An estimated 130-150 million people around the globe are living with chronic hepatitis C infection. Thanks to chimpanzees, there is now a one pill per day, 12-week cure that has already improved more than half a million lives.

As a scientific animal model, chimpanzees have played an integral role in advances against this group of deadly viruses. Without the use of these nonhuman primates with their close genetic relationship to people, many of the modern interventions, including a curative regimen for hepatitis C, might not be available today.

In a recent review article published in the ILAR Journal of the Institute for Laboratory Animal Research, Robert Lanford, of the Southwest National Primate Research Center and his co-authors present a wide-ranging, detailed look at how chimpanzee research has positively impacted human health specifically by helping bring about breakthroughs in the treatment of hepatitis.

The National Institutes of Health began chimpanzee breeding in the U.S. in 1960. The NIH has halted all further research using chimpanzee models, and Lanford points out that at research facilities and at Chimp Haven in Louisiana, “the animals are enjoying their retirement.”

In his summary, Lanford writes “entire generations are immune to HAV (hepatitis A) and HBV (hepatitis B) because of vaccines developed in the chimpanzee that are in widespread use globally.” With HBV chronic infection affecting more than 250 million people, he observes that “the loss of the chimpanzee model has stymied development of curative therapies for this infection.” Lanford goes on to suggest the scientific community needs to develop improved mouse models and even a new nonhuman primate model for this disease.

Over time, the article concludes, future generations will look back positively on the impact the chimpanzee animal model has had on human health. Hepatitis will be a disease of the past, much like polio and smallpox are today.

Researchers at the Oregon National Primate Research Center (ONPRC) have developed a new form of gene correction that will prevent the transmission of genetic disorders from mother to child, which may lead to a “revolutionary way” to treat inherited diseases. Dr. Shoukhrat Mitalipov and his 15-person lab are using a gene-editing technique that involves spindle transfer from the affected egg to the donor egg to address these heritable conditions.

The gene-editing technique described in this study, employed together with in vitro fertilization or IVF, could provide a new avenue for people with a known heritable disease-causing genetic mutation to eliminate the risk of passing the disease to their children. It could also increase the success of IVF by increasing the number of healthy embryos.

Dr. Mitalipov concedes his stem cell research has been controversial for some people, while many others see the human health benefits. “We produce stem cells using eggs. That’s always a controversial issue — where are you going to get eggs?” he said. “Even though egg donation to the reproductive field is a pretty standard procedure, [use of these eggs to generate] stem cells [has] always been questioned.”

While admitting there are concerns about how to ensure there’s no misuse of this scientific technology, “since these families clearly can benefit, I think it’s ethical we allow it,” Dr. Mitalipov said. “At the same time, if there are concerns that a clinic can use it for an unintended use, it can be regulated.”

However, he doesn’t think the technology will be misused. “There is no other nonmedical use for this technology,” he said. “It’s all toward the defective mitochondria and correcting it. In the U.K., they decided it case by case, at least at the beginning. Each family and IVF clinic has to submit an application. Something like that can be done here as well.”

A collaborative research team at the Yerkes National Primate Research Center and Georgia Tech is studying non-invasive imaging as a way to detect immune rejection of transplanted organs, thanks to a $2.4 million, five-year grant from the National Institute of Allergy and Infectious Diseases.

Currently, medical professionals use blood tests and biopsies – removing a small sample of the organ tissue – to monitor how well a new kidney or liver is adapting to its new home. But with each biopsy, the patient must endure a small surgery so the organ can be accessed yet again. These follow-up procedures can result in hemorrhaging and infection – a major problem for anyone, but especially someone still recovering from the trauma of a transplant.

Andrew Adams, MD, PhD, a researcher at the Yerkes National Primate Research Center and an assistant professor of surgery in Emory University School of Medicine, is part of the team working to identify a non-invasive method for monitoring organs post-transplant.

“Patients often require multiple biopsies to assess response to treatment, thus putting them at risk of complications each time they undergo a separate procedure,” says Adams. “In addition, a biopsy only samples a small part of the transplanted organ.” In other words, just because part of the organ is adapting, doesn’t mean all of it is.

