Tag Archives: Wisconsin National Primate Research Center

Child health benefits from studies of infant monkeys – Part 1

Health research with nonhuman primates takes place at many universities and research institutions in the US, among them centers funded by the National Institutes of Health (NIH).  A broad range of research aimed at better understanding maternal and child health takes place at these centers and depends, in part, upon humane, ethical scientific studies of infant monkeys.

A sample of the research areas and findings are highlighted below and provide a view of the value of developmental research. What even a short list shows is that the scope of scientific and medical research that informs pediatric health issues is large. It ranges from autism to childhood diabetes to leukemia to mental health to stem cell therapies.

Together, the findings from studies of infant monkeys have resulted in a better understanding of prenatal, infant, child, and maternal health. The scientific research has resulted in basic discoveries that are the foundation for a wide range of clinical applications and have also improved outcomes for premature and critically ill human infants.

Infant rhesus monkeys playing in nursery.  Wisconsin National Primate Research Center. @2014 University of Wisconsin Board of Regents

Infant rhesus monkeys playing in nursery. Wisconsin National Primate Research Center. @2014 University of Wisconsin Board of Regents

Studies of monkeys are a tiny fraction of all animal studies and are only conducted when studies of fish, mice, rats, or other animals are not sufficient to address the scientific question. Like all nonhuman animal studies, those of young monkeys are subject to rigorous ethical evaluation by scientists, by federal review panels, and institutional review boards that include veterinarians and members of the public.

The decision to conduct a study in nonhuman animals is one that rests on weighing both the potential benefit the work may provide and any potential for harm. The research below provides many specific examples of how and why the studies are conducted and their benefit. For each and every study, scientists, review panels, and ethics boards also consider the potential for harm that may result to the nonhuman animals that are involved. Whether there are any alternatives to the animal study is a requirement of the US system for ethical review and oversight. If there is no alternative, reduction in potential for harm is explicitly addressed not only by a set of standards for animal care, housing, handling, environmental enrichment, and medical care, but also by including only the number of animals needed to answer the scientific question. (You can read more about the review process, regulation, and care standards here and here).

Like other studies of nonhuman animals, those in young animals require serious and fact-informed ethical consideration. At the most fundamental level they challenge us to evaluate how we should balance work that ultimately can help children, the harm that may result from a failure to act, potential harm to animals in research. Consideration of how to balance the interests of children, society, and other animals is not an easy task. Nor is it one that is well-served by simple formulations.

Primate studies of early development have, and continue, to contribute valuable new insights and discoveries that improve the health and lives of many.  The examples below, from NIH-funded research programs across the US, demonstrate how the work contributes to public health.

Sources:  National Primate Research Centers Outreach Consortium. For more information about the NPRCs, see:  http://dpcpsi.nih.gov/orip/cm/primate_resources_researchers#centers

EXAMPLES OF PEDIATRIC RESEARCH WITH MONKEYS

Autism

Cerebral Palsy

  • One outcome of premature birth and accompanying brain injury can be Cerebral Palsy (CP). To date, studies at the Washington National Primate Research Center’s (WaNPRC) Infant Primate Research Laboratory (IPRL) have described the metabolome of normal birth and discovered new acute biomarkers of acute hypoxia‐ This multi‐modal approach will increase the likelihood of identifying reliable biomarkers to diagnose the degree of injury and improve prognosis by tracking the response to treatment after neonatal brain injury. (http://www.ncbi.nlm.nih.gov/pubmed/22391633, http://www.ncbi.nlm.nih.gov/pubmed/21353677)

Childhood Leukemia

  • Wisconsin National Primate Research Center (WNPRC) scientists James Thomson and Igor Slukvin turned diseased cells from a leukemia patient into pluripotent stem cells, providing a way to study the genetic origins of blood cancers as well as the ability to grow unlimited cells for testing new drugs for chronic myeloid leukemia, childhood leukemia and other blood cancers. (http://www.news.wisc.edu/18933 and http://www.ncbi.nlm.nih.gov/pubmed/21296996)

Diabetes and Childhood Obesity

  • Normal and obese marmosets were followed by Suzette Tardif at the Southwest National Primate Research Center (SNPRC) from birth to 1 year. At 6 months, obese marmosets already had significantly lower insulin sensitivity and by 12 months, they also had higher fasting glucose, demonstrating that early-onset obesity in marmosets resulted in impaired glucose function, increasing diabetes risk. (http://www.ncbi.nlm.nih.gov/pubmed/23512966)
  • Infant marmosets were followed by Suzette Tardif at the SNPRC from birth to 1 year. Feeding phenotypes were determined through the use of behavioral observation, solid food intake trials, and liquid feeding trials. Marmosets found to be obese at 12 months of age started consuming solid food sooner and drank more grams of diet thus indicating that the weaning process is crucial in the development of juvenile obesity in both NHPs and human. (http://www.ncbi.nlm.nih.gov/pubmed/23512878)

