Thanks to recent research conducted by scientists at the Oregon National Primate Research Center (ONPRC) at Oregon Health & Science University (OHSU), a new avenue to in vitro fertilization (IVF) could soon be opened for prospective parents who were previously told it was unadvisable or impossible.

A perfect embryo contains 46 perfect chromosomes, but some have more, and others have fewer. The result is a common abnormality known as aneuploidy, which occurs in as many as 80 percent of human embryos. Because aneuploidy has been linked to a risk of in vitro fertilization failure, miscarriage and certain genetic orders or birth defects, mosaic embryos— those with both normal and abnormal cells—have not been considered ideal candidates for IVF transfer.

For prospective mothers who only produce mosaic embryos, this can mean the IVF journey may end before it begins. But that could change very soon.

The ONPRC study, led by Shawn L. Chavez, PhD, an assistant professor of reproductive and developmental sciences at ONPRC at OHSU, and an assistant professor of obstetrics and gynecology, and physiology and pharmacology in the OHSU School of Medicine, is the first to confirm mosaic embryos can adapt and persist in development in a nonhuman primate model, resulting in positive IVF outcomes.

Using advanced time-lapse imaging and single-cell sequencing techniques to precisely track the development of mosaic embryos of a rhesus macaque, Chavez and team identified a relationship between mosaicism and two other biological processes: cell fragmentation and blastomere exclusion.

In utero and after IVF, large cells formed by the division of a fertilized egg, known as blastomeres, may break down into small pieces called cellular fragments. These fragments, it seems, can serve as a sort of cellular cleanup crew.

“We found that both the blastomeres and their fragments can act as trash bins within the embryo. As DNA-carrying cells divide and/or fragment, the embryo appears to naturally identify which blastomeres have genetic abnormalities and stop them from further development,” said Chavez.

He further explained that by the stage in which an embryo would implant into the uterus, these abnormal cells or DNA have been visibly excluded from the rest of the embryo, suggesting that imperfect IVF embryos could be considered for use in transfer and could possibly endure in utero.

According to Paula Amato, MD, an associate professor of obstetrics and gynecology in the OHSU School of Medicine, this discovery could positively impact IVF processes for humans in the future.

 “While selecting embryos with a normal chromosome complement is preferred and carries a high chance of pregnancy success, it is not a guarantee,” she explained. “For patients with only mosaic embryos available for transfer, these findings suggest that in some cases, these embryos will result in apparently normal pregnancies.”

Ongoing research will use live-cell time-lapse imaging to better understand the relationship between aneuploidy, cell fragmentation and blastomere exclusion within the embryo. The scientists believe these results could open up new avenues for testing mosaic human embryos.

“We expect that the overall results will be similar to the story of the ‘dark horse,’” said Chavez. “While not perceived as a contender at the start of the IVF race, a mosaic embryo may still be capable of winning and resulting in something wonderful.”

Medications like chemotherapy and radiation are highly effective in treating cancer and benign tumors, but these therapies can also increase the risk of infertility. One in three childhood cancer survivors carry this risk, and for those undergoing treatment prior to puberty, common fertility preservation processes for adults—such as sperm or egg freezing—are not an option. 

But there may be newfound hope.

Recent research from the University of Pittsburgh School of Medicine, Magee-Women’s Research Institute and Oregon National Primate Research Center (ONPRC) at Oregon Health & Science University has found immature testicular tissue can be cryopreserved, or frozen, and later used to restore fertility.

Using a nonhuman primate model of cancer survivorship, the researchers removed one testis each from prepubertal rhesus macaques and cryopreserved the immature testicular tissue. Later, the researchers thawed and transplanted pieces of the tissue under the skin of the same animal.

Approximately one year later, the testicular skin grafts were removed and compared to samples of the immature tissues. Not only were the grafts able to produce enough testosterone for the animal to undergo puberty, but they were also found to contain an abundance of mature sperm.

Scientists at ONPRC then used the samples to generate viable embryos through intracytoplasmic sperm injection, or ICSI, where individual sperm were recovered from the graft tissues and injected directly into an egg. The embryos were successfully transferred to recipient females, and in April 2018, a healthy female baby named “Grady” was born.

“The ability and choice to have a family should not be determined by the risks of necessary medical treatment,” said Carrie Hanna, PhD, director of the Assisted Reproductive Technology Core at ONPRC. “Grady represents an important step toward ensuring that children maintain their opportunity to have a family later in life, should they choose to do so.”

