Tag Archives: monkey

Child health benefits from studies of infant monkeys – Part 1

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

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

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

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

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

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

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

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

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

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

EXAMPLES OF PEDIATRIC RESEARCH WITH MONKEYS

Autism

Cerebral Palsy

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

Childhood Leukemia

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

Diabetes and Childhood Obesity

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

Diet

Environmental threats

HIV/AIDS

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

Huntington’s Disease

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

Lung Development and Function

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

Kidney Disease, Organ Transplants, Lupus

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


Memory Impairment

Polycystic Ovary Syndrome

Puberty Disorders

Prenatal and Mental health

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

Preterm Birth and Neonatal Outcomes

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

Regenerative Medicine

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

Stem Cells and Gene Therapy:

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

Tuberculosis and HIV

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

 

Harlow Dead, Bioethicists Outraged

harlow plaque jpeg (2)

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

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

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

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

Animal rights activists agreed, saying:

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

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

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

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

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

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

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

Statement from Psychologists:

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

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

Figure 1

Figure 1

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

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

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

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

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

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

Looking back while moving forward

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

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

Mother and infant swing final

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

 

 

 

 

 

 

 

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

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

Allyson J. Bennett, PhD

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

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

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

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

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

Spinal cord stimulation restores monkey’s ability to move paralysed hand

Today scientists at the Newcastle University Movement Laboratory announced that they have succeeded in restoring the ability to grasp and pull a lever with a paralysed hand using spinal cord stimulation. In a study undertaken in macaque monkeys they demonstrated for the first time that it is possible to restore voluntary movement in upper limb paralysis and tetraplegia, where there has been damage to the upper regions of the spinal cord that blocks the nerve pathways which pass messages to the muscles from the brain.

Macaque monkeys were key to Newcastle University paralysis breakthrough. Image: Understanding Animal Research

Macaque monkeys were key to Newcastle University paralysis breakthrough. Image: Understanding Animal Research

At this point some of you are probably thinking ‘Wait a minute, didn’t you just write about spinal stimulation being used to restore voluntary movement in paralysed human patients, why is this news?’ Well, it’s news because while both techniques use electrical stimulation they use it in very different ways, and will benefit paralysis patients in different ways.

In the study we discussed earlier this month Professor V. Reggie Edgerton and colleagues restored voluntary movement to the legs of 4 paraplegic men by using epidural stimulation to excite spinal nerve networks below the injury in a diffuse way. The method exploits the fact that spinal nerve networks are to some degree, “smart.” If certain sensory information is provided, for example pressure on a foot, the activated spinal cord can recognize this information and respond by generating a specific pattern of muscle activity, without requiring input from the brain. This activity can be enhanced with repetition and training, and also takes advantage of the fact that often even in spinal injuries that appear to be complete not all the nerve connections through the area of damage are broken, so once the network below the injury is activated these remaining nerve connections can be exploited to achieve conscious control over movement. However, epidural stimulation may not restore voluntary movement in spinal patients with most complete injuries, and it is not clear that the degree of voluntary control restored will be enough to allow all the patients treated so far to walk unaided.

Intraspinal microstimulation, the technique pioneered by the Newcastle University team led by Dr Andrew Jackson and Dr Jonas Zimmermann is very different. Rather than stimulating the spinal cord in a diffuse manner to increase activity in a non-specific way, it works by transmitting signals from the brain to specific spinal nerve circuits below the injury, in order to activate particular muscle groups (1). Working with macaque monkeys, they recorded the activity of individual nerve cells in the premotor cortex of the brain using a microwire array (similar to the brain machine interfaces used to control robot arms),  processed those signals in the computer, and then used the output from the computer to stimulate specific motor neuron circuits in the spinal cord via an implanted microelectrode array that in turn control the movement of the hand.

