Tag Archives: primate

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.

Understanding addiction: NIDA article highlights contribution of animal research

Professor David Jentsch is a highly respected UCLA neuroscientist who specialises in the study of addiction, one of the most widespread and serious medical problems in our society today. Sadly, by devoting his career to finding out how to better treat a condition that ruins – and all too often ends – many millions of lives in the USA and around the world every year, David has found himself, his colleagues, and his friends and neighbors under attack from animal rights extremists whose tactics have ranged from harassment, stalking and intimidation, to arson and violence.

Did this extremist campaign persuade David to abandon his research?

No chance!

In 2009 David responded to the extremist campaign against him and his colleagues by helping to found Pro-Test for Science to campaign for science and against animal rights extremism at UCLA, and has been a key contributor to Speaking of Research, writing articles on the role of animal studies in the development of new therapies for addiction, what his studies on rodents and vervet monkeys involve, and how addiction research can help us to understand obesity.

Vervet monkeys involved in David Jentsch's research program live in outdoor social groups to ensure optimal welfare

Vervet monkeys involved in David Jentsch’s research program live in outdoor social groups to ensure optimal welfare

This week the NIH’s National institute on Drug Abuse (NIDA) has published an excellent article on David’s ongoing research entitled  “Methamphetamine Alters Brain Structures, Impairs Mental Flexibility”, which highlights the importance of non-human primate research in identifying how addiction alters the brain and why some individuals are more prone to develop damaging methamphetamine dependency than others. You can read the article in full here.

Human chronic methamphetamine users have been shown to differ from nonusers in the same ways that the post-exposure monkeys differed from their pre-exposure selves. The researchers’ use of monkeys as study subjects enabled them to address a question that human studies cannot: Did the drug cause those differences, or were they present before the individuals initiated use of the drug? The study results strongly suggest that the drug is significantly, if not wholly, responsible”

This knowledge of how drug use disrupts brain function will be crucial to development effective clinical interventions for methamphetamine addiction, and the huge scale and devastating impact of methamphetamine use makes it clear that such interventions are desperately needed, as David highlights in the article’s conclusion.

Methamphetamine dependence is currently a problem with no good medical treatments, when you say a disease like methamphetamine dependence is costly, it’s not just costing money, but lives, productivity, happiness, and joy. Its impact bleeds through families and society.”

At a time when animal rights activists in many countries are pushing to ban addiction research involving animals, the NIDA article on the work of David and his colleagues shows why this work is so valuable, and just what would be lost if animal rights extremists are allowed to have their way.

Speaking of Research

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.

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.

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.

Professor Doudet vindicated as investigation rejects animal rights allegations.

Two weeks ago we discussed the targeting by Canadian animal rights group Stop UBC Animal Research (STOP) of University of British Columbia scientist Professor Doris Doudet. STOP alleged that Prof. Doudet had performed experiments on monkeys without the approval of the UBC Animal Care Committee, and then lied in a scientific paper to cover her tracks, though as we reported at the time their allegations of professional misconduct against her were based on a deliberate misrepresentation of the facts. We are now happy – though in the circumstances not very surprised – to learn that an independent investigation of Prof. Doudet’s work has dismissed the allegations made against her.

According to today’s report in the Vancouver Sun, the Canadian Council on Animal Care (CCAC) carried out a detailed review of the research undertaken by Prof. Doudet’s team, and found:

no evidence to support allegations of animal cruelty against a University of British Columbia research team related to the deaths of four macaque monkeys.”

An earlier report on CTV news adds that the CCAC investigation:

found no evidence to support allegations that UBC was subjecting monkeys to cruel research experiments that were not overseen by the UBC Animal Care Committee.”

The letter from the CCAC to STOP detailing the conclusions of their investigation can be read here.

We asked Prof Doudet her views about this week’s developments, welcoming the news she said:

It is distressing to be wrongly accused, but the truth prevailed and we are all grateful for it.  MPTP always had unexpected effects, not only in monkeys but in the humans who unknowingly injected themselves with it: Out of the more than 100 people who were exposed to the drug in the early 80s, only a handful developed severe parkinsonism and there is no way to predict who will have such a severe negative response. But the MPTP primate model and the knowledge gained from it have played an important part in the basic understanding of physiological mechanisms involved in the disease, and this has been key to the development of many therapies for Parkinson’s disease, including DBS and the current testing of many gene therapies.”

We too welcome this news, though we wonder whether a formal investigation was really required to confirm what had been patently obvious right from the start.

Speaking of Research

End of Primate Research at the University of Toronto?

Intended or not, comments by a university administrator and veterinarian in some Canadian news articles last week likely gave some readers a distorted view not only of the status of research at the University of Toronto, but of animal research more broadly. A pair of articles reported that primate research at the U of T had ended.  In one titled “University of Toronto stops research on live monkeys” a university official explains:

“They were our very last ‘non-human’ primates and we have no intention of using any more. Technology now lets us get the same information from smaller animals,” said Peter Lewis, the U of T’s associate vice-president of research.”

Except that the press coverage also says that the U of T scientist Prof. Barry Sessle, whose highly regarded research orofacial pain and neuromuscular function and dysfunction straddles both laboratory animal research and clinical research involving human subjects, will “continue to do monkey studies in partnership with a lab in Chicago.”  We are also aware that University of Toronto researchers undertake primate research even closer to home at another research institute in Toronto. Does the U of T administration exclude their own faculty from the “we” in the “we have no intention of using any more [primates]” statement?
In an article headlined “With last monkeys dead, U of T sees a shift in animal research,” the university’s veterinarian adds his view of the need for primates in research.