Diet

Environmental threats

HIV/AIDS

  • Scientists at the CNPRC developed the SIV/rhesus macaque pediatric model of disease, to better understand the pathogenesis of SIV/HIV in neonates and test strategies for immunoprophylaxis and antiviral therapy to prevent infection or slow disease progression. Drug therapies used to prevent the transmission of HIV from mother to infant were developed in nonhuman primate models at the CNPRC, and are now being successfully used in many human populations to protect millions of infants from contracting HIV. (http://www.cnprc.ucdavis.edu/koen-van-rompay/)
  • Development of topical vaginal microbicides to prevent babies from contracting HIV from their mothers during delivery was advanced by Eva Rakasz at the WNPRC and her collaborators. Dr. Rakasz was also a member of the National Institutes of Health study section, Sexually Transmitted Infections and Topical Microbicides Clinical Research Centers. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3032991/, http://www.who.int/hiv/topics/microbicides/microbicides/en/)
  • In a model of mother to child transmission, research at the WaNPRC and the ONPRC has shown that neutralizing antibodies can block infection at high doses and prevent disease and death at lower doses in one-month old monkeys exposed to a chimeric SIV that bears the HIV Envelope protein. Human monoclonal antibodies currently in clinical trials are in testing alone and in combination with drug therapy in this primate model as a less toxic alternative to supplement or supplant drugs in newborns. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952052/, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807376/)
  • In women who are HIV positive, prenatal consumption of AZT is useful for reducing the risk that the unborn fetus will contract HIV. Research done at the WaNPRC IPRL demonstrated that the effects of AZT on maternal reproduction and infant development were minimal and at the doses studied, no significant adverse health effects from prenatal exposure to AZT were predicted for pregnant women. (http://www.ncbi.nlm.nih.gov/pubmed/23873400, http://www.ncbi.nlm.nih.gov/pubmed/8301525)
  • A goal of Yerkes National Primate Research Center (YNPRC) infectious disease researchers is to identify the sources of the latent HIV reservoir so targeted cure strategies can be developed. A first step is to develop a novel model of SIV infection and cART treatment of nonhuman primate (NHP) infants to interrogate the SIV reservoir. The development of such a model will greatly facilitate future studies of SIV reservoirs and the design and testing of novel reservoir-directed therapeutic strategies before scaling to clinical trials in HIV-infected patients.
  • YNPRC infectious disease researchers found the percentage of CD4+CCR5+ T cells was significantly lower in all tissues in infant sooty mangabeys (SMs) as compared to infant rhesus macaques (RMs) despite robust levels of CD4+ T cell proliferation in both species. The researchers propose that limited availability of SIV target cells in infant SMs represents a key evolutionary adaptation to reduce the risk of mother-to-infant transmission (MTIT) in SIV-infected SMs. The researchers are applying their findings toward reducing the more than 300,000 cases diagnosed in children each year. (http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1003958)

Huntington’s Disease

  • YNPRC researchers have successfully created a transgenic, preclinical animal model of Huntington’s disease (HD). These animals, when followed from infancy to adulthood, show progressive motor and cognitive associated with neural changes similar with the disease patterns seen in humans. Not having such a model has been a major roadblock to developing effective therapies for the disease.
    (http//www.ncbi.nlm.nih.gov/pubmed/18488016; http//www.ncbi.nlm.nih.gov/pubmed/24581271)

Lung Development and Function

  • CNPRC research discovered a link between an infant’s temperament and asthma– research is leading towards the screening, prediction and prevention of lung disease in children. (http://www.ncbi.nlm.nih.gov/pubmed/21536834)
  • Research at the CNPRC has shown that exposure to high levels of fine particle pollution (e.g. wildfire smoke) adversely affects both development of the immune system and lung function(http://www.cnprc.ucdavis.edu/long-term-impact-of-air-pollutants/)
  • Childhood asthma research by the CNPRC focuses on understanding why children are highly susceptible to asthma, with the goal of identifying predictive biomarkers and discovering preventive treatments. These studies use a novel rhesus monkey model of house dust mite sensitization to investigate the pathogenesis of allergic asthma in pediatric and adult asthma. The goal is to define the relationship between pediatric asthma, development of mucosal immunity in the respiratory system, and exposure to the house dust mite allergen. (http://www.ncbi.nlm.nih.gov/pubmed/21819959)
  • Eliot Spindel at the ONPRC has shown that large doses of Vitamin C can protect developing lungs from the damage caused when mothers smoke. This work has been duplicated in clinical trials. (http://www.ncbi.nlm.nih.gov/pubmed/15709053)

Kidney Disease, Organ Transplants, Lupus

  • WNPRC scientists and surgeons at UW Hospital successfully tested a new compound, mycophenolate mofetil, in combination with other drugs in monkeys and other animals, and then in human patients in the 1990s. Their work has saved the lives of patients needing kidney or other organ transplants. These new therapies have also kept patients with chronic kidney diseases, including lupus nephritis, which strikes many children and teens, from needing transplants. (Hans Sollinger, Folkert Belzer, Stuart Knechtle, others.) (http://www.ncbi.nlm.nih.gov/pubmed/8680054, http://www.ncbi.nlm.nih.gov/pubmed/9706169, http://www.ncbi.nlm.nih.gov/pubmed/8821838


