Working together is always better—especially when it comes to curing infectious diseases. That’s why the National Primate Research Centers (NPRCs) across the country are collaborating to tackle the deadly Zika virus with a series of studies.

In one study, researchers at the California National Primate Research Center (CNPRC) discovered that Zika may still affect fetuses that show no signs of gross microcephaly (an abnormally small head), a common symptom of the disease. Four rhesus macaques were infected with Zika on days 41, 50, 64 and 90 of gestation, respectively. The macaque infected after 41 days experienced fetal death within a week, and the fetuses of the others showed brain calcifications and reduced brain cells—all without significantly reduced brain size.

An additional study at the CNPRC recently showed that infection of the fetuses of pregnant rhesus macaques produced brain lesions like those in human newborns with Zika. The models developed from these studies at the CNPRC can be used across study locations to examine more viruses and prevention methods.

During another study, Zika data from several of the NPRCs were compiled to show that the virus may cause a greater rate of miscarriage than previously thought in humans. Of nonhuman primates infected with Zika in early pregnancy, 26 percent experienced miscarriage or stillbirth even though they showed few signs of infection. Human studies have found that about five percent of women known to be infected with Zika do not carry to term or have stillbirths. This suggests that, in areas where Zika is prevalent, the number of virus-related miscarriages and stillbirths may be underestimated.

These studies show the benefits of taking a highly collaborative approach to research, which is a priority at the NPRCs. Through close communication and teamwork, our researchers are continuing to make breakthroughs to improve worldwide health.

Reviewed: June 2020

Forty years ago today, the United States Environmental Protection Agency (EPA) banned commercially manufactured polychlorinated biphenyls (PCBs), acting on evidence of their extreme environmental persistence and toxicity.

Five years before the April 19, 1979, ban, New Scientist published “US losing fight against PCBs – a new cancer risk?”, referencing its 1973 article by Allen and Norback (Vol. 57, p. 289) about changes in nonhuman primates at the Wisconsin Regional Primate Research Center exposed to PCBs.

“As far as the monkeys are concerned, the potential of PCB carcinogenicity is there,” senior author James Allen of the center’s experimental pathology unit stated in the article.

These early research findings were also described in the Summer 1973 issue of Primate Record, the Wisconsin center’s newsletter at the time. The narrative describes how three months of exposure to PCBs at 300 parts per million (ppm) in the animals’ diets resulted in liver enlargement, facial swelling, hair loss and gastritis of the type associated with cancer.

By that time, industrial accidents had at least twice contaminated human food supplies with up to 3,000 parts per million of PCBs. Levels of 28 ppm in milk and 35 ppm in certain fish had also been reported. In previous PCB studies with rats, liver enlargement was the only major reaction.

Quoting Allen, the final paragraph of the newsletter reads, “The discrepancy in clinical findings between the rat and monkey subjects in PCB tests again points to the inadequacy of testing drugs and chemicals only on organisms distantly related to man before certifying them as safe for humans…”

In 1975, the EPA cited the Wisconsin Primate Center team’s findings at its National Conference on Polychlorinated Biphenyls in Chicago. And in 1978, a paper by James Allen et al, published in Pharmacology Biochemistry and Behavior, fully described the toxic effects of PCBs on nonhuman primate health and pregnancy.

While no single study led to the landmark ban, several peer-reviewed studies like the monkey study contributed to the building body of evidence that PCBs cause cancer and other serious health problems. Today, these harmful chemicals are no longer produced in the United States.

—

Pictured above are PCB cleanup operations on Wisconsin’s Fox River circa 1989.

Photo credit: Wisconsin Department of Natural Resources

According to a new study by scientists at the Southwest National Primate Research Center (SNPRC) at Texas Biomedical Research Institute, marmosets can mimic the sleep disturbances, changes in circadian rhythm and cognitive impairment in people with Parkinson’s disease.

This is a significant development since an effective animal model that can emulate both the motor and non-motor symptoms of Parkinson’s gives scientists a better chance of understanding the processes responsible for changes in the brain caused by the disease.

