Did you know the rhesus macaque is the most widely studied nonhuman primate in biomedical research? The U.S. research colonies of rhesus macaques were founded primarily with animals imported from India decades ago and with the addition of Chinese-origin rhesus macaques over time. A deep understanding of their evolution and genetics is key to recognizing the origins of human traits and identifying disease genes of value to improving human health.

Rhesus macaques at the seven National Primate Research Centers (NPRCs) are key in the discovery and development of new and robust models of human disease and in evaluating the effect of genetic variation on experimental treatments prior to human clinical trials.  

In a recent publication in Science that detailed researchers’ use of advanced sequencing technology and analysis of more than 850 macaques across the seven NPRCs, researchers present a complete reference genome for the rhesus macaque. “In particular, we can now finally tackle some of the more complex regions of the genome and begin to understand how new genes evolve including the processes that have shaped them,” says University of Washington genome sciences professor and senior author in the paper, Evan Eichler, PhD.

In addition, the study identified animals that naturally carry potentially damaging genetic mutations, allowing researchers to better understand genetic variation and susceptibility to diseases of relevance to humans. So far, the findings reveal thousands of naturally occurring genetic variants (mutations), including those in genes linked to Autism Spectrum Disorder and other neurodevelopmental disorders in humans, such as SHANK3.

Jeffrey Rogers, PhD, associate professor at the Human Genome Sequencing Center and Department of Molecular and Human Genetics at Baylor College of Medicine and co-author of the paper explains, “Rhesus macaques are important for studies of conditions ranging from infectious disease (including COVID-19) to neuroscience, cancer and reproductive biology. A high-quality reference genome can aid researchers who are looking to understand the causes of various illnesses or aiming to develop treatments.”

The study is a great example of a broad collaboration across the NPRCs and other research centers in the U.S. that will continue to make a difference in human health. By identifying rhesus macaques that carry naturally occurring mutations, NPRC and other researchers are now able to examine biobehavioral traits associated with mutations. The researchers can also follow the monkeys’ offspring, and, in some cases, actually create new breeding groups to generate animals with specific genetic mutations and phenotypes. 

“This new information will lay the foundation for us to create naturally occurring models of human genetic diseases,” says Paul Johnson, MD, director of the Yerkes (now Emory) NPRC. “The development of these new models could have a profound impact on our ability to translate research in animal models into treatments and cures in people,” he continues.

To learn more about NPRC advances in genetics and genomics, explore additional research here. 

Scientific discovery is an ongoing process that takes time, observation, data collection and analysis, patience and more. At the NPRCs, our recent COVID-19 research is an example of the ongoing basic science process — how current research builds on previous discoveries and how discoveries help improve human health. This article from the National Institutes of Health (NIH) explains why basic science, such as the NPRCs conduct, is important and how taking time, as long as it takes, is a necessary part of scientific discovery.

Discoveries in Basic Science: A Perfectly Imperfect Process

Have you ever wondered why science takes so long? Maybe you haven’t thought about it much. But waiting around to hear more about COVID-19 may have you frustrated with the process.

Science can be slow and unpredictable. Each research advance builds on past discoveries, often in unexpected ways. It can take many years to build up enough basic knowledge to apply what scientists learn to improve human health.

“You really can’t understand how a disease occurs if you don’t understand how the basic biological processes work in the first place,” says Dr. Jon Lorsch, director of NIH’s National Institute of General Medical Sciences. “And of course, if you don’t understand how the underlying processes work, you don’t have any hope of actually fixing them and curing those diseases.”

Basic research asks fundamental questions about how life works. Scientists study cells, genes, proteins, and other building blocks of life. What they find can lead to better ways to predict, prevent, diagnose, and treat disease.

How Basic Research Works

When scientists are interested in a topic, they first read previous studies to find out what’s known. This lets them figure out what questions still need to be asked.

Using what they learn, scientists design new experiments to answer important unresolved questions. They collect and analyze data, and evaluate what the findings might mean.

