June 8, 2021

Tuberculosis (TB) is a serious infectious disease that typically affects the lungs. Spread of TB typically occurs in the air via coughs or sneezes. Treatment often poses a challenge to immunologists, as it represents a chronic infection characterized by persistence of the pathogen despite development of antigen-specific immune responses.

Researchers at Emory University and the Yerkes National Primate Research Center have completed the first study to report on temporal dynamics of Mycobacterium tuberculosis (Mtb)-specific T cell responses in latent Mtb infection. With it, they discovered the T cell response emerged as early as three weeks post infection and continued throughout the six-month study. 

“Because TB is the leading infectious disease killer, claiming 1.5 million lives every year, we want to know why some people who are infected with Mtb progress to TB disease while others remain asymptomatic and do not,” says Jyothi Rengarajan, PhD, lead author and associate professor of medicine, Division of Infectious Diseases, Emory University School of Medicine and a researcher at the Emory Vaccine Center and Yerkes National Primate Research Center. 

Because TB is difficult to assess in humans, researchers worked with primates because they develop and respond to the disease much like humans do

Rengarajan states, “Monkeys develop and respond to latent TB infection similar to the way humans do, which makes them an excellent translational model for studying the immunological basis for asymptomatic TB and then applying the results to humans and animals.”

Findings proved the rapid response of T cells, and knowing where to activate them (lungs versus blood) will help researchers create better treatments and even a vaccine to prevent TB infections.

NPRC researchers are working 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.

May 25, 2021

Each year in the U.S., millions of people receive general anesthesia, and a small proportion of those patients actually regain some awareness during their medical procedures.

A recently published study about brain activity representing consciousness could help prevent that potential trauma as well as help scientists define which parts of the brain are key to the conscious mind. Such information could lead to more accurate measurements of patients undergoing anesthesia, improve treatment outcomes for people who have consciousness disorders and help people in comas maintain a continuous level of consciousness.

Yuri Saalmann, a University of Wisconsin-Madison psychology and neuroscience professor, and his research team recorded electrical activity in about 1,000 neurons surrounding each of 100 sites throughout the brains of a pair of monkeys at the Wisconsin National Primate Research Center (WiNPRC). The researchers recorded activity during several states of consciousness: under drug-induced anesthesia, light sleep, resting wakefulness and roused from anesthesia into a waking state through electrical stimulation of a spot deep in the brain.

To sift out characteristics that best indicate whether the monkeys were conscious or unconscious, the researchers used machine learning. They input their large pool of data into a computer, told the computer which state of consciousness had produced each pattern of brain activity and asked the computer which areas of the brain and patterns of electrical activity corresponded most strongly with consciousness.

Surprisingly, the results pointed away from the frontal cortex, which is the part of the brain healthcare professionals typically monitor to maintain patient safety while under general anesthesia and the part most likely to exhibit slow waves of activity long considered typical of unconsciousness.

“In the clinic now, they may put electrodes on the patient’s forehead,” says Mohsen Afrasiabi, an assistant scientist in Saalmann’s lab. “We propose that the back of the head is a more important place for those electrodes because we’ve learned the back of the brain and the deep brain areas are more predictive of state of consciousness than the front.”

And while both low- and high-frequency activity can be present in unconscious states, complexity best indicates a waking mind. “You need more complexity to convey more information, which is why it’s related to consciousness,” says graduate student Michelle Redinbaugh. “If you have less complexity across these important brain areas, they can’t convey very much information. You’re looking at an unconscious brain.”

Read more about our consciousness research and how monkeys are helping improve patient care here.

May 18, 2021

Tuberculosis (TB) is a serious disease that mostly affects the lungs, but can also cause damage to the kidneys, spine or brain. TB spreads from person to person through small droplets transferred via coughing and sneezing. Symptoms of TB include severe coughing for over three weeks, chest pain and coughing up blood or mucus.

Even after years of research, tuberculosis still remains one of the world’s deadliest diseases— especially in low-income countries. While TB related deaths have decreased by 30% globally, 1.4 million people died from it in 2019. Fortunately, researchers at the Southwest National Primate Research Center (SNPRC) at Texas Biomedical Research Institute are getting closer to pinpointing a new way to treat and control TB.

“Single-cell RNAseq is a novel approach that has developed in the past three or four years. It’s an approach that allows us to look at the immune response more granularly, in higher resolution. We were able to identify an immune response to Mtb infection in single lung cells as the infection progressed to disease, in some cases, or was controlled in others,” stated Deepak Kaushal, Ph.D., director of SNPRC.

The study highlights that plasmacytoid dendritic cells, which sense infections in the body, overproduce Type I interferons—a response correlated with disease instead of control. This discovery gives scientists the information needed to alter vaccines.

Dr. Kaushal explains, “When we have a more precise understanding of how an infection develops, that knowledge can lead us to identify new drugs or therapies to treat disease and improve vaccines.”

Overall, the research being done by SNPRC may lead to finding a way to control and prevent TB. Learn more about our TB-related studies by visiting this link.   

May 11, 2021

Promising results from the Wisconsin National Primate Research Center (WiNPRC) are giving hope to the millions of people who live with Parkinson’s disease (PD). By grafting neurons from monkeys, WiNPRC researchers relieved the debilitating movement and depression symptoms associated with the disease.

