Monthly Archives: November 2011

A Closer Look at the Great Ape Protection Act (GAPA)

Posted on November 21, 2011 by | 2 Comments

The status and future of chimpanzee research in the US are at the heart of much discussion lately in both scientific and public spheres.  A committee convened by the Institute of Medicine (IOM) to consider the issue held a number of meetings and is expected to report its findings to the NIH by the end of this year. Legislation to end great ape research, also introduced in 2007 and 2009 (H.R. 1513: Great Ape Protection and Cost Savings Act of 2011;  S. 810: Great Ape  Protection and Cost Savings Act of 2011; GAPA), was again introduced last Spring.

Discussion of human relationships with the great apes, their role in research—past, present, and future—and our responsibility for their continued care deserve thoughtful, well-informed consideration by both the scientific community and the public.  One of the primary goals of Speaking of Research is to contribute to dialogue about animal research and to provide factual information that is sometimes missing from the public conversation.

In the case of chimpanzee research, their housing and care, and the GAPA legislation, it seems clear that there is uneven understanding of the current situation in the U.S., as well as lack of attention to the details and consequences of the proposed legislation were it to be enacted.  There has been significant and widespread discussion of whether chimpanzee research should continue.  What has received far less attention is what should happen to the chimpanzees should invasive research not continue. We take a closer look at GAPA here and also welcome others’ thoughts on the future of chimpanzee research, care, and housing in the U.S..

First up is the question of what exactly would be banned under GAPA.  The legislation is pitched as a measure to end invasive research with chimpanzees.  Much of the media coverage and discussion of chimpanzees in research also makes specific reference to invasive studies.

But what exactly does that mean?  The general definition given by the legislation is:

“The term ‘invasive research’ means any research that may cause death, injury,         pain, distress, fear, or trauma to a great ape, including—

– the testing of any drug or intentional exposure to a substance that may be detrimental to the health or psychological well-being of a great ape;

– research that involves penetrating or cutting the body or removing body parts, restraining, tranquilizing, or anesthetizing a great ape; or

– isolation, social deprivation, or other experimental manipulations that may be detrimental to the health or psychological well-being of a great ape.

Exclusions include:

– close observation of natural or voluntary behavior of a great ape, if the research does not require an anesthetic or sedation event to collect data or record observations;

– the temporary separation of a great ape from the social group of the great ape, leaving and returning by the own volition of the great ape;

– post-mortem examination of a great ape that was not killed for the purpose of examination or research; and the administration of a physical exam by a licensed veterinarian or physician conducted for the well-being of the individual great ape.

Physical Exam is defined as:

A physical exam conducted for the well-being of an individual great ape, as described in clause14 (i)(IV), may include the collection of biological samples to further the well-being of the individual great ape, the social group of the great ape, or the great ape species.”

It seems likely that when most people think of invasive research with chimpanzees they would probably consider studies that involve surgery or infectious disease.  Looking at the text above, it appears obvious that these would be precluded under GAPA.

What is less clear is whether noninvasive studies would also be disallowed under GAPA. Why?

First, because it precludes “research that involves … anesthetizing a great ape” something that is typically necessary to ensure both human and animal safety for studies that use noninvasive techniques such as neuroimaging (ex. magnetic resonance imaging, MRI; positron emission tomography, PET). Studies using MRI and PET with nonhuman primates are aimed at a wide spectrum of research addressing questions that range from evolutionary consideration of brain-behavior relationships to uncovering the effects of aging and factors that contribute to individual differences in health. Are these the types of studies—using equipment and techniques that are commonly used with humans– that typically come to mind as invasive studies? Probably not.

Whether anesthetizing a chimpanzee is an invasive procedure or one that is stressful is not clear-cut and is a question likely to generate a wide range of views among those with first-hand chimpanzee experience.  In part, it depends upon whether animals are trained to voluntarily, calmly, and cooperatively receive injections—something that is a best practice successfully implemented at many chimpanzee research facilities.  This video, shared with us by Dr. Steven Schapiro and the Michael E. Keeling Center for Comparative Medicine and Research  serves as an excellent illustration of the practice.

The video shows a chimpanzee voluntarily, and without coercion, working with his human caregivers to give a sample of blood in exactly the manner of a human blood donor. The chimpanzees shown here are part of a training program led by a long-time leading expert in behavior and primatology, Dr. Schapiro. The video shows a chimpanzee who voluntarily places and holds his arm in a tube to provide a technician with access to draw blood. The chimpanzee is not restrained and is not coerced. The technician cues the chimpanzee with a “clicker” which provides an audible cue to signal the animal. The chimpanzee remains calm throughout the process and receives treats. The curious and calm approach and observation by another chimpanzee also tells us that the entire process is one that is not stressful to the animals.

Much of the language surrounding GAPA appears to be designed to convey a very different impression of the care of chimpanzees housed in research settings. We believe that a more honest discussion of chimpanzees in research should include consideration of the full range of housing and behavioral management, including acknowledgement of best practices such as those illustrated in this video and practiced in a wide range of settings.

The second question about what GAPA would preclude surrounds behavioral and cognitive research.  Many of these studies depend upon testing animals individually by temporarily separating them from their groups. GAPA asserts that such studies would be allowed only under very stringent—and possibly impractical—conditions. The chimpanzee could be temporarily separated from his/her group, but only if it were able to leave and return by its own volition.

