Tag Archives: animal testing

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)

 

Pregnancy Kits to Ebola Treatment: Medical Tests & Disease Treatments Depend on Animal Products

Antibodies Part 1

There has been considerable discussion on this website about the use of animal studies to develop new medical treatments. But some animal-derived products such as antibodies also play a crucial role in diagnostic tests for some diseases and targeted treatments for others. In the last week, antibodies hit the front pages of newspapers and websites with the news that the ZMapp serum given to 2 Americans aid workers stricken with the deadly Ebola virus was a cocktail of antibodies. Developed through research in mice, the two components of this experimental serum - ZMab and  MB-003 – had only previously been tried in monkeys, but the results were very promising. As of this writing, both aid workers’ conditions had improved.

Mice played a critical role in developing the antibodies used to treat aid workers with Ebola. Tweet this!

Antibodies are proteins the immune system produces to identify and neutralize foreign objects such as bacteria and viruses. Antibodies “recognize” specific proteins, a property that makes them highly useful for a variety of purposes. For instance, antibodies can be used in diagnostic tests to determine whether a protein associated with a particular disease or medical condition is present in a patient’s blood, urine, saliva, or tissues. The home pregnancy test is an example of a diagnostic test that relies on antibodies. These tests detect the hormone human chorionic gonadotropin, a protein that is only present during pregnancy.  Many other medical tests also utilize antibodies; a few examples are:

  1. Tests to look for heart proteins in the blood such as troponin that indicate that a heart attack has occurred.
  2. Tests for the presence of the HIV (AIDS) virus in the blood.
  3. Tests for proteins present in the blood of patients with Lupus, an autoimmune disease where the immune system attacks the body’s own tissues.

A diagram showing the characteristic Y shape of an antibody molecule. It is able to grab two of its target molecules with the ends of the two arms of the Y.

Antibodies can also be used to treat disease. Certain antibodies can neutralize toxins such as snake venom.  Other antibodies are coupled to a toxin or other chemical, such that it is delivered only to cells carrying the protein that antibody recognizes.  For example, some cancer cells generate unique proteins so antibody-coupled drugs can be used to deliver a toxic agent to the cancer cells without harming other cells in the body. Antibody therapies have been effective in treating a number of types of cancer, including Hodgkin lymphoma and non-Hodgkin lymphoma, some forms of skin cancer, and some forms of breast cancer. Now we learn that antibodies may also be effective in treating Ebola.

Unique cell surface proteins on a cancer cell, which can be detected using antibodies.

Unique cell surface proteins on a cancer cell, which can be detected using antibodies.

There are two types of antibodies used for medical diagnostics and treatments: polyclonal antibodies and monoclonal antibodies. Both require animals in their production.

Polyclonal antibodies are produced by injecting the protein of interest (or part of it, called an antigen) into an animal.   Since this is a foreign substance, the animal’s immune system reacts to it by generating antibodies to fight off the intruder. Later, samples of the animal’s blood are removed and the antibodies isolated. Larger animals such as sheep, goats, and rabbits are often used for antibody production because they have enough blood in their bodies that large blood samples can be removed without harming them. Antibodies generated using this method are called “polyclonal,” because they came from many different immune cells known as B cells or B-lymphocytes.

Process for producing polyclonal antibodies

Process for producing polyclonal antibodies

To produce monoclonal antibodies, an animal (often a mouse) is injected with the partial protein or antigen of interest. Antibody-producing cells are later isolated from the animal, often from its spleen. Fast-growing but harmless tumor cells are cultivated in the lab and fused with the isolated antibody-producing cells. This produces a new cell type called a hybridoma that can be grown in the lab. Once it is confirmed that the hybridomas are generating antibodies against the right antigen, these hybrid cells can serve as factories to grow large numbers of pure monoclonal antibodies in the lab.

From: FASEB’s Breakthroughs in Bioscience Series.  Used by permission.

Monoclonal antibody production process

Alice Ra’anan and Bill Yates

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.

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.

Tweet for Science!

We have written thousands of tweets about animal research since we opened our accounts a little over five years ago. Now we want you to help us spread our Twitter messages.

We have created a list of short, tweet-able, facts on our new “Arguments For Animal Research” page. Each fact is followed by a “Tweet This” button which will automatically open your Twitter status page, with the tweet ready to go – all you have to do is press Tweet.

Clicking the Tweet this button will bring in up page like this

Clicking the Tweet this button will bring in up page like this

These short facts were inspired by Understanding Animal Research’s successful page entitled “40 reasons why we need animals for research”. While our list is currently limited to 29 facts, we hope to continue to add to our list until we surpass even UAR’s impressive list.