Memory Impairment

Polycystic Ovary Syndrome

Puberty Disorders

Prenatal and Mental health

  • Studies at the WaNPRC IPRL have provided important and therapeutically relevant information on the fetal risk associated with maternal exposure to antiseizure medication in infants born to women who have epilepsy (Phillips & Lockard, 1985, 1993). (http://www.ncbi.nlm.nih.gov/pubmed/23873400)
  • Human and animal studies at the SNPRC revealed that the intrauterine environment can predispose offspring to disease in later life. Mark Nijland showed that maternal obesity can program offspring for cardiovascular disease (CVD), diabetes and obesity. This study revealed significant changes in cardiac miRNA expression (known to be affected in human cardiovascular disease) and developmental disorders in the fetuses of obese baboons. (http://www.ncbi.nlm.nih.gov/pubmed/23922128)
  • Studies in the WaNPRC IPRL have demonstrated that prenatal exposure to relatively high levels of ethanol (alcohol) was associated with significant changes in the structure of the fetal brain. (http://www.ncbi.nlm.nih.gov/pubmed/23873400)
  • Recent findings from nonhuman primates studied by Ned Kalin at the WNPRC suggest that an overactive core circuit in the brain, and its interaction with other specialized circuits, accounts for the variability in symptoms shown by patients with severe anxiety. The ability to identify brain mechanisms underlying the risk during childhood for developing anxiety and depression is critical for establishing novel early-life interventions aimed at preventing the chronic and debilitating outcomes associated with these common illnesses. (http://www.ncbi.nlm.nih.gov/pubmed/23538303, http://www.ncbi.nlm.nih.gov/pubmed/23071305)
  • Developmental studies with nonhuman primates at the YNPRC have revealed that neonatal dysfunction of the amygdala, a key brain structure, has long-lasting effects on the typical development of brain circuits that regulate behavioral and neuroendocrine stress, resulting in long-term hyperactivity.  These findings may provide clues on the neural source of HPA axis dysregulation found in autism spectrum disorder, schizophrenia and affective disorders.  (http://www.ncbi.nlm.nih.gov/pubmed/23159012, http://www.ncbi.nlm.nih.gov/pubmed/24986273, http://www.ncbi.nlm.nih.gov/pubmed/25143624)

Preterm Birth and Neonatal Outcomes

  • Current research at the ONPRC incorporates studies directed at understanding the mechanisms of parturition, with emphasis on therapeutic interventions for preterm labor associated with reproductive tract infections and the prevention of subsequent adverse neonatal outcomes. Intra-amniotic infection by genital Ureaplasma species is a predominant cause of early preterm birth. Preterm infants often have life-long health complications including chronic lung injury, often leading to asthma and neurodevelopmental disabilities such as cerebral palsy. Research by ONPRC’s Dr. Grigsby has shown that administration of a specific macrolide antibiotic delays preterm birth and reduces the severity of fetal lung injury and most importantly central nervous system injury. Recently Dr. Grigsby has expanded the infant care facilities at the ONPRC with the addition of a specialized intensive care nursery (SCN); this has enabled new research initiatives to expand beyond the maternal-fetal environment to a critical translation point between prenatal and postnatal life. This one-of-a-kind nursery has the look and feel of a human neonatal intensive care unit and supports the cardiopulmonary, (including mechanical ventilation), thermoregulatory, and nutritional needs of prematurely born infants. (http://www.ncbi.nlm.nih.gov/pubmed/23111115, http://www.ncbi.nlm.nih.gov/pubmed/24179112)

Regenerative Medicine

  • Studies at the CNPRC have advanced the understanding of developmental timelines in the kidney, and applied these findings to new protocols and tissue engineering approaches to someday regenerate kidneys damaged by obstructive disease. (http://www.ncbi.nlm.nih.gov/pubmed/23997038)

Stem Cells and Gene Therapy:

  • The first pluripotent stem cell derived clinical trials to treat childhood blindness are now underway, using stem cell technologies discovered using monkeys first, then humans, by WNPRC scientist James Thomson in the 1990s-2000s. (https://clinicaltrials.gov/ct2/results?term=juvenile+macular+degeneration+stem+cell&Search=Search, http://www.ncbi.nlm.nih.gov/pubmed/18029452, http://www.ncbi.nlm.nih.gov/pubmed/9804556, http://www.ncbi.nlm.nih.gov/pubmed/7544005
  • To successfully treat human disease with stem cells, physicians will require safe, reliable, and reproducible measures of engraftment and function of the donor cells. Innovative studies at the CNPRC have revolutionized the ability to monitor stem/progenitor cell transplant efficiency in fetal and infant monkeys, and have used new noninvasive imaging techniques that demonstrated long-term engraftment and safety. (http://www.ncbi.nlm.nih.gov/pubmed/24098579)
  • Studies at the CNPRC have proven critical in gaining approval for investigational new drug (IND) applications to the FDA and conducting first-in-human trials of (1) an expressed siRNA in a lentiviral vector for AIDS/lymphoma patients,, and (2) achieving the overall goal of utilizing adeno-associated virus (AAV) expression of human acid alpha-glucosidase in 3 to 14-year-old Pompe patients who have developed ventilator dependence.

