Tag Archives: animal models

Guest Post: Predictability and Utility of Animal Models

This is a guest post on the utility of animal models in drug development, misconceptions about animal models, and alternative methods of drug development, by Dale M. Cooper, DVM, MS, Diplomate, American College of Laboratory Animal Medicine. Dr. Cooper has over 20 years of veterinary experience in private practice, and as a laboratory animal veterinarian in academic and pharmaceutical research.  He is committed to the welfare of research animals.

Part I  Predictability of Animal Models for Effects of Drugs in Humans

Mark Twain popularized an aphorism that “there are three kinds of lies: lies, damn lies, and statistics.”  While all of these strategies have been employed by animal activist groups to discredit animal based research, the misuse of statistics has the most significant impact, as the most believable lies have a kernel of truth to them. Such is the case with the intense efforts by animal activist groups to discredit the use of dogs and other animal models in biomedical research. The various statistics that are cited are that only 0.0002% of studies using animals result in an approved drug, over 90% of drugs shown to be safe or effective in animals fail to make it through human clinical trials, that animal models have a poor predictive value for the effects of drugs in humans, and that the a flip of a coin gives as good of a chance of predicting success in drug development as an animal model. Like all good lies, these statements have a kernel of truth, but are extremely misleading and demonstrate a significant lack of understanding of science and a general lack of critical thinking skills.

Graphs like this are misused to suggest that animal studies result in failures in human trials.

Experts in drug development understand the limitations of animal models, but they also understand their applications. There have been several publications that have retrospectively evaluated the value of animal models in predicting human safety across a variety of therapeutic areas and the overall percentage of human toxicities predicted by animal models is around 70% with variability between different species and body systems.  Predictability for some therapeutic areas are over 90%. When different models are used in combination, the predictability increases. It is also an established fact that only about 1 in 10,000 drugs tested make it to the market and that there is over a 90% attrition rate of drugs in human clinical trials.  How does this happen if animal models are predictive?

Studies that have evaluated the ability of animal models to predict clinical results in humans show very similar results, but the interpretation of the results is varied.  Authors who are acknowledged animal activists claim the results show poor correlation between results in animals and outcomes in humans (e.g ‘no better than a flip of a coin’). However, most scientists (and the FDA and NIH) assert that animal models predict outcomes in humans with good reliability. What is the disconnect? This is where statistics come in. The different papers argue over the use of a calculation for predictive value versus likelihood ratio. The results come out slightly different.  Predictive value calculations show better results for animal models than do likelihood ratio calculations, so animal activists tend to cite the likelihood ratios while overlooking the predictive ratios (see table below). I am not a statistician and therefore won’t weigh in on this point and will use the term ‘predictive value’ to refer to both terms.

What I feel is a far more relevant discussion is how we interpret positive versus negative predictive values.  In general, the positive predictive values of animal models are higher than the negative predictive values. What this means is that the presence of an effect in an animal model is a good indicator that the same effect will be seen in humans (positive predictive value).  However, if an effect is not seen in the animal that does not mean there won’t be an effect in humans (negative predictive value). Activists have focused on the negative predictive value, taking the position that because animal models don’t predict all effects in humans, they are not reliable and therefore, the use of animals in research is not scientifically justified. Is this a valid conclusion?  Let’s apply it to another risk assessment situation and see if this makes sense. Say I want to cross a road but don’t want to get hit by a car. My Mom taught me to look both ways and if I see a car coming I don’t cross the road. There is a positive predictive value to look before I cross. However, if I don’t see a car, that doesn’t always mean one isn’t coming. Depending on its speed or visibility there is still some risk when I cross a road. The negative predictive value of looking both ways isn’t as high as the positive predictive value. So do I bother to look both ways knowing it’s not 100% reliable?  Of course I do.  But I also do other things. I listen, I assess for visibility, I may look for a crosswalk or an overpass. Just like in drug development I understand the predictive value of my risk assessment and run more than one assessment.

The ignored statistics in Bailey’s papers on the prediction rates of animal research. PPV: positive predictive value, NPV: negative predictive value.

Unlike animal activists, biomedical scientists don’t have an agenda to limit the scope of research. We use the experimental systems that allow us to address the questions at hand to develop treatments that improve the lives of both humans and animals.  The models we are using are the ones that are the most successful. Animals are one type of model employed in biomedical research, but are by no means the only models.  Animal models are expensive and time consuming, and scientists recognize the emotional and ethical issues associated with animal research.  We are human and many of us have our own pets.  We bond with the animals we work with.  There is no incentive for us to employ an animal model that may negatively impact animal well-being if another model that does not negatively impact well-being works just as well.  The FDA requires animal data prior to clinical trials in humans, because they are also scientists and have come to the same conclusion — animal models provide essential data in predicting safety and efficacy of new therapies.

Part II Drug Development Without Animals

As discussed in a previous post, animal models are an important component of the development process for drugs and other medical treatments. But they are not the only method of research that is used.  Drug development is an iterative process.  Each study builds on data from other studies.  The process involves computer modeling, benchtop chemistry, a wide range of in vitro models to evaluate absorption, metabolism, distribution, receptor binding, gene expression, and even some aspects of toxicity. We use non-animal methods so much that over 90% of drug candidates are eliminated from consideration using in vitro assays before they even reach the phase of pre-clinical animal studies.

If animal activists groups or well-meaning scientists want to see more non-animal research methods developed and put into use, there is a process for this. The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) under the National Toxicology Program evaluates data to validate non-animal models for drug development in the US. There is a list of approved methods on their website. All of these methods were funded by the same research institutions that use animal models.  If activist groups wanted to make a significant impact on animal use in research, they might consider funding alternative research.  It is usually more effective to work on a problem rather than just talk about it.  The fact that we are still using animals isn’t because of a lack of trying, it is the limitation in our scientific knowledge. To build a model, you have to know a lot about the system you are modeling. In fact, it is possible there will never be a complete replacement of animal models in research. By the time we know everything to create the perfect model, we will have answered all of the research questions that can be asked.

The final stage of drug development involves clinical testing in human patients.  In vivo studies in animal models eliminate 90% of drug candidates from the development process before beginning clinical trials in humans, demonstrating their utility in de-risking the testing process in humans.. Over 1 million patients to enroll in clinical trials each year, yet there are few reports of serious adverse events relative to the number of patients in these trials.  When drugs fail during the clinical trial phase, the reasons are more often related to economics or strategy than they are to safety.  The testing in animals served an important purpose.