Parkinson’s disease affects one million people in the United States and 10 million people worldwide. With the aging population, the incidence of the neurodegenerative disorder is on the rise. Each year, 60,000 people are diagnosed with Parkinson’s in the U.S. alone. The hallmark symptoms include tremors, slow movements, balance problems and rigid or stiff muscles. However, non-motor symptoms—including disorders of the sleep-wake cycle and problems thinking clearly—can be just as difficult for patients to handle.

During the study, the researchers tracked marmosets using devices around their necks similar to popular human fitness tracking devices. They wanted to see if the marmosets with induced classic Parkinson’s motor symptoms could also serve as an effective model for non-motor symptoms. In addition, scientists videotaped the animals to monitor their ability to perform certain tasks and how those abilities were impacted over time by the disease.

As it turned out, the marmosets did exhibit both motor and non-motor symptoms similar to those experienced by humans with the disease.

“Most of the early studies in Parkinson’s have been conducted with rodents,” explained lead author and Associate Scientist Marcel Daadi, PhD, leader of the Regenerative Medicine and Aging Unit at the SNPRC. “But there are some complex aspects of this disease you simply cannot investigate using rodents in a way that is relevant to human patients.”

“This study is a great first step,” Dr. Daadi continued. “More studies are needed to expand on these non-motor symptoms in marmosets in the longer-term, and perhaps, include other nonhuman primates at the SNPRC like macaques and baboons.”

During an epidemic in 2014, the Ebola virus claimed more than 11,000 lives in West Africa. Now, a new outbreak of the deadly disease threatens residents in eastern Democratic Republic of the Congo. While there isn’t yet a cure for Ebola, scientists at Southwest National Primate Research Center (SNPRC) at Texas Biomedical Research Institute recently made two discoveries that could help us understand how the virus infects the body.

In the first study, Staff Scientist Olena Shtanko, PhD studied a cellular pathway called “autophagy,” which means “self-eating.” This pathway normally occurs inside the cell and destroys invading foreign material or recycles necessary nutrients. But Dr. Shtanko’s team, working with a live Ebola virus, discovered, to their surprise, that autophagy was also active near the surface of the cell.

The Ebola virus exploits autophagy to induce another process to gain entry to the cell. That process is macropinocytosis, a poorly understood mechanism during which the cell surface remodels to form membrane extensions around virions (virus particles), eventually closing to bring them into the interior of the cell. It is as if the cell reaches out and grabs the virus, bringing it inside its membrane, where virus proteins can begin to replicate.

“We were stunned to find that Ebola virus is using autophagy regulators right at the surface of the cell,” Shtanko stated. “Knowing that these mechanisms work together, we can start finding ways to regulate them.”

Shtanko believes that drugs targeting the interplay between the two processes could potentially be developed to treat Ebola and other health conditions not associated with viruses. The regulation of the autophagy proteins could be used to fight complex diseases where macropinocytosis is disrupted, such as cancer and Alzheimer’s.

Shtanko’s commitment to fighting Ebola has spanned multiple studies. Another team she worked with discovered the interaction between an Ebola virus protein and a protein in human cells. This interaction may be a key part of replication of the killer disease in human hosts.

During the study, researchers tested whether the interaction between an Ebola virus protein called VP 30 and a host (human) protein called RBBP6 influenced the life cycle of the virus. By removing RBBP6 or flooding the cell with it, the scientists found striking results.

When RBBP6n was removed, viral replication went up exponentially compared to when the protein was present. Shtanko said this interaction is significant because if scientists can figure out the process behind this replication, they can potentially manipulate it and stop the disease progression.

Both of these discoveries represent large leaps forward in understanding the Ebola virus and treating and preventing this deadly disease.