Have you got ideas for some more tweetable facts? Tell us in the comments below. They need to be 102 characters (including spaces) so that we can fit a link back to the page and our Twitter after it.

Remember to shout "For Science!" when clicking the Tweet this button. Cartoon by Saturday Morning Breakfast Cereal

Remember to shout “For Science!” when clicking the Tweet this button. Cartoon by Saturday Morning Breakfast Cereal

 

So, for science, it is time to get tweeting and make sure those around you know the important role that animals play in medical research. Perhaps try to post a pro-research message each week on Twitter.

Speaking of Research

Top marks for Speaking of Research website

The industry magazine Lab Animal occasionally reviews websites applicable to it’s readers. Earlier this year, they reviewed the Speaking of Research website. The article does a good job of relaying the history behind how Speaking of Research began and some background on the people involved. They also note that SR does a lot of reporting on situations with animal extremists in Europe and North America.

The reviewer goes through each section of the website giving their readership the basic idea behind each of the sections and points out a few of the more interesting items beyond just news items, including games, quizzes and an article on Gorgon aliens.

In reviewing our “AR Undone” section (now called “Animal Rights Pseudoscience”), which responds to 19 common myths used by animal rights groups, the reviewer described SR’s responses as “authoritative, heavily references and, in some cases, linked to other websites and documents.”

“This is an excellent, informative site … It’s a must read for any animal researcher.”

The Speaking of Research website is then graded on content, appearance and usability, receiving the maximum of five out of five paws in each category.

Speaking of Research website rating

Read the full article

We are very pleased to have received such high marks from Lab Animal and truly appreciate the review.

Pamela

Kicking off a new era for neuroprosthetics, or just the warm-up?

Tonight, if everything goes according to plan, a young person will stand up in front of a global audience numbering in the hundreds of millions, walk a few paces, and kick a football.  This by itself may not seem remarkable, after all this is the opening ceremony of the World Cup, but for the Miguel Nicolelis and the more than 100 scientists on the Walk Again project – and the millions watching from around the world – this will mark the triumph of hope and dedication against adversity, for the young person in question is paraplegic.

Image: Miguel Nicolelis

Image: Miguel Nicolelis

The exoskeleton that is being used in this demonstration is a formidable technological achievement, collecting nerve signals from non-invasive EEG electrodes placed on the scalp of the operator, and converts these into commands for the exoskeleton, while sensors on the operators feet detect when they make contact with the ground and send a signal to a vibrating device sewn into the forearm of the wearer’s shirt. This feedback, which has never been incorporated into an exoskeleton before, allows the operator to control the motion of the exoskeleton more precisely. While this is not the first EEG controlled exoskeleton to be tested by paraplegic individuals, videos released by the Walk Again suggest that it has allows for far quicker and more fluent movement than existing models.

 

A late substitution

What many viewers may not know is that the use of EEG (Electroencephalography) was not part of Miguel Nicolelis’ original plan, as late as spring 2013 he was planning to use an alternative technology, implanted microelectrode grids within the cerebral cortex of the operator. Unfortunately about a year ago it became clear that the implant technology he was developing would not be ready for use in humans in time to meet the deadline of the opening ceremony of the 2014 FIFA World Cup, so the team had to fall back on the more established technique of EEG.

Is this an issue? Well, to understand this you first have to know a little about the two approaches.

EEG is a very mature technology. Its development dates back to 1875 when Richard Caton observed electrical impulses on the surface of the brains of rabbits and monkeys. In 1912 Vladimir Pravdich-Neminsky published the first EEG in dogs, and in 1924 the first EEG in human subjects was recorded by Hans Berger. It has the advantage that it doesn’t require surgery, but also serious disadvantages. The main disadvantage is that it records the combined signals from millions of neurons across wide areas of the cortex simultaneously, and this makes it difficult to separate out the signal from the noise. By contrast microclectrode implants record the individual signals from just a few neurons.

A common analogy is that EEG records the sound made by the whole orchestra, whereas microelectrode implants record individual instruments.  The result is that EEG can only be used to give relatively simple commands “move leg forward” “back” “stop” “kick” and requires a great deal of concentration by the operator. It is unlikely that the performance cam be improved upon very much. By contrast the microelectrode implants, while requiring invasive surgery, have the potential to enable much finer control over movement.

