In an effort to study more treatments for HIV, researchers at the Wisconsin National Primate Research Center are focusing on a gene that cured two men of HIV.

Both men – Timothy Brown and Adam Castillejo – received bone marrow stem cell transplants to treat their leukemias. The cells came from donors with a rare genetic mutation that left their white blood cell surfaces without a protein called CCR5.

“Without CCR5, HIV can’t attach to and enter cells,” said Ted Golos, a University of Wisconsin–Madison professor of comparative biosciences and obstetrics and gynecology.

The mutation occurs naturally in fewer than 1 percent of people, suggesting it may not be associated with only positive health outcomes. So the University of Wisconsin researchers are looking to an animal model at the Wisconsin National Primate Research Center to better understand the mutation.

“Given interest in moving forward gene-editing technologies for correcting genetic diseases, preclinical studies of embryo editing in nonhuman primates are very critical,” said Igor Slukvin, UW–Madison professor of pathology and laboratory medicine.

Golos, Slukvin and colleagues used CRISPR to edit the DNA in newly fertilized cynomolgus macaque embryos. They delivered the CCR5-absent gene to one-cell fertilized embryos, thinking if they made the edit in the early embryo it should propagate through all cells as the embryo grew. That’s exactly what happened one-third of the time.

The researchers’ next goal is to transfer the embryos into surrogates to produce live offspring carrying the mutation. With specially selected  monkeys carrying the CCR5 mutation, the researchers would have a reliable way to study how successful the transplants are against the simian immunodeficiency virus (SIV), which works in monkeys just like HIV does in humans.

Anti-retroviral drugs have greatly increased survival in people with HIV, but they are not equally effective in all patients, and there are long-term consequences to consider. Studying an alternative approach might benefit more patients in the short-term while researchers seek long-term solutions to protect people from HIV infection.

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.”

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.

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.

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.

It’s been 25 years since University of Wisconsin-Madison scientist James Thomson, VMD, PhD, was the first in the world to isolate and culture primate embryonic stem cells. He accomplished this breakthrough with nonhuman primates (NHPs) at the Wisconsin National Primate Research Center (NPRC) in 1995, using rhesus monkey cells, and again in 1996 with marmoset cells. Thomson then published his world-changing breakthrough on human embryonic stem cell derivation in Science Nov. 6, 1998.

From these early discoveries, stem cell research has advanced to human clinical trials for treating both age-related and juvenile macular degeneration, heart disease, blood and immune system cancers, skin wounds, hearing disorders, spinal cord injury, graft-versus-host disease and more. Just as Thomson predicted in the 1990s, NHPs, which were instrumental to basic stem cell research 25 years ago, are now in demand for a wealth of preclinical studies necessary before human clinical trials can begin.

Thanks to advances in pluripotent stem cell research and also gene-editing, researchers are also making progress in understanding the underlying causes of Parkinson’s disease, diabetes, pregnancy disorders, sickle-cell anemia, autoimmune diseases, cartilage regeneration and much more. Universities and medical institutions today have well-established stem cell and regenerative medicine centers to help bring researchers and resources together to advance the field and educate the next generation of stem cell scientists, doctors, educators, business people and policy makers.

The main uses of stem cells today include basic research to understand the human body, discovering the genetic origins of disease, growing new cells and tissues for transplant medicine, and growing cells and tissues for testing pharmaceuticals in the lab before animal and human trials begin. Stem cell research is helping animals, too. Pets as well as research animals at the NPRCs naturally get cancer, diabetes, arthritis and other diseases that stem cell therapies may be able to treat.

It’s important to make sure therapies are based on well-designed and thorough clinical trials. The Federal Food and Drug Administration (FDA) recently cracked down on a number of rogue stem cell clinics that have offered untested, unapproved and even potentially dangerous medical interventions. Only a licensed physician with a patient under his or her direct care should recommend any stem cell therapy or other medical treatment.

Thanks to stem cell research breakthroughs pioneered at the NPRCs – and advanced by many researchers and doctors who have joined the field since – we are finally unraveling the mysteries of cell biology from early development through aging as never before. Read more here.

Researchers at the Wisconsin National Primate Research Center (WiNPRC) at the University of Wisconsin-Madison (UW) recently made a discovery that moves the scientific community one step closer to understanding and treating Parkinson’s disease. 

Parkinson’s, which affects more than 10 million people worldwide, progressively degrades the nervous system, causing tremors, loss of muscle control, cardiac and gastrointestinal dysfunction and other issues. The group at WiNPRC used gene-editing tools to introduce the disease’s most common genetic mutation into marmoset monkey stem cells and successfully reduce flaws in cellular chemistry. 

“We know now how to insert a single mutation, a point mutation, into the marmoset stem cell,” said Marina Emborg, professor of medical physics at UW. “This is an exquisite model of Parkinson’s. For testing therapies, this is the perfect platform.” 

The researchers used a version of the gene-editing technology CRISPR to change a single nucleotide—among more than 2.8 billion pairs—in the genetic code of the cells and give them a mutation called G2019S. 