Closing the loop: By recording neural activity in the brain and then using this to generate a stimulation pattern in the spinal cord, Newcastle scientists were able to restore voluntary movement in a temporarily paralysed macaque. Image: Zimmerman, J.B. and Jackson A. Frontiers in Neuroscience (2014).

Closing the loop: By recording neural activity in the brain and then using this to generate a stimulation pattern in the spinal cord, Newcastle scientists were able to restore voluntary movement in a temporarily paralysed macaque. Image: Zimmerman, J.B. and Jackson A. Frontiers in Neuroscience (2014).

Intraspinal microstimulation does involve more invasive surgery than epidural stimulation, but opens up the possibility of new treatments within the next few years which could help stroke victims and upper spinal cord injuries to regain some movement in their arms and hands. Intraspinal microstimulation may also benefit patients whose lower spinal injuries are too complete for epidural stimulation to enable them to walk, and provide them with a much finer degree of control over movement that could mean the difference between being able to move their legs and being able to walk fluidly.

To conduct this study, published today in the journal Frontiers in Neuroscience, the team first trained macaque monkeys to grasp and pull a spring-loaded handle in order to obtain a treat such as a piece of dried fruit or yoghurt. The monkeys were then temporarily paralysed, using a drug that wore off after about two hours. During that time the monkey had no movement in their hand and was unable to grasp, even though most of the brain was functioning normally. But when the stimulation circuit was switched on the monkey was able to control its own arm and pull the handle.

This is an advance that rests on decades of basic research to understand the pathways within the nervous system and applied research to develop the technology required to restore function, undertaken by thousands of scientists around the world. The microwire array used to record single neuron activity in the brain was developed through studies in macaques by the Newcastle team in 2007, while more recently they undertook a series of studies which examined different patterns of microarray electrostimulation of motor neurons in the upper spinal cord to identify those that could restore voluntary movement.

Commenting on their research Dr Zimmermann  noted that:

“Animal studies such as ours are necessary to demonstrate the feasibility and safety of procedures before they can be tried in human patients, to minimise risk and maximise chance of successful outcomes.”

The next stage will be to further develop the technology to eventually have a small implant for use in patients that can then form the link between the brain and the muscles, and Dr Jackson is optimistic that this technology will be available to patients within a few years

“Much of the technology we used for this is already being used separately in patients today, and has been proven to work. We just needed to bring it all together.

“I think within five years we could have an implant which is ready for people. And what is exciting about this technology is that it would not just be useful for people with spinal injuries but also people who have suffered from a stroke and have impaired movement due to that. There are some technical challenges which we have to overcome, as there is with any new technology, but we are making good progress.”

It’s tempting to think of intraspinal microstimulation and epidural stimulation as competing techniques, but this would be a mistake as it very likely that both will be used, separately or together, depending on the nature of an individual patient’s injury. The greatest benefits for patients may be achieved when these neurostimulation techniques are combined with other approaches such as regenerative medicine/cell therapy and active rehabilitation. In 2012 Jackson and Zimmerman published a review of neural interfaces in restoring movement which examined the evidence from both animal and clinical studies, which highlighted a process known as Hebbian plasticity which can be summarised as “cells that fire together wire together”. Evidence is mounting that stimulation of the spinal cord below the site of injury does not only bypass lost nerve pathways or awaken dormant neural networks, but actually promotes the development of connections between nerves on each side of the damaged area to create new pathways along which signals can be passed from the brain to muscles in the arms or legs.

Today we congratulate Andrew Jackson and Jonas Zimmermann – and the Wellcome Trust who funded their work – on their outstanding accomplishment, but we also remember that it is not happening in isolation. The true importance of the therapy published today that it is part of a neuroscience-driven revolution that will in a few years time begin to transform the lives of many thousands of people with spinal injury.  We may not be there yet, but the destination is at last in sight.

Paul Browne

  1. Zimmermann J.B. and Jackson A.”Closed-loop control of spinal cord stimulation to restore hand function after paralysis” Frontiers in Neuroscience, Published Online 19 May 2014.

