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.

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

Photo credit: Wisconsin Department of Natural Resources

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.”

Tuberculosis (TB) is the leading cause of death in AIDS patients. Unfortunately, no one knows exactly why the disease is such a significant threat in people with immune systems compromised by the HIV virus.

But researchers at the University of Pittsburgh and the University of Wisconsin–Madison recently reported in Infection and Immunity that a new nonhuman primate model using Mauritian cynomolgus macaques may help bring scientists closer to understanding the AIDS-TB link. The immune systems of these animals are similar to humans, and they are susceptible to both SIV (the nonhuman primate version of HIV) and Mycobacterium tuberculosis (which causes TB).

The paper’s authors included Shelby O’Connor, associate professor of pathology and laboratory medicine at UW–Madison and the Wisconsin National Primate Research Center (WiNPRC), and researchers from the University of Pittsburgh and WiNPRC.

The researchers used 15 macaques in the study. Of the eight monkeys infected with only M. tuberculosis, four animals survived more than 19 weeks following infection. In stark contrast, the researchers found that that all seven animals previously infected with SIV exhibited rapidly progressive TB following co-infection with M. tuberculosis and all had to be humanely euthanized after 13 weeks.  

“Our study demonstrated that pre-existing SIV dramatically diminishes the ability to control M. tuberculosis co-infection from the start,” said Mark Rodgers, senior research specialist at the University of Pittsburgh and the study’s lead author.

Senior author Charles Scanga, research associate professor of microbiology and molecular genetics at the University of Pittsburgh, added that this finding has much larger implications for research into the AIDS-TB link.

“For the first time, we have a well-characterized nonhuman primate model that will facilitate research into vaccines or therapeutics to battle TB in people living with HIV,” he said.

Parkinson’s disease is most widely known for causing muscle tremors and motor-control symptoms, but most Parkinson’s sufferers also exhibit damage to their hearts’ connection to the sympathetic nervous system. In fact, that damage is one of the first signs of Parkinson’s, but the connection is often not made until the more visible symptoms develop.

Researchers at the Wisconsin National Primate Research Center (WiNPRC) and the University of Wisconsin (UW-Madison) have found a new way to examine stress and inflammation in the heart that could serve as an early indicator of Parkinson’s well before the more common symptoms begin.

The heart damage is significant because it contributes to a tendency for Parkinson’s patients to suffer physical injury as a result of blood pressure fluctuations.

“This neural degeneration in the heart means patients’ bodies are less prepared to respond to stress and to simple changes like standing up,” said Marina Emborg, a University of Wisconsin–Madison professor of medical physics and Parkinson’s researcher at the WiNPRC. “They have increased risk for fatigue, fainting and falling that can cause injury and complicate other symptoms of the disease.”

The sympathetic nervous system signals the heart to accelerate its pumping to match quick changes in activity and blood pressure. Researchers at WiNPRC developed a method for tracking the mechanisms that cause the damage to heart nerve cells, then tested the method in the nervous system and heart of monkeys.

Ten rhesus macaque monkeys served as models for Parkinson’s symptoms, receiving doses of a neurotoxin that caused damage to the nerves in their hearts in much the same way Parkinson’s affects human patients. Once before and twice in the weeks after, the monkeys underwent PET scans, a medical imaging technology that can track chemical processes in the body using radioactive tracers.

The UW–Madison researchers used three different tracers to map three different things in the left ventricle of the monkeys’ hearts: where the nerves extending into the heart muscle were damaged, where the heart tissue was experiencing the most inflammation, and where they found the most oxidative stress.

The scans were accurate enough to allow the researchers to focus on changes over time in specific areas of the heart’s left ventricle.

“We know there is damage in the heart in Parkinson’s, but we haven’t been able to look at exactly what’s causing it,” said researcher Jeannette Metzger. “Now we can visualize in detail where inflammation and oxidative stress are happening in the heart, and how that relates to how Parkinson’s patients lose those connections in the heart.”

By tracing the progression of nerve damage and its potential causes, the radioligands can also be used to test potential new treatments. The researchers gave half the monkeys in the study a drug, pioglitazone, that has shown promise in protecting central nervous system cells from inflammation and oxidative stress.

“The recovery of nerve function is much greater in the pioglitazone-treated animals,” added Emborg. “And what’s interesting is this method allows us to identify very specifically the differences the treatment made—separately for inflammation and for oxidative stress—across the heart.”

The heart problems opened to examination by the new imaging methods are not limited to Parkinson’s disease. Heart attacks, diabetes and other disorders cause similar damage to nerves in the heart, and those patients and potential therapies could also benefit from the new visualization method.

The results suggest human patients could benefit from the radioligand scans, and Metzger wonders if it could help catch some Parkinson’s patients before their other symptoms progress.

