Tag Archives: animal research

A Philosopher’s Dream

A moral philosopher had the following dream:

First Darwin appeared, and the philosopher said to him, “Could you give me a fifteen-minute capsule sketch for your support of medical research using animals?”

To the philosopher’s surprise, Darwin gave him an excellent exposition in which he compressed an enormous amount of material into a mere fifteen minutes,  ending with a warning to the philosopher that “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. “ But then the philosopher raised a certain objection which Darwin couldn’t answer. Confused, Darwin scratched his head and disappeared.

Then Albert Sabin appeared.  He gave another detailed account of the importance of the work to the development of the Polio vaccine and concluded that “without the use of animals and of human beings, it would have been impossible to acquire the important knowledge needed to prevent much suffering and premature death not only among humans but also among animals.”  The same thing happened again, and the philosophers’ objection to Sabin was the same as his objection to Darwin. Sabin also couldn’t answer it at all, scratched his head and disappeared.

head-scratching

Then all the famous medical heroes of the past century paraded one-by-one to defend the work, and our philosopher refuted every single one with the same, singular objection.

After the last scientist vanished, our philosopher said to himself, “I know I’m asleep and dreaming all this. Yet I’ve found a universal refutation for all justifications of animal  research! Tomorrow when I wake up, I will probably have forgotten it, and the world will really miss something!”

With an iron effort, the philosopher forced himself to wake up, rush over to his desk, and write down his refutation. Then he jumped back into bed with a sigh of relief.

The next morning when he awoke, he went over to the desk to see what he had written.

It was,

“That’s what you say, but I am deeply skeptical.”

 

Jeffrey Kahn’s Odd Views on Animal Research

Professor Jeffrey Kahn visited UW Madison to discuss the use of monkeys in medical research.

He is the Robert Henry Levi and Ryda Hecht Levi Professor of Bioethics and Public Policy and the Deputy Director for Policy and Administration at the Johns Hopkins Berman Institute of Bioethics.

Professor Kahn has participated in numerous federal panels and chaired the influential Institute of Medicine (IoM) committee on the Use of Chimpanzees in Biomedical and Behavioral Research, which recommended that the NIH phase out most biomedical research on chimpanzees.

Because he is respected and listened to by those in charge of making policy decisions on matters of important medical research and public health issues, his talk at UW Madison drew much attention.

During his comments Prof. Kahn raised several objections about how animal research is regulated in the United States that deserve closer scrutiny.

Unfair application of the principles of utilitarian philosophy

Professor Kahn objected to justifying research based on utilitarianism on the grounds that it is unfair to consistently harm one group (non-human animals) for the benefit of another (humans).

However, the notion that pure utilitarianism forms the basis for an ethical defense of biomedical research is incorrect.

For example, a pure utilitarian view would also call for doing invasive experiments in mentally disabled human beings whose cognitive capabilities are comparable to those of animals used in research, or demand we forcefully harvest the organs of a potential human donor to save the lives of several others.

Of course, we don’t do any of these things. So it was perplexing to hear him state that utilitarianism is “how the system is set up.” 

No, it is definitely not.

Medical research with human and non-human animals is not based on a pure, utilitarian view.  Instead, it is partly based on a graded moral status perspective that posits we owe moral consideration to all living beings, but not to the same degree that we owe consideration to the lives of fellow humans. It is also partly based in our mutual recognition of equal, basic rights for all members of the human family.

These ethical considerations are embedded in federal regulations and NIH guidelines that call for minimizing the number of animal subjects used in any one study, the amount of suffering involved, and require the use the “lowest” species that can be expected to yield meaningful scientific answers.  It is also reflected in specific federal programs aimed at developing alternatives to animal use and, of course, in protections for human subjects.

It is true that NIH has never made explicit the ethical and philosophical principles underlying its research.  Nevertheless, the ethical principles etched in these regulations should be clear to anyone who spend the time to become familiar with them.

A misguided notion of scientific necessity

Professor Kahn views the “scientific necessity” of the work as inextricably linked to the ethics. His views are aligned with the conclusions of the panel that he chaired on chimpanzee research.  Within this framework a project would be morally justified only if all the following three conditions were met:

  1. No suitable alternative is available
  2. The work cannot be performed ethically on human subjects
  3. The work is required in order to accelerate the prevention, control and treatment of life-threatening or debilitating diseases

A large class of studies readily meet the first two requirements. When we seek information about the cellular and molecular mechanisms in a living organism, the technologies available to us at the present are invasive, and the work cannot be performed ethically in human subjects. If we could observe and manipulate molecular pathways and cells in living humans without jeopardizing their well being, then the work would be done in humans. But we don’t yet have such tools. No computer simulation, no in-vitro system, no MRI, no organs-on-a-chip currently available, provide an adequate alternative to animal studies.

