtually every corner of the globe, summarized their needs and problems in an effort to foster a more positive collaborative approach between the countries of use and the countries of origin of these nonhuman primate species. A critical question raised throughout the presentation was, “How can we better interact and perhaps use some of the existing programs as prototypical models while developing even better methods for the future?”
We all share in the concern for the destruction of these nonhuman primates’ habitat, which has forced many of these and other species into a pest-like status and has contributed to their destruction. Our international colleagues clarified their particular community needs as well as their cultural and philosophical differences. They described their concerns regard
ing the inadequacies of the existing infrastructure, regulatory burden, and transportation issues. These issues are both current and future concerns, which we intend to address in future meetings.
Dr. Robinson provided an overview of domestic nonhuman primate resources from the NIH perspective. He described the increase in nonhuman primate use, plans for the future, and resource concerns. There will be a subsequent meeting to elaborate on those concerns.
Dr. Beattie presented a unique snapshot of the private sector/private industry use of the nonhuman primate. The information was very revealing in terms of that industry’s direction and the needs we must fulfill.
At the close of the first day, we had a very detailed presentation of a long-awaited, newly published update of the National Academies publication Nutritional Requirements of Nonhuman Primates. It is greatly welcome and should be utilized in the field.
At the beginning of the second day, Dr. VandeBerg strongly supported the use of genetics and genetic tools in research that utilizes the nonhuman primate for some of the outstanding examples he gave as significant causes of human morbidity and mortality. He described how research could improve and be of higher quality through the use of increased technology and improved technology of genetics. The value of the nonhuman primate model could be expanded by using these tools to address disease issues.
Dr. Williams-Blangero strongly advocated better management of nonhuman primate colonies through the use of genetics. She urged greater attention to pedigree and to developing good pedigrees by focusing more on data collection and records of all types. She presented breeding strategies that could be used in colony management based on these genetic considerations. Southwest Foundation has developed software that is available to assist nonhuman primate colony managers.
Dr. Friedrich presented a detailed description of the prototypical antiviral infection in the nonhuman primate, from exposure and infection, to the initiation of immune mechanisms, to the assumption of control, and ultimately to disease. He pointed to the role the genotype of a particular nonhuman primate can play in helping to control the infection. He presented the example of the Mamu-A*01 MHC class 1 allele, which has highlighted the genetic interaction with viral infection and AIDS in the rhesus monkey.
Mamu-A*01 is perhaps the most important single factor that has led to this meeting. The discoveries are continuing, and other alleles have already been identified that further control MHC class 1 and class 2 alleles in AIDS pathogenesis, vaccine production, and research. The following questions arise: Where do we go; how much do we design these animals for research; and what is the cost of that design? By combining those
questions with Dr. Mansfield’s talk (described below), it is possible to visualize the ultra-genetically designed animal with the specific pathogen-free animal—with costs escalating to exceed those of the chimpanzee!
Mr. DeMarcus presented an overview of importation, quarantine, and transport concerns from the perspective of the CDC (Centers for Disease Control and Prevention) (see below).
Dr. Marthas focused on aspects of studying one species exclusively and suggested that we consider looking at the same species from different origins, that is Chinese-origin versus Indian-origin rhesus monkeys. Comparison of SIV (simian immunodeficiency virus) pathogenesis in those two particular types of nonhuman primates has shown that there are no significant differences. There has been more heterogeneity in the Chinese-origin rhesus monkey in considering a variety of factors, but basically the outcomes have been the same. Both have shown they have the ability to be infected. Both have shown progression to the disease, and the variability in both sets has been relatively similar. Those findings have emphasized the fact that genetic profiling of nonhuman primates, as much as possible before the design of experiments, could have a positive impact on the outcome of those experiments.
The fact that there is very little in the literature that scientifically compares differences between species is another important consideration that has emerged from this meeting. More scientific studies should be devoted to comparative studies between nonhuman primate species and making those species available for various types of research. Drs. Friedrich and Marthas’ presentations addressed this matter in terms of proposed action.
In the Microbiology session, contributors included Drs. Klein, Baskin, DeMarcus, Motzel, and Mansfield. Dr. Baskin presented an overview of specific micro-organisms (i.e., pathogenic organisms) in the nonhuman primate and associated concerns, including the more common but significant colony health concerns such as chronic colitis. He outlined the need to define the nonhuman primate (particularly the macaque) microbiologically.
One of the planned goals of this conference was to address microbiological standardization of various assays, reagents, and methodologies being used for testing in these animals, particularly in the macaque. These issues must be addressed in more depth and should be the subject of discussion in future conferences. Dr. Baskin made the appeal, as have others, for increased funding for infrastructure to provide better laboratories, better facilities, better necropsy facilities, better capability of microbiological assessment, and ample and adequate training.