If society chooses to take more risk in the patient population, it has the power to do so. However, based on the data regarding predictive value of non animal models, this would mean that 70% of the time someone in a clinical trial would be likely to experience toxicity from a drug about which little is known because the nature of it was not first characterized in animal models. This means the physicians would not know how to treat it or the prognosis. It is already a challenge to enroll the number of patients needed for clinical trials even when providing them a significant amount of information so they can make an informed decision to consent to enroll. Having even less information would not likely help with this.

Laboratory mouse.

It is also not clear that humans are a better model for testing drugs than are animal models. It is extremely difficult to control variability in a human test population, due to diet, lifestyle, and genetics, which reduces the statistical power of a given study population compared to a well-controlled animal study. Clinical trials in humans enroll thousands of patients, whereas animal studies use fewer than 100 animals in many studies to achieve similar statistical power.  Humans also have a long lifespan and studying the chronic effects of a drug is difficult in a clinical trial.  In contrast, in 2 years, a rodent undergoes all life stages, allowing assessment of the effects of chronic drug administration. Finally, it would be very unlikely that humans would consent to participate in studies evaluating fetal toxicity, and even if they did, the long duration of human pregnancy and low reproductive rate (1 offspring every 9 months) reduces the power of detection relative to a rodent model that produces 10 offspring in 3 weeks.

It is true that all of these issues will be considerations in patients after a drug is in general use. There is some inherent level of risk in medicine. However, the development and approval process using both animal and non-animal studies is the best that science can currently offer.

Part III The Big Picture of Animal Use

We can argue over the scientific merits of the use of laboratory vs animal vs human testing in drug development, and we can pontificate about the ethics of the decisions we make, but ultimately, we humans have choices to make.  Are we content with our level of health and well-being?  What sacrifices are we willing to make to consider the needs of animals?  The impacts we have on animals go far beyond what level of medical care we choose.  Animals serve as food sources, they work for and with us, and they provide for aesthetics and companionship.  How much of that will we give up to reduce our impacts on them?  If we go that far, we are still competing with them for food and shelter.  Is it possible to not impact animals?  I contend that the ethics of our society show a considerable level of care for animals.  The fact that we worry at all about their welfare is something that to the best of my knowledge, no other species on the planet would do given the same choices we have.

Working with animals in research is not a one-way street.  Animals benefit from veterinary treatments developed through the same research process as for human treatments, and the animals we work with in the research environment benefit from the high level of care and attention to their well-being that is provided to them. People care about them and for them. They experience medicine as part of their lives as do we all. If they were living outside of the research environment they would still experience medical issues as a normal part of life, but particularly in the case of non-companion species, would not necessarily have anyone to care for them.

I believe that the arguments proffered to discredit work with animals in research are largely based on biased and misleading interpretation of data.  Where there are valid data to use alternatives, these alternatives are already being used.  It is appropriate scientifically and ethically to continue to develop and validate new approaches for predicting drug safety and efficacy in the patient population, both animal and non-animal.  Animals are used humanely and also receive benefits from biomedical research.  Ultimately, there is a balance being struck between the needs of humans and of animals.  There is room for constructive dialog on where this balance should be, but I personally do not believe that this should occur using the regulatory and legal systems as a venue.  Science is too intricate and complex to be able to effectively address in this way.  There is a process in place at all research institutions (the IACUC) to ensure ethical and scientific review occurs on each experiment.  Those seeking to drive alternatives would do better to develop the science to validate these alternatives rather than manipulate public emotion and ultimately public policy or law.

~Dale M. Cooper, DVM, MS, Diplomate, American College of Laboratory Animal Medicine.

 

 

Guest Post: Sex, Drugs and the Validity of the Animal Model

Dr. Swapna Mohan is a post-doctoral fellow at the National Institutes of Health. She is a veterinarian and recently completed her PhD in Molecular Physiology from Cornell University, NY. She is interested in maximizing the use of animals in research and agriculture, while keeping with humane and ethical standards.

The FDA has approved “female Viagra” flibanserin (a drug not without its controversies), for treatment of hypoactive sexual desire disorder (HSDD) in women. The drug, marketed as Addyi was initially tested as an anti-depressant. Clinical trials however, showed a statistically significant rise in satisfying sexual events reported by pre-menopausal women. A pre-clinical study on Long-Evans rats reports an increase in sexual behavior in females who have had their ovaries removed. Similar studies have been conducted on marmoset monkeys.

This inevitably leads to the question- how good are animal models at predicting human sexual behaviors? For this, we need to define sexual behavior. In animals this is easily described as manifested pre-copulatory behaviors, such as solicitation and copulatory behaviors, such as lordosis (arching of back). In humans this is a decidedly more complex phenomenon involving motivation and desire. Add to that societally influenced behaviors such as propriety (inhibitions against seeming overeager, showing desire to only specific people), thoughtfulness and affection and you get a whole grid of reactions constituting human sexual behavior.

Leopard Geckos mating

So how useful is it to use animals in pre-clinical studies of sexual dysfunction and drug response? For this, we need to first assess human sexual dysfunction and the criteria for evaluating drug response. Sexual dysfunction, especially female sexual dysfunction, is a group of symptoms with unclear causes- they maybe physical (failure of genital response, pain), chemical (fluctuation of serotonin and dopamine), psychological (anxiety, depression) in nature or a combination of all three. While most of the neurochemical changes might produce similar effects in animals and humans, the same cannot be said for hormonal changes. For instance, it is well known that ovariectomized (ovaries removed) female animals and females not in estrus (the period in which animals are in heat) show no response to males, whereas in women there is limited effect of ovarian hormones on sexual behavior as evidenced by sexual activity at different times of the menstrual cycle, and in post-menopausal women. Moreover, the manifestation of effects in humans and animals is also different. While a female animal may show avoidant behavior and defensiveness towards males, humans are known to engage in sexual relations despite having low desire for other reasons such as to maintain the relationship and as part of a transaction.

Similarly, there are fundamental differences in the act of copulation itself among species. For example, in rats copulatory sessions consist of alternating elements of approach and avoidance, mainly paced by the female. The female approaches the male, and moves away after an act of sexual stimulation has taken place. In humans it is a continuous session generally, with no avoidance or breaks in between. However, approach behaviors and more importantly, motivation for these approach behaviors might be similar in humans and animals.