When preparing for motherhood, no mom-to-be should have to worry about a potentially life-threatening illness. And thanks to the work of researchers at Wisconsin National Primate Research Center (WiNPRC) at the University of Wisconsin-Madison (UW), we’re one step closer to controlling a disease which exclusively affects pregnant women.

Preeclampsia raises a mother’s blood pressure, threatening both her life and her baby’s. Symptoms usually include water retention and protein in the urine, as well as rarer and more severe effects like liver or kidney failure.

The disease is treatable if detected early and handled with regular prenatal care, but no one knows its cause or how to prevent it. However, two studies by WiNPRC researchers have offered promising insights.

In one study, researchers discovered testosterone levels in preeclamptic women are elevated two to three times above normal levels. Animal models of preeclampsia also showed patterns and levels of increases in testosterone mimicking those found in women. This correlated positively with vascular dysfunction and higher placental androgen (hormone) receptor gene expression.

In a closely related study, scientists using an animal model found maternal vascular adaptation to pregnancy is critical for blood flow through the placenta to the developing baby. If vasculature can’t properly adapt, the mother may develop preeclampsia and other hypertensive disorders.

These discoveries could help scientists create life-saving treatments.

“With these confirmed animal models of preeclampsia, we can now dig deeper to uncover the etiology and pathogenesis of preeclampsia to gain a better understanding of the disorder and advance treatments and preventions for women,” explained David Abbott, Ph.D., of WiNPRC.

In general, as humans, healthy aging impacts our cognitive and affective functions. Our cognitive capacity declines while our emotional lives become more positive and social relationships take a more central role.

The reasons for this are unknown, though scientists suspect it may be because humans have awareness of a limited lifetime. This could possibly lead to a greater interest in maintaining social relationships at the expense of the non-social world in the face of waning cognitive and physical resources.

However, a recent study conducted by researchers at California National Primate Research Center (CNPRC) found humans may be unique in this regard.

The scientists tested whether old rhesus macaques lost interest in non-social stimuli, collecting data from males and females between 4 and 30 years old. Each macaque was tested with a food puzzle outfitted with an activity monitor to evaluate their inclination to manipulate the puzzle in order to gain a food reward. The team found no indication older macaques were less interested in the puzzle than younger ones, nor were they less able to solve it.

These findings suggest there are no significant age-related changes in environmental exploration — at least in rhesus macaques — and indicate there is more research to be conducted to understand such social phenomena across species.

Could increasing just a single type of molecule in the brain alleviate anxiety? According to researchers at the California National Primate Research Center (CNPRC), it could indeed.

Anxiety disorders often emerge around adolescence and can continue to affect people for most of their lives. Researchers can now identify children who display an extreme anxious or inhibited temperament and determine that they are at risk to develop stress-related conditions as they transition to adulthood. However, little is known about how to effectively alleviate anxious symptoms.

CNPRC scientists recently conducted a study examining “dispositional anxiety”—the tendency to perceive many situations as threatening—in nonhuman primates. Researchers used an altered virus to boost levels of a molecule called neurotrophin-3 in the dorsal amygdala of juvenile rhesus macaques.

They found that this increase led to a decrease in anxiety-related behaviors, particularly behaviors associated with inhibition, a core part of the early-life risk for developing anxiety disorders in humans. Brain imaging studies of these animals found that neurotrophin-3 changed activity throughout the brain that contributes to anxiety.

Because current treatments work for only a subset of people and often only partially relieve symptoms, this finding provides hope for new methods of early-life intervention to treat people at risk for anxiety disorders, depression and related substance abuse.

Andrew Fox, an assistant professor in the UC Davis Department of Psychology and a researcher at the CNPRC, hopes that other scientists can further build on their research. The research team included a list of additional promising molecules for future investigation.

“We’re only just beginning,” noted Fox. “Neurotrophin-3 is the first molecule that we’ve been able to show in a nonhuman primate to be causally related to anxiety. It’s one of potentially many molecules that could have this effect. There could be hundreds or even thousands more.”

We can’t stop aging—but can we slow down its consequences?

Scientists at the Southwest National Primate Research Center (SNPRC) on the Texas Biomedical Research Institute campus are working to find an answer using an animal model that continues to prove effective in this area.