In human Parkinson’s patients, G2019S causes over-activity of an enzyme called LRRK2, which is involved in a cell’s metabolism. Other gene-editing studies have seen cells produce both normal and mutated enzymes at the same time.  

This new study, however, is the first to result in cells that make only enzymes with the G2019S mutation, which makes it easier to study what role this mutation plays in the disease. 

“The metabolism inside our stem cells with the mutation was not as efficient as a normal cell, just as we see in Parkinson’s,” said Emborg. “Our cells had a shorter life in a dish. And when they were exposed to oxidative stress, they were less resilient to that.” 

The mutated cells had shorter life and were less resilient to oxidative stress. They also showed lackluster connections to other cells. Stem cells can develop into many different types of cells found throughout the body. But when the researchers spurred the mutated stem cells to differentiate into neurons, they developed fewer branches to connect and communicate with neighboring neurons. 

“We can see the impact of these mutations on the cells in the dish, and that gives us a glimpse of what we could see if we used the same genetic principles to introduce the mutation into a marmoset,” says Jenna Kropp Schmidt, a WiNPRC scientist and co-author of the study.  

The researchers also used marmoset stem cells to test a genetic treatment for Parkinson’s. They shortened part of a gene to block LRRK2 production, which made positive changes in cellular metabolism. 

“We found no differences in viability between (the altered cells) and normal cells, which is a big thing. And when we made neurons from these cells, we actually found an increased number of branches,” Emborg says. “This (particular technique) is a good candidate to explore as a potential Parkinson’s therapy.” 

To learn more about how scientists across the NPRC network are combating Parkinson’s disease and other neurological disorders, 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

When fighting cancer, patients need every advantage possible, and new research results have shown a potential breakthrough that could help protect the health of those undergoing chemotherapy.

Scientists at the Wisconsin National Primate Research Center (WiNPRC) at the University of Wisconsin–Madison (UW) have developed a more efficient way to grow white blood cells, which serve as front-line defenders against bacterial infections but are often depleted during cancer treatment. Chemotherapy can leave cancer patients with a very low number of a specific type of white blood cell called neutrophils. This can result in febrile neutropenia, a dangerous condition marked by fever and heightened risk of infection.

This condition is usually treated with a transfusion of the white blood cells from a donor. But collecting enough neutrophils for transfusion is difficult, according to Igor Slukvin, MD, PhD, professor of pathology and laboratory medicine at the UW School of Medicine and Public Health, and the transfusions don’t always show the intended benefit in controlled trials.

“The complicated logistics of granulocyte collection, the need for pre-treating donors with G-CSF (a treatment that stimulates bone marrow to produce granulocytes) or steroids, difficulties in collecting a sufficient number of good quality granulocytes and the limited storage time of around 24 hours all hamper the utility of granulocyte transfusion for correcting neutropenia and may contribute to the inconclusive results observed in clinical trials,” he said.

Now, Sluvkin and a team of researchers have developed a method to generate neutrophils for weeks on end using stem cells. This solution replaces the standard, expensive, relatively inefficient and time-intensive process for neutrophil production.

Using modified messenger RNA, the technique sparks the production of a specific protein that guides the stem cells through a developmental process to become a sheet of hemogenic endothelium (found in blood vessels), which then begins producing neutrophils. These white blood cells can eventually be collected and administered to patients without some of the risk caused by other blood products often carried along in transfusions.

This technique produces neutrophils in as soon as 14 days, compared to as much as a month in previous studies, and can generate up to 17 million neutrophils from one million human induced pluripotent stem cells.

Notably, the scientists learned the neutrophils generated using this method are functionally similar to peripheral blood neutrophils and can phagocytize (surround and swallow) and kill bacteria.

These neutrophils also create opportunities to study other diseases, since white blood cells produced from stem cells carrying genetic disorders that weaken or otherwise affect the neutrophils will still retain those problems. The new production method could give researchers a ready source of malfunctioning cells and enable observation in the earliest stages of development.

The NPRCs are conducting stem cell studies at our locations across the nation. See more ways we’re applying this research to help solve a variety of health issues.

The Wisconsin National Primate Research Center (WiNPRC) has launched the newly improved Primate Info Net (PIN). The website provides resources for anyone interested in nonhuman primates.

Some of PIN’s most prominent features include primates in the news, educational resources, such as the always popular primate species fact sheets, informational services and research resources. Whether looking for a few nonhuman primate facts or more detailed information, PIN can provide the guidance you need.

Other features on the improved site include Ask Primate and the Career Center. Ask Primate allows anyone to inquire about any primate or primatology topic. The Career Center facilitates exploration of jobs and volunteer opportunities in primatology, as well as career guidance from scientists.

“We hope the relaunch of PIN will make learning about primates an enjoyable and informative experience,” says Jordana Lenon, Senior Editor, at WiNPRC. “We encourage you to explore the new PIN and to contact us with any questions about this updated resource. We hope you’re as excited as we are about PIN’s return!”