Ideally animal models should respond to the same causative factors as humans with altered sexual activity. But it is very hard to assess something like the quality of a relationship in laboratory animals, despite it being one of the main reasons for lowered sexual activity in women. So does this mean that animals are useless as models of sexual function? Not at all. It just means that the questions we ask should be much more specific and our studies should be designed to reflect species similarities rather than differences. For instance, instead of focusing on copulatory behaviors such penile movements and lordosis, recent studies have shifted their attention to behavioral manifestations of desire and excitement such as increased locomotion and time spent near individuals of opposite gender. Such behaviors by themselves have not been used as indicatives of sexual activity in the past, but are now being considered anticipatory sexual behaviors. Reduced pacing was tested for being indicative of sexually anticipatory behavior in female rats, and in one study on the effect of the drug bremelanotide this behavior was significantly altered. And sure enough, when the drug moved onto Phase II clinical trials it produced the expected increase in arousal in women viewing erotic films.

But there is a potential for bias when using animal models. Care should be taken when interpreting an animal’s responses and correlating it to human response. It is very easy to anthropomorphize an animal and its responses. To prevent this, a thorough understanding of the social and behavioral processes of the species is essential. An oft cited example of anthropomorphism bias is the courtship behavior study of the fruit fly, Drosophila. Males communicate to females with wing flapping and researchers predicted that wing-clipped males would be less successful in mating because of the inability to produce flapping sounds. When the experiment was carried out however, wing-clipped males performed better than control males! The authors go on to explain that because they did not understand the fly’s ability to sense vibrations in addition to hearing sounds, it escaped their notice that the wing-clipped males could now produce faster vibrations (wing-beats).

Grouses Humoncomics

Image courtesy of Humoncomics

So validation is required not only for the experiments and the animal model used, but also for the way data is interpreted from these animal studies. While outwardly the causes of lowered sexual desire in humans maybe many (workplace stress, relationship issues) the underlying neural mechanisms of most are analogous to that of animals (anxiety, depression, addiction). Ultimately, humans and animals are biological entities. Animal studies have been invaluable in providing data for pre-clinical research of a wide range of diseases and disorders. Especially in the case of therapeutics, an understanding of the basic underlying physiology makes it easier to predict mechanisms of action and possible side effects.

However, it’s useful to keep in mind that not every disorder can be treated with just pharmacological intervention. And because of various root causes that are not physiological in nature, sexual dysfunction falls into this category. So in such cases it’s especially important to have valid animal models that provide consistent information that can be extrapolated to humans. Of course, a lot of gaps exist in our understanding of behavioral processes. So animal models can only be used by carefully defining criteria for evaluation, and by constant assessment and evaluation.

Swapna Mohan, BVSC (DVM), MS, PhD

Acknowledgements: This research was supported by the Intramural Research Program of the NIH, The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Guest Post: CRPS Animal Models Explained

The following guest post is by Dr Rosie Morland. Dr Morland recently completed a PhD in neuroscience and pain studies at Imperial College, London, and she has a particular interest in how animal models can help increase understanding of complex pain disorders. You can read more from her on her blog. The article was originally published on the Burning Nights website which seeks to raise awareness about Complex Regional Pain Syndrome (CRPS) in the UK and Worldwide. It is republished with permission from the original author and Burning Nights website. CRPS, formerly called Reflex Sympathetic Dystrophy (RSD) is a chronic pain condition which usually affects the limbs and can result in prolonged pain. More information on CRPS can be found in this leaflet.

Developing Animal Models of CRPS/RSD Explained

In the last 20 years, research into Complex Regional Pain Syndrome (CRPS) has seen huge advances, taking it from a little understood and assumed-rare condition, to the realisation that it is an incredibly complex disorder that may in fact describe a whole group of related pain conditions.

Defining CRPS

CRPS often develops after a seemingly minor injury, which instead of healing normally triggers an over-reaction of pain and inflammation systems in the body.

The Budapest criteria are often used to diagnose CRPS. These look at four main categories of symptoms as shown below:

The Budapest Criteria CRPS

These symptoms are used to identify CRPS according to the following checklist:

  • A: Ongoing pain at an intensity which cannot be explained by the triggering event (e.g. a fall or fracture)
  • B: at least one sign (i.e. measured experience) from two or more of the four categories above
  • C: at least one symptom (i.e. reported experience) from three or more of the four categories above
  • D: A lack of alternative diagnosis

Hypothesis Experiment Results Conclusion

Developing Animal Models of CRPS

This last point highlights the difficulties both doctors and researchers face when trying to develop animals models of CRPS. Animal models can be incredibly informative when trying to understanding how painful conditions develop – they have been used to identify changes that occur at the cellular level in pain, helping to understand the changes that take place when pain changes from acute (useful & teaches us to avoid the dangerous things in life), to chronic (pain that just won’t go away). So far, pain researchers have found that the way the body reacts to pain depends on what caused the pain, and also to some extent on individual factors such as genetics, previous life experience, and lifestyle.

When developing animal models, the researcher must first establish that what they are doing is a valid and accurate representation of the human condition. This applies to both how the model is induced (i.e. what causes the condition), and what signs/symptoms can be detected. For CRPS, this situation is complicated by a lack of understanding of what causes the disease, huge variation in how patients experience the condition, and a reliance on reported symptoms. For researchers trying to develop accurate models, reported symptoms are the greatest challenge.

In CRPS, animal models usually take one of two forms:

  • A: Traumatic – based on traumatic conditions that can trigger CRPS, such as accidents
  • B: Immune – looking at how a dysfunctional immune system can contribute to CRPS

Most models are in this first category, and are based on evidence that CRPS develops following a relatively minor accident, such as a fall resulting in broken skin and/or bones. Such injuries affect the body in a number of different ways, and so are best looked at by breaking them down into elements, such as the effect of a fracture and subsequent bed-rest (‘immobilisation’); how nerves change the way they transmit pain signals when they are crushed by swelling, fractures, or other injuries; and how damage can happen when the blood supply is restored to an injured limb. Together, these models can identify how each different element of an injury contribute to the symptoms experienced.