Associate Professor Corinna Ross, PhD, and Professor Suzette Tardif, PhD, along with a team of researchers, conducted a study on adult marmosets (ages 2-17) that had been transferred to SNPRC from the New England Primate Center in 2015. Marmosets, in general, are recognized as an ideal nonhuman primate model of aging because they have relatively short lifespans and share age-related diseases similar to those of people.

Scientists took blood samples from the animals before and after the move, then re-evaluated them two years later. The team found that low levels of tryptophan metabolism were found to be associated with an increased risk of death.

Tryptophan is an amino acid that is linked to the production of serotonin, the chemical in the brain that contributes to feelings of happiness. Scientists aren’t yet sure whether serotonin influences aging, but there is a link between levels of tryptophan and health, Ross indicated.

The study also found that the metabolism of two other amino acids, betaine and methionine, were associated with aging regardless of environmental factors like stress. The results of the study suggest that the levels of metabolism of these three amino acids could be potential biomarkers for aging and related health issues.

This is “one of the first studies to discover metabo-lites (small molecules) [the levels of which] predict future mortality over a several year time span,” the authors concluded.

Following this study, marmosets may help scientists understand the subtleties of physiological aging and find ways to fight its negative health effects.

Curious about what other factors affect aging? NPRC research indicates the amount of calories you consume could have an impact as well.

Cells that harbor HIV, even while a person is on antiretroviral drugs, are referred to as the “reservoir”. Some of these cells might be able to self-renew/proliferate, thus continually replenishing the virus reservoir. The elusive task of “drying up” this reservoir is key in uncovering a cure.

Researchers at Yerkes National Primate Research Center (YNPRC) recently tested the possibility to block the reservoir self-renewal, working with macaques infected with SIV (Simian immunodeficiency virus) and targeting the Wnt/beta-catenin pathway during antiretroviral therapy. 

Wnt is a common signaling pathway, and beta-catenin is a central protein in that pathway. Beta-catenin regulates the balance between self-renewal and differentiation (changing to another cell type, more mature and shorter-lived) of memory T cells.

The team used PRI-724, a molecule that blocks interaction between beta-catenin and another protein beta-catenin needs to turn on genes. The researchers noted decreased proliferation of long-lived memory T cells and signs of more differentiation into shorter-lived cells that are more prone to die. However, short-term treatment with PRI-724 alone didn’t significantly reduce the size of the overall viral reservoir.

The scientists noted, though, it may be possible PRI-724 or a similar drug could be combined with other approaches for a longer time to make a greater impact.

They also pointed out this technique differs from the “shock and kill” approach that activates dormant infected T cells to trigger an immune system response. NPRC scientists are testing this approach in separate, ongoing studies.

The way that HIV—the virus that causes AIDS—spreads and progresses over time varies among people.

A recent study by scientists at Southwest National Primate Research Center (SNPRC) at Texas Biomedical Research Institute shows this variance may be at least partially explained by a genetic mechanism, a discovery that could open the door for more targeted treatments.

A team of scientists led by Assistant Professor Smita Kulkarni, PhD, and Mary Carrington, PhD, conducted the study, which revealed that a specific long “noncoding” RNA molecule influences a key receptor involved in HIV infection and progression. Dr. Kulkarni said that until the last decade or so, scientists thought many of these particular RNAs were “junk.” Thanks to recent developments in technology and genomics, however, the scientific community has been able to examine them further.

The team of researchers showed that the long non-coding RNA molecules impact the genes encoding an HIV co-receptor known as CCR5. Since CCR5 is critical for the HIV virus to enter the cell, its various expressions can affect the infection’s outcome. Genomic DNA from various groups, including Hispanics, African Americans and Japanese, showed that this is present across many ethnicities, which means it can likely be explained by a single functional mechanism.

“Finding functional mechanisms of the disease-associated gene regions will increase our understanding about how they regulate disease-associated genes and pathways,” Kulkarni explained. “We may be able to find selective targets for (HIV) therapy.”

Kulkarni further stated that these discoveries may have implications for the progression of other infectious diseases as well.

“There are many ways we can use the techniques we have learned through this study—what we have established in our lab,” she said. “We can apply it to many other pathogens currently being studied by scientists at Texas Biomed and at many other institutions.”

Understanding these mechanisms is just part of the equation in fighting HIV. See how other ongoing research at the NPRCs is helping purge HIV “reservoirs” from the body.

While no true cure for HIV/AIDS exists, patients can suppress the virus through a continuous regimen of medication. But now, scientists have discovered a new approach to dealing with HIV infection—one which could eliminate the need for such ongoing treatment.

