Oregon National Primate Research Center champions new methods for studies

It’s not every day you hear leaders say their goal is to eventually make their work obsolete.

“People think it’s counterintuitive, but my goal is we someday refine, reduce and replace the use of nonhuman primates in research,” said Skip Bohm, D.V.M., DACLAM, professor and director of the Oregon National Primate Research Center at Oregon Health & Science University.

“This has been a longstanding goal of scientists who use animals in research. We focus on the three ‘Rs, – refine, reduce, replace. Whenever possible, reduce the number of animals needed, refine our practices and replace animals with other methods. The more achievable goals with the current state of technology are to reduce the number of nonhuman primates we use for biomedical research and to develop minimally invasive techniques — refinement — with replacement being a long-term goal as the technology is further developed.”

Bohm came to OHSU in August 2023 with this vision in mind. A research veterinarian with deep experience in animal care, veterinary training and infectious disease research, Bohm said he believes OHSU is uniquely suited to lead the charge in using innovation and technology to reduce the number of animals needed for research. One of seven National Primate Research Centers in the U.S., with research spanning neuroscience, fertility and reproduction, genetics, diseases of metabolism and aging, and infectious disease, the ONPRC already has moved to using alternative methods whenever possible for research studies.

“I’m a veterinarian as well as a director of a National Primate Research Center, so I’m inherently thinking of things from an animal welfare standpoint, as well as advancing science,” he said.

NIH initiative promotes new approach methodologies

In 2022, the National Institutes of Health announced an initiative to promote research with new approach methodologies, known as NAMs. These can complement traditional animal models and, in some cases, may help refine or replace altogether the need for animal models in certain types of research studies. Bohm said OHSU already has many researchers using these methods, and now with increased support from NIH in this area, he hopes to push the envelope further.

“We are well-suited to improve these methods and move this forward because of the diversity of research happening at the ONPRC, and because we have already started this work,” he said.

The ONPRC houses one of the largest rhesus macaque colonies in the world, along with a much smaller number of other nonhuman primates, such as the cynomolgus macaque, Japanese macaque and squirrel monkeys. During the COVID-19 pandemic, demand for nonhuman primates for development of vaccines led to a global shortage of research animals. That shortage continues today.

“The shortage and continued demand for nonhuman primates in the future because of the need for vaccine development, as well as increased focus on diseases of aging, make it even more imperative that we develop new techniques to minimize the use of animals,” Bohm said.

Jon Hennebold, Ph.D., professor and associate director for research at the ONPRC, said the center had been working on these new methods years before the NIH initiative.

“Our researchers have been involved in this area for quite some time,” he said, listing more than a dozen current studies*. “And the work spans different scientific divisions. Eventually, though, it needs to be tested in vivo.”

Hennebold and Bohm explained one aspect of NAMs that is often misunderstood: the idea that tissue culture or simulation models can replace animals entirely. NAMs are considered complementary methods to the use of animals. While technology has progressed significantly over the past decade in the development of in vitro models, they are not yet adequately developed to replace animals in research. The study of interactions between complex systems cannot currently be fully replicated using nonanimal models. Animal models are still required to validate the data derived from alternative approaches and provide information for development of new approaches. The hope is that, by informing this new technology with animal-derived data, it will improve to minimize the use of animals in research in the future.

“As an example, take the area of neuroscience, especially in the field of cognition,” Bohm said. “It is impossible to determine loss of cognition from a cell culture. You can’t assess that response from an in vitro model.”

OHSU already using approaches to reduce animals used in studies

Using the NAMS approach, however, researchers can greatly reduce the number of animals used in research studies, even if they can’t eliminate their use entirely. Victoria Roberts, Ph.D., is an associate professor in the Division of Developmental and Reproductive Sciences at ONPRC. Roberts’ research focuses on placenta development and function in pregnant individuals. She recently had an abstract accepted for poster presentation at the Cell Symposia Conference in San Diego in August focusing on “engineering development and disease in organoids.”  

“The placenta is a remarkable organ that supports the growth and development of the baby. We can study it post-delivery, as the placenta is considered a waste product of pregnancy. A lot can be learned about how it functioned, but you can’t change an outcome at that point,” Roberts said, adding that the placenta is the foundation of a pregnancy and issues in the placenta lead to developmental issues in the fetus.

Her NIH-funded research starts in a nonhuman primate, which she uses to generate an organoid model. Organoids are three-dimensional cell culture systems derived from stem cells that mirror the cell composition and features of early tissue organization. They can be used to study physiological and pathological processes during development, homeostasis (internal stability of an organ), regeneration or disease. Organoids can model aspects of human development that are difficult to access, such as embryogenesis, when a fertilized egg becomes an embryo, and brain development. Generation of an organoid model from the nonhuman primate avoids the constraints of first-trimester human sampling and improves understanding of placenta structure and function in the early pregnancy period.

This method reduces overall animal use because organoids can be maintained and grown in culture for many months, allowing for multiple studies to be performed from one initial sample.

“Being able to do studies earlier in pregnancy on the placenta itself, within the first trimester, is essential to our research and helps us understand when things might start to go wrong,” Roberts said.

The next objective of Roberts’ research is to use a minimally invasive, ultrasound-guided needle biopsy technique to obtain placenta samples without terminating the pregnancy.

“This new approach method will allow us to generate organoids from the first trimester for the in vitro study of placental function that can be correlated with real-life pregnancy outcomes at full-term delivery,” Roberts said. “This will be a powerful tool for improving our understanding of early placental development using a method that can also be implemented in human pregnancy.”

Roberts’ research is the prototype for the direction that Bohm and Hennebold want to see the ONPRC move toward. To this end, the center is creating a pilot study program to provide funding support for the generation of new NAMs, or to further the study and characterization of existing NAMs.

“My hope is that a part of my legacy here at the ONPRC is that we revolutionize new approaches of doing research in animals to improve animal welfare, and at the same time, improve the science,” Bohm said. “We are investing resources in this area, but no one knows for sure how far these new methods may take us. It’s one of our areas of focus and in my opinion, the National Primate Research Centers and the ONPRC should be leaders in this area.”

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