Tag Archives: animal research

Stem cell therapy allows blind to see again, thanks to animal research

A team of scientists led by stem cell pioneer Professor Robert Lanza has reported today in the Lancet (1) the first evidence for the long-term safety of  retinal pigment epithelial (RPE) cells derived from human embryonic stem cells (hESCs) in patients who took part in a trial undertaken in four centres in the US. substantial improvements in vision were also recorded in almost half the treated patients, compared to no improvement in untreated patients.

This is the first time that clinical benefits have been demonstrated in the medium to long term in patients with any disese treated with hESC-derived cells, and is a major milestone in the development of the field of regenerative medicine. It’s an achievement that is due to many years of animal research.

Image:UCL/PA

Image:UCL/PA

The trial focused on 18 patients with two different types of macular degeneration,  Stargardt’s macular dystrophy and nine with dry atrophic age-related macular degeneration, that are common causes of blindness in adults and children and for which no effective treatments are currently available.

Nine patients with Stargardt’s macular dystrophy and nine with dry atrophic age-related macular degeneration received injections of 50,000 to 150,000 RPE cells behind the retina of their worst-affected eye. Robert Lanza, adjunct Professor at the Institute for Regenerative Medicine, Wake Forest University School of Medicine and Chief Scientific Officer at Advanced Cell Technology who funded the trial, describes the results:

The vision of most patients improved after transplantation of the cells. Overall, the vision of the patients improved by about three lines on the standard visual acuity chart, whereas the untreated fellow eyes did not show similar improvements in visual acuity. The patients also reported notable improvements in their general and peripheral vision, as well as in near and distance activities”

Professor Steven Shwartz, who led the team at the Jules Stein Eye Institute that took part in this trial, noted how important this result is to both the patients in this trial and the field of hESC-derived stem cell medicine.

Our results suggest the safety and promise of hESCs to alter progressive vision loss in people with degenerative diseases and mark an exciting step towards using hESC-derived stem cells as a safe source of cells for the treatment of various medical disorders requiring tissue repair or replacement,

You can listen to interviews with Steven Schwartz and several of the participants in this clinical trial in an NPR broadcast here.

In 2011 we discussed the launch of trials of these hESC-derived RPE cells, including some of those whose results are reported today,  at Moorfields Eye Hospital in London and the Jules Stein Eye Institute at UCLA. A paper published in the Journal Stem Cells in 2009 showed how studies in rodent models retinal degerneration paved the way for these trials by demonstrating that RPE cells derived from hESCs were safe and could restore vision:

Assessments of safety and efficacy are crucial before human ESC (hESC) therapies can move into the clinic. Two important early potential hESC applications are the use of retinal pigment epithelium (RPE) for the treatment of age-related macular degeneration and Stargardt disease, an untreatable form of macular dystrophy that leads to early-onset blindness. Here we show long-term functional rescue using hESC-derived RPE in both the RCS rat and Elov14 mouse, which are animal models of retinal degeneration and Stargardt, respectively. Good Manufacturing Practice-compliant hESC-RPE survived subretinal transplantation in RCS rats for prolonged periods (>220 days). The cells sustained visual function and photoreceptor integrity in a dose-dependent fashion without teratoma formation or untoward pathological reactions. Near-normal functional measurements were recorded at >60 days survival in RCS rats. To further address safety concerns, a Good Laboratory Practice-compliant study was carried out in the NIH III immune-deficient mouse model. Long-term data (spanning the life of the animals) showed no gross or microscopic evidence of teratoma/tumor formation after subretinal hESC-RPE transplantation. These results suggest that hESCs could serve as a potentially safe and inexhaustible source of RPE for the efficacious treatment of a range of retinal degenerative diseases.”

This work – and earlier studies of RPE cells derived from ESCs – built on decades of basic stem cell research, starting with the pioneering work of Gail Martin, Matthew Kaufman and Martin Evans in mice, and the subsequent derivation of ESCs in macaques and then humans by James Thompson and colleagues at the university of Wisconsin- Madison.

Laboratory Mice are the most common species used in research

The humble mouse has played a key role in the development of stem cell medicine.