The crux of the matter then boils down to the third condition, and therein lies the rub. When you are talking about the process of scientific discovery, this third condition is meaningless when applied to individual scientific projects. Science, as Professor Kahn himself points out, is not necessarily a predictable linear path from point A to point B, because it involves the exploration of the unknown. Science cannot promise that any one experiment can lead to a cure, nor can researchers know ahead of time which specific experiment or line of research will lead to a breakthrough. In Professor Kahn’s own words, “we call it research because we don’t know what the answer is.”  Why does he not realize that demanding a specific outcome in advance is out of the question?  One can only evaluate outcomes in retrospect, as Peter Singer has done offering in his approval for monkey studies in Parkinson’s research. Unfortunately, scientists on NIH study sections do not have the luxury of an oracle that can guide their decisions.

Instead, researchers understand that without animal studies we will not be able to develop new therapies and cures. Our expert scientific opinion is that were we to suspend animal research, most fields of biomedical research would come to a full stop. Meanwhile, patients and their families would pay the price of more human suffering.

Thus, the ethical question should be reframed as not whether one individual study is required but, in the case at the heart of this debate, whether the use of animal models is required to understand the molecular pathways underlying mental disorders so that we can  develop new treatments and cures for them.  Or more generally, if animals are required at all to advance medical knowledge and human health.  The scientific consensus in this matter, as indicated by a recent Nature magazine poll,  is overwhelming:

 

Bonus points should go to UW Professor Eric Sandgren who was nevertheless able to use Professor Kahn’s framework to explain, point by point, why he feels the studies under discussion can be justified. You may agree or disagree with his justification, but you cannot say he did not offer one. In contrast, Professor Kahn simply stated that he was “deeply skeptical” of the necessity of the work, despite acknowledging a lack of familiarity with the details of the study, nor bothering to explain the rationale for this view.

Given that the research at the center of this debate is aimed directly at anxiety disorders, a specific neurological condition that affects millions of humans, one might safely assume that Professor Kahn would express even graver doubts about basic research in animal subjects. He would have likely have rejected outright the research on olfactory cells that eventually allowed paralyzed people (and dogs) to walk again, among numerous advances in knowledge that have led to medical breakthroughs.

Professor Kahn ought to be reminded that the mission of the NIH is “to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability,” and try to understand better the inherent uncertainty and necessity of scientific research.

Do IACUCs and NIH study sections fail to evaluate scientific necessity?

Given his misguided view of necessity, it should not be surprising Professor Kahn believes that neither IACUCs nor NIH study sections are able to assess the scientific need for specific studies. He harshly criticized such committees for taking the claims of any one proposal at “face value.

That is a very strong statement… and a decidedly incorrect one, too.

First, the overall scientific direction of medical research in the country is established by our medical and scientific leadership. In the neurosciences, scientists are guided in their research by NIH’s Neuroscience Blueprint. Among the important scientific directions relevant to this particular discussion—ones that Professor Kahn should have known about—were the Blueprint Neurotherapeutics Network (to advance the development of new drugs for nervous system disorders) and the Blueprint Non-Human Primate Brain Atlas (to provide comprehensive data on gene expression in the rhesus macaque brain , from birth to four years old). Such work is expected to aid research on human brain development and its disorders.

Second, NIH study sections diligently assess proposals with an eye to which studies stand a better chance of advancing our knowledge of function and disease and therefore may have the greatest potential to lead to new cures or fundamentally advancing a field of study. In making their assessments, scientists who participate in study sections use their expertise to assess which research directions and pilot data look most promising. There is never a guarantee that any one study will produce a breakthrough. If there is any one premise it is that animal research has led to numerous advancements in knowledge and medicine that has benefited human and non-human animals alike. This is not taken at face value, rather, it is an indisputable fact of medical history.

Third, once the scientific merit of a proposal has been established, IACUCs provide an additional layer of local scrutiny and compliance oversight. It is perfectly reasonable for IACUCs to ensure the work at the institution maximizes the welfare of the animal subjects in each study, and NIH requires such an assurance for institutions that receive federal funding. (For the small minority of projects that have not yet received NIH review, the IACUCs seek local expertise to evaluate the scientific merit of the study.)

Is funding “unnecessary” research a waste of resources?

Another miscalculation derived from Professor Kahn’s flawed view of “necessity” is the claim that if research is “unnecessary” according to his definition, then it is also unethical, especially considering the limited funding resources we have available at the moment.