Tuberculosis and HIV

  • Mycobacterium tuberculosis (Mtb) is the causative agent of human tuberculosis (TB) with an estimated 8.8 million new TB cases and 1.4 million deaths annually. Tuberculosis is the leading cause of death in AIDS patients worldwide but very little is known about early TB infection or TB/HIV co-infection in infants. SNPRC scientist Marie-Claire Gauduin and colleagues have successfully established an aerosol newborn/infant model in nonhuman primates (NHPs) that mimics clinical and bacteriological characteristics of Mtb infection as seen in human newborns/infants. Aerosol versus intra broncho-alveolar Mtb infection was studied. After infection, specific lesions and cellular responses correlated with early Mtb lesions seen on thoracic radiographs were observed. This model will also allow the establishment of a TB coinfection model of pediatric AIDS. (http://www.ncbi.nlm.nih.gov/pubmed/24388650)

 

Part 4: Many voices speaking of animal research

We recently wrote about the many existing venues, activities, and materials designed to encourage public dialogue and informed discussion about animal research.  Many individuals, institutions, and organizations contribute to public outreach and education efforts, and also take active roles in dialogue about continuing changes in practice and policy concerning animal welfare and the conduct of animal research.  This post is the fourth in a series (Part 1, Part 2, Part 3) hosted by Speaking of Research to highlight a wide range of individuals and groups devoted to consideration of animal research.

The National Primate Research Centers Outreach Network

The eight National Primate Research Centers (NPRCs) are riding a wave of unprecedented communication, thanks to a new National Institutes of Health/Office of Research Infrastructure Programs (NIH/ORIP) outreach consortium. This consortium helps our members work together more effectively to educate the public on our many and varied educational programs.

Reaching thousands at the USA Science and Engineering Festival

One exciting result of the new consortium occurred April 27 to April 29 this year in Washington, D.C. Representatives from the National Primate Research Centers (NPRCs) spoke to an estimated 4,000 people who visited the NPRCs’ booth at the 2nd annual USA Science and Engineering Festival at the Walter E. Washington Convention Center.

The 2012 USA Science and Engineering Festival, which included a learning station hosted by the National Primate Research Centers, drew 150,000 people to the Walter E. Washington Convention Center in Washington, D.C., this April.

Billed as “the largest celebration of science in the U.S.,” the festival featured more than 3,000 interactive exhibits, more than 100 stage shows and 33 author presentations. More than 150,000 people attended. President Barack Obama promoted the festival in keynotes and public service announcements. Special visitors to the festival included The Myth Busters and Bill Nye the Science Guy, plus Nobel Prize winners, best-selling authors, astronauts, and even a rock guitar performance by NIH Director Francis Collins.

The NPRCs’ booth featured a set of touchable and inflatable real pig lungs representing healthy and cigarette smoke-riddled lungs. Our activity not only demonstrated how smoking harms the smoker, but also helped us convey how the Primate Centers have discovered that second hand smoke can stunt infant lung development. Our interactive display also included a flip board with questions and answers about animal research and care.

Volunteers from the National Primate Research Centers educated the public about the effects of smoking on infant lung development at the 2012 USA Science and Engineering Festival.

– The California NPRC outreach team spearheaded the NPRCs’ participation at the USA Science and Engineering Festival. Some of the consortium’s other recent activities   have included the following:

–  The Yerkes NPRC continues to host a booth on behalf of all of the NPRCs at the Society for Neuroscience’s annual meeting.

– Jordana Lenon (Wisconsin NPRC) represented the consortium at a PR/Media Forum sponsored by the New Jersey Association for Biomedical Research last October in Newark, N.J.

– Consortium participants plan to meet for the first time as a group this fall.

To share updates, materials and communicate effectively with one another­ — whether we’re planning for large events such as the USA Science and Engineering Festival, or sharing news releases and other announcements — center outreach specialists, supported by the NPRC directors and consortium facilitators, use a variety of websites and other e-media tools. We heartily contribute our share to the 188 billion emails still sent every day… and we still talk on the phone. So, although we’re working in three different time zones, from one coast to the other, we feel closer than ever in our working relationships. We plan to meet for the first time as a group this fall, and we all look forward to building new partnerships when we meet.

Students, lifelong learners benefit from many engaging programs

What are some of the many other outreach activities we plan and share? For one, we are fortunate to have developed thriving visitors programs at our centers. We host year-round K-12+ programs such as afterschool programs, campus science fairs, family science nights, science Saturdays, science teachers days, and many more activities, both on site as well as at schools and community venues. A few examples follow:

The Oregon NPRC’s tour program welcomes more than 3,000 people each year. The center also provides opportunities for young scientists to experience authentic research by supporting high school students and undergraduates in labs for summer apprenticeships.

At the California NPRC, many classroom outreach activities and lectures introduce K-12 students to nonhuman primates, biomedical research programs and careers. The center offers a large curriculum and classroom resources for teachers.

