March 3, 2021

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.”

 

February 23, 2021

Is gene editing the answer scientists have been looking for to eliminate diseases such as HIV?  

A research team at Temple University and Tulane National Primate Research Center (TNPRC) has focused  on removing DNA from viruses, one of the main ways  a virus survives treatments. Now, they’ve seen promising results  that may lead to a cure for HIV.  

The team has employed CRISPR technology, best described as “molecular scissors,” which can precisely cut and remove specific segments of DNA. When attached to a mild adeno-associated virus, these gene editing shears can be sent into the body to cut and remove  DNA from viruses, including HIV.  

They tested this on nonhuman primates infected with  simian immunodeficiency virus (SIV), a disease genetically similar  to HIV, and observed that the  gene editing molecules were able to enter SIV viral reservoirs in the lymph, spleen, bone marrow and brain to prevent the cells from making new virus within these reservoirs. 

Within just three weeks, the new treatment had eliminated nearly two-thirds of the virus that had managed to resist the antiretroviral therapy (ART) many HIV patients receive.  

Andrew MacLean, PhD, one of the principal investigators of the research project and associate professor of microbiology and immunology at TNPRC, views this as evidence a cure for HIV is a real possibility. 

“This is an important development in what we hope will be an end to HIV/AIDS,” MacLean said. “The next step is to evaluate this treatment over a longer period to determine if we can achieve complete elimination of the virus, possibly even taking subjects off of ART.” 

Co-corresponding author also includes Dr. Binhua Ling, one of the principal investigators of the research and previous associate professor of microbiology and immunology at TNPRC. Ling is currently an associate professor at Texas Biomedical Research Institute. 

A potential cure for HIV is just the beginning though. These “molecular scissors” will likely play a role in future efforts to cure diseases currently receiving treatments to make them manageable.  

The results are indeed promising, but the work of the NPRCs is never over. They will continue searching for the causes, preventions, treatments and cures leading to longer, healthier lives worldwide. Learn more about our HIV-related studies by visiting this link.   

February 15, 2021

Parkinson’s disease (PD) is characterized by motor-related symptoms, including tremors, rigidity and stooping posture. Lesser known is damage to nerves in the heart, which progresses over time, is independent of motor symptoms and is not responsive to current therapies.

Marina Emborg, senior scientist at the Wisconsin National Primate Research Center and University of Wisconsin–Madison professor of medical physics, has been working on preclinical models for treating PD for the past three decades. She says by the time patients are diagnosed, about 60 percent have serious damage to nerve connections in the heart.

“When healthy, these nerves stimulate the heart to accelerate its pumping to rapidly respond to changes in activity and blood pressure. Loss of this control causes patients to be less responsive to exercise, subject to intense lightheadedness upon standing and at high risk of falling.”

Emborg’s team, which includes scientists Valerie Joers, Jeanette Metzger, UW–Madison cardiovascular medicine professor Timothy Kamp and neurology professor Catherine Gallagher, had not been able to look at exactly what was causing the heart damage until now.

They mimicked PD cardiac neurodegeneration in adult rhesus macaques and then used positron emission tomography (PET) imaging to follow nerves within the monkeys’ hearts after they administered new-generation radiolabeled biomarkers (i.e., radioligands). The researchers were successful in detecting inflammation and signs of oxidative stress as nerves were deteriorating in real time.

The study suggests cardiac PET imaging combined with new-generation radioligands will be useful in detecting heart disease and evaluating new therapies that specifically target nerve disease within the human heart.

“Many doctors are not aware of this condition, which significantly affects PD patients’ health,” said Emborg. After the study results had been published, several people who have PD reached out to thank her for studying this aspect of the disease. She realized this study gave patients the evidence and confidence they need to talk with their doctors about treatments.

Other diseases share this problem as well, Emborg said. Diabetes, heart attacks and other disorders cause similar damage to nerves in the heart. People who have these health issues could potentially benefit from therapies tested with visualization models. 

Emborg envisions the day when this technique is credited with developing new therapies as well as predicting heart damage in those who have PD.

January 25, 2021

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

 

January 15, 2021

Autism Spectrum Disorder (ASD), which impacts communication and interaction abilities, affects 1 in every 54 children in the United States. In order to understand the biological basis of these types of human disorders, scientists must turn to translational animal models—research with animals that closely reflects the same processes in humans.    

Until now, there hasn’t been an effective way to identify which animals were ideal candidates for ASD research. But Kate Talbot, PhD, and her colleagues in the Neuroscience and Behavior Unit at the California National Primate Research Center (CNPRC) have optimized a screening tool—based on an ASD diagnostic tool used in humans—to do just that.  

ASD is classified by the National Institute of Mental Health as a developmental disorder that affects communication and behavior. It is a spectrum disorder, which means autism can present differently in symptoms and severity across individuals. This variability is part of what makes treatment of ASD more complicated. Rather than a primary treatment for ASD, doctors and patients have to work together to develop specific treatment programs.  

Talbot pointed out that studying disease biology directly in ASD patients is difficult in other animal models because they fundamentally lack the complex social cognitive abilities that are impaired in people with autism. But there is a subset of rhesus monkeys within the natural population illustrating low-social behavior similar to what is observed in humans with ASD. The difficult part is identifying enough of these animals early in their development to conduct the necessary translational research. 

Talbot and her team made a breakthrough in that area. The original macaque social responsiveness scale (mSRS) was a 36-item observation-based instrument similar to the Social Responsiveness Scale originally developed for human children. The mSRS was developed using a relatively small sample mostly composed of females, but due to the sample size and the fact that ASD is a particularly male-biased disorder (four males for every one female), the mSRS was difficult to translate to the human screening tool.  