Adams and his colleague at Georgia Tech, Phil Santangelo, are studying the use of positron emission tomography (PET) to monitor post-transplant progress. PET is already used to diagnose heart disease and monitor cancer. Using a variant called “immunoPET,” the researchers can see particular types of immune cells infiltrating the transplanted organ, alerting them to the possibility of rejection. The researchers are conducting the study with mice and nonhuman primates first and hope the results will prove successful so they can advance to human clinical trials.

Reviewed August 2019

In the United States, 64 percent of women of reproductive age are overweight and 35 percent are obese. New research at the Oregon National Primate Research Center (ONPRC) links an unhealthy diet during pregnancy to mental health disorders, such as anxiety and depression, in children.

The study, led by Dr. Elinor Sullivan, an assistant professor in the Division of Neuroscience at ONPRC at OHSU in Portland, Oregon, tested the effect of a maternal high-fat diet on nonhuman primates, tightly controlling their diet in a way that would be impossible in a human population. The study revealed behavioral changes in the offspring associated with impaired development of the central serotonin system in the brain. Further, it showed that introducing a healthy diet to the offspring at an early age failed to reverse the effect.

Previous observational studies in people had correlated maternal obesity with a range of mental health and neurodevelopmental disorders in children. The new research demonstrates for the first time that a high-fat diet, increasingly common in the developed world, caused long-lasting mental health issues for the offspring of nonhuman primates. “It’s not about blaming the mother,” said Dr. Sullivan.

“It’s about educating pregnant women about the potential risks of a high-fat diet in pregnancy and empowering them and their families to make healthy choices by providing support. We also need to craft public policies that promote healthy lifestyles and diets.”

Researchers assigned a total of 65 female Japanese macaques into two groups, one given a high-fat diet and one a control diet during pregnancy. Then they measured and compared anxiety behavior among 135 offspring and found that both males and females exposed to a high-fat diet during pregnancy exhibited greater incidence of anxiety compared with those in the control group. The scientists also examined physiological differences between the two groups, and found that exposure to a high-fat diet in early development impaired the development of neurons containing serotonin, a neurotransmitter that’s critical in developing brains.

Sullivan believes the findings provide evidence that mobilizing public resources to provide healthy food and pre- and post-natal care to families of all socioeconomic classes could reduce mental health disorders in future generations.

It can make a parent’s heart race – finding out your infant must undergo extensive surgery that requires general anesthesia. According to the U.S. Food and Drug Administration (FDA), approximately one million children under the age of four annually undergo surgery with general anesthesia, making understanding effects of early life exposure to anesthesia critical.

Yerkes National Primate Research Center researchers and their colleagues at Mt. Sinai’s Icahn School of Medicine set out to determine just that. Through animal research, the team discovered infant monkeys repeatedly exposed to a common anesthetic, sevoflurane, suffered impairment in visual recognition memory after the first year of life. Furthermore, results indicated the impairment may persist long term.

Dr. Maria Alvarado, first author and leader of the Yerkes team, noted, “Animal studies have shown exposure to general anesthesia in infancy can cause loss of cells in the central nervous system and long-term impairments in neurocognitive function.” This finding is consistent with previous human epidemiological studies, which have shown children with multiple exposures to general anesthesia before the age of four are at greater risk of learning disabilities and other cognitive impairments. Impairments may not become apparent until the child begins formal schooling.

The research team published these results in the British Journal of Anaesthesia, marking a significant advancement in anesthesia-related studies. Whereas past studies included variables for surgical procedures, the NPRC and Mt. Sinai teams eliminated these variables, allowing the team to focus specifically on the side effects of anesthesia. With this knowledge, the team is now conducting research to further clarify the extent and duration of these anesthesia-induced impairments.

“Our studies with rhesus monkeys are fundamental to making anesthesia exposure in infancy and childhood as safe as possible,” Dr. Alvarado explains.

Reviewed August 2019

Familiarity makes the heart grow fonder, at least when it comes to the prairie vole. This rodent species is monogamous, with partners forming lifelong bonds. Until recently, no one knew why. That “why” is exactly what researchers at the Yerkes National Primate Research Center at Emory University want to understand.

“Prairie voles were critical to our team’s findings because studying pair bonding in humans has been traditionally difficult,” said Dr. Elizabeth Amadei, a co-lead author on the research. “As humans, we know the feelings we get when we view images of our romantic partners, but until now, we haven’t known how the brain’s reward system works to lead to those feelings and to the voles’ pair bonding.”