The Wisconsin NPRC provides lab demos and hands on activities for middle school and high school students participating in the annual State Science Olympiad, as well in the National Science Olympiad hosted by the University of Wisconsin-Madison last summer.

The Yerkes NPRC promotes an  active speakers bureaus and tours of its large indoor/outdoor facility. Yerkes also sponsors an eight-week summer internship program for high school students. The center received more than 130 applications this year for 10 spots.

In addition to tours and community outreach programs, the Tulane NPRC hosts programs for college honor societies, summer scholars, biomedical students and career tech students. Every summer, the TNPRC mentors students who work with research technicians.

The Washington NPRC recently participated in a three-day science education event at the Pacific Science Center in Seattle. In July, WaNPRC will again host science teachers participating in the annual CURE (Collaborations to Understand Research and Ethics) tour and seminar, a program funded by an NIH Science Education Partnership Award.

Southwest NPRC is hosting “Science Teachers Day at Texas BioMed” this summer, with bus and walking tours, demonstrations, and an “Ethics of Animal Research” panel.

More than 4,000 people participated in activities at the National Primate Research Centers’ booth over the festival’s three days at the end of April.

Specific programs for life-long learners are also growing, such as Oregon’s Road Scholar Week, and Wisconsin’s Grandparents University and College Days participation, and Yerkes’ coordination of eight-week series for two university-based life-long learning programs. In addition to coordinating active speakers bureaus that reach business, patient advocacy and other civic groups, the NPRCs’ outreach specialists themselves are also sought after as invited educational speakers at national and international conferences.

As far as outreach and higher education, most of the NPRCs are located at major research and teaching universities. They have active veterinary care training programs, in addition to offering undergraduate, graduate and post-doctoral research training programs. The New England NPRC’s commitment to education is reflected in its summer programs for pre-baccalaureate and veterinary students. The Oregon, California, and Washington NPRCs host two to three dozen veterinary and vet tech students throughout the year in two-week externships.

Learn more about the National Primate Centers and other National Institutes of Health nonhuman primate resources for research starting here.

Jordana Lenon is the Public Information Officer and Outreach Specialist for the Wisconsin National Primate Research Center at the University of Wisconsin-Madison.

Polycystic Ovary Syndrome: Lessons From Monkeys

The following guest post is from David Abbott, a scientist at the Wisconsin National Primate Research Center and Professor in the Department of Obstetrics and Gynecology at the University of Wisconsin-Madison.  Professor Abbott recently spoke about the goals of his work and the use of monkeys in research in a public forum series hosted by the university.  The talk was followed by a panel discussion that included a clinician who treats girls with PCOS and Jon Levine,  director of the WNPRC.

David Abbott

I am a scientist leading a biomedical research program investigating the causes of polycystic ovary syndrome (PCOS) in women. I see a balanced consideration at the heart of the argument concerning our humane use of about 200 female rhesus monkeys in experimental procedures over the past 20 years in the service of reducing suffering in approximately 15 million American women who endure PCOS. Our systematic and responsible experimental investigation, which was approved after a thorough ethical evaluation by a University of Wisconsin Institutional Animal Care and Use Committee (IACUC), was the first to conclusively identify developmental origins for this women’s health disorder. It is also the first to provide epigenetic molecular insight into potential mechanisms underlying PCOS that can be targeted by future preventive therapies.

PCOS is one of the most common health disorders affecting women. The PCOS ovary makes too much testosterone and supports increased hair growth on the face and body. The enlarged ovary also grows too many egg-containing follicles, thus providing the enigmatic appearance of the polycystic ovary. PCOS follicles usually fail to mature and frequently fail to release an egg at ovulation, hence the lack of menstrual cycles and infertility associated with the disorder. In addition, PCOS overly contributes to obesity, new cases of type 2 diabetes among young women, gestational diabetes, sleep apnea and metabolic syndrome. All of these increase a woman’s lifetime risk of cardiovascular disease. In the words of leading clinical experts in the field:

It has become increasingly clear over the past several years that PCOS is a complex genetic disease resulting from the interaction of susceptibility genes and environmental factors. The insight that prenatal exposure to androgens can reproduce most of the features of the human syndrome in primates has led to a paradigm shift in concepts about the pathogenesis of the disorder.”1

Our PCOS-like monkeys provide insight into a potential origin for PCOS in women: exposure to too much testosterone during fetal life. This insight cannot be ethically gained from experimentation in humans. The inspiration to explore a fetal origin for PCOS, however, does come from humans. PCOS runs in families. Daughters born to women with PCOS are at increased risk for PCOS. So, I posed the question:  What if excess testosterone production, a hallmark of PCOS and its most heritable trait, is its cause? In other words, could too much testosterone produced by the fetal PCOS ovary reprogram multiple female organ systems as they develop, so that when mature, such widespread organ system dysfunction manifests the abnormalities we know as PCOS? Circumstantial evidence from genetic or tumor anomalies in humans indeed suggests that exposure of fetal girls to excess testosterone, alongside other abnormalities, results in PCOS. Humans, however, cannot ethically be used to test the hypothesis that fetal testosterone exposure, alone, causes PCOS.