Addendum 21st May 2014: Interesting to note the comment by the animal rights group the BUAV that “Claiming, as do some apologists for animal research, that this news is worthwhile because the electrical stimulation in the monkeys ‘was used differently’ is desperate, and overlooks the importance of human-based studies and the contribution they have made.” which only shows that their ignorance (or willingness to lie about) this subject. The BUAV article also includes the usual outlandish claims about the monkeys used in this study being terrified, deprived of food and water etc. completely missing the point that this study required the active alert participation of the monkeys, so they needed to be relaxed and cooperative throughout it.

All surgery was accompanied by appropriate anesthesia and pain relief so that the monkeys would not suffer, and the monkeys used in this study were trained over a period of time through positive-reinforcement to gradually accustom them to the test apparatus used so that it caused them no distress. The monkey’s access to water was not limited, and their access to food in the study was only restricted for a few hours so that they were not too full to be interested in the food reward. While there is no doubt that this was an invasive procedure (just as the procedure will be for human patients) the BUAV’s comments completely misrepresented it.

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.

First human stem cells created through cloning…thank Mitalipov’s macaques!

Today is one of those days that will go down in medical and scientific history, the day that scientists at Oregon Health and Science University led by Professor Shoukhrat Mitalipov announced that they had successfully created pluripotent human stem cells by cloning  skin cells. This is the first time that this has been accomplished in human cells, and is a major milestone in the developing field of regenerative medicine. It is also an achievement that rests on over a decade of careful studies of somatic cell nuclear transfer (SCNT) – the cloning technique they used – in monkeys by Professor Mitalipov and his colleagues.

A donor egg moments after injection of the skin cell nucleus. Image courtesy OHSU photos

A donor egg moments after injection of the skin cell nucleus. Image courtesy OHSU photos

An article on the ONPRC News highlights the importance of research in monkeys to overcoming the barriers that had foiled previous attempts to clone primate cells.

The Mitalipov team’s success in reprogramming human skin cells came through a series of studies in both human and monkey cells. Previous unsuccessful attempts by several labs showed that human egg cells appear to be more fragile than eggs from other species. Therefore, known reprogramming methods stalled before stem cells were produced.

To solve this problem, the OHSU group studied various alternative approaches first developed in monkey cells and then applied to human cells. Through moving findings between monkey cells and human cells, the researchers were able to develop a successful method.

The key to this success was finding a way to prompt egg cells to stay in a state called “metaphase” during the nuclear transfer process. Metaphase is a stage in the cell’s natural division process (meiosis) when genetic material aligns in the middle of the cell before the cell divides. The research team found that chemically maintaining metaphase throughout the transfer process prevented the process from stalling and allowed the cells to develop and produce stem cells.”

While this announcement, coinciding with publication of a scientific paper reporting their work that is published in the prestigious journal Cell (1), was a surprise, the fact that the team was led by Professor Mitalipov was not. Professor Mitalipov is one of the leading experts in reproductive biology, cloning and stem cell biology, and it was only back in March that we discussed how the technique of spindle-chromosomal transfer that he developed to prevent mitochondrial disease had been approved for human trails by the UK’s Human Fertilisation and Embryology Authority.