The type of experiment depends on the question and the field of science. A lot of what we know about basic biology so far has come from studying organisms other than people.

“If one wants to delve into the intricate details of how cells work or how the molecules inside the cells work together to make processes happen, it can be very difficult to study them in humans,” Lorsch explains. “But you can study them in a less complicated life form.”

These are called research organisms. The basic biology of these organisms can be similar to ours, and much is already known about their genetic makeup. They can include yeast, fruit flies, worms, zebrafish, and mice.

Computers can also help answer basic science questions. “You can use computers to look for patterns and to try to understand how the different data you’ve collected can fit together,” Lorsch says.

But computer models have limits. They often rely on what’s already known about a process or disease. So it’s important that the models include the most up-to-date information. Scientists usually have more confidence in predictions when different computer models come up with similar answers.

This is true for other types of studies, too. One study usually only uncovers a piece of a much larger puzzle. It takes a lot of data from many different scientists to start piecing the puzzle together.

Building Together

Science is a collective effort. Researchers often work together and communicate with each other regularly. They chat with other scientists about their work, both in their lab and beyond. They present their findings at national and international conferences. Networking with their peers lets them get feedback from other experts while doing their research.

Once they’ve collected enough evidence to support their idea, researchers go through a more formal peer-review process. They write a paper summarizing their study and try to get it published in a scientific journal. After they submit their study to a journal, editors review it and decide whether to send it to other scientists for peer review.

“Peer review keeps us all informed of each other’s work, makes sure we’re staying on the cutting-edge with our techniques, and maintains a level of integrity and honesty in science,” says Dr. Windy Boyd, a senior science editor who oversees the peer-review process at NIH’s scientific journal of environmental health research and news.

Different experts evaluate the quality of the research. They look at the methods and how the results were gathered.

“Peer reviewers can all be looking at slightly different parts of the work,” Boyd explains. “One reviewer might be an expert in one specific method, where another reviewer might be more of an expert in the type of study design, and someone else might be more focused on the disease itself.”

Peer reviewers may see problems with the experiments or think different experiments are needed. They might offer new ways to interpret the data. They can also reject the paper because of poor quality, a lack of new information, or other reasons. But if the research passes this peer review process, the study is published.

Just because a study is published doesn’t mean its interpretation of the data is “right.” Other studies may support a different hypothesis.

Scientists work to develop different explanations, or models, for the various findings. They usually favor the model that can explain the most data that’s available.

“At some point, the weight of the evidence from different research groups points strongly to an answer being the most likely,” Lorsch explains. “You should be able to use that model to make predictions that are testable, which further strengthens the likelihood that that answer is the correct one.”

An Ever-Changing Process

Science is always a work in progress. It takes many studies to figure out the “most accurate” model—which doesn’t mean the “right” model.

It’s a self-correcting process. Sometimes experiments can give different results when they’re repeated. Other times, when the results are combined with later studies, the current model no longer can explain all the data and needs to be updated.

“Science is constantly evolving; new tools are being discovered,” Boyd says. “So our understanding can also change over time as we use these different tools.”

Science looks at a question from many different angles with many different techniques. Stories you may see or read about a new study may not explain how it fits into the bigger picture.

“It can seem like, at times, studies contradict each other,” Boyd explains. “But the studies could have different designs and often ask different questions.”

The details of how studies are different aren’t always explained in stories in the media. Only over time does enough evidence accumulate to point toward an explanation of all the different findings on a topic.

“The storybook version of science is that the scientist is doing something, and there’s this eureka moment where everything is revealed,” Lorsch says. “But that’s really not how it happens. Everything is done one increment at a time.”

Alzheimer’s disease is far too common. In fact, the Alzheimer’s Association estimates that more than 5 million Americans are living with it, and one in three seniors die from the disease or something related. Patients experience a gradual decline of memory and other important brain functions, which can cause great difficulty in older age. Unfortunately, early detection of age-associated cognitive dysfunction—although crucial—remains a challenge for scientists and medical professionals. 