The existing research suggests an interaction between chemicals, such as oxytocin and dopamine, and brain regions, including the prefrontal cortex, leads to these lifelong bonds. That, however, wasn’t enough information for this team that wants to understand the specific neural process and neural networks.

So why do prairie voles mate for life? When a male and female vole interact for extended periods of time, the prefrontal cortex increases the activity of the nucleus accumbens, the brain’s reward system. The decision to engage in affiliative behaviors, such as cuddling and mating, strengthens the animals’ bond and increases overall pleasure for both voles.

While this research has led to additional questions about how the brain impacts the sensational and emotional components of love, it also has longer-term implications. According to Dr. Larry Young, co-author, director of the Emory Conte Center and chief of the Behavioral Neuroscience and Psychiatric Disorders Division at Yerkes, “this discovery is just part of the larger effort to understand how brain circuits works during natural social behaviors. The more we understand, the easier it is to tackle disorders, such as autism, which impair social functioning.”

Reviewed August 2019

There’s no love lost between the cardiovascular system and the world’s population – after all, heart disease is the leading cause of death around the globe. While scientists have long attempted to create vascular models to explore potential causes, preventions, treatments and cures for vascular disease, understanding just how each medical condition arises has hampered potential discovery.

A recent study authored by University of Wisconsin-Madison professor and Wisconsin National Primate Research Center scientist Dr. Igor Slukvin and Akhilesh Kumar, assistant researcher in his lab, might change all of that. Now, scientists are poised to get a better look at the fundamental development of the cells that make up blood vessels and how they can be more reliably cultured in the laboratory dish.

The new scientific advancement provides a blueprint for how vasculature arises at the earliest stages of development, allowing scientists to study the cells that compose blood vessels and devise new models for studying blood vessel disease. Critically, the discovery of methods to generate the building-block cells could set the stage for engineering blood vessels in the laboratory for disease modeling, drug screening and therapeutic purposes.

“Now, investigators will have access to a plethora of new research identifying cell type alternatives for vascular engineering,” said Kumar, noting that the new Wisconsin study, paired with the ability of the progenitor stem cells to proliferate and differentiate to different cell types in culture, can potentially accelerate the time it takes to grow vascular grafts.

Previously, identifying different vascular cell types in living tissue was the easy part; distinguishing cell types from cells grown in culture was a different story. In the study, Kumar made an important revelation – cells that compose blood vessels arise from a common progenitor. The ability to trace the developmental path that gives rise to the cells that make up blood vessels provides science a potent pathway to devise new cellular therapies.

Immediate application of this scientific research includes creating laboratory models for vascular disease to inform a better basic understanding of what goes wrong in killers such as coronary artery disease and certain genetic diseases that affect vasculature. Moreover, these cells can be used in high-throughput drug screens, accelerating the pace of development of new drugs and repurposing old ones to treat vascular ailments. Creating new blood vessels from scratch is still far from reality, but the new Wisconsin study is an essential step toward that goal.

Reviewed August 2019

On February 1, 2016, the World Health Organization declared the Zika virus to be a global health emergency. Spread by the bite of an infected mosquito, the Zika virus has moved rapidly across the Western hemisphere and is linked to potential birth defects.

A team of researchers at the University of Wisconsin-Madison, along with collaborators at Duke University and the University of California, Davis, is working to understand the threat Zika could cause to human pregnancies. Through their work with rhesus monkeys at the Wisconsin National Primate Research Center (WiNPRC), the researchers can uniquely understand the virus’ short and long-term effects.

“There are so many things about Zika infection we can’t study as well in pregnant humans – or fast enough to make a difference for a lot of people who may be infected,” says Dr. Dawn Dudley, a UW-Madison pathology research scientist. “The precise pathway that the virus takes from mom’s bloodstream to the fetal bloodstream, across that interface, cannot be studied except in an animal model.”

The research team, led by primate center scientist Dr. David O’Connor, monitored four pregnant rhesus macaque monkeys that were exposed to the Zika virus. Through regular assessment of maternal infection and fetal development, the researchers found evidence that the virus was passed efficiently to each fetus.

The infection spread inflammatory damage through the tissues that supported the fetus and its developing nervous system, suggesting that the virus poses a larger threat to human fetuses than originally theorized. In fact, three of the fetuses had small heads (although not quite small enough to diagnose microcephaly) and unusual inflammation of the eyes. However, the medical study did not find abnormal brain development.