“Across the country, Dr. Harapa has watched the appetite for research primates waning. Their cost and availability are factors, and universities do feel some ethical pressure, he said. “But the main reason is that people have just adopted other animals for their experimental needs – mostly rats and mice.

Comments by Lewis and Harapa raise a number of questions. Foremost, we wonder whether U of T might want to correct any possible misimpression that their comments apply only to their own research programs, which are apparently now suited by a restricted range of animal models?  For example, Lewis’ statement that: “Technology now lets us get the same information from smaller animals.” obviously applies to a subdomain of study, as do Harapa’s comments:

“We stopped using dogs and cats a few years ago too. We can do so much research now by genetically modifying a mouse,” said Harapa. “Under a sector microscope you would hardly know the difference between a human heart and that of a mouse.

While these thoughts may be relevant to specific work at U of T, they are obviously not meant to be applicable to the broad set of research questions under study elsewhere.  We are well aware that genetically modified mice and rats are an increasingly powerful tool for biomedical research, but they cannot yet replace species such as dogs, pigs and macaques in all necessary studies.

Some institutions may find it tempting to dodge public controversy by allowing a perception that the absence of on-site animal research reflects an institution’s commitment to not participate, support, or benefit from that work. Encouraging that public perception is an easy path to gain favor with animal activists and other opponents. But this is not a good path, if for no other reason than the fact that solving a research problem involves a range of animal models at various points in time. It is disingenuous to deny the value of research with a particular species because your institution has decided to discontinue working with that species. If nothing else, those inclined to dodge should consider that they are deriving benefit from the work of their colleagues at the institutions still willing to assume the risk and responsibility. That argues in favor of acknowledging the value of the work in your public statements.

It is unfortunate that these articles contain no comments by either Harapa or Lewis that might improve public appreciation of the value of a range of animal models, or any statement of support for the valuable research undertaken by Prof. Sessle, whose primate studies drew the attention of animal rights activists.

Allyson Bennett

Addendum 2012/03/12:

In a statement to the science journal Nature  UT associate vice-president of research Peter Lewis clarified some of his earlier statements, stating that:

There are many types of research that require the use of non-human primates. Our researchers are not engaged in any of them at the moment. If a proposed research project at [the University of Toronto] required the use of non-human primates and was scientifically and ethically justified, then we would endeavor to support it.”

While we welcome this statement we are less than totally satisfied by it, as we are aware of several research programs under the direction of UT researchers  that are very likely to require the use of non-human primates in the near future, including the stroke research discussed in the Nature News article and also research on other neurological conditions such as Parkinson’s disease. It may be the case that no research protocols involving non-human primates  are currently before the UT Office of Research Ethics, but there is every chance that in the coming months one or more will be submitted, even if the actual work will be done at the labs of an affiliated institute such as the Toronto Western Research Institute rather than UT itself. Will UT then issue another statement further clarifying their position?

Compliance at Work

One of the core principles at SR is that animal research should be conducted with the utmost care, responsibility and respect towards the animals.  All personnel involved in animal research should strictly follow the pertinent guidelines, regulations and laws.  Unfortunately, as in all human endeavors, there are isolated individuals who sometimes fail to adhere to established principles. The compliance system exists to detect such instances and take corrective action.

Recently, the USDA confirmed that an individual researcher at the University of Rochester was in violation of the Animal Welfare Act. The University was the first to discover the problem, reporting it to the USDA (the institution in charge of ensuring that the Animal Welfare Act is implemented), who confirmed the findings of non-compliance. The USDA were quick to identify the violations and publish the results, publicly, on their website.  This is an example of the compliance system at work.

As expected, animal rights groups, such as SAEN (warning: AR website), have used this opportunity to attack animal research, promising to “Expos[e] the truth to wipe out animal experimentation”. However, there are two important facts to consider:

  1. This was an isolated incident; and
  2. the system in place to deal with such incidents, responded appropriately.

We say the system responded appropriately in citing the University because the facts that are apparent about this case strongly indicate that this was an unacceptable deviation from established norms for the care and use of non-human primates in biomedical research laboratories.

With very few exceptions (for example, the need to restrict food in advance of anesthesia), monkeys must be fed every single day, with no exceptions or mistakes being permissible. What is worse, deprivation of food for multiple, consecutive days certainly produces profound distress in an animal that should have been identified by the combination of researchers, veterinary care providers and animal husbandry staff who were supposed to be carefully monitoring these animals every day. These animals were failed by the people who were responsible for their health and well-being. We hope that the Institutional Animal Care and Use Committee that supervises these research activities have taken comprehensive measures to ensure that an event like this never happens again.

Speaking of Research must condemn the actions the researcher in question.  Such behavior undermines the hard work that the rest of the animal research community does to ensure the highest standards of animal welfare. Furthermore, we commend the USDA and the University of Rochester for the actions they have taken to ensure that such violations do not occur ever again.

The success of our training, accreditation and compliance systems is not only measured by their ability to detect and correct isolated violations, but also in preventing them from occurring in the first place.   Here, we believe it is imperative to recognize the tens of thousands of persons that conduct their research with the utmost care, responsibility and respect towards the animals.