Anxiety disorders affect some 40 million Americans; more than 16 million Americans suffer from depression, according to the Anxiety and Depression Association of America. Researchers at the University of Wisconsin–Madison and the Wisconsin National Primate Research Center (WiNPRC) have discovered brain pathways in juvenile monkeys that may lead to the development of anxiety and depression later in life.

Extreme early life anxiety is a significant risk factor for anxiety disorders and depression in humans, and discovering a connection between two areas of the brain that are connected to anxious temperament in pre-adolescent rhesus macaques could be a significant breakthrough.

“We are continuing to discover the brain circuits that underlie human anxiety, especially the alterations in circuit function that underlie the early childhood risk to develop anxiety and depressive disorders,’’ said Ned Kalin, MD, chair of the psychiatry department at UW–Madison.

“In data from a species closely related to humans, these findings strongly point to alterations in human brain function that contribute to the level of an individual’s anxiety. Most importantly these findings are highly relevant to children with pathological anxiety and hold the promise to guide the development of new treatment approaches.”

The study used functional magnetic resonance imaging (fMRI) to study the connections between two regions of the brain. It builds on the group’s earlier study that used positron emission tomography (PET) scans to study metabolism in the same circuitry; fMRI detects oxygenation changes in blood while PET measures neuronal metabolic activity. Taken together, said Jonathan Oler, PhD, the study’s co-lead author, the new findings demonstrate that the degree of synchronization between these brain regions is correlated with anxious temperament.

“When we began this research, we knew so little about the brain regions involved, especially in primate species,’’ Oler says. “This study speaks to how important it is to study animals that are related to humans as they allow us to learn about the causes of human anxiety and by so doing we can potentially develop better treatment and hopefully prevention strategies.”

Oler and Kalin say their analysis suggests that the same genes that underlie the connectivity of this circuit also underlie anxious temperament. Studies underway in the Kalin laboratory are aimed at identifying gene alterations in the anxiety-related brain regions, and have the potential to lead to new treatments that are directed at the cause of anxiety rather than just the symptoms.

Elevated risk for diabetes and weight gain is a well-documented issue for post-menopausal women—but its biological cause isn’t as certain.

Contradicting past studies, researchers at the Wisconsin National Primate Research Center (WiNPRC) have learned that a naturally-occurring decline in one specific hormone may not be a significant factor in post-menopausal health risks, as previously thought. An article published July 19 in the International Journal of Obesity shows a much smaller role for ovarian estradiol—a steroid hormone—in female metabolism than previously thought.

In prior studies with adult female rodents, ovarian estradiol has been shown to regulate body weight, energy balance and other factors while also protecting against diet-induced obesity.

“We thought these actions also occurred in primates, but our research indicates otherwise,” said Marissa Kraynak, PhD, who co-authored the study with Ricki Colman, PhD.

To test the metabolic functions of ovarian estradiol in female nonhuman primates and discover what happens when the hormone is removed, scientists at WiNPRC selected the common marmoset monkey, which is modestly susceptible to diet-induced obesity. They studied the effects of estradiol depletion combined with diets higher in fat and sucrose, hypothesizing that this would increase body weight and decrease glucose tolerance.

“But we were surprised to see no changes in feeding behavior, activity or energy expenditure in our study monkeys,” Kraynak noted.

The study results suggest that ovarian estradiol may not be a major contributor to metabolic health in female primates. This also leaves open the intriguing possibility that estrogens produced elsewhere in the body—including the brain—may function in this capacity in both nonhuman primates and women.

Learning how the human body makes blood cells could lead to an array of off-the-shelf products for treating cancer and genetic diseases. Researchers at the University of Wisconsin-Madison School of Medicine and Public Health have used human stem cells to make blood-forming cells and demonstrated that they can function as the earliest cells from which various immune cells arise.

“It is critical to identify how nature makes blood cells and apply this knowledge as a tool to make blood cells in a culture dish,” said Igor Slukvin, professor of pathology and laboratory medicine and researcher at the Wisconsin National Primate Research Center. “These findings are important because we can now apply known pathways to improve production of pluripotent stem cells for cancer therapies.”

During embryonic development, blood cells emerge from vessels at several sites inside and outside the embryo. But the cells with the particular ability to become the type of stem cells that can produce blood cells are found only in the lining of the arteries. Using a chemical process in combination with a protein, the researchers produced an arterial type of cell that could be manipulated to create adult-type blood cells and open the way for treatments for blood cancers and other serious conditions.

Dr. Slukvin’s important research holds promise for developing an unlimited supply of blood cells for use in cancer and genetic disease therapies. Unlocking the pathway by which blood cells are created is a significant step toward longer, healthier lives for people around the world.

Want to live longer? Eat less.  