For example, consider a recent study of prosocial behavior in chimpanzees by Frans de Waal and colleagues that was published in the Proceedings of the National Academy of Sciences USA.  This study was positively featured on a Scientific American blog that also endorses GAPA. The study was conducted by bringing pairs of animals into a testing room containing tokens that they could exchange with the experimenter for a food reward. Their choices could result in both animals receiving food, or in a “selfish” outcome. The methods section doesn’t specify whether the animals were free to leave and enter the test room at their own volition, but it appears that they were not. If not, would we consider it invasive research?

A third question is whether GAPA would preclude studies that depend upon collection of biological samples that are acquired while animals are anesthetized for physical exams.  The language surrounding this is somewhat ambiguous, as it allows the sample collection if it is to “further the well-being of the individual great ape, the social group of the great ape, or the great ape species.”  What is not ambiguous is that, as written, GAPA would preclude even a simple blood draw—something humans routinely receive as part of medical care or even research—outside of an annual physical exam.

In sum, the issue of defining invasive research and the parameters of what should be allowed is clearly a complex issue. That complexity should be acknowledged in discussions of the future of chimpanzee research.  Virtually all of the procedures used in biomedical research involving chimpanzees that are regarded as invasive procedures are used in human beings in providing medical care.  The GAPA regards these procedures as acceptable if performed for the benefit of the individual great ape to provide care to that animal, but it is unacceptable if it is performed to gain knowledge that will improve the care of human beings or other great apes.

Similarly challenging are a range of other issues presented by consideration of the future of chimpanzees in the U.S., including decisions about their housing and care, as well as the source of long-term funding.

One premise of GAPA is that “research laboratory environments involving invasive research cannot meet the complex physical, social, and psychological needs of great apes.”  Sanctuaries are offered as the alternative for housing, yet little of the public discussion has focused on rigorous comparison of sanctuaries and research facilities in terms of either care offered or cost.

Finally, in this year’s iteration, the legislation has added language about “cost-savings” that appears to be based in analysis provided by the Humane Society of the United States (HSUS).  Whether the cost-savings claim is accurate or not remains open for debate.  Each of these issues will be covered in more detail in subsequent posts.

Whether the current legislation about great ape research passes or not, at this time it is perhaps more apparent than ever before that public interest in discussing the welfare of these animals is high. We hope that this interest carries over to serious discussion about the full range of issues and not only those that lend themselves to short-interest and emotive campaigns.

Allyson J. Bennett

*Disclosure – some of my collaborative research has involved behavioral and neuroimaging studies in laboratory chimpanzees.

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Opponents of animal research should refuse medical treatment

Posted on November 17, 2011 by | 86 Comments

In a new post, animal rights activist Rick Bogle bemoans that his side is often challenged with a natural question:

“Would you forgo medical treatment developed through animal research?”

We can safely assume that the vast majority of those that oppose animal research do not have any qualms about vaccinating their children and companion animals or that, in case of an accident, would rush to the nearest emergency room to be treated with the benefits of animal research.

Are they not hypocrites?

Mr. Bogle doesn’t think so.  In response he writes that to live true to our own challenge scientists must refuse all benefits obtained in ways we consider unethical as well.

Namely, he challenges us back with: (a) not traveling on roads built by slaves — if we really oppose slavery, (b) refusing the care of a doctor whose education was based partly on knowledge obtained by  Nazi physicians — if we truly oppose the Holocaust, and (c) for our daughters and wives to forgo gynecological care — as many of its techniques were apparently developed by Dr. J. Marion Sims using non-consenting human subjects.

This is a flawed argument.

It is clear that none of the unethical practices Mr. Bogle mentions are accepted nor widespread today.  Thus, by traveling on a road built by slaves one is not actively supporting slavery.  By accepting gynecological care, one is not actively supporting experiments in non-consenting human subjects.  And so on.

In contrast, the use of animals in medical research today is ubiquitous.  Animal research provides medical benefits that translate into longer and healthier lives.  There is a public demand for such benefits. If the desire for living longer and healthier lives vanished tomorrow, so would animal research, along with the rest of medical research.

Mr. Bogle’s challenge rests on a false analogy.

A proper analogy would be the following.  Suppose you oppose child and forced labor practices and you discover that a particular US company manufactures its products overseas under such labor conditions.

Would you still buy form such a company?  Is there any way in which you can rightfully say that you morally oppose forced labor but are nevertheless entitled to benefit from the cheap prices the company has to offer?

Of course not.

If you buy from such a company you are a hypocrite to the full extent of the word, as you are actively supporting, financing and perpetuating a practice you consider immoral.

Ethical principles are supposed to guide one’s moral judgements.  If you have strong moral principles you want to impart on the rest of society, you better be the first to be prepared to accept the consequences of such principles.

Mr. Bogle and his ilk should stop benefiting from our research immediately.

They should live by their beliefs, and we can help.

Until then, they are nothing more than hypocrites.

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Animal Models of Dystonia – Part II

Posted on November 13, 2011 by | 1 Comment

An invited post by Erwin Montgomery, M.D., and Michele A. Basso, Ph.D., University of Wisconsin, Madison.