Talbot and colleagues refined the mSRS by applying it to hundreds of male rhesus macaques across their development. They could then compare experimenter responses to the questionnaire directly to behavioral data collected on the animals throughout their lives. Now, the revised tool can determine with 96% accuracy which monkeys qualify as particularly low-social animals compared to their peers.   

“This instrument will be indispensable for advancing the field’s understanding of the developmental trajectory of core autistic symptomology in rhesus and other macaque monkeys, and it can be used as a primary outcome measure in fast-fail preclinical therapeutic testing efforts,” Talbot explained. 

Understanding autism and other neurological conditions is a primary goal of NPRC research. Find out more about our ASD-related studies by visiting this link.  

December 18, 2020

Researchers at Yerkes National Primate Research Center (YNPRC) have discovered a way to use cancer immunotherapy treatments to reliably shrink the size of the viral “reservoir” in simian immunodeficiency virus (SIV)-infected nonhuman primates treated with antiviral drugs.

In humans, antiviral drugs can suppress human immunodeficiency virus (HIV) to the point of being undetectable in blood, but the virus embeds itself in the DNA of specific immune cells (T cells). Each reservoir consists of T cells that continue to harbor the virus even during antiviral drug treatment.

According to the researchers, chronic viral infection and cancer produce similar states of “exhaustion.” T cells that could fight virus or cancer are present but unable to respond. In long-term HIV or SIV infection, T cells harboring the virus display molecules on the cell surface that make them targets for checkpoint inhibitors (cancer immunotherapy drugs designed to counteract the exhausted state).

In this study, researchers combined two cancer immunotherapy treatments to block the surface molecules CTLA-4 and PD-1 in nonhuman primates. In subjects that received both CTLA-4- and PD-1-blocking agents, researchers noted a stronger activation of T cells compared to only a PD-1 blockade.

“We observed that combining CTLA-4 and PD-1 blockade was effective in reactivating the (SIV) virus from latency and making it visible to the immune system,” said Mirko Paiardini, PhD, an associate professor of pathology and laboratory medicine at Emory University School of Medicine and a researcher at YNPRC.

In previous studies, shrinkage of the viral reservoir has been limited and inconsistent when researchers use single checkpoint inhibitors or other immune-stimulating agents. During this study, however, combination-treated animals showed a consistently measurable and significant reduction in the size of the viral reservoir.

Despite these findings, the combination treatment does not prevent or delay viral rebound once antiviral drugs are stopped. Paiardini suggested the approach may have greater potential if combined with other strategies, for example a therapeutic vaccine, or it could be deployed in a target-rich environment, for example during ART interruption when the immune system is engaged in intercepting and fighting the rebounding virus. Other HIV researchers have started to test those tactics, he indicated.

It is also noteworthy the equivalent combination of CTLA-4 and PD-1 blockade in humans has been tested in the context of cancer treatment, and while the two drug types can be more effective together, patients sometimes experience adverse side effects like severe inflammation, kidney damage or liver damage. Fortunately, the combination-treated animals in this study did not experience comparable events.

Finding a complete HIV cure is still critically important because problematic issues, like social stigma and the long-term toxicity and cost of antiretroviral drugs, remain. 

To learn more about how NPRC scientists are working toward effective treatments—and ultimately a cure—visit this link.

December 15, 2020

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. This is why the NPRCs support establishing a strategic reserve of NHPs to be used in times of national health crises. 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.

December 7, 2020

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.

November 30, 2020

Could a promising discovery about viral latency help scientists effectively combat human immunodeficiency virus (HIV)?

The primary obstacle to a cure for HIV infection is the reservoir, or immune cells that harbor the inactive virus when someone is being treated with antiretroviral drugs. One of the leading research strategies for eliminating HIV from the body is “shock and kill,” which involves activating a dormant virus from within these immune cells where it hides, then eliminating it. A key challenge, however, has been finding a safe way to “wake up” the virus from its latent state.

In two complementary studies—one from the Yerkes National Primate Research Center (YNPRC) of Emory University and another from the University of North Carolina at Chapel Hill—researchers report they have come closer to that goal.

The studies relied on two animal models of HIV infection. Each took a different approach, but both yielded promising results, bringing the virus out of its hiding places even in the presence of antiretroviral drugs that stopped it from replicating for months.

“If our goal is to cure HIV/AIDS, then we have to disrupt viral latency,” said Guido Silvestri, MD, chief of microbiology and immunology at the YNPRC. “What we’re doing now is a new combination approach that provides unprecedented levels of virus reactivation.”

Both approaches were tested at the YNPRC in monkeys infected with SIV, a close relative of HIV, and treated with antiretroviral drugs. At UNC, tests were also conducted in mice transplanted with human immune cells. The results represented the first occurrence of a successful systemic HIV induction in humans or an animal model with human cells that was then replicated in a completely different species infected with a different virus.

In one study, 12 monkeys were treated with the drug AZD5582, and just one experienced a temporary fever and loss of appetite—a promising sign. In the other study, researchers stimulated the cells that are the main viral hosts (CD4+ T cells) while also depleting another kind of immune cell (CD8+ T cells), which normally keeps the virus in check. The scientists indicated both the stimulation and depletion components were necessary to see SIV re-emerge.

Neither intervention mentioned above, however, reduced the size of the viral reservoir. Once the animals were taken off antiretroviral drugs, viral levels rebounded. The scientists indicated that in future studies, the initial viral reactivation needs to be combined with other modes of treatment, such as antibodies directed against the virus itself.

Want to learn more about how researchers are working toward a cure for HIV? Take a look at some other related studies from the NPRCs, including this one about reducing the viral reservoir.

November 24, 2020

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.

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