The key publication by Professor Mitalipov and his colleagues was in 2007 (2) when they reported that they has successfully produced two rhesus macaque embryonic stem cell lines through SCNT.  In their 2010 commentary “Cloning of non-human primate: the “road less travelled by” “ Professor Mitalipov and his co-authors describe this study and  subsequent modifications that they made to the SCNT technique to further improve its efficiency in primates. Their many modifications covered changes to the way in which the nuclei of the cells were visualised and manipulated, changes in the conditions under which the donor nucleus and enucleated egg are fused, and precise regulation of the reactivation of the fused cell. One key innovation was the use of the coat protein from the Sendai (HVJ-E) virus to improve the efficiency of cell membrane fusion between the skin cell nucleus and egg cytoplasm while prolonging the activity of a protein called  maturation-promoting factor (MPF) that keeps the egg in the correct cell cycle stage to allow the introduced nucleus to integrate. Avoiding premature activation of cell division in the egg turned out to be even more difficult  in human cells. Initially the technique they had used successfully in macaques failed to yield stable stem cell lines from cloned human cells, and the problem appeared to be that the eggs were still activating too quickly following fusion, but as Professor Robin Lovell-Badge of the MRC National Institute for Medical Research explained to the Science Media Centre earlier today, they were able to make an additional tweak to their method, by adding a shot of caffeine to the mix.

The idea of using caffeine came from previous experiments they had performed with monkey eggs. Caffeine inhibits certain protein phosphatase enzymes that are involved in the degradation of “maturation promoting factor (MPF)”, a factor that is essential for controlling the cell cycle machinery in the egg.”

It is worth noting that they found that while they could produce embryonic stem cell lines using this technique, macaque embryos created using it failed to develop normally when implanted into female macaques, indicating that while this technique is viable for therapeutic cloning it cannot be used for reproductive cloning.

Professor Mitalipov discusses the first macaque stem cells produced through cloning in 2007.

The potential uses for stem cells produced through this therapeutic cloning technique are myriad; the fact that you can take a person’s own adult cells and convert then into pluripotent cells that can differentiate into any cell type makes them ideal for many transplant purposes, ranging from bioengineered replacement tissues to genetically engineered cell transplants to cure inherited disorders, and of course stem cells created from cloned adult cells from people with a wide range of diseases can be used to create a huge range of in vitro disease models to improve our understanding of the biological process at work and hasten the development of new therapies.

Of course there is already another technology that allows scientists to reprogram cells to a pluripotent state, in 2006 induced pluripotent stem (iPS) cell technology burst onto the scene and quickly became the methodology of choice for many stem cell researchers, with the first clinical trial in human patients expected to start later this year. Has human therapeutic cloning missed the boat?  In an excellent commentary in Nature News on today’s announcement David Cyranoski points out that there is evidence (from studies comparing  SCNT with iPS cells in mice) that cells produced through SCNT are more completely reprogrammed to an embryonic state than iPS cells. So, it is likely that each technique will have its advantages and disadvantages depending on the goal of the research…and in scientific research it is always a good idea to have more than one horse in the race.

We congratulate Professor Mitalipov and his colleagues at OHSU on another stunning scientific achievement, one that will advance medicine, and no doubt be read about by students for many years to come!

Speaking of Research

(1) Tachibana M. et al. “Human Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer” Cell, published online 15 May 2013 DOI:10.1016/j.cell.2013.05.006

2) Byrne J.A. et al. “Producing primate embryonic stem cells by somatic cell nuclear transfer.” Nature. 2007 Nov 22;450(7169):497-502. PubMed:18004281

Brain Awareness Week: The Role of Animals in Neuroscience

If you’re a regular reader of the Speaking of Research science blog you will know that we are very interested in neuroscience – in fact several of us are neuroscientists – so you won’t be surprised to learn that we have been following events during Brain Awareness Week (#brainweek on twitter).  Brain Awareness Week is a global campaign to increase public awareness of the progress and benefits of brain research that is organized every year by the Dana Foundation in partnership with over 100 research institutes, medical charities and universities around the world.

We thought it was a good opportunity to see what new resources on the use of animals in brain research are available from key organizations involved in Brain Awareness Week, and BrainFacts.org – a public information initiative whose launch we reported last May – delivered the goods. Brainfacts.org have been busy since we last reviewed their website, and their pages on animal research in neuroscience have grown into an excellent resource that covers a wide variety of topics including how animal research is planned, undertaken and regulated, and case studies of where animal research has made key contributions to advancing neuroscience.  Among the resources are articles written by neuroscientists and excellent videos.