A population of female rhesus monkeys housed at the Wisconsin National Primate Research Center at the University of Wisconsin, Madison, held the key to testing this possibility. Between about 1970 and 1985, these otherwise normal female monkeys were exposed to fetal male levels of testosterone during gestation when their mothers were given testosterone conjugate as part of other studies. Independent of this work, I collaborated with an Ob/Gyn specialist, as well as scientists from a variety of biological science disciplines, in a multidisciplinary research approach to examine whether testosterone-exposed female monkey offspring exhibit PCOS traits in adulthood. We proposed controlled and systematic experimental approaches in grant submissions to the National Institutes of Health, who funded this research.

Our work demonstrated that the ovaries of adult female monkeys exposed to testosterone during fetal life produce too much testosterone and, when enlarged, such ovaries grow too many follicles. The testosterone-exposed monkeys also ovulate infrequently, leading to intermittent or absent menstrual cycles. Eggs retrieved from the ovaries of testosterone-exposed monkeys, when fertilized in vitro, show impaired embryonic development. These results from monkey studies led to a human study that demonstrated eggs retrieved from the ovaries of PCOS women had altered gene expression. This was an unappreciated PCOS defect and provided an unexpected mechanism by which PCOS-related abnormalities could be passed from one human generation to the next.

Perhaps the most translatable lessons from the testosterone-exposed monkeys came from examination of their metabolic abnormalities. We found many of the metabolic derangements accompanying PCOS in women, including insulin resistance, impaired insulin response to glucose, type 2 diabetes mellitus (T2DM), hyperlipidemia and increased abdominal fat. As in PCOS women, monkey insulin and glucose impairments were reversed after six months of daily treatment with the insulin sensitizer pioglitazone. The insulin sensitizer approach was so successful that the Primate Center adopted it as the first treatment for all monkeys that developed T2DM naturally since this is known to accompany obesity and aging in monkeys, as well as in humans. Insulin sensitizer treatment of testosterone exposed monkeys also allowed us to normalize their menstrual cycles, demonstrating that insulin is involved in suppressing ovulatory cycles, which also occurs in PCOS women. Thus not only did fetal testosterone exposure create a remarkable mimic of PCOS in monkeys, it emulated a key part of the pathophysiological mechanism found in women with the disorder.

The close replication of PCOS in monkeys prompted examination of what occurs during fetal and infant development before adult PCOS traits emerge, which opens the way to earlier targeting of treatment in humans. We found that testosterone injections given to pregnant monkey mothers actually impaired their ability to regulate blood glucose. In addition, the fatter the monkeys were before they conceived, the more susceptible they were to testosterone diminishing insulin regulation of glucose during pregnancy. As in humans, maternal inability to regulate blood glucose results in increased fetal exposure to glucose and increased fetal and neonatal growth. The infant monkeys previously exposed to testosterone and high glucose as fetuses exhibit high insulin responses to glucose that will likely cause insulin-induced accumulation of fat and muscle and relatively fat offspring beyond their heavier infant weight. Since these infants also have elevated androstenedione levels, reproductive- and metabolic-related antecedents of PCOS in monkeys are pronounced from birth. These findings encourage clinical studies aimed at establishing childhood biomarkers for subsequent adult PCOS, especially since PCOS mothers taking the insulin sensitizer metformin before and during pregnancy give birth to daughters who do not go on to develop ovarian hormonal abnormalities at 2-3 months of age.

More recently, with mapping of the rhesus monkey genome and collection of intra-abdominal (visceral) fat samples from infant and adult monkeys exposed to testosterone as fetuses, we quantified how fetal programming changed the methylation patterns of gene promoter sites, and thus increased or decreased relevant genes expression in a fat depot intimately involved in controlling insulin regulation of glucose. Pathway and network analyses revealed commonalities in changed DNA methylation between infants and adults, implicating altered signaling of transforming growth factor beta (TGF-beta) in determining PCOS-related traits. This is an exceptionally relevant molecular result because a gene variant determining a component of TGF-beta signaling, known as fibrillin 3, has been repeatedly associated with PCOS in women. Fibrillin 3 is also only prominently expressed in human ovaries at a gestational age equivalent to the age at which our monkeys were exposed to testosterone. One aspect of testosterone (and glucose) mediated changes in gene expression in monkeys may therefore provide a molecular mimic of the gene variant associated with PCOS in women. Such molecular mimicry establishes testosterone-exposed monkeys as unparalleled models for establishing preventative therapies targeted at PCOS.

Subsequent testosterone exposure studies on mice, rats and sheep by other scientific teams, undertaken because of the monkey results, emulate some or most of our original findings. While non-primate studies consolidated fetal testosterone exposure as an origin for PCOS traits in adulthood, they also caused fetal growth restriction, something that is not common in women with PCOS and is not found in testosterone exposed monkeys. Fetal growth restriction is caused by diminished placental supply of nutrients and leads to adult metabolic disease distinct from that of PCOS. Testosterone exposed monkeys are thus the most human-like animal model for PCOS and provide an established biological platform for therapy directed studies.