That was the finding of a previous study by researchers at the Wisconsin National Primate Research Center (WiNPRC). And now, those same researchers may have discovered why.

“We knew that restricting calories helps monkeys to live longer, healthier lives, but we did not understand the basis for this extraordinary finding,” said Rozalyn Anderson, a professor and medicine and one of the study’s authors. Anderson worked closely with WiNPRC’s Dr. Ricki Colman, whose colony of rhesus monkeys was studied. “We are now at the beginning of a very exciting journey to discover how calorie restriction works on the molecular level.” Colman is a WiNPRC senior scientist and assistant professor at the University of Wisconsin-Madison.

Two groups of rhesus monkeys were studied for two years – one fed a normal diet while the other ate a diet with 30 percent fewer calories. The research team focused on the liver, because that is where nutrients are processed, and because it plays a key role in metabolic health. Through their research, the team catalogued more than 20,000 molecules in the rhesus liver and analyzed the data.

What the researchers found is that the lower calorie diet changed the way the liver was working, including how it metabolized proteins, carbohydrates, and lipids. Most surprising? The fact that calorie restriction was changing the metabolism on a genetic level using RNA processing.

“Although for some it will not be a surprise that metabolism is important to how calorie restriction works, we are talking about a dietary intervention after all,” said Anderson. “What is more interesting is the recent work showing profound metabolic effects in a whole host of age-associated diseases that are otherwise unrelated. We think that the metabolic response to calorie restriction is at the very heart of its ability to delay aging and the onset of age-related disease.”

While the implications of this discovery are still forthcoming, it’s certainly significant. In the meantime, keep on living, breathing, and eating – just not too much eating.

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

‘Hippies’ are not all human; nonhuman primates have their own flower children. The muriqui monkey boasts famously low rates of aggression, spending much of its time hugging and socializing, and displays no hierarchy among males and females. Yet, through the work of a Brazilian-American research group led by Karen Strier, professor of Anthropology at the University of Wisconsin-Madison, the muriquis have emerged as a charismatic animal in need of help as habitat delines and populations dwindle.

In the effort to preserve the 2,300 muriquis in the wild, the research group asked an all-important question – What data do we need?

This question is especially important for studying multiple populations with differing habitat requirements, like northern and southern muriquis. Previous studies failed to maintain consistent methods, which produced results that were not comparable, so this team’s efforts are groundbreaking. “We think this may be one of the most comprehensive efforts to analyze the data monitoring needs for ensuring the survival of an endangered animal,” says Strier.

The study identifies genetic uniqueness and geographic importance as two key measurements that indicate whether a population can be used to enhance genetic diversity. Sex ratio and the proportion of females carrying babies allow scientists to understand population change. Methods should address feasibility, since many species inhabit locations impossible to reach, and be wary of fringe sites, as outlier populations are especially sensitive to climate changes.

Scientists are already applying this methodology to the northern and southern muriqui populations. The team is hopeful these methods can be used to study and save other endangered species.

The peaceful primates’ luck is looking up, as new muriqui reserves and abandoned farms make for hospitable environments to call home. “Seeing the resilience of nature makes me more determined than ever,” explains Strier. “We can’t reverse the past assaults to the planet, but we can do everything we can to stop them and give the animals and plants a chance to come back.”

Reviewed August 2019

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Photo credit: Wisconsin National Primate Research Center

While the public’s nervous obsession with Zika may be over, medical researchers still have questions. Can the virus survive in a nonhuman host? Can the blood of that nonhuman host infect others? For researchers at the National Primate Research Centers, it’s questions like these that drive their curiosity and compel them to find answers.

Scientists at the Wisconsin National Primate Research Center wanted to know if a mosquito bite can turn a nonhuman mammal into a virus carrier. To investigate this, they let Zika-carrying mosquitoes infect rhesus macaques. They then compared those monkeys and their symptoms to macaques that the researchers had injected with Zika.

The differences were small but significant. “It’s a difference of a couple days to what we call peak viremia,” says Dawn Dudley, a UW-Madison pathologist. Viremia is the medical term for when the virus enters the bloodstream. At that point, it can migrate from the spot of initial contact to other regions of the body where it may lie dormant, waiting to be passed on to someone or something else.

It’s unclear why the virus moves slower when delivered through a mosquito bite. “The biology of the disease probably depends a lot on how the mosquitoes transmit that disease – mechanically how they do it, and biologically what comes along with the virus when the mosquito bites,” says Tom Friedrich, a UW-Madison professor of pathobiological sciences.

The virus was also less likely to affect the central nervous system tissues of mosquito-bitten macaques.

Despite these differences, the virus never became strong enough to infect mosquitoes who fed on the macaques. “But that doesn’t mean other nonhuman primates couldn’t do that,” says Dudley. And with more questions, there’s always more research.

Reviewed August 2019