Based in part on some of the findings of altered learning in rodent models, a primate model of dystonia was developed. This model revealed that repetitive stimulation of fingers not normally stimulated together resulted in dystonic postures of the hand and sensory abnormalities. Using electrophysiological methods in the monkeys, the investigators found that the representation of the fingers in the somatosensory cortex was much more disorganized in the dystonic animals after the repetition training than before. This finding is further support for the idea that dystonia results from faulty neuroplasticity and that the electrophysiological mechanisms identified in the rodent may underlie the cause. Clinician-scientists have since extended this to human patients with dystonia and indeed, are finding similar sensory abnormalities in humans with dystonia as those seen in monkeys with learning-induced dystonia. The prevalence of focal dystonia in musicians and other professionals who perform repetitive movements is also consistent with the faulty neuroplasticity hypothesis of dystonia. Behavioral treatments of patients with focal dystonia based on these ideas of learning discovered and understood from work performed in animal models is being met with some success.

There is presently no cure for dystonia. Other than the behaviorally-based treatments used in focal dystonia, the treatments for most cases of dystonia involve drugs that minimize, but do not eliminate symptoms. Moreover, the drugs – those that influence the neurotransmitters acetylcholine or dopamine – used for treatment are often associated with uncomfortable side-effects. Botulinum toxin is used to alleviate symptoms of focal dystonia. The toxin acts to temporarily paralyze the muscles receiving the injection. This helps reduce and even eliminate the sustained muscular contractions and therefore the pain, associated with dystonia. Of course this treatment is temporary and requires repeated injections to maintain effectiveness.

A recent surgical treatment that is being explored for severe cases of dystonia, in which traditional medical therapies do not work, is called deep brain stimulation. In this procedure, stimulating electrodes are placed within the brain at selected locations. The electrodes are attached to a connecting wire that runs from the top of the electrodes in the scalp, behind the ear, down the neck and then attaches to a battery pack called a pulse generator that is implanted under the skin just below the collarbone. This pulse generator provides a constant source of electrical stimulation to the targeted brain region and acts like a pacemaker for the brain, roughly akin to the way pacemakers operate to control the rhythmic activity of the heart.  The video below illustrates on such treatment case.

How did it come about that stimulating the brain with electrical current could alleviate symptoms of disease? After the discovery, using frogs, that nerves and muscles were electrically excitable by Luigi Galvani in 1791, other pioneering researchers began to stimulate the brains of humans and animals using electrical current. Prior to Galvani’s finding, the idea to do this would not have even occurred to anyone. Most notable of the work based on the findings of Galvani, is the work around the same time, of Luigi Rolando, Pierre Flourens in humans and Eduard Hitzig, Gustav Fritsch and David Ferrier in dogs and monkeys. These pioneers discovered that they could use surgical procedures to introduce small electrodes into the brain and provide electrical current to surface and deep brain regions. They also discovered that passing electrical current into the brain influenced behavior and had little side-effects. Victor Horsley and Robert Clarke invented the stereotactic method for neurosurgery. Their method improved considerably the surgical technique of placing electrodes into the brain. Their invention was published in 1906 and is still in use today for human and animal neurosurgery with only slight modifications. Using animals such as cats and monkeys (Walter Rudolf) and a famous bull (Jose Delgado), scientists went on to develop the technique of implanting electrodes into the brain permanently to stimulate deep brain structures. These scientists showed for the first time that electricity could be delivered to the brain of animals and could alter the behavior of the animals, all while the animals were moving around freely. This brought the technique out of the confines of the surgical theatre and opened the door for the possibility of using chronic, deep brain stimulation to treat humans with disease.

In the early 1980s, Irving Cooper boldly introduced electrical stimulation of different regions of the brain in an effort to relieve the symptoms of dystonia in humans. Without the work of scientists such as Ferrier and Delgado showing that the method of electrical stimulation was efficacious and safe in animals first, it is unlikely that Cooper would ever have thought to do this in humans. Initially Cooper targeted areas in the brain such as the internal capsule and the thalamus and indeed, his patients found relief.  Today, deep brain stimulation is used to treat symptoms of dystonia although the regions of the brain are different from those targeted by Cooper. The reason different brain regions are targeted is also based on the confluence of experimental work in animals and clinical work in humans. For example, anatomical work in animals provided scientists and clinicians with a much more detailed wiring diagram of how different brain regions are connected and interact. This has led to the refinement of electrode placement in patients. The clinical experience of surgeons together with detailed follow-up of the outcomes of surgery provides further refinement of electrode placements. Animal studies demonstrated that the effects of the deep brain stimulation propagate throughout the entire basal ganglia-thalamo-cortical system. This appreciation led directly to human studies investigating other potential targets for deep brain stimulation such as the globus pallidus external division and the putamen. Indeed, knowing whether or not the influence and efficacy of deep brain stimulation is due to stimulation of neuronal elements local to the stimulated target or at some distance simply cannot be addressed in humans. Studies such as these with animals, mostly non-human primates, are continuing to provide insight and possibilities into alternative brain structures to target that may have better efficacy or reduced side-effects.

A second area in which animal research has had direct benefits to humans is in understanding how deep brain stimulation works. The original theories about how deep brain stimulation resulted in beneficial effects were based on clinical experiments in humans alone.  Surgeons compared the effects of deep brain stimulation to those of effects of destructive lesions of the same brain areas, such as pallidotomy and thalamotomy.  Based on these comparisons, high frequency electrical stimulation was thought to inhibit or suppress the brain regions that were being stimulated – just like the more permanent lesions would do. Whereas, low frequency stimulation was thought to electrically excite the brain areas.  Thanks to animal research, we now know that this is not the case. Animal studies, including some from our laboratories, demonstrated very clearly that certain neuronal elements were activated with high frequency electrical stimulation.