Scientists at Texas Biomedical Research Institute’s (Texas Biomed) Southwest National Primate Research Center (SNPRC) recently made progress in this regard when they published findings indicating the baboon could be a relevant model to test therapeutics and interventions for neurodegenerative diseases, such as early-stage Alzheimer’s and others. 

The scientists observed a steep age-related cognitive decline in baboons about 20 years old, which is the equivalent of a 60-year-old human.  

“This is the first time a naturally-occurring model for early-stage Alzheimer’s has been reported,” explained Dr. Marcel Daadi, Associate Professor at Texas Biomed’s SNPRC. “(The baboon) model could be relevant to test promising drugs, to better understand how and why the disease develops and to study the areas of the brain affected in order to determine how can we impact these pathways.” 

Neurodegenerative diseases are related to the aging of brain cells and synaptic loss, which is a loss of the lines of communications inside the brain. Previous studies have pinpointed the prefrontal cortex (PFC) of the brain as one of the regions most affected by age. The PFC plays a key role in working memory function as well as self-regulatory and goal-directed behaviors, which are all vulnerable to aging.  

To observe whether these functions are impacted by aging in baboons and determine whether the baboons at varying ages could discern and learn new tasks, Dr. Daadi and his team separated the baboons into two groups based on age (adult group and aged group) and performed a series of cognitive tests. 

“What we found is that aged baboons lagged significantly in performance among all four tests for attention, learning and memory,” Dr. Daadi said.  

The researchers noted that a delay or inability to collect rewards increased in older baboons, suggesting a decline in motivation and/or motor skills. The team also demonstrated that aged subjects show deficiencies in attention, learning and memory. The findings are consistent with human studies that have suggested a sharp decline in brain systems function and cognition around 60 years. 

Until now, rodents have been the primary lab model to test therapeutic interventions for neurodegenerative diseases. But mice don’t always reflect human processes, so a nonhuman primate like the baboon could prove to be a more effective model for testing. 

“The failure rate in clinical trials of Alzheimer’s disease therapeutics is extremely high at about 99.6%, and we need to change that,” said Dr. Daadi. 

He indicated that the next steps would include performing imaging and examining biomarkers to better understand the origins and nature of the disease. 

The fight against Alzheimer’s is ongoing, and NPRC scientists are on the front lines. To learn more about the work happening at our locations around the country, visit this link. 

Research with animals is crucial to improving human and animal health. Animals in research provide unique insights not available with other scientific models, and they help scientists determine safety and effectiveness of preventions, treatments and cures. During the COVID-19 pandemic, animals in research have been especially important in accelerating the development COVID-19 vaccines as well as better diagnostics and additional treatment options.

At the NPRCs, we’re helping fill a critical role in halting COVID-19 by leading NIH-funded studies at our centers. We’re also participating in the public-private partnership ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) to develop treatments and vaccines by sharing our knowledge, resources and animals, including conducting preclinical studies with NPRC monkeys for some of the leading industry vaccine candidates.

Scientific collaboration is especially important during a pandemic when time is of the essence and, in this case, animal resources are limited. At the onset of the pandemic, monkey importation was halted, putting increasing demands on the NPRC animal colonies, which were already limited in quantity and availability. The NPRCs account for only 1 in every 5 nonhuman primates (NHPs) used in U.S.-based research, so the limited supply at a time of high demand impacts NPRC COVID-related studies as well as pre-pandemic studies under way at the NPRCs and those in planning stages.

The NPRCs remain dedicated to our other areas of study, including research into HIV/AIDS and other infectious diseases, the neurosciences, cardiovascular and respiratory health, genetics and transplant medicine. 

We are also committed to meeting the future needs of animals for NIH-funded research. We are already growing our on-site breeding colonies when time, space and funding permit, strategically assigning animals to research protocols, harmonizing across centers for efficient use of animals and increasing rigor and reproducibility to facilitate collaboration and consistency across research labs. These strategic steps now further position the NPRCs for the translation of our research advancements from cell and animal models to humans, and are indicative of our commitment to help people across generations and the world live longer, healthier lives. 