Today’s announcement is a major milestone in regenerative medicine, and one that id justifiably being celebrated, but we should also remember the many years of careful research that has led up to this moment. As with many medical advances much of the early research on embryonic stem cells was undertaken without any immediate clinical application in mind, but it nevertheless created the knowledge that is now driving an important emerging field of medicine. This is a lesson we need to remember when we donate to charities, when we discuss the importance of research with others, and most of all when we go to the ballot box!

Paul Browne

1) Schwartz SD et al. “Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies” Lancet published onlin3 15 October 2014. Link.

2) Lu B et al. “Long-term safety and function of RPE from human embryonic stem cells in preclinical models of macular degeneration.”
Stem Cells. 2009 Sep;27(9):2126-35. doi: 10.1002/stem.149.

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)

 

Nobel Prizewinner John O’Keefe warns of threat to science from overly restrictive animal research and immigration rules

In an interview with the BBC yesterday 2014 Nobel laureate  John O Keefe has warned of the dangers posed by regulations that restrict animal research and the free movement of scientists across borders.

“It is an incontrovertible fact that if we want to make progress in basic areas of medicine and biology we are going to have to use animals.

“There is a worry that the whole regulatory system might begin to be too difficult, it might be constrictive.”

Professof John O'Keefe, 2014 Nobel Laureate in Medicine or Physiology. Image: David Bishop, UCL.

Professof John O’Keefe, 2014 Nobel Laureate in Medicine or Physiology. Image: David Bishop, UCL.

His concerns are well founded. Our post yesterday discussed the key role of recordings of single neuron activity in rats to the discoveries made by John O’Keefe, May-Britt Moser and Edvard Moser. The post also discusses two other advances made through basic research in animals whose impact in medicine has been recognized by awards, deep brain stimulation in Parkinson’s disease, and infant massage in preterm babies. Nevertheless in many countries around the world there is increasing pressure from animal rights groups on politicians to restrict, and even ban, animal research. Scientists have a key role to play in ensuring that important basic and translational research, and we welcome John O’Keefe’s statement,  it’s an example that scientists around the world should follow.

The issue of immigration is another important one for science, and John O’Keefe knows this better than most. Born in New York, he completed his PhD at the University on Montreal under the supervision of renowned Psychologist Ronald Melzack, before moving to the UK to undertake a postdoctoral fellowship, and credits the research environment in the UK and at UCL for giving him the opportunity to make his discoveries, and later May-Britt and Edvard Moser spent time as postdoctoral researchers at his laboratory.  For science to flourish scientists must be free to travel to centres of excellence in other countries, to learn skills and establish collaborations that are key to success in many fields of research in the 21st century. This freedom is under threat from narrow-minded isolationism in many countries, for example earlier this year Switzerland found its position as a leading scientific nation undermined by a new immigration law that threatens its ability to recruit talented scientists from abroad, and has disrupted its participation in a key EU research programmes.

John O’Keefe’s warning is a reminder that the threats to scientific research can come from many directions, and of the need for supporters of science to be ready to take action to defend the freedoms on which science is built.

Speaking of Research

Why Animal Research-based Criticisms of the Ice Bucket Challenge are Misguided

The following is a guest post by Caitlin Aamodt, a neuroscience graduate student at the University of California, Los Angeles.

Amyotrophic Lateral Sclerosis (ALS) is a debilitating motor neuron disease that progressively destroys the neurons required for voluntary movement, speech, and eventually breathing and swallowing, killing patients in just three to five years.  Through the Ice Bucket Challenge the ALS Foundation has raised over $100 million in funding while simultaneously providing a platform for over three million people to voice their support for scientific research.  But the wildly successful social media campaign was not without its critics.  Some were hesitant about the idea of wasting clean water, a luxury that isn’t afforded to many parts of the world and one that is growing more and more precious as the drought in the West worsens.  Others, particularly religious leaders, were unhappy with researchers’ use of embryonic stem cells, citing a conflict with their belief that life begins at conception.  But one of the most common criticisms, and the most dangerous, is that organizations that fund animal research should not be supported.

Aamodt Article Fig

Pete Frates, for whom the ice bucket challenge was created.