One powerful example of the confluence of human and animal work that is bearing fruit is to study patients who have received deep brain stimulation treatment to understand the pathophysiological changes in the brain. In this way, abnormal neuronal signatures can be used in the development of animal models of dystonia in the future. We are taking such an approach in our work. In the Basso laboratory we study how the basal ganglia and one of its target structures, the superior colliculus contribute to how we make decisions about where to look. We are particularly interested in how these decisions are made when sensory information is unavailable or ambiguous. We use non-human primates as a model because the brain regions responsible for vision and eye movements are very well-studied in this species and are very similar to those in humans. Indeed, a large amount of the functional magnetic resonance imaging work performed in humans has confirmed the findings discovered in monkeys over the past 30 years. We have found that monkeys will rely on their previous experience or memories to help guide their choices when sensory information is ambiguous or uncertain. We are actively searching for electrophysiological signatures of these processes in the brains of the monkeys. As a next step we are asking, do patients with disease have difficulty making decisions when faced with uncertainty? As it turns out, our preliminary data suggest that patients with the movement disorder Parkinson’s disease do have difficulty making choices when faced with uncertainty. When sensory information is available to guide the decision, the difficulties are less apparent. We are hoping to test patients who have had deep brain stimulation implants soon to assess whether this treatment improves the cognitive symptoms.

Parkinson’s disease is a neurodegenerative disease that results in profound movement symptoms and involves the basal ganglia. Dystonia is different from Parkinson’s disease most notably because dystonia is not associated with neuronal degeneration. Nevertheless, dystonia shares some significant characteristics with Parkinson’s disease. For example, some patients with dystonia show rigidity that is common in patients with Parkinson’s disease. Some patient with Parkinson’s disease show focal dystonias such as blepharospam, a sustained contraction of the eyelid closing muscle. In some patients, the blephparospam can be so severe that the patient is rendered functionally blind. Thus, based on work developed largely within cognitive neuroscience in the non-human primate model, we are planning to extend our cognitive studies to patients who have dystonia and who are being treated with deep brain stimulation. Our goal is to assess the cognitive symptoms seen in these patients and to assess whether deep brain stimulation influences these processes. We can then go back to the laboratory with answers from our human work to explore the development of a monkey model of the cognitive symptoms seen in movement disorders.

As another example, Montgomery is revealing the pathophysiological properties of the human brain circuits in basal ganglia diseases like dystonia and Parkinson’s disease. By extending to humans sophisticated, electrophysiological and statistical techniques that were developed in animals, Montgomery is recording the abnormal electrophysiological signatures of the brains of patients while they are undergoing surgery for the treatment of their disease. These experiments shed light on how the physiological properties in the brain go awry in disease. Most interesting will be to then compare these unhealthy electrophysiological signatures from human brains to those from healthy non-human primate brains to uncover mechanisms of symptoms.

There is still a great deal about dystonia and its treatment that we do not know and it is only with the continued confluence of animal and human neuroscience do we stand a chance of unlocking the mystery and providing relief for patients who suffer from dystonia.

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Animal Models of Dystonia – Part I

Posted on November 9, 2011 by | Leave a comment

An invited post by Erwin Montgomery, M.D., and Michele A. Basso, Ph.D., University of Wisconsin, Madison.

Dystonia is a neurological disorder of movement characterized by sustained muscle contractions affecting one or more sites of the body. Dystonia frequently causes twisting and repetitive movements and abnormal postures resulting in relentless pain. If dystonia affects one part of the body it is called focal. If dystonia affects more than one site in the body it is referred to as generalized dystonia (see video below). Although generalized dystonia is a relatively rare disease, a familiar example of a focal dystonia is writer’s cramp. Dystonia may be inherited or caused by trauma at birth, by infection, by poisoning or may be drug induced such as occurs sometimes with neuroleptic treatment for psychotic symptoms. The main treatment available for dystonia is pharmacological and provides relief of symptoms only, often with serious side-effects. There is no cure for dystonia.

Dystonia is associated with a number of genetic mutations in humans. For example, DYT1 dystonia is caused by a mutation in the TOR1A gene. In its mutated form associated with dystonia, the gene has a unique 3-base pair deletion. This gene encodes for the production of a protein called Torsin A. When the protein is produced by the mutated gene it is missing one of a pair of glutamic acid residues making it function abnormally. DYT1 is inherited in an autosomal dominant manner with reduced penetrance. This means that the offspring of an affected individual or an asymptomatic individual known to have a TOR1A mutation have a 50% chance of inheriting the mutation and a 30% to 40% chance of developing symptoms of dystonia. The occurrence of the DYT1 mutation is relatively rare, less than 1% of the overall population carries the mutated gene. Interestingly, among Ashkenazi Jews, the frequency is at least 3-5 times higher.