Young macaques form an important part of our work at the NPRCs, helping us discover new ways of treating deadly diseases like tuberculosis, HIV/AIDS, Zika and more. Two researchers at Southwest NPRC at Texas Biomed recently went the extra mile to ensure these baby monkeys had a place to call their own.

https://www.kens5.com/video/news/local/eradicating-tuberculosis-with-the-help-of-macaques/273-4c1dd11c-90e8-40bf-9f51-16157308fe1f

Right now, kidney transplant recipients are required to undergo a lifelong regimen of immunosuppressive medications so their white blood cells won’t reject the new organ. But scientists at the Wisconsin National Primate Research Center (WiNPRC) at the University of Wisconsin-Madison (UW) are working to create conditions in recipients that will allow their bodies to accept transplants without the need for drugs.

In an ongoing study utilizing nonhuman primates, hematopoietic stem cells (HSC; cells that can become any other blood cell) are driven from the bone marrow of the potential donor into the blood. They are then collected from the blood and frozen, using methods like those used in humans to harvest cells for transplantation into cancer patients. Next, the kidney is transplanted from donor to recipient. Then, the recipients undergo targeted treatments for two weeks with immune-depleting agents and radiation to prevent rejection. After the last radiation treatment, the donor’s set-aside blood containing the HSCs is infused into the recipient.

If these cells are accepted along with the kidney, this is called a state of mixed chimerism; the resulting immune system is part-donor and part-recipient. The subjects are then placed on immunosuppressive drugs for eight months, during which time the investigators examine whether the transplanted kidney is doing its job, and whether the infused HSCs are actually multiplying.

“We are seeing that the donor HSCs survive and differentiate to join the components of the recipient’s immune system,” said Dixon B. Kaufman, MD, PhD, one of the researchers and chair of the UW Division of Transplantation. “This combined system appears to be much more accommodating to the new organ than what we observe in traditional transplantation.”

A critical next step, according to the researchers, is to come up with a new standard of care that works for most, if not all patients, as everyone’s immune system reacts differently to disease, surgery and postoperative care.  

“We hope to provide a successful system for other major organ transplants (as well),” Kaufman said. “Saving lives, along with reducing the cost to patients and the healthcare system with a one-and-done transplant approach, where the patient need not take a regimen of drugs, nor have to worry about a second organ transplant if the first gives out, is the holy grail of this work.”

HIV-1, the virus that causes AIDS, remains a potent global threat, especially in sub-Saharan Africa and other low-income areas. And while new treatments over the past 40 years have greatly improved the prognosis for those infected, prevention of HIV-1 infection by vaccines or immunoglobulins is not yet established.

That may change with a finding at the Southwest National Primate Research Center (SNPRC) in San Antonio, Texas. A team led by Dr. Ruth Ruprecht has shown for the first time that an antibody called Immunoglobulin M (IgM) can be effective in preventing infection in the mucosa after exposure to the virus. This is significant because an estimated 90% of new HIV-1 cases are caused through exposure in the mucosal cavities such as the lining of the sexual organs or rectum.

Rhesus monkeys at the SNPRC on the campus of the Texas Biomedical Research Institute were treated with a man-made version of IgM. Thirty minutes later, the same animals were exposed to simian-human immunodeficiency virus, a hybrid virus containing elements of the monkey and human immunodeficiency virus. Four of the six animals treated this way were fully protected against the virus.

“IgM can grab multiple particles like HIV-1 and SHIV very quickly and does not let go,” said Dr. Ruprecht. “Our study reveals for the first time the protective potential of IgM. It basically opens up a new area of research – IgM can do more than it has been given credit for.”

IgM, which had been thought by most scientists to have too short-lived a protective effect, may now lead the way to an effective barrier against HIV-1 infection.

Ever wonder how your brain knows what a certain object is, even if the object is mostly hidden? Researchers at the Washington National Primate Research Center (WaNPRC) at the University of Washington (UW) may have discovered an explanation for this phenomenon.

Researchers studied brain signals and tracked eye movements in rhesus monkeys while the animals played a computer game in which they attempted to identify half-hidden, two-dimensional objects and specific shapes.