Initially it may seem harmless.  One might see a post about it in their Facebook feed and think, “Oh, so-and-so really has a soft spot for animals,” and then continue on without giving much thought to the implications of what they just read.  The issue can become murky, since the vast majority of people support the idea that animal abuse is wrong.  However, animal research is not abuse, and it is dangerous to voice opposition without considering the implications of what that really means.

What would one have to do to really extract him- or herself from taking advantage of the benefits of animal research?  To start this would involve declining any and all vaccinations, accepting vulnerability to dying from disease.  This actually extends to any intravenous injection, so all life saving therapies involving this simple procedure would be eliminated.  Death from blood loss due to a traumatic injury could not be prevented by a blood transfusion.  All surgeries would be off the table.  The basic antibiotics we take for granted would no longer be an option. No insulin treatment for diabetics.  No dialysis for those suffering from kidney failure.  Any hope for those suffering from breast cancer or depression would be lost.  Even the most recent medical advances, such as transplanting organs engineered from a patient’s own stem cells, would all be unavailable.  With these and countless other treatments directly resulting from animal research you would think that these activists would be sending us thank you cards instead of blind criticisms!

Could this hypocrisy be mitigated by any validity to their claims?  Absolutely- except for the fact that these concerns have already been addressed and protections already put in place.  Researchers and lay people alike want to ensure that no animal needlessly suffers.  Multiple oversight committees govern research activities conducted at universities. All federally funded research centers have an Institutional Animal Care and Use Committee (IACUC) made up of experts in the field as well as lay people to ensure that experimental design is deemed humane by both scientists and people unfamiliar with research practices alike.  Considerations include alleviating pain and side effects, minimizing the number of animals used, ensuring that animals are used appropriately and only when necessary, overseeing their healthcare and living facilities, and even requiring that a plan be in place to save the animals in the event of a natural disaster.  Research animals should be respected, and in keeping with that ethical consideration IACUC and many other oversight organizations ensure that they receive the best possible care.

The general perception of animal rights activists is that they are well-intentioned, if uninformed, individuals who are exercising their First Amendment right to protest whatever they want.  Unfortunately the reality is that their members include dangerous extremists willing to harass and carry out attacks on researchers.  At UCLA researchers are all too familiar with anti-research terrorism.  In 2006, 2007, and 2008 firebombs were planted at the homes of UCLA scientists.  In 2007 Dr. Edythe London’s home was flooded, along with a threatening note.  Dr. David Jentsch’s car was set on fire while he was in his home in 2009.  The terrorists also left a note filled with razorblades detailing a fantasy about sneaking up on him and slitting his throat.  On-going harassment includes yelling slurs at scientists outside their home.  In 2011 they referred to the daughter of holocaust survivors as “Hitler with a cunt,” and directed the homophobic slur “You cocksucking bastard” among others toward another researcher.  These extremists even directed their terrorism toward the children of Dr. Dario Ringach.  In 2010 they put on masks and banged on his children’s windows to terrify them and sent letters threatening to target them at school.

In the words of Dr. David Jentsch, “The anger generated by their failure to make a persuasive argument to the public, amplified by their sense of self-righteousness, is sufficient to convince them they are entitled to use violence to achieve their goals.”  We can no longer afford to be silent.  Animal research saves lives.  Anybody who reaps the benefits of animal research while claiming to oppose it should be made aware of this hypocrisy.  It is also essential that we banish the myth that modern-day biomedical research animals are tortured.  There are many layers of protections in place to ensure that they receive the best possible care.  There is no excuse for terrorism.  Nobody should fear for their lives or that of their children, especially researchers who dedicate their lives to scientific progress.  Now is the time to disseminate the truth about animal research and stand up for the welfare of all biomedical researchers.  The next time you hear someone claim to oppose the ice bucket challenge on the grounds of animal research be sure to speak up and educate them.  Society needs to hear the voices of the scientifically literate.  Don’t let them be drown out by ignorance.

