Tag Archives: Allyson J. Bennett

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)

 

Harlow Dead, Bioethicists Outraged

harlow plaque jpeg (2)

The philosophy and bioethics community was rocked and in turmoil Friday when they learned that groundbreaking experimental psychologist Professor Harry Harlow had died over 30 years ago. Harlow’s iconic studies of mother and infant monkeys have endured for decades as the centerpiece of philosophical debate and animal rights campaigns.  With news of his death, philosophers worried that they would now need to turn their attention to new questions, learn about current research, and address persistent, urgent needs in public consideration of scientific research and medical progress. Scientists and advocates for a more serious contemporary public dialogue were relieved and immediately offered their assistance to help others get up to speed on current research.

To close the chapter, psychologists at the University of Wisconsin provided the following 40 year retrospective on Harlow’s work and its long-term impact (see below).

Internet reaction to the scientists’ offering was swift, fierce, and predictable.

“We will never allow Harlow to die,” said one leading philosopher, “The fact is that Harlow did studies that are controversial and we intend to continue making that fact known until science grinds to a halt and scientists admit that we should be in charge of all the laboratories and decisions about experiments. It is clear to us that we need far more talk and far less action. Research is complicated and unpredictable–all that messiness just needs to get cleaned up before research should be undertaken.”

Animal rights activists agreed, saying:

“For many decades Harlow and his monkeys have been our go-to graphics for protest signs, internet sites, and articles. It would simply be outrageously expensive and really hard to replace those now. Furthermore, Harlow’s name recognition and iconic monkey pictures are invaluable, irreplaceable, and stand by themselves. It would be a crime to confuse the picture with propaganda and gobbledygook from extremist eggheads who delusionally believe that science and animal research has changed anything.”

Others decried what they viewed as inappropriate humorous responses to the belated shock at Harlow’s passing.

“It is clear to us that scientists are truly diabolical bastards who think torturing animals is funny. Scientists shouldn’t be allowed to joke. What’s next? Telling people who suffer from disease that they should just exercise and quit eating cheeseburgers?” said a representative from a group fighting for legislation to outlaw food choice and ban healthcare for non-vegans and those with genetic predispositions for various diseases.

A journalist reporting on the controversial discovery of Harlow’s death was overheard grumbling, “But what will new generations of reporters write about? Anyway, the new research is pretty much the same as the old research, minus all the complicated biology, chemistry, and genetic stuff, so it may as well be Harlow himself doing it.”

A fringe group of philosophers derisively called the “Ivory Tower Outcasts” for their work aimed at cross-disciplinary partnerships in public engagement with contemporary ethical issues made a terse statement via a pseudonymous social media site.

“We told you so. Harlow is dead. Move on. New facts, problems require thought+action (ps- trolley software needs upgrade, man at switch quit)”

Harlow himself remained silent. For the most part, his papers, groundbreaking discoveries, and long-lasting impact on understanding people and animals remained undisturbed by the new controversy.

Statement from Psychologists:

Harlow’s career spanned 40+ years and produced breakthroughs in understanding learning, memory, cognition and behavior in monkeys1 (see Figure 1). In a time period where other animals were generally thought of as dumb machines, Harlow’s work demonstrated the opposite — that monkeys, like humans, have complex cognitive abilities and emotional attachments. Harlow and his colleagues developed now classic ways to measure cognition2,3. For example, the Wisconsin General Test Apparatus (WGTA; see Figure 1), in which monkeys uncover food beneath different types of colored toys and objects, allowed scientists to understand how monkeys learn new things, remember, and discriminate between different colors, shapes, quantities, and patterns.

The discoveries of Harlow and his colleagues in the 1930s and forward provided the foundation not only for changes in how people view other animals, but also for understanding how the brain works, how it develops, and –ultimately–how to better care for people and other animals.

Figure 1

Figure 1

In the last decade of his long career, Harlow, his wife Margaret– a developmental psychologist, and their colleagues, again rocked the scientific world with a discovery that fundamentally changed our biological understanding.3 Contrary to prevailing views in the 1950s and before, the Harlows’ studies of infant monkeys definitively demonstrated that mother-infant bonds and physical contact—not just provision of food—are fundamentally important to normal behavioral and biological development. Those studies provided an enduring empirical foundation for decades of subsequent work that shed new light on the interplay between childhood experiences, genes, and biology in shaping vulnerability, resilience, and recovery in lifespan health.

For a brief time at the very end of his career, Harlow performed a small number of studies that have served as the touchstone for philosophers, animal rights groups, and others interested in whether and how animal research should be done. The most controversial of the studies are known by their colloquial name “pit of despair” and were aimed at creating an animal model of depression. In this work, fewer than 20 monkeys were placed in extreme isolation for short periods (average of 6 weeks) following initial infant rearing in a nursery.

At the time, the late 1960s, the presence of brain chemicals had recently been identified as potentially critical players in behavior and mental illnesses like depression and schizophrenia. New understanding and treatment of the diseases was desperately needed to address the suffering of millions of people. Available treatments were crude. They included permanent institutionalization– often in abject conditions, lobotomy (removing part of the brain), malaria, insulin, or electric shock therapies. As some scientists worked to uncover the role of brain chemicals in behavior and mood, others worked to produce drugs that could alter those chemical networks to relieve their negative effects. In both cases, animal models based on similar brain chemistry and biology were needed in order to test whether new treatments were safe and effective. It was within this context that Harlow and his colleagues in psychiatry studied, in small numbers, monkeys who exhibited depressive-like behaviors.

By the 1970s and over the next decades, scientists produced medications that effectively treat diseases like schizophrenia and depression for many people. The therapies are not perfect and do not work for everyone, which is why research continues to identify additional and new treatments. Regardless, there is no question that the suffering of millions of people has been reduced, and continues to be alleviated, as a result of new medications and new understanding of the biological basis of disease.