The contribution of animal research to brain research has been highlighted by several recent media reports of important advances in brain science. These have ranged from a study in mice that demonstrated that high salt intake can increase the activity of a class or immune cells known as Th17 cells that have been implicated  in the early development autoimmune disorders such as Multiple Sclerosis, to a study that showed how brain implants could enable rats to sense infra red light with great potential for the development of sensory prosthetics to complement recent advances on the control of robotic limbs, to the identification in rats of a protein that plays a key role in enabling some brain cells to survive following a stroke and may lead to new therapies.

Today there was another great piece of research (1) to report as a team of stem cell researchers at UW Madison led by Professor Su-Chun Zhang  and Professor Marina Emborg chalked up another first, demonstrating for the first time that it is possible to transplant neurons generated using iPS cell techniques from a monkey’s own skin cells into their brain, where they develop into several types of mature brain cell.

GFR labelled neuron. Image courtesy of Yan Liu and Su-Chun Zhang, Waisman Center

GFR labelled neuron. Image courtesy of Yan Liu and Su-Chun Zhang, Waisman Center

The success of this study is enormously promising for the future of personalized stem cell therapies for Parkinson’s disease, stroke and other brain disorders, as the report in the University of Wisconsin Madison News makes clear.

Because the cells were derived from adult cells in each monkey’s skin, the experiment is a proof-of-principle for the concept of personalized medicine, where treatments are designed for each individual.

This neuron, created in the Su-Chun Zhang lab at the University of Wisconsin–Madison, makes dopamine, a neurotransmitter involved in normal movement. The cell originated in an induced pluripotent stem cell, which derive from adult tissues. Similar neurons survived and integrated normally after transplant into monkey brains—as a proof of principle that personalized medicine may one day treat Parkinson’s disease.

And since the skin cells were not “foreign” tissue, there were no signs of immune rejection — potentially a major problem with cell transplants. “When you look at the brain, you cannot tell that it is a graft,” says senior author Su-Chun Zhang, a professor of neuroscience at the University of Wisconsin-Madison. “Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope.”

Rhesus macaques play a key role in brain research...

Rhesus macaques play a key role in brain research…

It’s interesting to note that the development of green fluorescent protein (GFP) labelling that played a crucial role in allowing Profs. Zhang and Emborg’s team to distinguish transplanted cells from host cells in the monkey brain was made possible by research in the nematode worm Caenorhabditis elegans , a tiny worm that itself plays a perhaps surprisingly important role neuroscience.

...as do nematode worms!

…as do nematode worms!

These discoveries and advances impact on many areas of brain research, and have the potential to benefit those suffering from a wide variety of brain diseases and injuries, so it is fitting that in Brain Awareness week we salute the researchers whose ingenuity and hard work makes them possible.

Speaking of Research

1) Marina E. Emborg, Yan Liu, Jiajie Xi, Xiaoqing Zhang, Yingnan Yin, Jianfeng Lu, Valerie Joers, Christine Swanson, James E. Holden, Su-Chun Zhang “Induced Pluripotent Stem Cell-Derived Neural Cells Survive and Mature in the Nonhuman Primate Brain” Cell Reports, Published online 14 March 2013, DOI: 10.1016/j.celrep.2013.02.016

Safeguarding medical progress means supporting animal transport

The following guest post is from Eric Raemdonck, who has a background in the aviation transport industry. Eric recently launched the Advancing Animal Research blog, whose purpose is to ” establish bridges between the aviation world, the life sciences, health care, pharmaceutical, animal research industries,  educational institutions and their  affiliate or representative associations as well as Governmental organisations”.

Facing a virulent campaign by animal rights activists, a growing number of airlines around the world now refuse to transport certain species of research animals, chiefly non-human primates (NHPs).  This worrisome development not only threatens medical progress, but also puts the health and welfare of those animals at risk.