To learn more about the NPRCs’ ongoing efforts to combat COVID-19, visit this page.

Editor’s Note, 2/22/21: The New York Times covered the research monkey shortage in today’s issue. Read the story here.

Tuberculosis (TB) and HIV are two of the world’s deadliest infectious diseases, and they’re far worse when they occur together. Now, Southwest National Primate Research Center (SNPRC) researchers at Texas Biomedical Research Institute have pinpointed an important mechanism that could lead to a new mode of treatment for this co-infection.

It’s been long-assumed the reason people with HIV are more likely to develop TB is a depletion of specific immune cells. However, SNPRC scientists showed other effects of viral co-infection play a crucial role in this process.

Using data from nearly 40 rhesus macaques, the research team found lung-specific chronic immune activation is responsible for the progression of TB. Chronic immune activation is a dysfunction of immune pathways that create molecules (cytokines and chemokines) that fight off pathogens such as bacteria, viruses and fungi.

Professor and SNPRC Director Deepak Kaushal, PhD, used an analogy to explain what this dysfunction caused by an HIV infection does in the body.

“It’s like all the taps and faucets in your house are turned on full blast all the time,” he said. “You are going to lose a lot of water. With this dysfunction, all cytokines and chemokines are constantly being produced to the highest levels. This dysregulates the body’s ability to fight off other infections.”

Even with antiretroviral therapy (ART) for people with HIV, chronic immune activation still persists. Kaushal said this study shows, “we need to develop approaches to target chronic immune activation,” perhaps with a drug that would be an additional therapy to ART.

Kaushal said he is hopeful new treatment strategies could reach the clinic within a decade, and the effects could be huge. Up to a fourth of the world’s population is infected with TB, and this co-infection is considered a global syndemic, meaning the diseases are pandemics infecting people all around the world, and they promote each other.

Understanding TB is a priority for NPRC scientists, and this study is a continuation of the groundbreaking research being done across the organization. Just last year, researchers explored the possibility of treating the disease using a cancer drug.

Talking about animals in research may not be part of everyday conversations – unless you work in research, are learning more about it or want to stop it. But if everyone knew how critical animals have been in 2020 to fast-track a safe and effective COVID-19 (coronavirus) vaccine, would that change?

Earlier this year, the National Institutes of Health (NIH) called upon the National Primate Research Centers (NPRCs) – as NIH has for HIV/AIDS, Ebola, Zika and other infectious disease threats – to identify animal species for studying the SARS-CoV-2 virus and developing safe and effective vaccines to block it.

The NPRCs went to work and within a few months had discovered how valuable nonhuman primate models (NHPs), especially macaques, are for studying SARS-CoV-2. The NPRCs found the virus infects rhesus, pigtail and cynomolgus macaques, so these animals were included in research programs that resulted in several vaccine candidates in the pipeline by summer’s end. In addition, other key models for SARS-CoV-2, such as mice and hamsters, contributed to the broadening knowledge of how best to tackle the disease in humans. This rapid pace of discovery was possible due to the NPRC researchers applying their expertise fighting other viruses, especially HIV/AIDS.

As with those other viruses, the NPRC researchers closely studied SARS-CoV-2 transmission routes and pathogenesis – this time focusing on the respiratory virus’ activity in the lungs and its impact on cells, tissues and organs. The researchers also conducted detailed genetic studies on the virus to help pharmaceutical researchers use pieces of the virus’ genetic code to fashion vaccine candidates and test them for safety and effectiveness in macaques.

Translating the biomedical research findings into the human population requires going from up to a few dozen monkeys in research to thousands of human volunteers in clinical trials; for COVID-19, more than 200,000 volunteers have enrolled in four promising clinical trials. As announced in November 2020, the Moderna and Pfizer mRNA vaccines tested on rhesus macaques were more than 90 percent effective in preventing COVID-19 in widespread (Phase 3) human clinical trials and are now on track for emergency FDA approval.