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

Looking back while moving forward

Nearly 50 years later, it is difficult to imagine the time before MRI and neuroimaging and before the many effective treatments for depression, schizophrenia and other diseases. It is perhaps even more difficult to imagine a time in which people believed that genes and biology were destiny, that other animals were automatons, or that mothers were only important because they provided food to their children. Casting an eye back to the treatment of monkeys, children, and vulnerable human populations in medical and scientific research 50 years ago, or even 30 years ago, is difficult as well. Standards for ethical consideration, protections for human and animal participants in research, and the perspectives of scientists, philosophers, and the public have all continued to change as knowledge grows. Yet, what has not changed is an enduring tension between the public’s desire for progress in understanding the world and in reducing disease and the very fact that the science required to make that progress involves difficult choices.

There are no guarantees that a specific scientific research project will succeed in producing the discoveries it seeks. Nor is there a way to know in advance how far-ranging the effect of those discoveries may be, or how they may serve as the necessary foundation for work far distant. In the case of Harlow’s work, the discoveries cast a bright light on a path that continues to advance new understanding of how the brain, genes, and experiences affect people’s health and well-being.

Mother and infant swing final

Mother and juvenile rhesus macaque at the Wisconsin National Primate Research Center. @2014 University of Wisconsin Board of Regents

 

 

 

 

 

 

 

In the 30 years since Harlow’s death, new technologies and new discoveries—including brain imaging (MRI, PET), knowledge about epigenetics (how genes are turned on and off), and pharmacotherapies—have been made, refined, and put into use in contemporary science. As a result, scientists today can answer questions that Harlow could not. They continue to do so not because the world has remained unchanged, or because they lack ethics and compassion, but because they see the urgent need posed by suffering and the possibility of addressing global health problems via scientific research.

Harlow’s legacy is a complicated one, but one worth considering beyond a simple single image because it is a legacy of knowledge that illustrates exactly how science continues to move forward from understanding built in the past. An accurate view of how science works, what it has achieved, what can and cannot be done, are all at the heart of a serious consideration of the consequences of choices about what scientific research should be done and how. Harlow and his studies may well be a touchstone to start and continue that dialogue. But it should then be one that also includes the full range of the work, its context and complexity, rather than just the easy cartoon evoked to draw the crowd and then loom with no new words.

Allyson J. Bennett, PhD

The author is a faculty member at the University of Wisconsin-Madison.  The views and ideas expressed here are her own and do not necessarily represent those of her employer.

Suomi SJ & Leroy, HA (1982) In Memoriam: Harry F. Harlow (1905-1982). American Journal of Primatology 2:319-342. (Note: contains a complete bibliography of Harlow’s published work.)

2Harlow HF & Bromer J (1938). A test-apparatus for monkeys. Psychological Record 2:434-436.

3Harlow HF (1949). The formation of learning sets. Psychological Review 56:51-65

4Harlow HF (1958). The nature of love. American Psychologist 13:673-685.

Pictures in need of accurate words: University of Florida animal photos

Pictures of a cat spay clinic misrepresented as a laboratory horror shop circulated the internet recently to support appeals to “end animal testing.” Speaking of Research wrote about it here “Fact into fiction: Why context matters with animal images,” noting the importance of understanding the facts and context for photographs.

This picture was used to misrepresent animal research

This picture was used to misrepresent animal research

In the cat spay clinic case, the photos were from a newspaper article. We have written previously about images of laboratory animals that have made their way to the internet via leaks, undercover operations, and open records release. In all cases, several points remain true. Images are powerful. Providing accurate information about the images is important. It is also true that there are important differences between the sources and ways that images are obtained. Those obtained via infiltrations and undercover operations may be from manipulated situations, or  small fractions of hours of recording, in both cases providing a deliberately misrepresentative view. Photos obtained from institutions via open records release can also be used to misrepresent laboratory animals’ care and treatment and can be the centerpiece in “shock” campaigns. Their value is obvious from even a quick survey of high profile attacks on research, as we’ve written about previously (here, here, here). As in the case of the spay clinic images, conflating veterinary and clinical care with scientific research is also common and further serves to confuse the issues.

Can the laboratory animal research community do a better job of providing context for images of animals?  Yes.

Knowing what the images show and why matters, particularly to people who would like to engage in serious and thoughtful consideration to inform their point of view and judgments. In absence of context and facts, the audience is left without key knowledge and an opportunity to educate is missed. Yet all too often the opportunity is missed and the images remain in public view without comment or context from those who could provide a better understanding of what the photographs show.

In reviewing laboratory animal photographs that appear on animal rights sites, it is obvious that there are generally two types: those from activities directly related to the scientific project and those related to veterinary care or housing and husbandry. In terms of providing context and information, the two differ with respect to their source and which personnel may best explain the content of the photographs.

What does the image depictSome images may be of actual scientific research activities. These may be of animals engaging in an activity directly related to the science question under study. For example, the images may illustrate how animals perform a cognitive or memory task, how they navigate a maze, or how a particular measurement is obtained. The Max Planck Institute for Biological Cybernetics website provides an example of this, with description and photographs of rhesus monkeys and cognitive neuroscience research. Another type of image directly related to the scientific project may be of a surgery or procedure. An example of this is found in pictures of a surgery involved in cat sound localization research (photos here, video here). In each case, it is not particularly challenging to provide additional information and context because the activities are typically also explained in the protocols, grants, and scientific papers about the study.

Images of clinical veterinary care, husbandry, and housing appear frequently in activist campaigns and public view. For example, pictures of routine physical examinations, health tests, unexpected injuries unrelated to scientific procedures, or photos of animals in their normal housing, have all appeared via various sources. Many times– perhaps more often than not– the activity depicted in the images would not be obvious to a lay audience because it remains unexplained.