Background concept illustration Immune system health medical word cloud wordcloud

Background concept illustration Immune system health medical word cloud wordcloud

As the immune system is incredibly complex, and it has been difficult to identify a unique “signature” for the immune response in CRPS, there are fewer researchers looking at the immune aspects of CRPS. However, a recent study found that disrupting the activity of a certain type of immune cell (B cells) in mice decreases CRPS-like behaviours such as pain and negative vascular changes following a fracture. This suggests that being able to control the immune reaction could decrease the chances of developing CRPS following an injury. Other studies have looked at the effect of nerve inflammation, as present following a minor injury, and what factors are responsible for the transition from normal immune response to injury, and the uncontrolled response immune seen in CRPS.

Another recent study looked at the role of the immune system from a different angle, by injecting serum from CRPS patients into mice. Samples from CRPS patients have been shown to have high levels of inflammation, and when this was injected into mice, they showed CRPS-like symptoms that not seen in mice injected with serum from healthy volunteers. This suggests there is something different in the serum of CRPS patients that could explain the different reaction to injury. However, in this study, the patient group was selected to be similar, and as CRPS can present in a wide variety of ways, these results are only relevant to that specific patient group. Studies are already in progress to try and link what is seen in serum to specific symptoms experienced, so in the years to come, we can expect a lot more work like this.

Measuring Symptoms in Animal Models

Once a model has been made, the researcher must then find ways of testing for the signs/symptoms reported by patients. Not all of these are easy to detect in animals, pain being one of the most difficult. Most methods of measuring pain in animals look only at hypersensitivity. Hypersensitivity, or the perception of pain greater than would be expected, can be measured in animals by looking at how different models change responses to increasing temperature (up to 48°C), and increasing force (using a hair-like instrument – von Frey Hairs). However, pain is not just a sensory experience, and is always associated with emotional symptoms, which are just as damaging to the sufferer, and much more difficult to measure in animals. To study this aspect of pain, researchers look at changes in the natural behaviour of the animal, such as how readily they explore a new space (theory: pain decreases the perceived risk of exploration), and also how they react to other animals (theory: animals in pain behave differently around other animals based on whether they are familiar or a risk). It is very important when studying pain to ensure that any treatments developed tackle both the sensory and emotional aspects of pain.

As discussed, most models used to study CRPS are limited in their application, as they focus on a very specific set of conditions, such as bone fracture models only being applicable to CRPS patients who developed the condition via fractures, or the immune serum study only applying to patients which fit the same profile.

By looking at a range of different symptoms of CRPS, and how they compare across different models, researchers should be able to build up a detailed picture of what factors contribute to each symptom and how they can be combatted.

It is important to recognise that advances in CRPS research are reliant on identifying the biological changes responsible for the symptoms of CRPS, and without a definitive cause the only way to do this is to look at a range of different models. As we learn more about the processes happening in the body that are responsible for each symptom, and how they change during disease progression, we get closer to developing useful treatments that take into account all the different ways CRPS patients experience the condition. The personal nature of the pain experience, combined with the variation in symptoms experienced in CRPS mean there is never, alas, going to be a one-size-fits-all treatment, but with greater understanding, diagnoses could become more accurate, and appropriate treatments, based on the unique symptom profile of the patient could become a reality.

Some interesting open access articles on models of CRPS:

Linnman, C et al. (2013) ‘Inflaming the brain: CRPS a model disease to understand neuroimmune interactions in chronic pain,’ Journal of Neuroimmune Pharmacology & NCBI NIH. June 2013. Vol 8 (3) pp 547-563. Available from: < http://www.ncbi.nlm.nih.gov/pubmed/23188523> doi: 10.1007/s11481-012-9422-8

Cooper, M.S., Clark, V.P. (2013) ‘Neuroinflammation, neuroautoimmunity, and the co-morbidities of complex regional pain syndrome,’ Journal of Neuroimmune Pharmacology & NCBI NIH. June 2013. Vol 8 (3), pp 452-469. Available from: <http://www.ncbi.nlm.nih.gov/pubmed/22923151&gt; doi: 10.1007/s11481-012-9392-x

Dr Rosie Morland

Why is alcohol research with nonhuman animals essential?

The following guest post is from Jeff Weiner, a Professor in the Department of Physiology and Pharmacology at Wake Forest School of Medicine.  Dr. Weiner is the Director of an NIH-funded translational research grant that employs rodent, monkey and human models to study the neurobiological substrates that contribute to alcohol addiction vulnerability.  He is also a founding Co-Chair of a new Animal Research and Ethics committee established by the Research Society on Alcoholism.

Jeff Weiner

Jeff Weiner

I am a neuroscientist who directs a translational research program which uses humans, monkeys, and rodents to study  the neurobiological mechanisms associated with increased vulnerability to alcoholism. As an addiction researcher, I am frequently asked why we need to study this topic or why we need to use animal models in our work. I’ve often heard people say that “alcoholism is not really a disease” or that “alcoholics just lack the will to quit drinking”. Others have asked “what can we possibly learn about alcoholism by studying monkeys or rats”?   Well, there are some very good answers to these questions.

First of all, alcoholism is most definitely a disease. While it may be more difficult to diagnose than other illnesses like cancer or diabetes, there is overwhelming evidence, from human and animal studies, that excessive alcohol exposure profoundly changes the brain (and many other organ systems). We now know that alcohol-induced changes in brain activity can last for a very long time, even after the drinking behavior stops, that these neuronal alterations actually make it harder for an addict to quit, and much more likely to relapse when they finally do stop drinking. This research may help to explain why alcohol use disorders affect 5-8% of the US population at a cost to the economy in excess of 180 billion dollars and that alcohol accounts for 4% of the global burden of disease1.

Alcohol consumption USA alcoholism (2)Unlike Huntingon’s disease, alcoholism is not caused by a single gene defect. However, basic research has shown that a complex interaction between our genes and environmental factors, like chronic stress and exposure to traumatic events, can dramatically increase susceptibility to alcohol use disorders. These findings may help to explain why members of our military and their families are disproportionately affected by alcoholism.

Animal research has contributed greatly to the advancement of treatments for alcoholism. Animal models of alcohol use disorders have played an essential role in the discovery of two FDA-approved medications for the treatment of alcohol addiction (naltrexone and acamprosate). In addition, many new pharmacotherapies that have shown promise in animal models are currently being tested in human clinical trials. These new medications may prove even more effective at treating alcohol addiction.