It is perfectly legitimate for a society to assess how it distributes its resources, but in doing so the entire budget ought to be considered.

One may ask, for example, how Professor Kahn feels about resources spent on drones for the military, the Hubble telescope, unmanned trips to Mars, funding for theoretical physics, game theory, or the Arts.

Or, more to the point, one could ask for a more detailed justification of why society should spend its resources on philosophers and bioethicists?

Should society prioritize the support of bioethics over the development of a vaccine for Ebola or a cure for cancer, Alzheimer’s or Parkinson’s?

Which is one more crucial to our social welfare and which is more “unnecessary”?

Who will direct medical research?

Scientists must participate more in public life because social policies need to be decided on the basis of rational grounds and facts. These include important issues ranging from climate change, to the goals of the space program, to the protection of endangered species, to the use of embryonic stem cells or animals in biomedical research.

When scientifically inaccurate statements emanate from someone who has demonstrable influence on public policy decisions, scientists have a duty to speak up and correct the mistakes.

Animal research poses a legitimate moral dilemma. Decisions to pursue different lines of research that are perceived as controversial — be it research involving animals subjects or embryonic stem cells — cannot be assessed fairly without the active participation of scientists, physicians, patients and their families, because all are stakeholders in the work.

Unless these stakeholders get involved in such debates, we may find that their interests are not taken into account when the future direction of medical research is determined.

Dario Ringach

 

Paralyzed man walks again after olfactory cell transplant, thanks to animal research

Today, almost 30 years after Prof. Geoffrey Raisman first identified their potential to repair nerve damage in mice, the BBC reports that olfactory ensheathing cell transplantation has been successfully used to enable Darek Fidyka, who was paralyzed from the chest down in a knife attack in 2010, to walk again.

The paper reporting the transplant, which was carried out by surgeons in Poland and  led by Geoffrey Raisman of the UCL Institute of Neurology, is published today in the journal Cell Transplantation (5). The technique involves taking specialized cells known as olfactory ensheathing cells (OECs) from the patient’s own patient’s olfactory bulbs, and then grafting these cells at the site of injury, where they promote nerve cell growth to bridge the gap and restore function. An added advantage in using the patient’s own cells is that it avoids the problem of rejection by their immune system.

Speaking earlier today Geoffrey Raisman described the results as “more impressive than man walking on the moon”. He’s not to far wrong, this achievement shows what is possible for regenerative medicine, and is the result of decades of basic and translational research. Indeed, whereas only 12 people have  walked on the moon, this new technique has the potential to help many thousands of people to walk again here on earth.

2014 has been an extraordinary year of progress restoring function after spinal injury, in May we saw how epidural stimulation allowed 4 paralyzed men in the US to move their legs again, while scientists at Newcastle University in the UK used closed loop electrostimulation to restore voluntary movement in temporarily paralyzed monkey arms. These techniques, and now OEC transplantation, show that many cases of paralysis are potentially reversible. Not every technique will be appropriate for every patient, and it will take much additional research before they are widely available, but together they represent a huge advance.

Darek Fidyka learns to walk again following OEC transplantation. Image BBC News.

Darek Fidyka learns to walk again following OEC transplantation. Image BBC News.

In each case it is an advance that rests on many decades of careful research in both animals and in human subjects, in particular basic research that uncovered the role of specialized cells and provided scientists with the knowledge about organization and function of the brain and spinal cord that enabled these pioneering therapies to be developed.

In a post in 2012 I discussed how Geoffery Raisman’s research led to the successful testing of olfactory ensheathing cells in injured dogs, and I’m reposting that article here:

Paralysed dogs walk again thanks to nasal cell transplants…and Professor Raisman’s rats. (published 19 November 2012)

This morning the BBC News carried a report on a medical breakthrough – and it is not a term I use lightly – that has enormous implications for people who have been paralyzed following spinal cord injuries. A team at the University of Cambridge led by Professor Robin Franklin Department of Veterinary Medicine, along with colleagues at the MRC Centre for Regenerative Medicine in Edinburgh succeeded in restoring the ability to walk with their hind legs to dogs which had been paralyzed by spinal injury. To do this they removed a special type of cell called the olfactory ensheathing cell (OEC) from the nasal passageways of the dogs, grown them in culture until a sufficient number had been produced, and then transplanted them at the site of injury. Many of the dogs which received the transplant were subsequently able to walk with their hind legs if supported by a harness, and some even able to walk without being supported by a harness, whereas dogs which received a control injection did not recover the ability to move their hind legs.