A common image – tuberculosis skin test

One of the best examples of misunderstood images is found in pictures of an anesthetized macaque monkey with a needle injecting something in its eyelid. The picture circulates the internet with various captions opposing “animal testing.”   What does this picture show?

tb imageIt is a skin test, commonly used in human and nonhuman primates, for early detection of tuberculosis. A small amount of tuberculin (non-harmful) is injected just under the skin. In almost all cases, the primate does not have tuberculosis and the skin remains normal. If the primate—human or not—does have a reaction to the test, indicated by redness and some swelling, it provides evidence of possible tuberculosis infection. That person, or monkey, then receives additional testing and preventive measures for treatment and to avoid infecting and harming others.

Tuberculosis testing is routinely performed as a health procedure in humans who work in hospitals, schools, with children and with others who may be vulnerable. In settings where nonhuman primates are housed, tuberculosis testing is often routinely performed with all human personnel and with the other animals. Why? Because tuberculosis is a rare disease, but one that can be a threat to the animals’ health and thus, precautions are necessary to ensure their health. The difference between human and monkey tb testing is that for humans, the injection is given without pain relief or anesthesia, via a needle inserted into the forearm.

Aside from the momentary discomfort of the injection, the test is painless and without irritating after-effects. In monkeys, the injection is typically given while the animal is anesthetized and is placed just under the skin of the upper eyelid. Why the difference? It is a simple reason—the key to the test is looking for redness or slight swelling. In monkeys, the forearm is fur-covered and it would be very difficult to detect a reaction in an unobtrusive way.

University of Florida monkey pictures

Not surprisingly, the monkey tb test photo is one that seems to appear in an ongoing campaign against the University of Florida. In response to several years of attacks on their animal research programs, public universities in Florida are pursuing new action to shield personal information about their personnel from public disclosure.   We’ve written previously about an ongoing campaign of violent threats, harassment, and protest by local activists (here, here, here).

In parallel to other campaigns, photographs are a centerpiece of the current attacks on animal research. As reported by Beatrice Dupuy in the Independent Alligator:

“Disturbing pictures of primates being examined by researchers are featured on the organization’s website along with posters with quotes like “stop the holocaust inside UF, free the monkeys.” After a three year lawsuit, the organization, formerly named Negotiation is Over, obtained UF’s public veterinary records last April. The researchers named in public records were the first ones to be targeted by animal rights activists, said Janine Sikes, a UF spokeswoman.”

What are these “disturbing pictures of primates being examined by researchers”?

The photographs <warning: link to AR site> are of macaque monkeys that appear to be receiving routine veterinary care or are simply in fairly standard housing. While the activists claim these photos are evidence of maltreatment at the hands of researchers, they likely are mostly of routine veterinary procedures. For example, two appear to be of an anesthetized macaque monkey receiving a tattoo, another two of an anesthetized monkey receiving a tuberculosis test, while others show the reddened skin that rhesus macaques exhibit normally in the wild and captivity. One photo depicts what looks like a stillborn infant macaque. Without context or confirmation, it isn’t surprising that the photographs can be interpreted in many ways.

UF’s spokesperson says: “The university wants to be very open and honest about its research,” … “It wants to stop these personal attacks against our researchers.”

One place to begin is to provide straightforward and accurate context for the images of laboratory animals that have been released. While those with experience in laboratory care of nonhuman primates can view the images and be reasonably certain that they are mostly of clinical veterinary care, it is only the UF veterinary, animal care program, and scientific personnel that can provide accurate information. Other universities have done exactly that when faced with the same situation. In “An Open Letter to the Laboratory Animal Veterinary Community and Research Institution Administration”   we wrote:

“While scientists can address questions about the scientific side of animal research, we need the laboratory animal care and veterinary staff to provide their expertise in service of addressing public questions about clinical care and husbandry.  If they do not, it will be no surprise if the public view of animal research is disproportionately colored by the relatively rare adverse events and the misrepresentations of animal rights activists. Many believe that it is possible—and perhaps acceptable—to ignore this part of reality in order to focus on more immediate demands for time, energy, and resources. Consider, however, that a fundamental part of the AWA, accreditation, regulation, and professional obligation is actually to ensure communication with the public that supports animal research.  Thus, it is our entire community who share a primary obligation to engage in the dialogue that surrounds us.”

We have consistently condemned the extremists who have targeted UF scientists and others with outrageous harassment. Tactics designed to elicit fear and terror do not have a place in democratic society and do nothing to promote fair and civil dialogue about complex issues.

At the same time, we believe and have written often, that the scientific and laboratory animal community, including scientists, veterinarians, and institutional officials should consider that better education and explanation are key to building public dialogue and understanding of research. Furthermore, as highlighted in this case and others, releasing photographs, records, and other materials without providing context serves no one well. Providing straightforward explanation of the veterinary practices, housing, husbandry, and care of laboratory animals not only gives context to photographs, but also should not be that hard to do.

Allyson J. Bennett

More information and resources:

Raising the bar: What makes an effective public response in the face of animal rights campaigns:  http://speakingofresearch.com/2013/02/20/raising-the-bar-what-makes-an-effective-public-response-in-the-face-of-animal-rights-campaigns/

Time for a change in strategies? http://speakingofresearch.com/2013/06/24/time-for-a-change/

A detailed response to a PETA video accusing a primate lab of mistreatment:  http://speakingofresearch.com/2008/07/04/peta-out-with-the-new-in-with-the-old/

Speaking of Research media briefing (pdf):  Background Briefing on Animal Research in the US

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook or Twitter.

Fair partners in dialogue: Starting assumptions matter and they should be spelled out

The importance and need for civil, open dialogue about the complex set of issues involved in use of animals is among the points of agreement between members of the scientific community, the public, animal rights activists, and others.  Speaking of Research, along with others, has consistently advocated for such dialogue and has engaged in it via a number of venues, including our blog, public events, conference presentations, and articles.

Such dialogue often takes place without clear specification of the starting positions held by the people engaged in the conversation. The problem with this approach was recently highlighted by Dario Ringach in his posts about a series of public forums on ethics and animal research (here, here, here).

The basic position of those engaged in animal research is obvious in part by the nature of their work. Furthermore, the very structure of the current regulations and practices reflect– both implicitly and explicitly– a set of positions on the ethical and moral considerations relevant to the use of animals in research.