The researchers used induced pluripotent stem cells from the monkeys’ own bodies to make dopaminergic neurons. which produce dopamine, a chemical that transmits signals between nerve cells. PD damages these neurons and disrupts the signals, making it progressively harder for people who have PD to coordinate their muscles for even simple movements and causing rigidity, slowness and tremors, which are the disease’s hallmark symptoms. Patients — especially those in earlier stages of Parkinson’s — are typically treated with drugs, such as L-DOPA, to increase dopamine production.

“Those drugs work well for many patients, but the effect doesn’t last,” says Marina Emborg, a Parkinson’s researcher at WiNPRC. “Eventually, as the disease progresses and their motor symptoms get worse, they are back to not having enough dopamine, and side effects of the drugs appear.”

To develop additional treatment options, the researchers used real-time magnetic resonance imaging (MRI)  to inject millions of dopamine-producing neurons and supporting cells into each monkey’s striatum, an area of the brain that is depleted of dopamine as a consequence of the ravaging effects of Parkinson’s.

Half the monkeys received cells from other monkeys (an allogenic transplant), and the other half received grafts made from their own induced pluripotent stem cells (called an autologous transplant). The allogeneic monkeys’ symptoms remained unchanged or worsened, but the autologous monkeys began making significant improvements within six months and even more within a year — dopamine levels doubled for some and tripled for others.

Emborg says examples of the improvements included the autologous animals moving more and grabbing food much faster and easier. She adds, “Although Parkinson’s is typically classified as a movement disorder, anxiety and depression are typical, too. Symptoms that resemble depression and anxiety — pacing, disinterest in others and even in favorite treats — abated after the autologous grafts grew in.”

These promising results add to the growing body of NPRC research into improving lives for people who live with PD. Read more about our PD research here.

April 27, 2021

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 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

April 20, 2021

Alzheimer’s disease (AD) affects more than 5.5 million Americans per year. This staggering prevalence makes it a high-priority disease for researchers to develop better treatments and even a cure. Researchers at California’s National Primate Research Center (CNPRC) are among those pursuing answers and believe the disease actually begins decades before the first signs of cognitive decline are triggered. 

Until recently, testing has primarily been done on transgenic mice that express a human version of amyloid or tau proteins, but these studies have proven to be difficult to translate into new medications for the human population. In contrast, nonhuman primate (NHP) models may yield new treatments by providing a closer biological link between the laboratory and clinic. 

“Humans and monkeys have two forms of the tau protein in their brains, but rodents only have one,” said Danielle Beckman, postdoctoral researcher at the CNPRC and first author on the paper. “We think the macaque is a better model, because it expresses the same versions of tau in the brain as humans do.”

Beckman and her team recommend adding an intermediate step for translational research: “If we can test therapies that work in mouse models prior to investing millions or billions of dollars into clinical trials, we really think it’s going to make an impact in having a new drug on the market. I think we really need to be open about new animal models for diseases.”

Visualization of biomarkers in the brain of NHP models may provide the key into the progression of Alzheimer’s disease. So far, teams have monitored signs of neuron death and performed positron emission tomography imaging. The effects of neurodegeneration were observed rapidly; within three months, end-stage tangles were present. And within 6 months, the progress of neurodegeneration increases markedly.

While it is still unknown whether the treated animals will present the full spectrum of Alzheimer’s Disease, including severe cognitive impairment, the initial observations have set the stage for the next steps in testing tau‐based therapeutics for AD patients. Research with monkeys is again proving critical to finding answers that can improve millions of lives worldwide. 

To learn more about the work happening at our research centers around the country, visit this link

April 13, 2021

As the coronavirus (COVID-19) pandemic continues, scientists at the Wisconsin National Primate Research Center (WiNPRC) have kept their focus on the tiniest shifts in the virus’ genetic material.

Beginning with the first known case of the virus in Wisconsin in February 2020, researchers in the WiNPRC’s Global Infectious Disease Division have been sequencing the genomes of as many virus samples as they can process, reading each letter of genetic code.

It’s critical to expand virus genome sequencing across the U.S. as COVID-19 shifts and evolves, sometimes into more contagious variants. The more people the virus infects, the more likely genetic mutations will happen.

“The current estimate is that it makes one of those mistakes — a mutation — for about every two new people infected,” says Thomas Friedrich, WiNPRC scientist and University of Wisconsin–Madison School of Veterinary Medicine professor. As different viruses take various paths to infect more people over time, he adds, they accumulate different combinations of mutations. Researchers can use those combinations like fingerprints to track how different lineages of the virus spread through space and time.

Drawing samples from patients in Dane County and nearby Milwaukee County, Friedrich and WiNPRC colleague David O’Connor, UW–Madison School of Medicine and Public Health professor, have sequenced viruses from more than 3,200 infections. Their most pressing concern is keeping watch for virus variants believed to be more adept at infecting people or possibly carrying mutations that make vaccines and common treatments less effective. They post surveillance results online as soon as sequences are complete.

Nationally, fewer than 0.5 percent of all viruses have been sequenced. In Dane County, the researchers have sequenced 5 percent of all cases, a figure that represents their decades of experience and their work at WiNPRC to stay ahead of global HIV, influenza and Zika virus pandemics.

A coordinated sequencing system in the U.S. could help end this pandemic and the next. “You will see a benefit for HIV, for influenza, for whatever comes along,” O’Connor says. “You want to be able to track which viruses are circulating because it will save lives.”

Note: The UW–Madison researchers received funding from the Centers for Disease Control and Prevention’s SPHERES program (Sequencing for Public Health Emergency Response, Epidemiology, and Surveillance), Fast Grants (a group of nonprofits and private donors) and the Wisconsin Partnership Program. 

March 22, 2021

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.

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.