This is a major medical advance, and the first time that cell transplantation has been demonstrated to reverse paralysis in a real-life situation where the injury involves a combination of damage to the nerve fibre and to surrounding tissues, and there is a significant delay between injury and treatment, and while the therapy did not completely restore function it marks a very significant step towards a therapy that can be evaluated in a human clinical trial. It also of course is a very promising therapy for dogs that have suffered spinal injuries, for example after being hit by a car, and as such is an excellent example of the One Health concept which seeks a closer integration of human and veterinary medicine.

As with many breakthroughs this one did not happen overnight, indeed it is the result of decades of research. The story really begins in 1985 when Professor Geoffrey Raisman at University College London (for a good overview of his work see the UCL spinal Repair Group homepage) was studying the unique ability of nerve fibres in the olfactory system to grow and make the connections with central nervous system – an ability that other adult nerve cells lack and which is probably retained in the olfactory system due to the importance of preserving the ability to smell despite exposure of nerve cells in the nasal passages to toxins in the environment (a good sense of smell being crucial to survival for many mammalian species). He found that in a part of the brain termed the olfactory bulb of mice and rats a specific type of glial cell, cells that act to support and regulate the activity of the nerve cells along which nerve impulses travel , were responsible for creating the pathway along which the olfactory nerve fibres could regenerate (1).

Studies in rats were key to unlocking the potential of olfactory ensheathing cells in repairing spinal injuries. Image courtesy of Understanding Animal Research

This discovery suggested that if these specialized olfactory ensheathing cells (OECs) were transplanted at the site of spinal cord injury they might promote the growth of a bridge of nerve cells that would reconnect the severed pathway and restore function. In a series of experiments in rats Professor Raisman and colleagues demonstrated that OEC transplantation could repair a variety of different types of spinal cord injury, in order to restore function, for example to improve the ability to breath and climb following spinal cord injury (2) and to restore the ability of rat paws to grasp in order to climb following lesion of the spinal nerve that runs from the spinal cord down through the arm (3). Other scientists provided additional key information, for example scientists at the University of New South Wales in Australia demonstrated that OECs could be isolated from the nasal mucosa as well as from the olfactory bulb (4), and that these can also repair spinal cord injuries, an important step since obtaining OECs from the nasal mucosa is far more straightforward and safer than harvesting them from the brain. These discoveries, and the refinement of OEC transplant techniques over the past 2 decades by scientists such as Prof. Raisman, paved the way for the “real life” veterinary study reported today. A human clinical trial of this technique cannot be far off, though it is worth noting Prof. Raisman’s words of caution to the BBC concerning what has been achieved and what is still to be done:

“This is not a cure for spinal cord injury in humans – that could still be a long way off. But this is the most encouraging advance for some years and is a significant step on the road towards it…This procedure has enabled an injured dog to step with its hind legs, but the much harder range of higher functions lost in spinal cord injury – hand function, bladder function, temperature regulation, for example – are yet more complicated and still a long way away.”

In this respect it is worth noting the other approaches to repairing spinal cord injury, for example using other glial cell known as astrocytes and the use of electrical stimulation have produced promising outcomes in animal studies and early human clinical trials. Indeed, a clinical study of electrostimulation that we discussed last year reported “improved autonomic function in bladder, sexual and thermoregulatory activity that has been of substantial benefit to the patient”. In the future these different approaches may be combined to maximize the benefit to the patient, but it is still far too early to say which techniques will best complement each other. One thing we can be sure of is that turning these very promising technologies into effective treatments – perhaps even cures – for paralysis will require further research, both in the lab and in the clinic.

Paul Browne

1) Raisman G. “Specialized neuroglial arrangement may explain the capacity of vomeronasal axons to reinnervate central neurons.” Neuroscience. 1985 Jan;14(1):237-54. PubMed: 3974880

2) Li Y, Decherchi P, Raisman G. Transplantation of olfactory ensheathing cells into spinal cord lesions restores breathing and climbing.” J Neurosci. 2003 Feb 1;23(3):727-31. 12574399

3) Ibrahim AG, Kirkwood PA, Raisman G, Li Y. “Restoration of hand function in a rat model of repair of brachial plexus injury.” Brain. 2009 May;132(Pt 5):1268-76. Epub 2009 Mar 13. PMID: 19286693

4) Lu J, Féron F, Mackay-Sim A, Waite PM. “Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord.” Brain. 2002 Jan;125(Pt 1):14-21. PMID: 11834589

5) Tabakow P et al. “Functional regeneration of supraspinal connections in a patient with transected spinal cord following transplantation of bulbar olfactory ensheathing cells with peripheral nerve bridging” Cell Transplantation, published online 20 November 2014 http://www.ingentaconnect.com/content/cog/ct/pre-prints/content-CT-1239_Tabakow_et_al

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/