For example, in the U.S., the laws and regulations that govern animal research mandate that proposals for use of vertebrate animals (including rats, mice, birds) provide, among other things:  1) a justification of the potential benefits of the work; 2) an identification of potential harms and means to reduce them; 3) evidence that alternatives to using animals are unavailable; 4) use of the least complex  species; and 5) much detail about the animals’ care and treatment, including the qualifications and training of the personnel involved.  Consideration of these issues occurs not only at the stage of IACUC evaluation, but throughout the scientists’ selection of questions and studies to pursue, peer review and selection of projects for funding (more here). Furthermore, the entirety of the project must proceed in compliance with a thorough set of regulations designed on the basis of the 3 Rs – reduce, replace, and refine (for more about regulation see here, more about 3 Rs, here).

In other words, while there is always room for continued improvement, the structure is designed to require that the major ethical and moral considerations relevant to animal research be addressed by those involved in performing and overseeing the work. This structure also incorporates explicit consideration of changes that arise from new knowledge.  That includes evolving knowledge about different species’ capacities and needs, as well as the development of alternatives to animal-based studies for particular uses.  It also includes  advances in our scientific understanding that demonstrate greater need for basic research that requires use of animals to address key questions.

One of the important purposes of dialogue is to communicate diverse viewpoints and values on animal research. One key to understanding those viewpoints and values is consideration of the basic starting assumptions, or positions, from which they arise.

What are the positions of those who oppose laboratory animal research?  In some cases, these are clearly stated.  In the case of absolutists, the position is that no matter what potential benefit the work may result in, no use of animals is morally justified. This extends across all animals – from fruit-fly to primate. Furthermore, all uses of animals, regardless of whether there are alternatives and regardless of the need, are treated identically. In other words, the use of a mouse in research aimed at new discoveries to treat childhood disease is considered morally equivalent to the use of a cow to produce hamburger, the use of an elephant in a circus, or a mink for a fur coat.

In this framework, the focus often excludes consideration of the harms that would accrue as a consequence of enacting the animal rights agenda. For example, the harm to both humans and other animals of foregoing research or intervening on behalf of animals.  As a result, while the absolutist position is often represented as one that involves only benefits and no harms, this is a false representation. While some animal rights groups are clear about their absolutist position, others—to our knowledge—are not.

On the other hand are those who avoid identifying directly with an absolutist position, but instead focus on the need for development of alternatives to use of animals.  This is a goal that may be widely desired and shared. It does not, however, address the question of what should be done in absence of alternatives and in light of current needs that can only be addressed by animal studies. In turn then, this position is silent with respect to moral and ethical consideration of a broad swath of research and fails to offer a framework to guide current actions.

We believe that the goal of promoting better dialogue would be assisted by making these positions clear and we provide a starting place below.  We welcome additions by individuals and groups, as well as clarification or correction if any are unintentionally misrepresented.

_______________________

People for the Ethical Treatment of Animals: Offers clear statement of absolutist position. “PETA has always been known for uncompromising, unwavering views on animal rights. PETA was founded in 1980 and is dedicated to establishing and defending the rights of all animals. PETA operates under the simple principle that animals are not ours to eat, wear, experiment on, or use for entertainment.”

In Defense of Animals:  Offers clear statement of absolutist position.  “We work to expose and end animal experimentation”

New England Anti-Vivisection Society:  Offers clear statement of absolutist position. “Is NEAVS against all animal experiments? Yes. For ethical, economic and scientific reasons, NEAVS is unequivocally opposed to all experiments on animals and works to replace them with humane and scientifically superior alternatives that are more relevant and predictive for humans.”

Alliance for Animals (Madison, WI):  Offers clear statement of absolutist position.  “It is Alliance for Animals’ guiding principle that all animals, human and nonhuman, should never be treated as the property of another.” AFA is a non-profit 501(c)3 animal rights organization whose fundamental belief is that all animals, human and nonhuman, should not be treated as the property of another.

Stop Animal Exploitation Now:  Offers clear statement of absolutist position.“Exposing the truth to wipe out animal experimentation.”  And: “To promote through education the prevention of suffering and cruelty to any of God’s creatures, human or otherwise, including, but not limited to their diet, their health, and their living conditions. To promote through education the elimination of the use of animals in biomedical research and testing, their use as food, or their use for any and all commercial purposes; and to protect the environment in which we all live, so that no living beings suffer from its destruction or pollution.”

Humane Society of the United States:  Does not, to our knowledge, offer a clear position on whether it is morally acceptable to use animals in research when there is no alternative. What they do say“As do most scientists, The HSUS advocates an end to the use of animals in research and testing that is harmful to the animals. Accordingly, we strive to decrease and eventually eliminate harm to animals used for these purposes.”

Physicians Committee for Responsible Medicine:  Does not, to our knowledge, offer a clear position on whether it is morally acceptable to use animals in research when there is no alternative.  What they do say“We promote alternatives to animal research and animal testing.”

_______________________

For those engaged in dialogue about the ethical and moral considerations related to the use of non-human animals in research , even this brief list makes clear that it is important to ask participants to begin by putting their basic starting assumption forward.  Why?  For one reason, because those assumptions are key to identifying whether there are potential areas of agreement or none at all.

For example, discussing refinement of laboratory animal care with an absolutist—someone fundamentally opposed to animals in laboratories—misses the point. No amount of refinement would make the work acceptable to them. In this case, the more critical questions for discussion would include consideration of the relative harms and benefits of failing to perform research for which there are currently no alternatives to animal-based studies.  Consideration of species’ capacities and criteria for differential status– if any– would also be a useful starting point.

What about dialogue with those individuals and groups who do not provide a clear position?  Does it matter?  Some would argue that it does not because the dialogue is only concerned with animal welfare and with reducing harm to nonhuman animals, or with pushing forward to develop non-animal alternatives for some types of research. In fact, framed in this way, most scientists are not only in the same camp, but are also the people who work actively to produce evidence-based improvements in welfare and development of successful alternatives.