The insight thus gained into developmental programming of PCOS in approximately 15 million women in the US from over 20 years of humane, controlled and systematic use of about 200 rhesus monkeys is substantial and unique. Monkeys are such close human relatives that they best enable translation of research findings into human application. In our case, they permit exploration of insulin regulating therapies during pregnancy, such as metformin, as potential preventative therapies and they permit evaluation of consequences for offspring development, as monkey gestation and infant and juvenile development closely emulate the human. The quality of the scientific findings yielded by our studies was made possible by the highest standards of veterinary care, animal husbandry, nutrition, social housing and environmental enrichment that permit our monkeys healthy and well-cared for lives. Our research program is a humane and considered use of monkeys in the service of reduced suffering in women.

David Abbott, Ph.D.

Department of Ob/Gyn and Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI

1 Dunaif A, Chang RJ, Franks S, Legro RS. 2008. Polycystic Ovary Syndrome. Current controversies, from the Ovary to the Pancreas. Pp. vii. Humana Press, Totowa, NJ.

Interview with a Primate Researcher

Wisconsin National Primate Research Center Director Jon Levine has kindly allowed us to reproduce a piece previously posted in On Wisconsin.

Question and Answer with Wisconsin National Primate Research Center Director Jon Levine

Work flows from “the best of reasons,” says new director of primate research center.

Administering a big research center at the forefront of biomedical science is challenge enough. Running one with 1,500 monkeys is the test of a lifetime. But that is exactly the matchup for Jon Levine, the Northwestern University neuroscientist recruited to UW–Madison in late 2010 to run the Wisconsin National Primate Research Center (WNPRC). For Levine, leading one of the nation’s eight national primate centers is an opportunity to promote the kind of science that led to human embryonic stem cells and remains our best hope for beating diseases such as Parkinson’s and AIDS. At the same time, the center is a magnet for controversy, as the use of monkeys in biomedical research is contentious.

Q: Many people hear about the Primate Center only when there is an issue — or a perceived issue. If there is one thing people should know about the center, what would that be?

A: That researchers and staff are passionate about their work, and that they are wonderful, caring people committed to advancing the cause of human and animal health. The average person knows very well the suffering a family member or friend may endure in disease or injury; unfortunately, few are aware of the importance of biomedical research with non-human primates in developing therapies and strategies for preventing these conditions. I want everyone to know why we do what we do — because we are deeply committed to bringing about a future in which HIV can be prevented, the ravages of Parkinson’s disease can be stalled or reversed, and infertility, complications of pregnancy, and metabolic diseases such as diabetes can be successfully treated.

Q: What do you tell someone — a child, for example — who asks you about the use of monkeys for biomedical research?

A: That we are the good guys. We play by the strictest of rules, intended to ensure the humane and careful utilization of a precious resource. And we have the best of reasons for the work we do. I do not hesitate to give children an explanation in terms they can appreciate. For example, many kids know someone who has been diagnosed with some form of leukemia. We are developing methods to take blood cells from cancer patients and reprogram them into “induced pluripotent stem cells” — make them younger versions of themselves, before they became cancerous. Those induced cells can lead us to an understanding of how blood cells become cancer cells and how we might better treat leukemia.

Q: What do you think we can look forward to in the way of scientific advances from the center in the next few years?

A: I could fill pages with advances I hope will be realized. I’ll mention one that I think could enable progress in many others: transgenesis. The ability to induce, block, or alter the expression of specific genes in the mouse is now routine and has made it the standard for most studies of the genetic mechanisms underlying human disease. However, there are many aspects of human physiology and disease that can only be faithfully reproduced in non-human primates. We are undertaking new approaches to manipulate gene expression in non-human primates. We hope to target genes involved in neurodegenerative diseases such as Parkinson’s, metabolic diseases such as type 2 diabetes, and developmental disorders such as autism.

Rhesus Monkeys are used to try to find treatments for illnesses like Parkinson’s

Q: What will be the greatest challenge for the Wisconsin National Primate Research Center over the next decade?

A: The major challenge for federally funded research institutions is to sustain funding from the National Institutes of Health (NIH) and other sources, especially through times of austerity, flat budgets, and increasing costs. I’m confident, however, that the talented researchers and staff at the WNPRC will keep us positioned to renew our base grant funding from the NIH. I am also certain that researchers who use non-human primates on campus will continue to successfully compete for individual research funding. Nevertheless, given the special costs of research with monkeys, and the preciousness of the resource, we will be looking at new sources of support. Over the longer term, the center’s biggest challenge will be to replace and/or renovate portions of our infrastructure. My vision for a new WNPRC building complex may have to wait until the economy recovers over the next few years — but it is a goal that I hope we can realize.

Article reprinted with permission from Jon Levine and On Wisconsin http://onwisconsin.uwalumni.com/departments/qa/jon-levine/

Photos courtesy of WNPRC

Who’s Afraid to Talk about Animal Research?