Research with animals connects these vaccines with other SARS-CoV-2 scientific advancements just as it has made connections among NPRC HIV/AIDS studies, the results from which facilitated the rapid pace to COVID-19 discoveries. Improving human and animal health – that’s what NPRC research with animals does, and that’s worth talking about any day.

Learn more about research with animals scientific advancements here.

One primary objective of tuberculosis (TB) research is to discover how to treat people with the latent (or inactive) form of the disease so they don’t develop symptomatic TB.

Now, a breakthrough study from the Yerkes National Primate Research Center (YNPRC) and Southwest National Primate Research Center (SNPRC) has revealed how a specific combination of antibiotics could help.

For the study, the scientists created a latent infection in a group of rhesus macaques. They then treated half of the animals with a once-weekly combination of two antibiotics—isoniazid and rifapentine—for three months. The other half was untreated.

Numerous factors—including HIV infection, diabetes, aging or other diseases—can cause latent bacteria to become symptomatic and infectious again. To test whether the antibiotics had cleared bacteria from their lungs, both treated and untreated animals were infected with SIV (Simian immunodeficiency virus), which mimics HIV in humans. 

Of the animals that had no treatment for latent TB, 70 percent developed active TB after SIV infection. However, none of the animals that had the three-month course of antibiotics developed active TB after SIV infection, which suggests the treatment cleared the bacteria and prevented reactivation.

Because the current treatments for latent TB are lengthy, and many patients don’t finish them, a shorter treatment cycle like the one demonstrated in this study could be highly beneficial.

“The antibiotic treatment we used for this study is a new, shorter regimen the CDC recommends for treating humans with latent tuberculosis, but we did not have direct evidence for whether it completely clears latent infection,” explained Jyothi Rengarajan, PhD, Associate Professor of Medicine at Emory University and the Yerkes National Primate Research Center. “Our experimental study in macaques showing almost complete sterilization of bacteria after treatment suggests this three-month regimen sterilizes humans as well.”

The researchers at the NPRCs are working daily to find new potential treatments and cures for this infectious disease. Take a look at some of our other recent studies to learn about the progress we’ve made toward a TB-free world.

According to the World Health Organization, malaria infection affects an estimated 200 million people and kills more than 400,000 people worldwide every year—most of them children. Plasmodium parasites cause the disease, and malaria spreads to people by the bite of infected Anopheles mosquitoes. While important information, the scientific community still has much to learn about malaria in order to limit its impact.

“We don’t know what is inside malaria infections,” explained Ian Cheeseman, PhD, Assistant Professor at Texas Biomedical Research Institute, which is home to the Southwest National Primate Research Center (SNPRC). “We don’t know how many different genetically distinct strains of parasites there are. We don’t know how related they are to each other. We don’t know how many mosquitoes they came from.”

To help answer these questions, Cheeseman and an international team of collaborators turned to a process called single cell genome sequencing. This technology allows for individual malaria parasite cells to be isolated and their genome amplified before being analyzed by a genome sequencer, which enables researchers to capture the genetic mutations present in a single cell. The process has been adopted by cancer researchers to understand how tumors evolve, but this study marked the first time the technology has been used to study malaria transmission.

The team examined single malaria-infected cells from patients in Malawi, a country heavily affected by the disease. Patients who donated malaria-infected blood samples used in this study reside in Chikhwawa, a region with a large mosquito population where people may be bitten by a malaria-infected mosquito every 48 hours.

The single cell sequencing approach applied in this study provides a new perspective on how often bites from an infected mosquito lead to a malaria infection. What researchers discovered went against conventional wisdom, as nearly all the infections they studied likely came from one mosquito bite each.

