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 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.

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.   

August 18, 2020

For some, a summer internship is merely a stepping stone into their career. But for Brendan Creemer, a junior biology major at Portland’s Lewis & Clark College, a recent summer internship meant so much more.

Creemer has Usher syndrome, a genetic disorder that causes progressive vision loss and deafness. He spent much of the summer in the laboratory of the Oregon National Primate Research Center (ONPRC) at Oregon Health & Science University (OHSU) with neuroscientists Martha Neuringer, PhD and Trevor McGill, PhD, working on a method to improve the ability to use stem cells as a possible treatment for the disorder.

For more than 40 years, Neuringer has taken on high school and college summer interns, but Creemer is the first intern to live with the often-debilitating symptoms of Usher syndrome.

“I’ve been working for many years on retinal diseases and potential therapies without that personal connection,” said Neuringer, a professor in the Division of Neuroscience at the ONPRC and research associate professor of ophthalmology in the OHSU School of Medicine. “It’s all the more motivation when you know what it’s like for someone facing this.”

Creemer sought out the internship after learning about the research through the OHSU Casey Eye Institute.

“You have that choice to either give up and assume everything is hopeless or choose to take action and not only help yourself but others around you as well,” he wrote of his experience.

Creemer’s summer project focused on a key issue for stem cell therapies: rejection of transplanted cells. When stem cells are delivered as therapies for any health issue, they are perceived as “non-self” by the recipient and attacked by the immune system. Creemer analyzed a possible method to suppress the immune system in rodents, which was then tested to see if it enhanced the survival of retinal stem cell transplants.

“It makes it so much more palpable and real when you see how someone deals with their limitation and overcomes it,” Neuringer said. “It was a perfect match.”

The scientists at the NPRCs across the country are focused on solving myriad genetic disorders. Discover more of our latest research here.

September 30, 2019

Do certain changes in genes influence a person’s propensity to develop obesity? That’s what researchers at Texas Biomedical Research Institute, home to the Southwest National Primate Research Center, are aiming to find out in a new study.

The Centers for Disease Control (CDC) calls U.S. obesity an “epidemic,” with 40% of adults and 19% of children considered obese. Within children, however, there are disparities among ethnicities. Hispanic children have the highest rate of obesity at 26% compared to African American (22%), Caucasian (14%) and Asian (11%) children.

The team will be studying an area of research called epigenetics—which describes changes to DNA, RNA or proteins that are affected by both the environment and genetic makeup.

“If we start at the cellular level and then look at whole organisms like the human body and how we use energy, then we can identify pathways that are involved in the development of obesity and also potentially mechanisms by which we can intervene and treat obesity,” explained Associate Scientist Melanie Carless, PhD.

The first phase of the study will involve a group of 900 Texas Hispanic children who have a high propensity for obesity. Scientists will examine whether physical data like caloric intake, physical activity, energy expenditure, metabolic rate and glucose levels are related to another factor called DNA methylation to increase risk for obesity. In the second phase, scientists will compare changes in blood with changes in muscle tissue and muscle cells and see how these changes correlate. The third phase will involve the use of CRISPR (a new technology used to alter DNA sequences and modify gene function) to change the methylation levels in cells and see how this impacts energy use.

The information gathered from the study could lead to more targeted drug therapies for obesity, or someday, editing to correct an underlying issue at the DNA level. This could improve public health in a number of ways.

“Obesity can be a huge factor in serious medical problems including diabetes, high blood pressure, atherosclerosis and heart disease,” said Carless. “We need to understand how obesity develops at a young age and the impact this might have on health later in life. If we can start to reduce the rates of obesity in the U.S., we will start to see a decline in multiple other disorders.”

September 23, 2019

We all know that proper diet and exercise are supposed to help us maintain a healthy weight. But in some cases, genetics may make it incredibly difficult to keep excess fat away.

Texas Biomed researcher Raul Bastarrachea, MD, and the team at Southwest National Primate Research Center (SNPRC) recently set out to discover why exactly some people are naturally inclined toward obesity. In the process, they found a mutation that affects leptin — a protein produced by fat cells that travels to the brain and signals to the body that there is enough fat and no more food is needed.