“Basically, when the task is simple, (the) visual cortex works just fine, but when the task becomes difficult, there needs to be communication between a higher brain region involved in memory and learning,” Anitha Pasupathy, PhD, Associate Professor at the UW School of Medicine Department of Biological Structure, said about the results of the study.

These findings make the researchers wonder if impaired communication between the brain’s thinking and sensory parts might lead to certain difficulties, like confusion in cluttered surroundings, for people who have autism or Alzheimer’s.   

“This, for us, is a very exciting demonstration because it breaks open a whole lot of questions we can ask about how different brain areas interact to solve this important problem of visual recognition,” noted Pasupathy.

The scientists said the next step in their research is to determine if more brain areas are involved in recognizing objects with more complex images.

—

Photo credit: Kathy West for the California National Primate Research Center

The 2015-16 Zika outbreak in Brazil caused many babies to be born with severe brain abnormalities. It also prompted researchers at the Southwest National Primate Research Center into action. With a colony of 300 marmosets, they worked from findings which showed that Zika antibodies were present in wild marmosets, meaning they had become infected with the mosquito-borne illness. Specifically, male marmosets have been shown to mimic human disease when infected, leading researchers to ask whether pregnant female marmosets would show similar effects of infection. Marmosets have also shown symptoms similar to humans when infected with Lassa virus, Ebola, dengue and West Nile.

“There is strong interest in the scientific community in developing animal models to understand Zika virus with the goal of developing vaccines and therapies,” said lead author Dr. Suzette Tardif, a Scientist at Texas Biomedical Research Institute and Associate Director of Research at the Southwest National Primate Research Center. “We believe marmosets may be an especially relevant model for effects on infection in pregnancy.”

“We have a theory that the placenta may be a reservoir for the Zika virus, which would explain why there’s so much of it because we find a huge number of infected cells there,” said Dr. Jean Patterson, a researcher at Texas Biomedical Research Institute. She has proposed further studies on the impact of west Nile and other viruses in pregnant marmosets in an effort to pinpoint the link between these emerging diseases and fetal developmental problems in both marmosets and humans.

Researchers exposed pregnant marmosets to the Zika virus during the first half of pregnancy, which caused those pregnancies to end about two weeks after infection. The fetuses also showed evidence of brain abnormalities. For this reason, marmosets may be the “canary in a coalmine” for studying the effects of Zika on human pregnancy and fetal development.

Most of us enjoy listening to our favorite tunes while in the car or relaxing at home—but could music serve an even deeper purpose in our lives?

In September, Larry Sherman, PhD, a professor in the Division of Neuroscience at the Oregon National Primate Research Center (ONPRC) at Oregon Health & Science University (OHSU), joined OHSU research scientists Marc Freeman, PhD, and Erick Gallun, PhD, for an on-stage discussion about research exploring the importance of music for brain development and healing. The researchers were accompanied by internationally-renowned opera singer Renée Fleming.

Sherman, who has performed a series of talks explaining how listening and practicing music can influence brain development and delay cognitive decline in aging, said the soaring feeling of inspiration when we’re playing, singing or listening to music is rooted in brain chemistry. He cited research which has shown magnetic resonance imaging (MRI) reveals a spike in endorphins and dopamine among people exposed to music, which generates a feeling of belonging and of community.

Fleming added that one of the latest iterations of music therapy involves forming drumming circles for people struggling with addiction. Gallun suggested this technique may be soothing because the drumming echoes a rhythm from the earliest possible point of the brain’s development.

“When you’re in the womb, there are only a few things you can hear,” Gallun said. “One is your mother’s heartbeat.”

Fleming recently spent two hours in an MRI machine as part of a Sound Health initiative supported by National Institutes of Health (NIH) to study the specific neural circuits involved in the interaction between music and the brain. She believes that music can have a therapeutic effect, especially for underserved youth populations struggling with social and mental health issues.

“Music can really make a difference in their lives,” she said.

Reviewed: June 2020