Significance of NWM models in biomedical research


The NIH Office of Research Infrastructure Programs (ORIP) convened in August of 2018 a Scientific Expert Panel Forum on “Challenges in Assessing Nonhuman Primate (NHPs) Needs and Resources for Biomedical Research”. The final report of that Forum reaffirmed that NHPs serve as critical animal models for many research areas, including infectious diseases; social, cognitive and behavioral research; reproductive biology; regenerative medicine; aging and neuroscience research [https://orip.nih.gov/about-orip/research-highlights/nonhuman-primate-evaluation-and-analysis-part-1-analysis-future-demand-and]. It was concluded that, among the NHP species considered, the common marmoset (Callithrix jacchus, MAR), a type of small monkey native to South America, is a research model of increasing importance for biomedical research in the United States and globally. The same conclusions were reached by another expert panel convened by the National Academy of Sciences, which also mentioned that MAR may be particularly useful for the development of new disease models using genetic engineering and assisted reproductive technologies [https://www.nationalacademies.org/our-work/nonhuman-primate-model-systems-state-of-the-science-and-future-needs].

One of the Key Recommendations (recommendation #7) of the 2018 Report of the ORIP Expert Panel Forum was to “Provide support for the development of species-specific reagents, assays, and technologies for multiple NHP species, beyond those for rhesus macaques. Additional reagents, assays, and technologies are needed to advance science in those fields that rely on other NHP species.” 

In terms of animal model development, New World Monkeys (NWM) offer attractive advantages over Old World species, such as cheaper and simpler husbandry, they are smaller and easier to handle, and have shorter generation times, all while still maintaining a greater evolutionary proximity to humans compared with other animal models [https://www.sciencedirect.com/science/article/abs/pii/S0168952512001436]

Besides MAR, other important NWM species utilized in biomedical research in the USA include the squirrel monkeys (Saimiri sps., SQM) and the owl monkeys (Aotus sps., OLM). SQM are an important animal model in neuroscience, drug addiction, and malaria vaccine research, as well as fundamental evolutionary biology; OLM also serve a significant role in malaria vaccine development.

A NIH RePORT search of federal funding for 2021, showed that there were 133 active projects and subprojects using MAR, totaling more than $ 113 million (M) distributed among 14 national institutes (NI). Among NIH institutes, there were 20 projects sponsored by the NI of Neurological Disorders and Stroke (NINDS, more than $ 36 M), 18 projects at the NI Aging (NIA, more than $ 9M), 15 projects at the NI of Mental Health (NIMH, more than $ 23M), 10 projects at the NI on Deafness and Other Communication Disorders (NIDCD, more than $ 3M), 7 projects at the NI of Allergy and Infectious Diseases (NIAID, $ 6M), and 10 projects at the Office of the Director (OD, more than $ 15M). Other institutes that sponsor projects using MAR included N Eye Institute (NEI), NI of Child Health and Human Development (NICHD), NI of Biomedical Imaging and Bioengineering (NIBIB), NI of Diabetes and Digestive and Kidney Diseases (NIDDK), NI of Dental and Craniofacial Research (NIDCR), N Cancer Institute (NCI) and NI on Drug Abuse (NIDA). 

Similarly, 2021 federal funding for research projects using SQM included 7 NIH institutes sponsoring 19 projects and subprojects totaling $ 13M; among these studies, the most funds include 6 projects at NIAID ($ 5M), 4 projects at NIDA ($ 3M), 2 at NINDS ($ 1.2M), and 2 at NEI ($1.8 M). 
As for research including OLM, there were 12 active projects, 9 of which were projects sponsored by NIAID including more than $ 5M in funding. 
During the period between 2015 and 2021 (PubMed search Jan 2021), there were more than 1,300 publications related to marmoset research, 280 manuscripts for the SQM, and 130 papers associated with OLM.

Recognizing that demand for MAR in particular is clearly outpacing availability of animals, ORIP and NIA have increased the resources destined to the expansion of breeding colonies at some National Primate Research Centers (NPRC). The entire NPRC MAR population stands at approximately 700 animals housed at Southwest and Wisconsin NPRC, with smaller populations of MAR that exist at other institutions in the U.S. (e.g., University of Nebraska at Omaha, Johns Hopkins Medical School, MIT, University of California at San Diego, University of Pittsburgh) typically supporting the efforts of few investigators. Overall, it is estimated that there is a U.S. MAR research population of less than 2,000 animals; of those animals, less than 10% are available for expanded use as the large majority are already committed to on-going projects or to production. Both WNPRC and SNPRC are committed to supporting the research needs of the community and are planning to double the size of each of their breeding populations over the next several years, increasing the number of breeding pairs at each site from approximately 30 to 80 pairs. NIH also supports the Squirrel Monkey Breeding and Research Resource (SMBRR), part of the Michale E Keeling Center for Comparative Medicine and Research (KCCMR), University of Texas MD Anderson Cancer Research Center, in Bastrop, TX. This breeding colony, with 500 animals, has been supported with a P40 since 1980, and it is the only source in the world of the Bolivian squirrel monkey (Saimiri boliviensis boliviensis), utilized by NIH grantees, the NIH intramural research program, and federal agencies, including the FDA and NSF. KCCMR also manages the Owl Monkey Breeding and Research Resource (OMBRR), which breeds about 325 owl monkeys for malaria studies sponsored by NIAID and the Gates Foundation.

One critical shortcoming of NWM is the limited number of immunological reagents that are currently available. It is estimated that while the human lineage diverged from OWM about 23 million years ago (MYA; range 21-25), this separation is estimated to be 33 MYA (range 32–36) for NWM (3). Thus, each NWM subfamily resulted from an evolutionary diversification early since this group diverged from OWM and evolved in South America in the absence of other primates, resulting in many species for which there is no close analogy among extant primates (4). Due to this divergence, the amino acid differences between some human and NWM proteins make many monoclonal antibodies (mAbs), developed for the identification of human biomarkers, unable to bind to the MAR homologs.

In summary, this R24-funded resource specifically addresses the development of immunological reagents and assays specific for molecules that are common biomarkers of inflammation and metabolism in humans, and that are not currently available for three species of NWM with increasing importance in biomedical research. As described above, development of these reagents is of trans-NIH interest, since they will increase the translational value of the MAR, SQM, and OLM, and will expand the scientific data obtained from precious samples derived from these animals. Letters of support from 23 colleagues with active research projects and from investigators leading NIH-sponsored NWM breeding colonies attest to the significance of this proposal.