Simply put, leptin is a hunger suppressor.

In the study, Bastarrachea and team examined the case of two sisters in Colombia who started their lives as normal-weight babies but who quickly experienced childhood-onset severe obesity. Both were found to have a mutation in the leptin gene on chromosome 7, causing their leptin levels to be so low they were below the detection limit of the manufactured test kit.

The gene mutation forced the leptin proteins to be “misfolded,” rendering them ineffective and destroying their function.

When researching the genetics of the family, scientists noted these women were children of lineal consanguinity, which means several generations before them married blood relatives. This is a common practice in about a fifth of the world population, mostly in the Middle East, West Asia and North Africa, and increases health risks for children of these unions, including rare diseases caused by recessive genes.

Bastarrachea noted a greater understanding of this mutation and its causes is another step toward fighting global obesity.

“We keep learning more and more about the role of fat in normal-weight people,” he noted. “By researching what goes wrong when genes don’t code correctly for the production of leptin, we are coming closer to answers that could help millions of people with metabolic disorders.”

To help get those answers, the SNPRC is looking at obesity within its nonhuman primate (NHP) colony. 

“Fortunately, we have less than 5% obesity in our 2,500 NHPs and an even lower rate of diabetes at 1.5%, due to the low-carb Purina chow they eat and the activity they display given the comfortable size of their housing,” said Bastarrachea. 

Occasionally, a few of SNPRC’s baboons may experience excessive growth leading to excess body fat. 

“We speculate these animals may have particular gene mutations that mimic the extreme obese phenotype of the few individuals reported in scientific literature. We consider our baboon subgroup a valuable model of extreme obesity given NHPs share up to 98% genetic similarities with humans, thus allowing obesity study results in NHPs to be easily translated to humans,” Bastarrachea concluded. 

September 14, 2018

Batten disease is a rare and fatal genetic neurological condition that affects the ability of cells to process waste materials. Those materials build up in brain cells and result in a range of symptoms including seizures, vision loss, motor and speech difficulty, slowed learning and personality changes. Eventually, children with Batten disease become blind, wheelchair-bound and bedridden, having lost all their cognitive function. Most affected children die in their early teens.

Researchers at the Oregon National Primate Research Center (ONPRC) at OHSU have discovered a naturally occurring disease in Japanese macaques that mimics the progression of Batten disease in humans. The finding holds promise for developing gene therapies to treat the disease. Human clinical trials could start within five years.

Trevor McGill, PhD, research assistant professor of ophthalmology in the OHSU School of Medicine, said the discovery will accelerate the development of new gene therapies for Batten disease.

“It affects small children and it’s fatal,” McGill said, “and we’ve got the necessary tools in hand here at OHSU to fix it.”

A multidisciplinary team of veterinarians and scientists at ONPRC made the discovery and confirmed that a small population of Japanese macaque monkeys carries a genetic mutation that causes one form of the disease. It’s the only known model for the disease among nonhuman primates in the world.

“This has truly been a collaborative effort, bringing together the expertise of clinical veterinarians and pathologists, scientists with collective expertise in primate behavior and genetics as well as brain and retinal degeneration,” said Anne Lewis, D.V.M., PhD, head of pathology at the primate center.

“The discovery of this nonhuman primate model of Batten disease will advance our ability to develop and test a gene therapy strategy to replace the normal version of the protein that is missing in this disease,” said Jodi McBride, PhD and assistant professor of neuroscience at ONPRC.

Additionally, she said, this new discovery also opens up promising avenues for developing biomarkers of the disease’s progression using advanced imaging techniques such as MRI and PET scanning.

“We don’t have great imaging biomarkers for this disease aside from the gold standard of MRI and so we’re also interested in using this new model to develop imaging techniques that will allow us to determine how successful we are at clearing out the buildup of cellular debris in the brain with potential treatments.”

The ONPRC scientists said that their goal is to quickly develop interventional strategies that can be used to help treat the children suffering from this devastating and fatal disease and offer hope to their families.

September 7, 2018

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.

August 2, 2017

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.”

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