A pioneer of brain implant technology

There is no doubt that for over a decade Miguel Nicolelis and his colleagues at the Duke University Center for Neuroengineering have been among a very select group of scientists at the forefront of brain implant research, demonstrating that implanted electrodes could be used to control a simple robotic arm in rats in 1999 and in monkeys in 2000 (1). In 2012 Nicolelis highlighted the importance of animal studies to progress in the field in an article for Scientific American:

The project builds on nearly two decades of pioneering work on brain-machine interfaces at Duke—research that itself grew out of studies dating back to the 1960s, when scientists first attempted to tap into animal brains to see if a neural signal could be fed into a computer and thereby prompt a command to initiate motion in a mechanical device. Back in 1990 and throughout the first decade of this century, my Duke colleagues and I pioneered a method through which the brains of both rats and monkeys could be implanted with hundreds of hair-thin and flexible sensors, known as microwires. Over the past two decades we have shown that, once implanted, the flexible electrical prongs can detect minute electrical signals, or action potentials, generated by hundreds of individual neurons distributed throughout the animals’ frontal and parietal cortices—the regions that define a vast brain circuit responsible for the generation of voluntary movements.”

In 2008 the Duke University team showed that microelectrode arrays implanted in the cortex could be used record the neuron activity that controls the actions of leg muscles (2), and that this could be used to control the movements of robotic legs.

It was this that spurred Nicolelis to try to develop a mind-controlled exoskeleton that would be demonstrated at the World Cup opening ceremony.

Brain Machine Interfaces – from monkeys to humans.

So, if brain implant technology to control an exoskeleton wasn’t ready for 2014, when will it be ready?

The answer is probably very soon, as this approach has already been demonstrated successfully in humans.

In 2008 we discussed how Andy Schwartz and colleagues at the University of Pittsburgh had succeeded in developing a brain-machine interface system where microelectrode arrays implanted in the motor cortex of macaque monkeys allowed them to control the movement of a robotic arm with a degree of dexterity that surprised even the scientists conducting the study.

Then in 2012 we reported that Jan Scheuermann, quadraplegic for over a decade due to a spinal  degenerative disease, was able to feed herself with the help of two intracortical microelectrode arrays developed by the University of Pittsburgh team.

 

What happens now?

Tonight’s demonstration will mark the culmination of an extraordinary year-long effort by scientists and patients, but it also marks the public debut of a revolution in brain machine interface technology that has been gathering pace over the past decade, largely unnoticed by the mass media.

Miguel Nicolelis has come in for some heavy criticism for the cost of the Walk Again project, and for raising hopes too high, but the criticism is largely unfair. His team set themselves an extraordinarily ambitions target, and that they have fallen a little short is understandable. Once they have recovered from their exertions they will no doubt set to integrating the exoskeleton technology that they have developed with the implant technology that they are developing back in the lab at Duke University.

And that technology is increasingly impressive, more advanced implant systems that allow monkeys to simultaneously control two virtual arms, microelectrode arrays that allow signals from almost 2,000 individual neurons to be recorded simultaneously (3) (in contrast the already very capable BrainGate implant system used by the University of Pittsburgh team records from less than 100 individual neurons) potentially allowing for much more subtle and delicate control, and interfaces that will allow sensory information from prosthetics to be transmitted directly into the brain. We will certainly be hearing from Miguel Nicolelis and his colleagues at Duke – and their colleagues and competitors around the world - again very soon.

So tonight, as you watch the opening ceremony, remember this; for Brain Machine Interface technology as much as for the World Cup itself, this is just the warm up!

Paul Browne

p.s. And of course BMI controlled robotic exoskeletons are just one promising technology under development to help paralysed people, stem cell therapy, epidural stimulation and intraspinal microstimulation have all delivered impressive results in recent studies.

1) Wessberg J, Stambaugh CR, Kralik JD, Beck PD, Laubach M, Chapin JK, Kim J, Biggs SJ, Srinivasan MA, Nicolelis MA. “Real-time prediction of hand trajectory by ensembles of cortical neurons in primates.” Nature. 2000 Nov 16;408(6810):361-5.

2) Fitzsimmons NA, Lebedev MA, Peikon ID, Nicolelis MA. “Extracting kinematic parameters for monkey bipedal walking from cortical neuronal ensemble activity.” Front Integr Neurosci. 2009 Mar 9;3:3. doi: 10.3389/neuro.07.003.2009. eCollection 2009.

3) Schwarz DA, Lebedev MA, Hanson TL, Dimitrov DF, Lehew G, Meloy J, Rajangam S, Subramanian V, Ifft PJ, Li Z, Ramakrishnan A, Tate A, Zhuang KZ, Nicolelis MA.”Chronic, wireless recordings of large-scale brain activity in freely moving rhesus monkeys.” Nat Methods. 2014 Jun;11(6):670-6. doi: 10.1038/nmeth.2936.

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