The problem, however, is that real-time, critical decision-making about human use of other animals in research is not simple.  It does require serious, fact-based consideration of the full range of harms and benefits, including consideration of the welfare of both human and nonhuman animals.  It also requires clarity about alternatives, where they exist and where they do not.  And it requires some understanding of the time-scales in which knowledge unfolds – often decades – and a basic appreciation for the scientific process.

It is easy to argue that developing non-animal alternatives should be prioritized. But this argument does little to address the question of what to do now, what we do in absence of these alternatives, and what choices we should make as a society. Those questions are at the center of dialogue and the core issues with which the scientific community and others wrestle.  To address them productively, and in a way that considers the public interest in both the harms and benefits of research, requires articulation of starting assumptions and foundational views.

Allyson J. Bennett

A Closer Look at How Animal Research Progresses from Idea to Study

Unfortunately, the “how” and “why” of the research process is of much less interest, and receives far less attention, than the “what did they find?!” part of research. The latter is what you’ll see—if we’re lucky from the science outreach perspective— on television, in the science and popular media, Facebook, Twitter, and conversations world-wide. Meanwhile, the former will be relegated to websites of federal agencies, scientific societies, and animal research advocacy groups and are read less widely.  In fact, it is entirely possible that a great many bets could be won by wagering that the public generally doesn’t care to read up on regulation or processes governing the research behind the cool discoveries that make news.

In the case of animal-based research (and some other controversial fields), the “how” and “why” do sometimes generate some public interest because they are keystones in considering questions about its ethical basis and evaluation.  Public understanding and discussion of the process by which science moves forward is important. It provides appropriate context for fact-based dialogue about the ethical evaluation, decision-making, and regulation that govern a wide range of science conducted within our democratic system. Thus, many scientists and advocates not only welcome public interest in the conduct of science, but also actively promote thoughtful, engaged, and informed collaboration on efforts for improving research practices.

Why? One reason is that the ultimate benefactor from scientific studies is the public and, within a democratic society, it is for all of us to decide whether the benefits of those studies outweigh their costs.  Another reason is that scientists are generally sensitive and responsive to societal views, but feel an obligation to ensuring that these views are informed by facts as well as emotional appeals.  This is an issue that is not at all unique to animal research. It also appears in discussions of other topics that can elicit controversy, including for example: evolution, climate change, use of embryonic stem cells, and vaccines.

For animal research, the challenges inherent in serious evaluation of its costs and benefits are not trivial. Nor is it amendable to flashy, sensationalized, and emotion-evoking campaigns.  Simplistic approaches to this issue are not useful and do a disservice to all of us.

From our perspective, it is both disappointing and frustrating to find that understanding of the process by which science moves from idea, to the conducting of the study, to the dissemination of the findings, to the evaluation of those findings receives far less attention than would be needed in order to rationally discuss the research.  Why?  Because the reality of how science is actually conducted is centrally relevant to conversations about science.  And while this is an obvious statement, it is also clear from many portrayals of science by opposing groups that the basics of scientific process and conduct are often missed in the discussion.

In the case of laboratory animal research, the starting point of many opponents is an absolutist position in which the conditions for animals, the ultimate outcome of the research, and its benefits, are irrelevant. They are irrelevant because the starting assumption is that the use of animals is morally unacceptable. For those who hold this view, there is no benefit that would justify the animal use.  There are others who hold a less absolute view and, like us, believe that the use of animals in research begins with moral and ethical consideration that requires thoughtful, fact-based weighing of both relative harm and benefit.  One major part of this evaluation is identifying whether alternatives exist to meet the same goal.  Another is identifying as closely as possible what harm may be incurred, the probability and extent of benefits. Each of these considerations is integral to regulation of animal research in the U.S. and elsewhere. They are also considerations that are so integral to the scientific process that they operate far beyond those stages typically identified as the “checks” for ethical and humane conduct of animal research (e.g., IACUC review, federal oversight).

long haul slide

How scientific research moves from idea stage, to conducting a study, to success or failure, to critical review, to dissemination and use of findings is a process that can appear somewhat opaque to public view.  The pieces of information required to construct the general pathways are publicly available.  Putting them together, however, is not necessarily straightforward for those without immediate interest, expertise, or engagement.  So while the information is neither hidden nor made secret, it is of the type that can be easily misunderstood or misrepresented.

Should this gap in basic understanding and perspectives on how scientists’ ideas move from thinking to reality concern us?  The answer is yes.  Among other reasons, the gap serves as an impediment to an informed evaluation of science.  It also weighs heavily against productive dialogue about core issues of public interest.

How does an animal research project move from scientist’s idea to finished study?

In general, the process looks like this:  Scientists generate ideas that are based in careful study of what is known, what is not known, what methods already exist, what facts we have.  They next critically evaluate and review relevant previous literature and data–  often soliciting others’ expert knowledge–  to determine whether the idea is novel (has not already been tested),  of potential importance or significance, and feasible.

Thus, while some may have the impression that scientists roll out of bed in the morning, or have an aha-moment- then  move straight to the lab to conduct whatever study occurred to them via dream – this is not the way it typically works.

As illustrated, deciding on whether an idea is worth pursuing or not is driven by many factors. If the resulting data would have little potential benefit, few scientists are likely to pursue it. Why?  Because scientists have a lot of ideas and it makes no sense to expend energy on one that won’t be useful in terms of providing significant new knowledge or understanding.  It is also true that such ideas are unlikely to compete successfully in the different arenas of expert scientific review, including review for funding, publication, and citation.

research process

If a scientist judges his/her idea worth pursuing, the next step is likely to decide whether the study is feasible or practical. What does this mean?  In short, this is a question that revolves around ethical, economic, and practical issues.  On the ethical side, for animal research the scientist will consider animal welfare and treatment, any potential for harm.  Next, on the financial and practical sides, the scientist will consider how much the study will cost and whether the necessary work can even be done. During this initial stage the scientist will also critically evaluate whether the existing literature and facts provide adequate and strong platforms for the proposed study, or whether more basic and background data are needed to guide decisions before moving forward.