Since the discovery of the mutation in the TOR1A gene there have been many studies in animals designed to understand the role of the gene and its protein product, Torsin A in producing the disease. As a result of the discovery of the gene, researchers have been able to produce rodent models that express the mutated gene. This allows a detailed study of the role of the protein in the function of the whole animal. The discovery of the gene also allowed cell culture models to be developed in order to study the fundamental cellular biology of the protein that is implicated in producing the symptoms of dystonia. For example, animals with the mutated gene allowed for the discovery of where in the body the product of the gene was localized. We now know that Torsin A appears in brain cells and acts as a chaperone protein, assisting other cellular proteins to reach their final destinations and to form and maintain their 3D structure within cells. Torsin A plays a critical role in cellular functions related to the destruction of proteins that may be harmful to cells as well as the movement of organelles throughout the cell. This latter role for Torsin A may be most critical during the development of the brain and current research is suggesting that this role may hold the key to unlocking the mystery of how Torsin A results in the devastating symptoms of dystonia. Using this knowledge cell culture models are being developed in which drugs that target particular cellular functions can be assessed for their viability as a treatment for the disease symptoms.

Genetic models in rodents also led to the finding that the electrophysiological properties of brain circuits are malfunctioning in dystonia. One model of how dystonia arises is through a faulty learning mechanism – or faulty neuroplasticity. In a region of the brain called the basal ganglia, some neurons contain the neurotransmitter dopamine. This neurotransmitter is thought to play a role in certain types of learning. The cerebral cortex communicates with another region of the basal ganglia called the striatum. A simple model for how learning takes place in this circuit is that when signals from the cerebral cortex to the striatum are activated and there is a simultaneous signal from the dopamine neurons to this cortico-striatal synapse, behavior is enhanced or learned. If dopamine binds to one type of receptor the efficacy of the cortico-striatal synapse is reduced and the behavior is minimized or unlearned. If dopamine binds to a second receptor type the efficacy of the cortico-striatal synapse is enhanced and the behavior is learned. A second neurotransmitter called acetylcholine interacts with dopamine to either increase or decrease the likelihood of this plasticity taking place. Using animal models scientists have discovered that these different receptor types are localized to different neuronal cell types within the striatum and that acetylcholine is localized in one particular neuronal cell type within the basal ganglia, thus giving rise to different circuits involved in learning and unlearning behaviors. Interestingly, this type of neuroplasticity is altered in the brain of rodents containing the mutated gene that results in dystonia in humans. Indeed, in recent experiments using similar measures of neuroplasticity in humans reveals that patients with dystonia often have faulty neuroplasticity. A wonderful review of the confluence of human and animal studies revealing the learning and plasticity alterations in patients with dystonia appears in a recent paper.

In the next part of this post we will explore how, based in part from the findings rodent models, a primate model of dystonia was developed and how such work is bringing hope to dystonia patients worldwide.

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Animal research unleashes the power of human embryonic stem cells

Posted on November 7, 2011 by | 1 Comment

For more than a decade now embryonic stem cell research has been one of the most high profile – and indeed controversial – areas of medical science, and it is an emerging field that owes a lot to animal studies performed by pioneers like Gail Martin of UCSF.

Recently the field has begun to live up to its promise with the announcement last year that the first patient had been enrolled in the first ever clinical trial of a human embryonic stem cells (hESCs), a trial that seeks to evaluate the safety of the hESC-derived oligodentrocyte progenitor cells in patients with spinal cord injury.  We discussed the role of animal research in the development of this therapy by Geron Corp in a post on this blog back in 2009.

In September of this year embryonic stem cells were in the news again with the announcement that clinical trials of retinal pigment epithelial cells (RPEs) derived from hESCs for the treatment of an inherited form of blindness known as Stargart’s Macular Dystrophy, are taking place at Moorfields Eye Hospital in London and the Jules Stein Eye Institute at UCLA. The development of this therapy was led by Professor Robert Lanza, Chief Scientific Officer at Advanced Cell Technology, and Adjunct Professor at Wake Forest University School of Medicine, and rests on animal studies which showed that RPE cells derived from hESCs were safe and could restore vision in rodent models of Stargart’s Macular Dystrophy, as a study publishes in the Journal Stem Cells in 2009 makes clear:

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.”

Spinal Injury and Stargart’s Macular Dystrophy are only two of many diseases where hESC based treatments are offering hope of improvement, for more than a decade scientists have been investigating in animal models the use of embryonic stem cells to treat Parkinson’s disease, a degenerative disorder caused by the loss of nerve cells in the brain that produce the neurotransmitter dopamine and results in severe movement impairment. Now, a report in the Guardian newspaper describes how, after years of dedicated research, scientists have overcome a major of technical hurdle and paved the way for the evaluation of hESC therapy for Parkinson’s disease in human clinical trials. The Guardian report stresses the importance of studies in mice, rats and monkeys to evaluating the efficacy and safety of hESC-derived dopamine producing cells:

In a series of experiments, the team gave animals six injections of more than a million cells each, to parts of the brain affected by Parkinson’s. The neurons survived, formed new connections and restored lost movement in mouse, rat and monkey models of the disease, with no sign of tumour development. The improvement in monkeys was crucial, as the rodent brains required fewer working neurons to overcome their symptoms”

The study, which those with a subscription to Nature can read here, is very promising, and hopefully it won’t be very long until we are reading about the start of another clinical trial of hESC derived cells.

It is worth noting that despite fierce opposition from its opponents, public support for human embryonic stem cell research remains very high, a level of support that owes much to the willingness of scientists and research charities such as the Michael J. Fox Foundation for Parkinson’s Research to speak out in support of this important work.  While polls indicate that a clear majority of Americans support animal research, that majority could be larger, and the lesson from the stem cell debate is that the public are willing to listen to the arguments put forward by scientist. It is up to all of us who value animal research to do our bit to ensure that the majority in favor of animal research grows; after all, it can’t be right that more Americans support hESC medicine than support the animal research on which it depends!