Part 1:  Outreach and Education Programs by the Nonhuman Primate Research Community

One of the misleading claims often made about members of the community of scientists and others engaged in, or supportive of, animal research is that they don’t talk with the public about their work. To the many scientists and others actively involved in a broad array of both formal and informal education, outreach, and community engagement efforts it is obvious that there is, in fact, a great deal of talking about animal research. At the same time, as with any other aspect of science or area of public interest, there is always a need for more outreach and more public engagement.

Speaking of Research encourages new outreach efforts and increased participation in dialogue about the responsible use of animals in humanely-conducted and ethical research. For those seeking to become more involved in speaking out about animal research there are many sources of information and existing programs that provide good ideas, models, and assistance in setting up new efforts.

This post will begin a series that highlights different approaches to science outreach and education, particularly those focused on research with nonhuman animals.  We begin with community outreach and education programs at primate research centers.  Many primate centers have active outreach programs built around educational objectives and service to local schools, including programs that provide opportunities for K-12 students to learn about research, internships for college students, and tours of their facilities.  The focus on educational outreach and opportunities for students is in keeping with the role of scientists as educators.

The California National Primate Research Center (CNPRC) is one with a long-standing educational program.  Initiated in 2003, “the Education Outreach Program (EOP) was developed as a free, public-service program to introduce K-6 students to nonhuman primates, general health science concepts, animals in research, and biomedical research programs and careers. It supports the California Science Content Standards. This program has been a huge success with the classes visited since it began in June 2003. Comments we have received indicate that the children, as well as the adults, have a greater understanding of primates and health sciences, and the positive benefits that the primate center has on their lives.”  The CNPRC website includes links to the curriculum for their outreach program as well as many resources for teachers.

The Oregon National Primate Research Center also has an active outreach program, with its mission described as:  “Scientists have a responsibility to communicate their research findings to the public, and ONPRC scientists and administration take this responsibility seriously. The Office of Education Outreach hosts tours for over 3,000 visitors to the Center each year.”  As well, “ONPRC scientists speak to Center visitors, serve as mentors for teachers and students, and visit area classrooms. In addition, they participate in various programs through OHSU’s Science Education Opportunities Office (SOAR), and collaborate with several local and regional institutions, including Saturday Academy, OMSI, and the Northwest Association for Biomedical Research (NWABR).”

Rhesus Monkeys at ONPRC

Outreach programs at the Wisconsin National Primate Research Center and the Tulane National Primate Research Center also support interactions between local schools and scientists engaged in primate research.  At the University of Texas MD Anderson Cancer Center’s Keeling Center for Comparative Medicine and Research, a description of outreach programs illustrates an approach that, like others, includes many different audiences:  “The Department of Veterinary Sciences plays a vital role in helping to develop an appreciation for and an understanding of biomedical research by offering teachers, regional youth and the public a unique avenue to actively participate in the research process. Our formal education programs provide opportunities for individuals to dramatically increase their content knowledge in the sciences; access to scientists, veterinarians and other career role models in the sciences to both educators and students; practical hands-on student activities that coordinate with national science standards and curricular frameworks; and professional development for employees.”

At the Wake Forest University Primate Center the community outreach and education program “serves the community by providing children in grades K-12 and their teachers with opportunities to visit the WFUPC and learn about biomedical research. These tours are designed to give visitors educational information about nonhuman primates and the unique role that they play in translational research, to highlight the wide range of human health disorders that are addressed by the Translational Science Institute and the WFUPC, and to educate children about careers in science.”

Among the sources for educational and outreach materials about nonhuman primates are those provided by the American Society of Primatologists (ASP). ASP has a long history of encouraging and supporting “the development of educational programs in primatology” and “promoting improved instruction regarding primates.”  Their website includes helpful links and materials for teachers and others “looking for ideas on incorporating nonhuman primates into their lesson plans and anyone interested in learning more about nonhuman primates.”

Finally, the Primate Info Net (PIN), begun in 1995, provides many resources, links, and helpful educational material to those interested in primates, primate research, and outreach activities.  The PIN is maintained by Lawrence Jacobsen Library at the Wisconsin National Primate Research Center (WNPRC), University of Wisconsin-Madison. “Primate Info Net is designed to cover the broad field of primatology, providing original content and links to resources about nonhuman primates in research, education and conservation. Through email lists and other resources, PIN also supports an informal ‘primate information network’ comprised of thousands of individuals around the world working with nonhuman primates in a variety of roles.”

There are many other ongoing outreach, education, and community engagement efforts. Those highlighted here provide just a few examples of the types of programs that encourage interaction.  Speaking of Research encourages scientists and others supportive of animal research to get involved in public outreach activities through the broad range of existing programs such as those highlighted above, but also by developing new initiatives.  Members of the Speaking of Research Committee work actively in many different types of public outreach and education and are available to share advice and experience with others.  We encourage you to use the comments section or to write posts to share your own experiences and programs and, by doing so, help to continue to build networks for supporting and increasing these efforts.

Allyson J. Bennett, Ph.D.

The views expressed on this blog post are mine alone and do not necessarily reflect the views of my employer, Wake Forest University Health Sciences.