In fact, one recent example illustrates just how powerful animal models of alcohol addiction can be. In 2008, researchers at the Scripps Research Institute in La Jolla, CA used a sophisticated rodent model of alcohol dependence (that they had spent years validating) to show that an FDA-approved anticonvulsant drug called gabapentin might be particularly effective at reducing the escalation in alcohol drinking that occurs after rats have become physically dependent on this drug2. Other researchers at Scripps quickly followed up on these exciting findings and recently completed a carefully controlled, clinical trial testing gabapentin in treatment-seeking alcoholics.   The results of this study, recently published in JAMA Psychiatry, revealed that gabapentin significantly reduced alcohol intake and dependence-associated symptoms like craving, depression, and sleep disturbances3. While much more work needs to be done to confirm these promising initial findings, these studies clearly demonstrate how effective animal models can be in our quest to discover better treatments for this devastating disorder.

It is worth noting that the vast majority of animal research on alcoholism is with rats and mice. Rodents can effectively model many elements of addiction including symptoms of tolerance, dependence, withdrawal, and relapse. Non-human primate models of alcoholism have also proven invaluable in helping to translate discoveries from rodent models to humans.

It is also worth mentioning that all animal research is regulated at multiple levels and by multiple entities. At the federal level the United States Department of Agriculture (USDA) is charged with enforcing the regulations under the Animal Welfare Act (AWA). This Act also requires that animal research be overseen and monitored by local animal care and use committees at the institutional level. Furthermore, research funded by the National Institutes of Health (NIH) must also meet standards for animal care and use as set forth by the Public Health Services (PHS) Policy.

So, while some may still question whether or not alcoholism is really a disease, it seems difficult to argue against the idea that more research is needed to address the huge medical and socio-economic costs associated with alcohol use and abuse. It also seems clear that animal models are a valuable tool that are accelerating the drug discovery process and helping to bring urgently needed treatments to the clinic.

For more information: http://www.niaaa.nih.gov/

References

  1.             Rehm J, Mathers C, Popova S, Thavorncharoensap M, Teerawattananon Y, Patra J. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet. Jun 27 2009;373(9682):2223-2233.
  2.             Roberto M, Gilpin NW, O’Dell LE, et al. Cellular and behavioral interactions of gabapentin with alcohol dependence. J Neurosci. May 28 2008;28(22):5762-5771.
  3.             Mason BJ, Quello S, Goodell V, Shadan F, Kyle M, Begovic A. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA internal medicine. Jan 2014;174(1):70-77.

Guest Post: Characterising high fructose corn syrup self-administration in laboratory rats

It’s January, and across the country millions of people have promised themselves that they will eat less, loose weight and become healthier. But why do some people eat more than others? No matter what they try there seems to be no way to stop their overeating. Public education is a powerful tool to combat some of these issues but what happens when it turns into an addiction? It is challenging to provide accurate information when food addiction is a little studied field. In an effort to answer these questions scientists can use laboratory rodents to explore neurobiological mechanisms involved in relapse to drug-seeking behavior, comorbid mood and substance dependence disorders, as well as perseverative reward seeking. These complex answers cannot be solely obtained though human patients because the physiological and psychological mechanisms that influence food addiction are not fully understood.

AnneMare Levy is a PhD student and Francesco Leri is an Associate Professor of Neuroscience and Applied Cognitive Science in the Department of Psychology at the University of Guelph. In the article below these scientists explain how and why the development of a new animal model to understand the addictive properties of some foods is necessary and how its use can begin to answer some of these questions. They believe that through studying rats their findings could lead to novel pharmacological interventions for obese individuals that could help them selectively reduce intake of unhealthy foods.

The views expressed below are that of the authors alone and do not necessarily reflect the views of her employer or institution.

Overconsumption of foods high in sugars and saturated fats is an important contributing factor to the modern epidemic of overweight and obesity1, which are leading causes of metabolic disorders and cardiovascular diseases2. It is therefore important to understand why patterns of excessive food intake develop and persist despite the negative health consequences. Considerable evidence supports the hypothesis that, for some people, addiction to food may motivate these behaviours3-4. In fact, behavioural and neurobiological similarities between obesity and drug dependence support the “food addiction” hypothesis5-8 and studies in both humans and laboratory animals have identified a variety of biological and behavioural indicators of “food addiction”9-12.

The food addiction hypothesis suggests that similar to drugs of abuse, particular foods should reinforce behaviours that lead to their consumption. Therefore, to assess the addictive potential of such foods, we adapted procedures commonly used for studying the reinforcing properties of drugs of abuse (i.e. operant intravenous drug self-administration) to the investigation of operant self-administration of sweet solutions delivered directly into the mouth of rats. To this end, an intraoral cannula was surgically implanted13 into the cheek of rats and the animals were subsequently trained to press a lever to voluntarily receive a test solution directly into their mouth; hence the term intraoral self-administration. The sweet solution selected for testing was high fructose corn syrup (HFCS) because, although controversial14, there is evidence that HFCS may be linked to the modern epidemic of obesity15.

corn-syrup

The disadvantage of requiring minor surgery to employ this procedure is offset by several advantages that make intraoral self-administration in rats optimal for studying the reinforcing properties of sweet solutions. First, an operant response (i.e., pressing a lever) is required to obtain an infusion and therefore it is possible to modify the schedule regulating the relationship between response requirement and delivery of intraoral infusions. Hence, by employing a progressive ratio (PR) schedule16, whereby more lever presses are required to get more sweet solution, it is possible to assess how much an animal “wants”17 the next infusion and by employing a continuous schedule of reinforcement, whereby each lever response is reinforced, it is possible to measure total intake, escalation of intake, and the development of bingeing behaviour.  Second, intraoral self-administration allows testing of any concentration and any volume of any water-soluble food additive. The importance of controlling and manipulating concentration/volume ratios is mandatory in experiments where intake can be modulated both by the caloric value of a solution (i.e., nutrient-specific satiety) and by how much of that solution can be consumed within a given period of time (i.e., fullness)18. Third, intraoral self-administration shortens the delay between the operant response and the delivery of the primary reinforcer, a factor that plays an important role in the acquisition and maintenance of operant behaviour19-21. Finally, this procedure allows for the delivery of passive intraoral infusions of controlled quantities of the test solution.  This makes it possible to measure orofacial responses of “liking” (objective hedonic reaction such as tongue protrusions)22 as well as administer priming infusions23 of the test solution prior to tests of reinstatement of sweet-seeking behaviour.