Paul Browne

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Putting Animal Rights Extremists on the Hate Map

Posted on November 4, 2011 by | 45 Comments

Those who believe themselves to be morally righteous have a virtue — they are usually candid in their public statements.  With an absolute conviction in their world views, it is not surprising they also have a rather loose tongue.  The hate and violence that lives within animal rights extremists is always near the surface.  This was evidenced in a recent interview by Camille Marino of the extremist site “Negotiation is Over” with Leah Nelson, a journalist with the Southern Poverty Law Center, a well-known and respected nonprofit civil rights organization dedicated to fighting hate and bigotry in our society.

The SPLC blog is worth a read as it will raise the eyebrows of anyone that has a minimal respect for our democratic institutions, highlighting the hateful speech that comes from the fringe of the animal rights movement.  Apparently, Ms. Marino had second thoughts about the views she offered to the journalist and attempted to backtrack.  The SPLC Editor refused, noting that:

Marino was fully aware during the interview that she was talking with a blogger from the Southern Poverty Law Center, even volunteering that she is familiar with the SPLC’s history of denouncing radical animal rights activists like the Animal Liberation Front (ALF). She approved a transcript of her interview, writing in an E-mail, “I think you captured everything I said perfectly.” Hours later, Marino contacted the blogger and said she wanted to withdraw her consent to be quoted, saying that she did not want to be quoted on “a blog filled with the most contemptible groups of racists, bigots, madmen, and hatemongers … groups that I despise.

It was too late for that…  the SPLC editor further explained:

Following widely accepted journalistic practice that once an on-the-record interview is conducted, permission cannot be withdrawn, Hatewatch decided to publish quotes from the interview.”

Of course, Ms. Marino is accompanied in her crusade against the use of animals in biomedical research by Dr. Steve Best (Caution: extremist website), Professor of Philosophy at the University of Texas at El Paso, an active contributor and participant in the NIO web-site and vocal defender of Marino’s words and actions.  Dr. Best has previously been banned from entering the UK.  He was deemed a threat to the “public good” and “public order” and joined a list that also includes Islamic extremists and neo-nazis.   Here is an example of the kind of speech that probably prompted the Home Office to keep such individual away from British soil:


Hopefully, and given the available evidence, SPLC will take the logical step of declaring animal rights extremist groups like NIO hate groups.  This is, after all, what these groups are and, hopefully, they will formally be recognized as such in the SPLC hate map where they belong.

Of course there are many who do not need to be told that animal rights extremist groups like Negotiation is Over and the Animal Liberation Front are hate groups.  The University of Florida students newspaper “The Independent Florida Alligator” recently published an editorial strongly condemning the harassment of students and scientists by extremists, indicating that any students who may be targeted by extremists will find a lot of support among their fellow students, and in California the neighbors of scientists target by extremists have made their support for their harassed neighbors very clear. We’ve also seen the success of the Pro-Test movement in Oxford a few years ago, when students, scientists and members of the public joined to express their support for animal research, and delivered a decisive blow to the campaigns of harassment, intimidation and violence then being waged by animal rights hate groups in the UK.

Extremism and hate can be defeated, and the first step in doing so is to recognize it for what it is, and we applaud the SPLC for once again doing so.

Speaking of Research

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Predictions and Animal Models of Human Disease

Posted on November 3, 2011 by | 1 Comment

Some animal activists argue human disease cannot be modeled in animals.  They think physiological differences between species imply that treatments developed by means of animal research will not translate to humans.

Prediction through the development of models is no doubt a goal of scientific work.  Predictions are the fruits of theories that can be tested experimentally. If a prediction is false so is the theory, and a new one must be generated based on prior knowledge and the specific way in which the data falsified the theory.

Unfortunately, those that claim animal models are not predictive of human response take some literary license in restating the above along the following lines:

Predictions, generated from hypotheses, are not always correct. But if a modality or test or method is said to be predictive then it should get the right answer a very high percentage of the time […]

If a modality consistently fails to make accurate predictions then the modality cannot be said to be predictive simply because it occasionally forecasts a correct answer. The above separates the scientific use of the word predict from the layperson’s use of the word, which moreclosely resembles the words forecast, guess, conjecture, project and so forth. […]

Many philosophers of science think a theory (and we add, a modality) could be confirmed or denied by testing the predictions it made.

This language delicately nudges one to equate different concepts, namely theory, hypothesis, modality and method. In this deceptively innocuous equation, resulting from either an honest misunderstanding or mischievous intent, lies the foundation to a seriously flawed argument.

Consider the domain of physics. Here, physicists put forward mathematical theories of some natural phenomenon which, in turn, generate testable predictions. If a prediction is falsified, so is the theory. When this occurs, scientists seek to understand how the data depart from the prediction and use prior knowledge and intuition to develop a new working hypothesis, which is embedded in a new theory.

Mathematics is the language of physics — its methodology. Obviously, by using mathematics one can create many different theories. The overwhelming majority of them will be false. Science is difficult because most of the time our ideas turn out to be wrong.