For that fraction of studies that survive the scientist’s own critical examination—and likely that of his/her collaborative group and colleagues—the scientist may decide to pursue the work. If so, for animal research the next step will be to write a proposal to the Institutional Animal Care and Use Committee (IACUC) in order to conduct a study.  In the U.S., IACUSs are among the main venues for thorough review of animal studies.  We have written previously about IACUCs and there is more information here.

In brief, the IACUC is comprised of individuals with veterinary and scientific expertise, as well as a public representative.  Animal studies do not proceed until the IACUC has reviewed and approved a proposal.  What do these protocols contain?  You can see some here, this site contains links to protocol forms from a range of institutions.  Although institutions vary in the format of applications, among other things, they include: information about what the study is designed to test, why it should be conducted, the literature review and strategies used to ensure that it is not unnecessarily duplicative, that alternatives do not exist, the number of animals proposed and justification for both the number and the species,  detailed description of all procedures,  and other details about the animals’ care and treatment.  In other words, the full range of information that the review committee will need in order to evaluate whether the study meets standards.

Is the IACUC process perfect in evaluating study protocols? No.  It is, however, the current system mandated by federal law and it is one that generally functions well to protect animal welfare.  It is also an evolving system, with scientists, veterinarians, federal agencies, science and animal welfare advocates engaged in its ongoing evaluation and improvement. Some of the criticisms of the existing system, however, neglect consideration of the larger context, the process by which research unfolds. For example, critics point to the fact that IACUCs approve the majority of studies put before them as evidence that “almost anything” a scientist could dream up receives approval.  In reality, IACUCs only review proposals that scientists write and submit. This means that the IACUC only sees study proposals that have already received some critical evaluation and that likely already fall within the constraints of current guidelines, practices, and norms.  Scientists, like others involved in animal research, take part in training and education about the range of issues related to animal welfare, humane treatment, and regulatory requirements.  As a result, they are generally not likely to write protocols that diverge from acceptable practices.

Following IACUC approval, the scientist may then begin conducting the study. It is often the case however, that IACUC approval is not the final step between idea and study.  Instead, for a new project, the scientist must also write a proposal to a funding agency in order to secure financial support for the research. In many cases in academic research, funding for these studies comes from federal agencies such as the National Institutes of Health or the National Science Foundation.  Competition for these funds is high and the majority of applications are not successful.  Those proposals that are funded have undergone rigorous review by a panel of scientists whose expertise is within the area of the proposal.  The criteria for review vary by agencies, but include very close examination of the significance of the research question, evaluation of its potential for success, scrutiny of the methods, expertise of the investigator, and quality of the facilities in which the research will be conducted.  The appropriateness of the animals chosen for study, their number, and their treatment are also subject to critical evaluation and discussion.  In sum, beyond IACUC review, many animal studies—including all of those funded by NIH, NSF, and other agencies— undergo another level of external expert scientific review.

Take-home message?  The evaluative process between a scientific idea, the conduct of a study, the results, and their evaluation, use, and further discovery is one with many steps and significant consideration.  The potential harm and benefit of each study receives review at each stage as well, both within and outside.

Research aimed at addressing basic, translational, or clinical questions relevant to advancing our scientific understanding and medical progress for humans and other animals is ultimately all aimed at questions with significance to many.  At the same time, it is also absolutely true that the benefits of research are not always directly or immediately apparent.  We simply do not know the answers before we conduct the work.  Furthermore, we can be confident—drawing from real conclusions from the history of science – that important, meaningful, generative breakthroughs are not entirely predictable.  As a result, it is no easy task to construct a metric by which to evaluate the potential benefit of research and to weigh that against any harm incurred during its conduct.

Considered carefully, the history of animal research and animal welfare are quite clear with respect to how the accomplishments of research and consideration of mutual interests in animal welfare provide the basis for progress in ethical and humanely-conducted animal research.   Public interests are served by dialogue based in fact and in clear accurate articulation of ethical frameworks from which animal research is considered.  Understanding the multiple levels at which research projects are evaluated from scientific and ethical perspectives is an integral starting point for this discussion.  Science doesn’t occur through simple processes or via a single stage of evaluation; nor should public dialogue about this complex issue.

Allyson J. Bennett

Bridging the gap: Monkey studies shed light on nature, nurture, and how experiences get under the skin

“Is it nature or nurture?”
“How does that work? How can social experiences actually change someone’s brain?”
“So early experiences matter, but how much?  Is it reversible? How long does it last? Is there a way to change the course?”

All of these are popular questions that I hear from students, community members, clinicians, and other scientists when I talk about my research with monkeys.  The nature vs. nurture question is one of high public interest.  It is one that is at the center of our understanding of who we are and how we come to be that way.  And it is a very old question.  Yet it is also one that continues to resonate and become even more intriguing as new discoveries rapidly change what we know about biology and genes, and illuminate with increasing specificity the ways in which nature and nurture together play dynamic roles in shaping the development of each individual.

For example, through research with humans, monkeys, rats, mice and other animals, we know that genes are not only involved in differences between individuals’ behavior, health, and biology, but also that an individual’s social environment and childhood experiences can actually change how genes behave and, in turn, have biological consequences.  In other words, those previous gray areas surrounding exactly how nature and nurture work together are now being filled in with a more specific understanding.

Why does this matter? There are many important reasons. Among them, it is this specific information that allows us to develop better prevention, intervention, and treatment strategies for those negative health outcomes that follow adverse experiences. One example of this can be found in our rapidly advancing knowledge of how brain neurochemistry, which plays a major role in mental health disorders, is affected both by genetic differences between individuals and also by early life experiences. This knowledge provides not only the basis for developing treatments that target the specific neurochemicals involved in a disorder, but also provides important clues for early identification and intervention for those at risk. At the same time, understanding that experiences have long-lasting consequences on biological pathways involved in lifetime health underscores the importance of public policies that work to promote better early environments.