These sobering results suggest that, as they grow, human babies who were exposed to the virus may develop more Zika-related disease pathology. Research teams are currently working to understand how Zika interacts with other infections, how the effects of early pregnancy infection differ from later infection, and whether antiviral therapies could manage the effects of congenital Zika syndrome.

Reviewed August 2019

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Photo credit: Wisconsin National Primate Research Center

The World Health Organization estimates that about 225 million women in developing countries would like to delay or stop childbearing but are not using any method of contraception.

Dr. Jeffrey Jensen of the Oregon National Primate Research Center is working to develop a low-cost, safe and highly effective method of nonsurgical permanent contraception that will meet the needs of women in low-resource regions, but also be of interest to women in resource-rich countries.

“When women have completed their family size, or wish to not have children, many prefer a noninvasive, effective and permanent form of birth control,” said Jensen. “Particularly in low-resource settings where there is no choice but to continue bearing children, women benefit greatly from a safer form of permanent contraception.”

“Many of the patients I see have had good success with reversible contraception methods, but still desire a permanent method,” he continued. The only permanent form of contraception currently available to women is tubal ligation, which “requires, at a minimum, one counseling visit, one pre-operative visit, and one half-day in the day surgical unit or procedure room. The inconvenience and time burden for my patients provides a strong motivation for me to come up with a better approach.”

Dr. Jensen believes that the approach to permanent contraception should be the same for women in lesser developed as in more developed nations. To be acceptable in regions with low resources, like sub-Saharan Africa, women and health care providers need to know that a method is safe and well-accepted by well-to-do women in resource-rich nations, he says.

With a grant from the Bill & Melinda Gates Foundation, Jensen launched the Oregon Permanent Contraception Research Center at the Oregon National Primate Research Center.

Jensen’s team uses nonhuman primates to study nonsurgical approaches to permanent contraception for women, because of the unique anatomic features and reproductive physiology they share with women. Using the baboon model, Jensen’s research has demonstrated that transcervical administration (similar to the placement of an IUD) of a single dose of polidocanol foam can result in a high rate of tubal occlusion and prevent pregnancy. The addition of doxycycline may improve efficacy, and refinements of the approach to demonstrate safety are in progress as the team hopes to transition the research into early phase clinical trials in women.

Updated August 2019

Research from the California National Primate Research Center (CNPRC) is paving the way for future studies where the possibility of birthing gene-edited monkeys that can serve as models for new therapies is greatly increased. CNPRC scientists efficiently used CRISPR/Cas9 technology to modify the genes of rhesus macaque embryos.

Clustered Regularly-Interspaced Short Palindromic Repeats (CRISPR) is essentially a DNA segment that scientists can manipulate using a system known as CRISPR/Cas9 to edit the genes within organisms. CRISPR/Cas9 seeks and targets specific genes in organisms that are linked to diseases by utilizing a single strand of RNA as a guide to target specific genes for editing.

But the technology can also be imprecise – causing off-target effects to genes that were not intended to be targeted.

“One of the problems with the CRISPR/Cas9 approach is that you have to target the gene,” said Catherine VandeVoort, the core scientist at the CNPRC who collaborated with Keith Latham of Michigan State University and Dr. Daniel Bauer at Harvard Medical School for the study. Latham designed the CRISPR/CAS9 system used in the CNPRC project. “When you have a very short (gene) sequence that you are targeting, it may show up in different places, in another part of the DNA strand instead of where you intend. It can cause off-target effects.”

While rodent-based research models are good for studying diseases in the early stages of research, rodents differ from humans in many anatomical and physiological ways. Alternatively, nonhuman primates share many similarities to humans.

However, while the monkey research model is better for studying human disease, it is much costlier than rodent-based models. “In monkeys, we can’t afford any off-target effects and so we asked ourselves, ‘How can we make this more efficient?’” VandeVoort said.

To minimize the risk of the off-target effects, the study used a two-pronged approach to increase the efficiency of the CRISPR/Cas9 targeting.

The scientists successfully edited the genes of the monkey embryos with 85 percent efficiency. That study demonstrated the first time in the U.S. that this method could effectively be used in monkey embryos. VandeVoort said the embryos used in the study were not implanted in recipient female monkeys, but that a future study will transplant the embryos with a goal of creating a gene-edited monkey.

Reviewed August 2019

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