The study was conducted at the Wisconsin National Primate Research Center (WiNPRC) with the University of Miami (UM) Miller School research team, the Frederick National Laboratory for Cancer Research in Maryland and the Gene Therapy Center at the University of Massachusetts Medical School.

In the study, researchers used an adeno-associated virus (AAV) to deliver gene products into the muscle cells of nonhuman primates, turning the cells into “factories” which produce genetically engineered antibodies indefinitely.

One primate in the study had an exceptionally positive response to the new approach. After receiving a single injection of the AAV-delivered antibodies, its HIV viral load immediately dropped below the limit of detection and has remained undetectable for more than three years.

According to Ronald C. Desrosiers, PhD, professor of pathology at UM and a longtime HIV researcher, this result provides proof of concept that this approach can deliver a functional cure for HIV.

“Our goal is to be able to deliver these potent broadly neutralizing antibodies with one shot so the patient is good for life,” he explained. “But more research needs to be done.”

While such a technique—known as anti-retroviral drug therapy— may suppress viral replication in HIV-infected humans, or SIV- or SHIV-infected monkeys, the study’s authors say it is not a cure. Removal of antiviral drugs results in a rebound of plasma viral loads in the vast majority of individuals. Because of this, repeated infusions are needed to maintain a protective concentration.

In addition, while two other monkeys in the study also maintained long-term viral suppression, the AAV delivery method triggered a defensive immune system response which inactivated the antibodies. The muscle cell-produced antibodies were seen as foreign antigens, resulting in an anti-drug reaction, which can also occur in some patients receiving antibodies for treating Crohn’s disease, rheumatoid arthritis or other conditions.

“Now, we have to solve this anti-drug antibody problem so that we can generate a robust response in virtually all humans,” said Desrosiers, noting this could be a significant breakthrough for world health. “One advantage to this AAV approach is that it could be readily applied throughout the developing world, where antiretroviral therapies are not readily available. An easy ‘one-shot’ approach could make a huge difference in addressing this global epidemic.”

Rhesus macaques have long been considered the prime model for AIDS vaccine research because these monkeys’ immune systems are analogous to humans.

In fact, most medications approved to treat HIV in humans to date have resulted from biomedical research with macaques, much of it performed at the National Primate Research Centers.

Now, for the first time, scientists have used a genetically engineered herpesvirus to achieve significant vaccine protection against the AIDS virus in monkeys. Only live attenuated strains of simian immunodeficiency virus (SIV) – the monkey version of HIV – have previously provided similar protection.

This finding, supported by multiple NIH grants, comes from research at the University of Miami and the Wisconsin National Primate Research Center (WiNPRC). Lead researcher Mauricio Martins is an assistant professor working with long-time AIDS vaccine research experts and NPRC collaborators Ron Desrosiers and David Watkins in the Department of Pathology, Miller School of Medicine, University of Miami.

Although several approaches to an AIDS vaccine show promise, molecularly cloned SIVmac239 is difficult for antibodies to neutralize, just as HIV-1 is in human infection, and a variety of approaches have had great difficulty achieving protective immunity against it, the authors reported.

“These latest results demonstrate for the first time significant protection against acquisition of SIVmac239 by any vaccine regimen other than live-attenuated SIV vaccines,” said Martins.

Four out of six vaccinated monkeys were protected against infection following repeated viral injections over four months, whereas five out of six control animals became infected over the same time span — and those five acquired it the most quickly of all the animals. Animal care and humane euthanasia were administered throughout this study by WiNPRC veterinarians as needed and under the guidelines of the American Veterinary Medical Association.

The herpesvirus used in the study was rhesus monkey rhadinovirus (RRV). The genetically engineered strain, rRRV-SIVnfl, produced not only replicating RRV, but noninfectious SIV, both working together to elicit a safe and strong enough response to fight off SIV infection. It is crucial for any prophylactic vaccine to recognize and kill all virus particles before they invade T-helper cells, take over their machinery and create more viruses. In AIDS, when those viruses eventually burst out, they kill their host cells, destroy the rest of the immune system and eliminate the body’s defenses against lethal opportunistic infections.

Further work is needed, the authors say, to define the critical components necessary for eliciting this protective immunity, evaluate the breadth of the protection against a variety of strains, and explore how this approach may be extended to humans.

Photo credit: National Institute of Allergy and Infectious Diseases