I am one of the many scientists who are devoted to work aimed at better understanding how many different kinds of early experiences can influence a wide range of health outcomes during an individual’s lifespan. My own part of this work primarily includes non-invasive studies with monkeys and focuses on developmental questions about behavior, aspects of brain chemistry and development, and genetics. For example, I use neuroimaging (MRI) to look at how brain development can be affected by early life experiences and we have monkeys play videogames, solve puzzles, and respond to mild challenges so that we can better understand their learning, memory, cognition, and temperament.

Part of my work involves studying how middle-aged monkeys (15+ years old) who were raised in infancy with their mothers differ from monkeys nursery-reared in infancy with their peers. The two groups have the same experiences following the early life period, and during infancy and throughout their lives, both groups are housed in enriched environments with excellent diets, toys, and medical care. Although my current work is focused on a small number of nursery-reared animals, it does not involve creating new animals or a nursery. It depends on healthy animals who have been part of our work for many years and, as with all of our studies, we treat these animals humanely, with careful attention to providing them with healthy diets, environmental enrichment (e.g., a variety of toys, puzzles, fresh fruit and vegetables, and foraging opportunities), and excellent clinical care by veterinarians.  We do this because we care about the animals’ well-being and also because our studies depend upon healthy animals.

Adult rhesus macaque

There are less than a handful of studies concerned with how monkeys’ early rearing influences their behavior and other aspects of health in middle- and older-age. As a result, although we have a strong platform of knowledge about the effects of early life experience in younger animals, we know very little about whether these effects persist into older age, about what systems are affected, and the degree to which individuals vary.

This study, like those of others who study the effect of different early life experiences on a range of health outcomes, is aimed at uncovering the biological basis of a key finding relevant to human health. We know from human studies that a wide range of early experiences, including not only childhood neglect and abuse, but also poverty and other types of adversity, are associated with negative health outcomes later in life. In humans, however, it is impossible to truly disentangle the effects of early adverse life experiences from differences in diet, environment, access to medical care, and other factors that vary across the lifespan. Animal studies allow us to control many of the factors that vary widely in humans and have consequences on health. For example, animals with different early experiences have the same environment and experiences afterwards, including healthy diets and excellent medical care. As a result, when we find significant differences in behavior, brain chemistry, brain structure, and immunology between animals with different early experiences we know that these differences are not due to disparity later in life.

Early experiences do not tell the whole story, however, as we know from the common observation that two individuals who experience the same early environment or challenging experiences, may wind up with very different health pathways.  Part of the obvious reason for this is genetic variation. Understanding how differences in genes contribute, however, and which biological pathways are affected or how permanent those effects may be, are now the real questions that remain to be fully answered. Animal studies provide one of the critical ways to view the interplay and roles of genes, environments, and experiences. This is because, unlike in human studies, animal studies can make use of strong experimental control and mechanistic approaches in order to compare the biological and behavioral responses of individuals who have similar genes and different environments, or individuals with different genes in the same environment.

Another part of my research involves studying how genes affect an individual’s response to the environment and how that occurs at a biological level.  The kinds of questions that we address include:  When two individuals experience the same stress, or the same environment, why are some relatively unaffected (resilient) and others more vulnerable?  What genes play a role in this difference?  What biological systems?  My work, along with that of my colleagues, has demonstrated that genetic factors play a crucial role in how individuals differ in terms of their resilience or vulnerability to early adversity. It is through studies with monkeys that my colleagues and I were able to first identify how interplay between specific genetic variation and early experiences together influence brain chemistry that influences a wide range of behaviors and aspects of health.  This finding in monkeys preceded and spurred subsequent similar studies in humans that continue to show that for most complex traits, genes do not always predict an individual’s destiny; environments have tremendous influence; and understanding individual differences requires consideration of both nature and nurture. As a result, we not only now know more about the genetic and biological underpinnings of individual differences in vulnerability to early life stress, but we also can move forward in identifying the specific ways that this occurs.

In all of these studies, our goal is to produce new understanding about how early experiences affect individuals throughout their lives.  Furthermore, like other biomedical animal research, our goal is to produce information that is relevant to human health and to address questions that are raised by challenges to human health but that cannot be addressed in studies of humans. In other words, aspects of similarity between human and nonhuman primate genetics and biological response to experiences are central to the rationale and success of the research. Studies with monkeys are a small, but important, part of the research aimed at uncovering how early experiences affect health.  As with most areas of research, new understanding and progress depend upon bridges between studies that use different populations (both human and other animal) and that draw from many different areas of expertise. Work in this area has progressed through the efforts of psychologists, neuroscientists, behaviorists, geneticists, molecular biologists, immunologists, physicians, population epidemiologists, sociologists, and others. In other words, the question is of interest from many perspectives and is addressed with interdisciplinary approaches that make it possible to build connections between findings so that the results of basic research can provide useful evidence to inform better health practices, clinical care, and public policy.

Why are these studies and findings important?  In short, because they provide us with a way to better understand the specific biological mechanisms by which early life events affect health.  As a result of decades of research in both humans and other animals, we know some of the specific biological, neural, immunological, and genetic pathways that are affected. These studies have informed progress in our understanding of the importance of early childhood experiences for lifelong health, the biological basis of mental health disorders, and the potential to change health trajectories through early identification of risk and appreciation of individual differences. Through the combined force of basic and clinical studies, we will continue to progress in understanding how genes, experiences, and biology interact. In turn, this understanding will continue to help in pinpointing mechanistic targets and shedding new light on those avenues for prevention, intervention, and treatment that improve human and animal health.

Allyson J. Bennett, Ph.D.