“We found that complex malaria infections are predominantly caused by a single mosquito bite transmitting many genetically diverse but related parasites into the bloodstream of a patient,” said Standwell Nkhoma, MSc, PhD, lead author on the study and a Malawian national.

Knowing this will enable scientists to design more effective interventions to block mosquitoes from spreading malaria and build better models to predict malaria transmission patterns and the spread of drug resistance. While a diagnosis of malaria is often treatable with drugs, the rise of antimalarial drug resistance is a major threat to malaria control across the world, as resistance to artemisinin and piperaquine, two common antimalarial drugs, continue to spread.

To learn more about how NPRC researchers are making progress toward controlling and eliminating infectious diseases worldwide, visit this link.

The seven National Primate Research Centers (NPRCs) are participating in SciFest All Access 2020. This is the virtual answer to the postponed USA Science & Engineering Festival, which is recognized as the nation’s top science and engineering festival for K-12 students, college students, educators and families. Happening now through Oct. 3, registered participants can visit the NPRCs in the “Exhibit Portal, Health & Medicine Zone II.”

The NPRC booth includes links to NPRC.org, our collective website, as well as individual web pages for the seven centers. All pages are filled with educational resources and links to help you learn more about our research, the scientific advancements we’re making and the care we provide our research animals. Direct access links to these seven pages are provided below.

NPRC representatives will be “on site” at SciFest All Access answering questions registered participants submit via the “Ask a Question” link in the booth. We’re also answering questions participants email us at nprcoutreach@gmail.com.

You can learn even more about the NPRCs’ research to improve human and animal health by visiting NPRC.org and following us on Twitter at @NPRCnews.

We look forward to joining thousands of students, educators and families at this year’s SciFest All Access!

SciFest All Access NPRC Web Pages

California NPRC

Oregon NPRC

Southwest NPRC

Tulane NPRC

Washington NPRC

Wisconsin NPRC

Yerkes NPRC

Tuberculosis (TB) kills 1.6 million people every year and is one of the top 10 causes of death globally. And while it’s been kept under control in most places, more than 95 percent of cases and deaths are in developing countries, according to the World Health Organization (WHO).

Traditionally, it’s been difficult to prevent and treat TB in such regions, which is why Southwest National Primate Research Center (SNPRC) researcher Professor Jordi Torrelles, PhD, is focused on making a change. He developed a TB test that has been adapted for the challenging conditions typically encountered when diagnosing TB in developing countries.

“The way it’s done now, it takes 42 to 60 days before you get results from a TB test,” Torrelles said. “That’s before the patient is informed of results. When you factor that in, it’s more like 65 to 80 days from when the patient gives a sputum sample to when they learn whether they have TB.”

Torrelles traveled to Mozambique, Swaziland and South Africa in early 2019 to establish research collaborations for testing this cheaper, faster, easier way to diagnose TB. The current widely-used, commercially available TB test costs 608 USD. Torrelles’ improved version has a projected cost of just 9 USD.

What’s more, the current test does not indicate if a person is infected with drug-resistant strains of TB. Patients with these strains are even more difficult to treat, as they do not respond to the most commonly used TB drugs, requiring expensive, lengthy treatment. Torrelles and team started with what’s known as an “agar” test—which shows if the patient is infected with TB and whether the bacteria type or strain is resistant to three commonly used drugs for treatment—and developed a special color plate that can test for resistance to 11 drugs. They created two versions: one diagnostic, the other a treatment-tracking version to check if the patient is responding to the treatment.

In the past, results have usually been returned in 21 days for TB strains that can be treated with drugs, and up to 80 days for drug-resistant strains. If the SNPRC team’s new test plates are kept refrigerated, results can be seen as soon as three to 14 days, Torrelles said. And while many health care facilities in developing countries don’t have access to refrigeration, the improved diagnostic test doesn’t require it. Even if kept at room temperature, results can be interpreted between three and 19 days.

TB research is a top priority for scientists across the National Primate Research Centers (NPRC) network. Check out more ways we’re working to eliminate the disease for good.