The objective of this study was to characterize HFCS self-administration behaviour in laboratory rats. It was important to establish a reliable animal model of self-administration because it will allow future studies to identify and manipulate the neurobiological substrates that are responsible for the escalation and maintenance of excessive food intake. Moreover, using this animal model, the rats will be able to self-administer solutions for extended periods of time (i.e. months) to establish how sweeteners, such as HFCS, may contribute to the development of metabolic disorders.  For all experiments, rats were surgically implanted with an intraoral cannula while under an anaesthetic. Post-operative care included administering analgesic, daily flushing of the cannula with an anti-bacterial solution as well as closely monitoring weight gain and food intake. Following recovery, rats received one 3-hour self administration session per day, whereby, rats were placed into a standard operant chamber and trained to lever press to receive intraoral infusions of different concentrations of HFCS (8%, 25%, and 50%) on either continuous or PR schedules of reinforcement, as previously described.

It was found that the behavioural profile of rats responding for HFCS is similar to the pattern of intake observed when rats self-administer drugs of abuse24-25. Using intraoral self-administration, it was established that on a continuous schedule of reinforcement, rats acquire and maintain intraoral self-administration of a wide range of HFCS concentrations (8%, 25% or 50%), and that rats adjust their self-administration behaviour according to the different concentrations (i.e., rats self-administer twice as much a 25% solution than a 50% solution)13.  Furthermore, higher concentrations of HFCS engender higher responding on the PR schedule of reinforcement, suggesting that increasing the HFCS content likewise increases the reinforcing value of the solution. The relationship between operant responding and HFCS concentration on continuous and progressive ratio schedules is similar to the dose-response relationships observed when rats self-administer drugs of abuse24.

It was further noted that total intake of 25% HFCS escalated over three weeks of testing, possibly reflecting the development of “bingeing” behaviour9,13. In fact, after a week of self-administration, rats displayed a clear period of elevated intake during the initial 90 minutes of each self-administration session and this “loading” increased in magnitude over the weeks of training. This effect is reminiscent of escalation of drug intake and increased loading that are observed when rats have prolonged and/or repeated access to drugs of abuse26.

The results of these experiments also indicated that HFCS is reinforcing because of its caloric content. Even though 0.1% saccharin (a non-caloric sweetener)27 and 25% HFCS produce similar hedonic reactions (i.e. the perceived palatability of the two solutions is similar in tests of taste reactivity17), 0.1% saccharin could not maintain self-administration at the same level that 25% HFCS. Moreover, when substituted for HFCS, a wide range of saccharin concentrations (0.01%, 1.0%, and 10%) significantly reduced self-administration behaviour, indicating that HFCS reinforcement is largely determined by its caloric content rather than its palatability.

Taken together, these experiments indicate that intraoral infusion of HFCS reinforces lever-pressing in rats, and this behaviour was maintained primarily by the caloric content and not the palatability of the solution made available for self-administration.  In these rats, stable self-administration was maintained for up to three weeks, it was concentration-dependent, and rats developed a tendency to “binge” on HFCS at the start of sessions. Using intraoral self-administration, future studies should investigate the possibility that HFCS engenders other “addictive-like” behaviors, and whether escalation of HFCS self-administration can be causally linked to the development of metabolic changes (i.e., weight gain, insulin resistance) associated with obesity and type-2 diabetes.

AnneMarie Levy & Francesco Leri

University of Guelph

University of Guelph

Department of Psychology, NACS

References

1. Barry D, Clarke M, Petry NM (2009) Obesity and Its Relationship to Addictions: Is Overeating a Form of Addictive Behavior? Am J Addict 18: 439-451.

2. World Health Organization (2013) Obesity and overweight Fact sheet N°311. Available: http://www.who.int/mediacentre/factsheets/fs311/en/index.html#. Accessed 20 June 2013.

3. Davis C, Carter JC (2009) Compulsive overeating as an addiction disorder: a review of theory and evidence. Appetite 53: 1-8.

4. Ifland JR, Preuss HG, Marcus MT, Rourke KM, Taylor WC, Burau K, Jacobs WS, Kadish W, Manso G (2009) Refined food addiction: a classic substance use disorder. Med Hypotheses 72: 518-526.

5. Avena NM, Bocarsly ME, Hoebel BG, Gold MS (2011) Overlaps in the nosology of substance abuse and overeating: the translational implications of “food addiction”. Curr Drug Abuse Rev 4: 133-139.

6. Volkow N, Wise RA (2005) How can drug addiction help us understand obesity? Nat Neurosci 8: 555-560.

7. Fortuna J (2012) The Obesity Epidemic and Food Addiction: Clinical Similarities to Drug Dependence. J Psychoactive Drugs 44: 56.

8. Levy AM, Salamon A, Tucci M, Limebeer CL, Parker LA, Leri F (2012) Co-sensitivity to the incentive properties of palatable food and cocaine in rats; implications for co-morbid addictions. Addict Biol:  doi: 10.1111/j.1369-1600.2011.00433.

9. Avena NM, Rada P, Hoebel BG (2008) Evidence for sugar addiction: behavioural and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev 32, 20-39.

10. Gearhardt AN, Davis C, Kuschner R, Brownell KD (2011) The addiction potential of hyperpalatable foods. Curr Drug Abuse Rev 4: 140-145.

12. Johnson PM, Kenny PJ (2010) Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat Neurosci 13:  635-644.

13. Levy AM, Limebeer CL, Ferdinand J, Shillingford U, Parker LA, et al. (2014) A novel procedure for evaluating the reinforcing properties of tastants in laboratory rats: operant intraoral self-administration. JoVE: in press.

14. White JS (2008) Straight talk about high-fructose corn syrup: what it is and what it ain’t. Am J Clin Nutr. 88: 1716S-1721S.

15. Bray GA, Nielsen SJ, Popkin BM (2004) Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity, Am J Clin Nutr 79: 537-543.

16. Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66: 1-11.

17. Berridge, K. C., & Robinson, T. E., Parsing reward. Trends in Neuroscience 26 (11), 507-501(2003).

18. Houpt, K. A. Gastrointestinal factors in hunger and satiety. Neuroscience and Biobehavioural Reviews 6 (2), 145-164 (1982).

19. Panksepp, J. & Trowill, J. A. Intraoral self injection: I. Effects of delay of reinforcement on resistance to extinction and implications for self-stimulation. Psychonomic Sciences 9 (7), 405-406 (1967)

20. Mazur, J. E. Effects of rate of reinforcement and rate of change on choice behaviour in transition. Journal of Experimental Psychology 50 (2), 111-128 (1997).