Caitlin Aamodt
UCLA neuroscience graduate student

References

[1]  http://www.alsa.org/about-als/what-is-als.html
[2] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4137497/
[3] http://www.alsa.org/news/media/press-releases/ice-bucket-challenge-082914.html
[4] http://www.refinery29.com/2014/08/73360/grimes-als-ice-bucket-challenge-peta
[5] http://www.animalresearch.info/en/medical-advances/timeline/
[6] http://grants.nih.gov/grants/olaw/tutorial/iacuc.htm
[7] http://unlikelyactivist.com/2014/02/03/join-pro-test-for-science-to-end-the-age-of-terror/
[8] http://unlikelyactivist.files.wordpress.com/2014/02/arson.jpg
[9] http://scienceblogs.com/ethicsandscience/2010/02/23/time-to-get-mad-time-to-speak/
[10] http://fbresearch.org/als-ice-bucket-challenge-for-a-cure/

Urge the U. S. Surgeon General to Voice Support for Animal Research

Your scientific activism is only a click away.

A new petition in Change.org urges the U. S. Surgeon General, Rear Admiral Boris D. Lushniak, to voice support for the humane, and regulated use of animals in medical research.  It reads:

There is a growing pressure from animal rights organizations that would deny Americans the health benefits derived from the use of animals in medical research.

Opponents of animal research represent a small minority of the population, but they engage in misleading, visible and vocal campaigns that can impact the ability of scientists to conduct medical research with animals.

The scientific consensus is clear — recent polls by Nature Magazine and the Pew Research Center show that 92% of scientists believe that animal research remains essential to the advancement of biomedical sciences.

We call on the U. S. Surgeon General to publicly recognize the past contributions of the humane use of animals in research that has improved the well-being of human and non-human animals, and to stress the essential role they continue to play in advancing medical science and knowledge.

By acting on this petition the U. S. Surgeon General would be publicly reaffirming the scientific consensus and join the many medical and scientific organizations that have already adopted resolutions in support of the responsible and regulated use of animals in research.  These include the American Medical Association, the American Academy of Neurology, the American Heart Association, the American Veterinary Medical  Association, the Society for Neuroscience and the Federation of American Societies for Experimental Biology, among others.

Please consider signing the petition and share it with your colleagues and friends!

Thank you!

The marchers begin to walk towards the center of the UCLA

Ask the U. S. Surgeon General to Voice Support for Animal Research!

Crash course in medical history

Opponents of animal research often portray two of the pioneers of experimental physiology, François Magendie (1783-1855) and his student Claude Bernard (1813-1878), as deranged, vicious, and sadistic individuals who derived pleasure in harming animals. Moral philosophers Peter Singer and Lori Gruen convey this sort of message in their book “Animal Liberation: A graphic guide”.

Portrayal of Claude Bernard in Singer and Gruen's book

Portrayal of Claude Bernard in Singer and Gruen’s book

A quick look at how Claude Bernard’s face is portrayed in their book is sufficient to get a sense of Singer and Gruen’s feelings towards scientists who engage in animal research. The peculiar use of quotes around ‘experiment’ in the caption suggests they believe the work did not qualify as legitimate scientific research, nor that it could contribute any benefits to mankind. Such view fails to consider the historical context of their experiments.  In particular, one could ask how were human patients treated by their physicians of the time.

Here is a brief summary of 19th century medicine —

The theory of counter-irritation was in vogue. To counter-irritate basically meant causing additional wounds to the patient as a form of treatment. One technique involved inserting inflamed limbs were into giant anthills. More convenient was produce large blisters by means of a fire iron or acid. In 1824, an article in the Lancet by Dr. Abernathy suggested that a 1 foot square blister was probably a bit too large — several small blisters were indicated instead.  A third method of counter-irritation involved making a saw-shaped wound and inserting dried peas or beans into it. The doctor would then ensure the wound remained open, keeping it from healing, from weeks to months, replacing the peas and/or beans as necessary.

Leeches were used in vast quantities and for many purposes.  Physicians would lower leeches down patient’s throats.  Hundreds of them would be used to bleed a man’s testicle over days. Leeches were also applied to the vagina to relieve “sexual excitement” and, not to discard other orifices, doctors would push them up the anus. It was noted that during these procedures there was always a possibility that some of the leeches would get lost inside the patient body which, according to the physicians of the time, resulted in  “very annoying accidents”.