Part 2: University of Toronto ends live primate research – Outsourcing Controversy

 Earlier this week we wrote about the University of Toronto’s public statements concerning the end of their on-site primate research. A number of broader questions were raised by considering similar cases and articles.  Among them, what does it mean for a university to claim that it does not engage in a particular type of research?  In the case of the University of Toronto, the same article announcing the end of their primate research indicated that Univesity of Toronto researchers will continue primate studies at other institutions. 

Although this seems like a small point that concerns only a single animal research program, it is illustrative of larger questions and issues that deserve more thoughtful consideration.  One is what it means to say that a researcher, institution, or nation does or does not conduct a particular type of research. It is not at all obvious, and thus is an easy thing to manipulate in public presentation. For example, ask the following questions:

  1. Does that mean only that they do not house animals and conduct studies, or do not conduct that work independently on their own campus or within their own borders?
  2. Or does it mean that they not only do not conduct the work, but also do not support the work in any way, with collaborative effort, resources, or their approval? 
  3. Or does it mean that they not only do not conduct the work, but also do not support the work and would refuse any benefit arising from the work?

It is not only the University of Toronto ending its housing of monkeys and instead relying on collaborative opportunities in the U.S.that raises these questions. The point is also well illustrated in considering whether Canada and other countries are, or are not, involved in biomedical research with chimpanzees. One of the frequently raised points used to argue against ape research is that biomedical research with chimpanzees is conducted in only two countries — the U.S. and Gabon.  But what does that mean? And is that really true?

In fact, a recent CTV news show highlighted the fact that studies for Canadians are performed at a U.S. chimpanzee research facility funded largely by a federal grant to maintain national research resources in the U.S.  The fact that Canadians are involved in chimpanzee research is not hidden in any way, but is easy to misconstrue.

In Canada, there’s no outright ban, but no one is actually doing it.

Instead, Canadians commission studies at research facilities like the New Iberia Research Center in Louisiana, the largest facility of its type in the world. It’s home to nearly 7,000 primates, 360 of them chimpanzees.”

It is not only Canadians. Scientists from a number of other countries engage in behavioral and biomedical research collaboration involving chimpanzees housed in U.S. research institutions. Furthermore, when the Netherlands became the last European country to ban chimpanzee research almost a decade ago, it was acknowledged that because the opportunity for chimpanzee research remained in the U.S.everyone could be assured of continuation of the work without the cost, controversy, or responsibility of having to maintain the possibility within their own country.  A 2003 article highlights this point:

The end of European ape research, long sought by animal rights activists, was accelerated by a report published in 2001 by the Royal Netherlands Academy of Sciences (KNAW). It concluded that high costs and decreasing scientific need had made chimp studies all but superfluous. In rare instances where ape research will be crucial to combat a human disease, the panel said, large colonies funded by the National Institutes of Health (NIH) in the U.S. would be better equipped.

However, even in parliament itself some hypocrisy was acknowledged. Because ‘if the occasion arises’, the government quoted the KNAW report, Dutch researchers would still be free to do experiments abroad. Observed House member Bas van der Vlies (SGP): ‘Since through a back door [the Netherlands will profit from [ape research elsewhere, I see no reason for us to start beating our chests like gorillas.’”

The point made by Bas van der Vlies is a good one and one especially relevant now as the U.S. weighs legislation to end invasive chimpanzee research.  It is also more broadly relevant because it underscores why the decision of single entity, institution or nation, to end a particular type of research must be viewed within the context of the range of alternative opportunities and avenues that will serve the overall goal.  In other words, the decision to ban an avenue of research means one thing if that choice will result in a true end to the work. The same decision is inherently less risky if it is cushioned by knowledge that another institution or another country is committed to maintaining that research avenue and shouldering the accompanying burdens.

It is also true that the decision to “end” a particular kind of work is often more reflective of different types of cost considerations.  For example, note increasing outsourcing of animal research to other countries with less developed regulatory structure and lower costs. Whether that is good for animal welfare, science, research institutions, and the public is a topic of discussion among scientists and is one that should be given more thoughtful public consideration. We believe the US public is better served by advocating for reasonable improvements in animal welfare while keeping important medical research at home. The adoption of unrealistic policies and regulations that dramatically increase the cost of the work, while not significantly impacting on the well-being of the animals, will help drive the research overseas, with negative consequences on the biomedical leadership of our country and uncertain consequences for the well-being of the animals.  

So how do we tell the difference between individuals, institutions, and countries genuinely committed on moral or ethical grounds to ending particular types of research, rather than in only displacing it to others?  One piece of evidence would be for those claiming that the work is either unnecessary or unethical to also make clear that they do not simply outsource the work to other institutions or countries. 

Another would be for them to decline any benefits from the work.  For example, although we are aware of no efforts underway to preclude citizens of countries that disallowed such work to benefit from the findings or any advances made through chimpanzee biomedical research, for example hepatitis C vaccines currently under development, it would seem that this would be an easy way for people to affirm their commitment to the global picture. (Whether it should be habitat countries or a world-wide body who provides consent on behalf of the wild apes for whom conservationists are arguing should benefit from vaccines developed from research in laboratory studies of nonhuman primates might be a separate issue.)

What is gained from considering this more complicated picture?  In the case of the recent University of Toronto press coverage, a reminder that it is disingenuous at best to solicit public approval by disavowing research that the institution has conducted, has benefited from, and will continue to be involved in — albeit with the majority of risk and cost assumed by other institutions. In the case of chimpanzee research, a reminder that as long as non-U.S. interests benefit from and participate in studies conducted in the U.S., it is not accurate to claim that it is only the U.S.that sanctioned and benefited from such work.  And that includes the apes in Africa who could benefit from the vaccines developed via laboratory research in theU.S. and elsewhere.

Finally, we would advise a critical eye towards any articles in which universities, pharmaceutical companies, or countries claim that they are not engaged in primate or other animal research.  Those who have simply chosen to do the same work elsewhere or via collaboration should be clear about their involvement. Similarly, those whose work depends on data, tissues, or animal models developed by others, or at other institutions, should acknowledge a responsibility and involvement in the live animal work as well. 

Allyson J. Bennett