21. Samaha, A. N., & Robinson, T. E. Why does the rapid delivery of drugs to the brain promote addiction? Trends in Pharmacological Sciences 26 (2), 82-87 (2005).

22. Berridge, K. C., & Kringelbach, M. L. Affective neuroscience of pleasure: reward in humans and animals. Psychopharmacology (Berl) 199 (3), 457-480 (2008)

23. Shaham, Y., Shalev, U., Lu, L., De Wit, H., & Stewart, J. The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl) 168 (1-2), 3-20 (2003).

24. Deroche-Gamonet V, Belin B, Piazza PV (2004) Evidence for addiction-like behaviour in the rat. Science 305: 1014-1017.

25. Carroll ME, Lac ST (1997) Acquisition of IV amphetamine and cocaine self-administration in rats as a function of dose.  Psychopharmacology 129: 206-214.

26. Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282: 298-300.

27. Miller SA, Frattali VP (1989) Saccharin. Diabetes Care 12: 74-80.

Animal welfare inspectors clear UW-Madison cat research of PETA allegations, important hearing research continues

A second federal agency charged with oversight of animal research has completed a thorough investigation of an animal rights group’s complaints about sound localization research with cats at the University of Wisconsin. Summary of the result:  “there was no direct noncompliance with the PHS Policy or serious deviation from the provisions of the Guide for the Care and Use of Laboratory Animals.”

We have written previously (here, here, here) about reviews conducted by the United States Department of Agriculture (USDA). This time the report is from the National Institutes of Health (NIH) Office of Laboratory Animal Welfare (OLAW).  Once again, the complaint by PETA is based on hundreds of pages of records that the animal rights group received from the UW via open records requests.  In response to these complaints both federal agencies have sent teams that include veterinarians to look at the animals, records, and research at UW-Madison.

new graphic - AR cycle 10.07.13 ajbIn addition to the USDA and OLAW reviews, during this period the NIH institute funding the sound localization project, the National Institute on Deafness and Communication Disorders (NIDCD), also took action. NIDCD suspended one part of the research— but not the entire project— from April-September 2013 when the final report was issued. Whether the suspension was the result of PETA’s allegations is not clear. What is clear is that the NIH and scientific community have long supported and valued this specific research and– more broadly–  the contribution of animal models to success in this field and advances in scientific understanding and human health. The PI of this work, Professor Tom Yin, has been funded by NIH for many years. As is the case of all NIH-funded research, a competitive expert scientific panel provides rigorous critical analysis of the proposed science. Only a small fraction of proposals are identified as valuable, worthwhile, and likely to succeed. In this case, the PI’s research was deemed justifiable and worthy following scientific review, NIH review, and IACUC review. Furthermore, the scientific contributions Yin’s work is evident in many ways. For example, it is widely cited in the field (e.g., over 5000 citations of his scientific papers). Yin discusses the targeted research in these videos:

In brief, Professor Yin’s laboratory conducts fundamental basic research that has resulted in better understanding of complex brain function and how hearing works. By using a combination of electrophysiological recordings, anatomical studies and behavioral studies, the lab is studying the mechanisms used by the brain to put together inputs from the two ears to improve hearing. The scientific discoveries have public benefit because they provide foundational understanding with broad applicability. Knowing how the brain integrates sound received by both ears and how that allows for localization of sounds is an important part of work towards improving the quality of life and functioning of millions of people with hearing impairment.

Many types of research in this area require recording and studying a real functioning brain, there are no non-animal alternatives. Cats are among the best animal models for this work for a number of reasons. Among them: most of the information we have about the auditory system comes from studies in cats, they are nocturnal hunters with excellent sound localization abilities, and what we know about the cat’s nervous system shows that it is very similar to that of humans. The importance of cats and other animal models to research in this field is widely acknowledged, including by this year’s Lasker-DeBakey Clinical Medical Research Award, and particularly the work of Graeme Clarke, which laid the foundations for the development of multichannel cochlear implants through studies in cats and rats.

As we have discussed previously, consideration of the use of animals in research includes not only weighing its potential benefits, but also evaluation of the animals’ welfare. The welfare of all of research animals is a priority and one that is ensured through the careful efforts of research, veterinary, and animal care personnel. Furthermore, oversight of animals’ care and treatment occurs at individual, institutional, and federal levels. A small number of cats (less than a dozen) participate in UW-Madison’s sound localization research. The cats are healthy and well-adjusted to their work, play, and living environments as was documented in the OLAW report. In that report, external reviewers who had thoroughly reviewed the lab and records, examined the animals, and interviewed the animal care and veterinary personnel, research staff, and scientists were satisfied with the animals’ condition and treatment.  Potential for pain or suffering is minimized through careful efforts: Surgery is performed under deep anesthesia, just like surgery for humans. Infections are a risk, but they affect the animals only a fraction of the time they are in study. Furthermore, infections are caught early through extensive and careful monitoring, treated immediately and resolved quickly in all but a very small number of cases. In no cases are they allowed to be untreated or to cause suffering or unrelieved pain.

OLAW’s summary conclusion, released September 30, confirmed that the research and animal treatment were appropriate: “there was no direct noncompliance with the PHS Policy or serious deviation from the provisions of the Guide for the Care and Use of Laboratory Animals.” Furthermore, the report concluded that PETA’s specific allegations were unsupported. The report also acknowledged UW’s efforts to continue refinement in the animals’ care and treatment:  “OLAW found that while the specific allegations did not accurately reflect the entire clinical and research condition of the cats, changes were made to enhance the care of the animals and potentially improve research outcomes.” Furthermore, the report includes many extremely positive descriptions of the animals’ condition and care.

UW responded:

“The OLAW investigation is the third review of the lab and its animal subjects by the federal government, all instigated by PETA within the past year. To date, none of the many allegations of mistreatment made by the organization to the U.S. Department of Agriculture or OLAW have been substantiated. ‘Contrary to the misleading claims made by PETA, the conclusions cited in the OLAW report reflect our view that the animals in the study are in excellent health, are well treated and cared for, and used to further important research in an appropriate and humane manner,’ says Dan Uhlrich, UW-Madison associate vice chancellor for research policy.  ‘Significant university and federal resources have been repeatedly redirected to respond to these unfounded allegations. This is a questionable use of scarce and valuable public resources, which we feel damages the best interests of the public, science, affected researchers, and the dedicated animal care and veterinary staffs responsible for the health and wellbeing of our animals.”