We learned from Mr. DeMarcus’ presentation that in terms of species, Macaca fascicularis (cynomologus) accounted for more than 80% of all non
human primates imported to the US during the fiscal year 2001. That number represented a huge portion of nonhuman primates coming into the United States, with the rhesus accounting for the second greatest number, at 13%. All other primate species were almost negligible in terms of numbers used.
Importantly, the mortality figures for importing quarantine were exceedingly low, at 0.7%. That low figure represents a major change over the years. I can remember when the percentage was much higher, and I think that change is very positive. We may have blundered in many other areas, but this change is a great improvement over the past. Mr. DeMarcus also emphasized animal transportation issues and the emerging needs regarding quarantine issues and limited airlines.
Dr. Motzel presented a comparative study in which she confirmed that tuberculosis in the nonhuman primate is not a disease of the past but will always be a threat. No single method of testing primates for the disease is infallible, and it is imperative to use multiple tests and a multiple means of diagnosis. Dr. Motzel compared the African greens, the cynomolgous, and rhesus monkeys and showed us once again that the African greens are extremely sensitive to this infection, as are the rhesus monkeys for the most part. The cynomolgous monkeys, for whatever reasons, are much more tolerant of infection by M. tuberculosis.
Unfortunately, testing every 6 months may not be enough because as Dr. Motzel pointed out, it is already too late when the first sign (usually a cough) becomes evident. At that point, other animals have already been exposed. She emphasized the need to constantly review the testing. She pointed to radiological methods that were effective in detecting specific, early pulmonary forms.
Dr. Mansfield’s presentation focused on one example of how to derive and create an SPF (specific pathogen-free) colony. He described the need to survey for an array of nine viruses. In spite of the great difference between the rodent and the nonhuman-primate fields in terms of genetic and microbiological definition, we appear to be approaching a better genetically and microbiologically defined macaque for research.
Many individuals discussed transportation issues for nonhuman primates in terms of regulatory issues and transportation impeding the supply of reliable animal models. We repeatedly focused on airline problems in this meeting, which surely should be one subject of a future meeting.
Many overviews were presented from several different perspectives: Dr. Garnett from OLAW (Office of Laboratory Animal Welfare); Dr. DePoyster from USDA; Dr. Kreger from the US Department of Fish and Wildlife. Drs. Rapley and Hsu focused on conservation efforts, and Dr. Hsu described Chinese resources and which airlines transport nonhuman primates from China. This topic is very practical because the
Chinese airlines serve not only China but also the entire Southeast Asian resource needs (e.g., both China and China Southern Air serve Indonesia).
The speakers identified the following agencies as the major regulatory “drivers” of transportation: IATA (International Air Transport Association); CITES (Convention on International Trade in Endangered Species of Wild Flora and Fauna) concerns; USDA; and US Fish and Wildlife. All of these agencies would benefit from a coordinated approach as well as increased understanding of the issues surrounding transportation of nonhuman primates. Often we can satisfy one regulatory agency but not satisfy another. We need to identify and resolve overlapping and conflicting requirements to develop a nonhuman-primate plan that is truly international in scope.
As a transportation issue, the limited number of airlines came to the fore again and again, as well as the delays in transport, which are caused by many factors. Again, the problems are regulatory permits, the routing of air traffic, and the various reasons that traffic must go one place or another.
In the final panel discussion, we discussed strategies to integrate all of our mutual concerns as we utilize the nonhuman primate. Participants called for the rapid development of an international primate plan that is needed now. ILAR appears to be the best suited organization to facilitate this endeavor. ILAR is nongovernmental, yet its Council members have access to scientific and management expertise related to US research and a representative knowledge of the other countries that should play a central role in developing a successful international plan. As Dr. Zurlo stated, plans are already under way to develop a transportation workshop or study. Hopefully, we will then proceed with the plan for microbiologically standardizing specific nonhuman primates (particularly the macaque and perhaps baboon) and for more genetic standardization.
I would like to echo Dr. VandeBerg in thanking both ILAR and NCRR for hosting this workshop. Thanks are due Drs. Abee and Klein for their assistance with this summary, and all of the ILAR staff for a very beneficial meeting.
DR. ZURLO (Joanne Zurlo, Director of ILAR): I have nothing to add to what has been said already; however, I do want to offer my heartfelt thanks to the speakers at this meeting. The presentations were beyond expectation, and we owe the success of the meeting to the speakers’ preparation and participation. A very, very special thank you is due the Program Committee, who made the meeting possible through their inspiration and ideas for topic development. Thanks are also due ILAR Council because the work of the Institute functions through its Council, a very strong and important group with which I am privileged to work. Additional thanks are due the audience, for tremendous participation in the