But one’s ability to conjure up large numbers of incorrect theories does not invalidate mathematics as a method in the physical sciences. Mathematics can in fact be used to arrive at accurate descriptions of how matter behaves. It makes no sense to describe this state of affairs by stating that mathematics (the modality) gets it right occasionally.

A similar situation arises in the domain of biomedical research. Researchers create models of disease in animals by trying to replicate what they believe are the essential components at play. These animal models can then be used to generate predictions for therapeutic interventions, which can then be tested in human clinical trials. If a prediction is falsified, so is that specific animal model of the disease.

When this happens, scientists seek to understand how the data depart from the prediction, what factors were ignored that might play a role, and use prior knowledge and intuition to develop a better, improved model. In the course of developing and refining such a model, scientists will go through many such cycles. A model is expected to be valid if and only if it captures all the key ingredients of the human condition.

The fact that one can postulate inaccurate animal models of human disease does not invalidate the whole methodology of animal research, it merely shows the work is difficult. But animal models can in fact be successful.

knockout mice, animal research, animal rights

A laboratory mouse in which a gene affecting hair growth has been knocked out (left), is shown next to a normal lab mouse. (Courtesy NIH)

One of the proponents of the idea that animal research cannot be used to predict human response to disease is Dr. Ray Greek who was recently interviewed by Steven Novella for the Skeptics Guide to the Universe (as it turns out, Dr. Greek won a bid to appear in the podcast).

There is an interesting part of the exchange where Dr. Novella attempts to explain hat some models have indeed been extremely predictive of human response.  Starting at 15:45min into the program he gives Dr. Greek the example of a how SOD1 mutant mice have helped in the treatment of ALS.  The model “is a home run for humans with SOD1 mutation”, he said.

Dr. Greek’s reply was simply “Well, let’s face it.  If you study 10,000 genetically modified mice there is bound to be one that you are going to hit a home run with.”

In the eyes of Dr. Greek and the animal rights activists that adhere to his views, the type hard scientific work that leads to the development of a predictive model of human disease boils down to a mere chance discovery.

Dr. Novella tries insists that such a characterization of animal research as not predictive is meaningless — it is as if one were to ask “Does surgery work?”.  The answer, he says, is “of course, some surgeries work and some don’t, and you have to ask which ones work and for what [...] You [Dr. Greek] want to make a final pronouncement for surgery as a medical intervention.”

But there is little hope of getting the message across.

Dr. Greek retreats to discussing toxicology testing and declares disease research to be, well… “more complicated.”

Dr. Novella appears to politely give up in frustration and rapidly moves on with the rest of his show.

We sympathize.

Indeed, genetically modified mice have been and continue to be a very useful tool to dissect the roots of human disease and develop new treatments.  This includes the study of type II diabetes using mice with mutations in the glucokinase gene, the shaker1 mouse as a model of human genetic deafness, the role of genes in inherited psychiatric disorders, in cancer research in general and for the development of successful new therapeutics for breast cancer in particular, in the advance of new treatments for lupus, and Duchenne muscular dystrophy, and so on.

The Nuffield Council on Bioethics has a full chapter dedicated to how genetically modified animals are used in the study of human disease.

It is absurd for anyone to claim such advances are the product of chance.  They are the product of the hard work of dedicated individuals who spend countless hours in laboratories around the world with the goal of advancing the well-being of those affected by disease.  They are the product of those that go to bed thinking about how a protein may work, why muscles may weaken, how a tumor spreads, or why memory fails, in the hope of waking up the next day with some new ideas. They are the product of those that are determined to solve some of the most complex puzzles of biology that afflict human kind.  They are the product of talented students, staff and scientists that together work to rid the world of disease.  They are the product of science.

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YES to Animal Welfare and NO to a Ban on Animal Research

Posted on November 2, 2011 by | Leave a comment

The following is a guest piece by Prof. Michael Hengartner of the Basel Declaration. An organization founded in Germany to promote well-regulated humane research using animals.

The Goals of the Basel Declaration and the Basel Declaration Society

Animal welfare and scientific and medical progress are not contradictory. More than 800 international researchers have already shown their commitment to accepting greater responsibility in animal experiments by signing the Basel Declaration and supporting the corresponding organization. The Basel Declaration Society aims for a more impartial approach to scientific issues by the general public, and more trusting and reliable cooperation with national and international decision makers.

In November 2010, life science researchers from Switzerland, Germany, Sweden, France and the UK addressed the challenges of animal research and adopted the “Basel Declaration”. This document marks an unprecedented effort by the scientific community to achieve more trust, transparency and communication around animal research. The event was echoed in international media, among them the Scientific American, the Medical Tribune and nature.

“The high quality of medical care today would not have been achieved without research in animal experiments. It is important to inform society about the major significance of research using animal experiments for the health of humans and animals,”

- Prof. Dr. Burkhard Ludewig, Director of the Medical Research Center, Institute of Immunobiology, Kantonsspital St. Gallen, Switzerland.

Signatories to the Basel Declaration commit to accepting greater responsibility in animal experiments. They also sign up to intensive, unprejudiced dialogue with the general public. This dialogue is factual, and focuses on achieving concrete goals. The signatories additionally demand that animal experiments needed to obtain research results remain permitted, now and in the future.

“The Basel Declaration came about not in response to any specific occasion, but as a spontaneous voluntary commit­ment by the scientific community to the best-possible approach to indispensable animal experiments. We present a picture of our modern animal experiment-based science, the deliberation process, the basic conditions and our approach to the issue of animal experiments and show openly what we do and why,”

- Prof. Dr. Stefan Treue, Director, German Primate Center, Göttingen, Germany.