What about mental disease? A common treatment involved psychiatrists spinning patients in centrifuge-like machines a hundred of times per minute. This is how unruly patients came to understand the authority of the doctor, with one of them asserting that the more lively his intimidation towards the apparatus the more charitable the effects of the therapy.”  

rush

Benjamin Rush’s tranquilizer chair

Benjamin Rush, one of the founding fathers and signatories of the Declaration of Independence, adopted some of these same methods and developed them further.  He would pour acid on his patients backs and cut them with knives to allow the discharge “form the neighborhood of the brain”.  Rush also developed the famous “tranquilizer chair” where patients were restrained for up to entire days — the chair had a convenient hole for defecation at the bottom.

Bloodletting was used to treat a number of ailments.  It also often led to death.  One famous incident involves George Washington, who in 1799 suffered from a bad sore throat and died shortly after a visit by three different doctors who, altogether, took about half of his blood volume. The famous medical journal The Lancet derives its name from the tool used in these procedures.

Given Singer and Gruen’s depiction of animal research one must also ask — How did human surgeries look back then?  By all accounts they were the most excruciating, traumatic and dangerous experience for patients.  As an example, the novelist Fanny Burney recounted part of her experience with a mastectomy as follows:

I mounted, therefore, unbidden, the Bed stead & M. Dubois placed me upon the Mattress, & spread a cambric handkerchief upon my face. It was transparent, however, & I saw, through it, that the Bed stead was instantly surrounded by the 7 men & my nurse. I refused to be held; but when, Bright through the cambric, I saw the glitter of polished Steel I closed my Eyes. I would not trust to convulsive fear the sight of the terrible incision. Yet — when the dreadful steel was plunged into the breast cutting through veins arteries flesh nerves I needed no injunctions not to restrain my cries. I began a scream that lasted unintermittingly during the whole time of the incision & I almost marvel that it rings not in my Ears still? so excruciating was the agony. When the wound was made, & the instrument was withdrawn, the pain seemed undiminished, for the air that suddenly rushed into those delicate parts felt like a mass of minute but sharp & forked poniards, that were tearing the edges of the wound. I concluded the operation was over Oh no! presently the terrible cutting was renewed & worse than ever, to separate the bottom, the foundation of this dreadful gland from the parts to which it adhered Again all description would be baffled yet again all was not over, Dr. Larry rested but his own hand, & — Oh heaven! I then felt the knife (rack)ling against the breast bone scraping it!

Ms Burney was lucky to have survived to describe her experiences.  Most surgeries taking place in surgical theaters simply ended up in death.

The above were some of the common practices of medicine a mere 200 years ago. Magendie was one among the main critics of the dominant medical theories (humorism and vitalism) and the use of unproven methods on human patients. On the use of animals in research he said at a meeting [] I beg my honorable colleague to observe that I experiment on animals precisely because I do not wish to experiment on men.  That is what he felt about medicine — it was nothing short of human experimentation.

In the introductory pages of his Journal de Physiologie Expérimentale Magandie, he added:

“What subject is indeed more fertile in gross errors and absurd beliefs than that of health and disease? Consider the painful disquietude you would produce in the minds of the majority of men if you said to them:There are no such things as rheumatismal humour, gouty humour, scabby virus, venereal virus, and so forth.  Those things which are so designated are imaginary things, which the human mind has created to hide from itself its own ignorance.’   The chances are that you would be taken for a lunatic just as it but recently befell those who maintained that the sun was immovable and the earth turned.”

Any honest reading of medical history has to give credit to the experimental physiologists who put medicine in the right track to become what it is today. The handful of physicians and psychiatrists that speak against animal research should remember that from Hippocrates to the early 19th century, their profession caused more harm than good to their patients.  They ought to be reminded that it was the work of the experimental physiologists that turn this around.  Charles Darwin acknowledged this fact when he wrote:

[] I know that physiology cannot possibly progress except by means of experiments on living animals, and I feel the deepest conviction that he who retards the progress of physiology commits a crime against mankind.

As experimental medicine advanced, so did our ability to treat the potential pain and suffering animals may experience in research.  Animal welfare laws were established. Today, the vast majority of animals participating in research benefit from the use of modern anesthetics and analgesics. The public and our representatives recognize that responsible, regulated animal research has continued to produce new therapies and cures through the years — benefiting humans and non-human animals alike. Stopping the work and depriving future generations of new advances would be immoral.

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.