Animal rights extremists are trying to put a chokehold on the airline industry’s service to biomedical research via social media write-in campaigns, demonstrations at airline offices around the world, and even protests at the homes of airline executives.

Everyone concerned with the future of biomedical research must actively reject these tactics of intimidation and harassment, and stand in support of those airlines that continue to transport animals safely, comfortably and quickly to where they are needed to advance the quest for treatments and cures.

As a former secretary of the International Air Transportation Association’s Live Animals and Perishables Board, I can attest that airlines that transport animals employ highly skilled specialists and focus on finding the quickest routes possible to ensure the health of the animals en route to research institutions.

Animal research remains a small but vital component of the research and development process for new medicines.  Without the ability to move research models from one country to another, or from breeder to research institution, crucial scientific research seeking new treatments for heart disease, cancer, spinal cord injuries, epilepsy and numerous other ills could come to a halt.

As things stand, almost every commercial airline in the world, save but a handful, now refuses to transport non-human primates for research, even though many have policies in place allowing for the transport of NHPs for other purposes.

The United Kingdom has perhaps the most stringent laws and oversight on the use of animals in research, yet no U.K.-based air carrier is willing to transport NHPs destined for research into the country.  In the United States,  very few commercial carriers remain to do the job.  Airlines of other nations, upon which research institutions are increasingly relying for their animal transportation needs, are also feeling the pressure from activists and some have already given way to demands that they no longer carry laboratory animals.

Why is this happening?  Why are airlines targets?

As research institutions themselves become increasingly adept at blunting the impact of activists’ campaigns, leaders in the animal rights movement are now looking toward those companies with whom the research community works or relies upon for services.  ‘Stop research animal transportation and you stop animal research’ is the thinking behind the actions of animal rights extremists in targeting airlines.

Animal extremist campaigns against the airlines, such as the British Union for the Abolition of Vivisection’s Primate Cargo Cruelty and various Internet petitions attract thousands of signatures.   PETA also has an action alert on its web site, calling on readers to “Ask Airlines to Stop Shipping Monkeys to Be Tortured.”

Social media tools such as Facebook, YouTube and Twitter are used extensively in these campaigns to solicit support, donations, and calls for immediate action to change airline policy to include a ‘no-fly’ regulation for research animals.

The message to their followers is clear: only a few airlines remain, and by working together activists can put a stop to this practice.  The message to the airlines is equally clear: change your transportation policy or we will tell the public to no longer fly with you.  Through email campaigns alone,  some lasting only a few hours, several airlines have made the decision to stop transporting research animals.  This was done without any consultation with the companies involved and without  any notice.  This has occurred while airlines continue to transport animals for other industries and passengers.

Straightforward security steps taken by airlines and research institutions alike can blunt the impact of many of the activists’ campaign tactics, and protect the airlines and others involved in the global supply chain. Additionally, there are steps that concerned individuals may take to help ensure that safe and humane transport of laboratory animals will continue.

1/Stand by the airline industry and voice your support through associations such as AALAS – American Association for Laboratory Animal Science (www.aalas.org),   CALAS—Canadian Association for Laboratory Animal Science (www.calas-acsal.org) ICLAS – International Council for Laboratory Animal Science (www.iclas.org) and other scientific and professional organizations that advocate for both biomedical research and laboratory animal welfare.  Ensure that the issue of protecting humane research animal transportation is on their agendas.

2/Ensure that your elected officials appreciate the importance of animal research, and ask them to look into the problem of the declining pool of available airlines for the continued transport of research animals.

3/Inform others as to the humane and judicious nature of animal research, and why it is still needed.  Underscore its achievements and the medical progress to which it has contributed.  Information and links to resources to get you started are here on the Speaking of Research site, and on my Advancing Animal Research blog at http://research4drugdiscovery.blogspot.ca/

Eric Raemdonck