The goal is to make the Basel Declaration the worldwide ethical guideline on animal research, comparable to the Helsinki Declaration which defines ethical guidance on research into humans.

“Basically we have long regarded the principles behind the Basel Declaration as a matter of course, because no researcher performs animal experiments unnecessarily. The Basel Declaration establishes a platform for us on which we can network internationally in order to demonstrate this to the public more clearly still. The message is evidently getting across: For the first time we are now engaged in sustained dialogue with representatives of critical organizations in a spirit of genuine partnership that bring all sides together more than any extremist slogans do,”

- Prof. Dr. Rolf Zeller, Department of Biomedicine at the University of Basel, Switzerland and first President of the Basel Declaration Society, which was founded in September 2011.

The Basel Declaration Society celebrates its first birthday

Sign the Basel Declaration!

“The aim is for as many researchers as possible to learn of our initiative and affiliate themselves with it. We invite all colleagues and the general public to accept this offer of a genuine dialogue and to really live this Basel Declaration,”

- Prof. Dr. Michael Hengartner, Dean of the Faculty of Mathematics and Natural Sciences, Institute of Molecular Biology, University of Zurich, Switzerland.

Everybody involved in animal research or animal care around the world is asked to sign the Basel Declaration, and to become a member of the Basel Declaration Society. Doing so marks a commitment to strengthen public awareness of the importance of animal models in experimental biomedical research, to foster communication between researchers and the public, and to enhance acceptance of the Basel Declaration.

Animal research is under ever-increasing public and governmental scrutiny, even though its importance for biomedical innovation and the necessity of animal experiments to further knowledge in basic research are beyond controversy.

Scientists and technical staff conducting animal experiments face increasing public distrust, and often even aggressive rejection. Media covering the topic frequently lack objectiveness.

This is why already more than 800 international leading scientists have signed the Basel Declaration, to show their conviction that responsible animal research and the sustainable advancement of science and medical progress are compatible.

We hope you will join them with your signature.

Better education

“Animal experiments will remain necessary in biomedical research for the foreseeable future, but we are constantly working to refine the methods with animal welfare in mind,”

- Prof. Dr. Michael Hengartner, Dean of the Faculty of Mathematics and Natural Sciences, Institute of Molecular Biology, University of Zurich, Switzerland.

Advancing the knowledge, implementation and use of 3R principles to reduce, replace and refine animal experiments plays an important role in embedding the Basel Declaration in daily practice. All stakeholders, i.e. everyone engaged in experimental research, the general public and authorities/decision takers, must be made more aware of 3R principles and their current implementation. Moreover, 3R-related issues must be an integral part of scientific publications, and peer reviewers must be better informed about the use, dissemination and quality control of 3R methods. More research is required that captures results in a comprehensive and validated database related to 3R technology and methods.

The 3R principle (replace, reduce, refine) has its origins with William M. S. Russell & Rex L. Burch, who published their “Principles of Humane Experimental Technique” in 1959. These principles are regarded internationally as the guideline for avoiding or reducing animal experiments and the suffering of laboratory animals:

  • Replacement: replacement of animal experiments by methods that do not involve animals
  • Reduction: reduction in the number of animals in unavoidable animal experiments
  • Refinement: improvement in experimental procedures, so that unavoidable animal experiments

More than a piece of paper

On October 16-18, 2011, more than 80 international life sciences researchers and signatories to the Basel Declaration met in Berlin. Their aim was to continue making a constructive and active contribution to the debate taking place in society. They request that the incorporation of the new EU Directive on the protection of animals used for scientific purposes into national law by January 2013 happens consistently in all European countries, and to the highest standards – like those in Switzerland.

Animal Welfare is a high priority for scientists

The Swiss severity classification system helps to identify the impact of scientific procedures on the health and well-being of experimental animals. A thorough severity degree classification is essential for improvement in line with the 3R principles. It helps to define humane endpoints in advance, and to assess progress in refinement, project by project. Participants in the Berlin conference recommend the implementation of severity classification systems, and voluntary use of such systems by the scientific community in countries where these are not yet mandatory.

Obligation to the public

Berlin conference delegates unanimously agreed that science must not only take a clear stand on the responsible handling of laboratory animals, but also has to show greater transparency towards the general public. To make their motivation and methods more comprehensible to the public and decision makers, the researchers committed to cooperate more closely with politicians, the media and schools, and to give greater importance to the communication of science. As a first step they presented position papers, developed in working groups, to representatives of the European Parliament, the EU Commission and the Federal Swiss Veterinary Office FVO.

The Basel Declaration signatories acknowledge the need for greater discussion of animal experiment issues and also of the risks of research approaches and possible misuse of new technological developments. In addition, they declare their intention to communicate not only results und scientific controversies, but also processes and approval procedures, in order to foster a deeper understanding of research.

“We realize that society funds our research and has a lot of justified questions on the subject of animal experiments and on research in the life sciences. Our aim is to engage in an in-depth, sustained and transparent dialogue. This reduces anxieties and promotes acceptance of views – on both sides,”

- Prof. Dr. Michael Hengartner, Dean of the Faculty of Mathematics and Natural Sciences, Institute of Molecular Biology, University of Zurich, Switzerland.

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