The OLAW summary report, including 36 appendix exhibits, can be found on their website. The UW has also shared detailed information about the research, the reviews, and the animal program with the broad public via its website, release of hundreds of records, and videos in which the scientist and others speak about the value of the work and how it is conducted.  In other words, as we’ve noted before, there are many venues for the public to learn more about the work, its conduct, and the detailed process of regulatory oversight.

What was PETA’s response?

Hint:  It did not include acknowledgement that OLAW, USDA, and the University of Wisconsin gave serious consideration to PETA’s complaint, performed a thorough investigation, and provided a detailed, specific public response on each of the allegations that the animal rights group raised. Nor did PETA’s response include an acknowledgement that perhaps they were wrong.  And nothing in their public responses indicated – front and center – that PETA’s mission and objective is to end all animal research. PETA’s position is fundamentally absolutist. Regardless of animals’ welfare and regardless of the consequences for the public that benefits from responsible, ethical and humanely-conducted animal studies, PETA is opposed to all use of nonhuman animals. Thus, there are presumably no conditions under which PETA would find laboratory animal research acceptable. (We welcome correction from PETA if this is a misrepresentation of their position.)

It is not surprising then that, as reported in the Wisconsin State Journal, PETA’s spokesman did not accept the OLAW conclusion, but rather vowed:  “This campaign is going to continue until that lab is empty and there are no cats in it,’” Goodman said without specifying the group’s next steps.”

PETA’s next steps in its quest to close the laboratory will probably include some of the characteristic stunts for which they are famous. At the UW this has included small protests on campus, the PETA mobile billboard truck driving around Madison, and an actor and PETA staffer gaining media coverage for disruption and arrest at a UW System Board of Regents meeting. Review of their campaign strategy thus far provides a few other clues for what to expect at the UW and elsewhere. For example, last week PETA set up at the campus job fair to recruit for an “undercover investigator.”  PETA’s Jeremy Beckham netted a local television interview with the tactic. Not a new tactic for animal rights groups, as seen in this campaign directed at Oregon Health Sciences University several years ago.

As we’ve written before however, focusing on these stunts and underestimating the broader gains that PETA has made and that negatively affect science and public interests can be a mistake.  In the case of this campaign and all of the associated events, two things in particular are worth notice by the broader community.  First, the way in which PETA used the openness of records and the public responsiveness of the regulatory process to feed their campaign; and second, the use of emotive tactics that encourage harassment of scientists and others in research institutions. The graphic above captures the general strategy used by many activist groups, highlights the costs, and raises a number of questions. In particular, one question that merits serious discussion is how to better assess the full range of actual costs and critical evaluation of realized benefits to animal welfare, science, and public interests.

Despite the conclusion of multiple federal reviews that failed to support their allegations, PETA is continuing to smear the research and to promote petition and email campaigns to the NIH, UW-Madison, and others. As one of the exhibits in the OLAW report shows, the NIDCD received 562 phone calls and approximately 190,000 emails about cat research. While that represents a tiny fraction of the American public and likely includes many form messages, its inclusion in the OLAW report suggests it may have been relevant to the NIH’s response.  No doubt that number increased after PETA linked a form email to its mixed martial arts assault on scientists videogame in order to encourage players to complain to NIH about the UW research.  Of course the game also encourages players to entertain the idea of harming scientists. As we’ve seen before, these highly emotional tactics can have the general effect of eliciting threatening and disturbing messages from those who follow PETA. For example, this recent tweet:

Beth Carter 10.5.13 tweet

The PETA campaign and response following the USDA and OLAW reports makes their objective clear once again:  to end research and close labs. Nothing new there. The question to ask now however, is how research institutions, scientists, federal agencies, and the public should respond to campaigns like this. In particular, this set of events provides additional strong evidence that there is little broad value in engagement with groups that have a singular agenda and little interest in serious dialogue, accuracy, or acknowledgement of the complex issues and choices in animal research conducted for public benefit.  For scientists and research institutions interested in dialogue and better understanding of animal research, using that time and energy to communicate directly with the public about their research, why they are doing it and what it involves makes more sense.

More here:

https://speakingofresearch.com/2012/09/20/defending-science-and-countering-falsehood-at-the-university-of-wisconsin-madison-2/

https://speakingofresearch.com/2012/10/12/as-predicted-uw-cleared-peta-caught-lying-again/

https://speakingofresearch.com/2013/02/08/a-lesson-in-hypocrisy-as-peta-cries-foul-over-one-cats-death-while-secretly-killing-hundreds-more/

A Closer Look at How Animal Research Progresses from Idea to Study

Unfortunately, the “how” and “why” of the research process is of much less interest, and receives far less attention, than the “what did they find?!” part of research. The latter is what you’ll see—if we’re lucky from the science outreach perspective— on television, in the science and popular media, Facebook, Twitter, and conversations world-wide. Meanwhile, the former will be relegated to websites of federal agencies, scientific societies, and animal research advocacy groups and are read less widely.  In fact, it is entirely possible that a great many bets could be won by wagering that the public generally doesn’t care to read up on regulation or processes governing the research behind the cool discoveries that make news.

In the case of animal-based research (and some other controversial fields), the “how” and “why” do sometimes generate some public interest because they are keystones in considering questions about its ethical basis and evaluation.  Public understanding and discussion of the process by which science moves forward is important. It provides appropriate context for fact-based dialogue about the ethical evaluation, decision-making, and regulation that govern a wide range of science conducted within our democratic system. Thus, many scientists and advocates not only welcome public interest in the conduct of science, but also actively promote thoughtful, engaged, and informed collaboration on efforts for improving research practices.

Why? One reason is that the ultimate benefactor from scientific studies is the public and, within a democratic society, it is for all of us to decide whether the benefits of those studies outweigh their costs.  Another reason is that scientists are generally sensitive and responsive to societal views, but feel an obligation to ensuring that these views are informed by facts as well as emotional appeals.  This is an issue that is not at all unique to animal research. It also appears in discussions of other topics that can elicit controversy, including for example: evolution, climate change, use of embryonic stem cells, and vaccines.

For animal research, the challenges inherent in serious evaluation of its costs and benefits are not trivial. Nor is it amendable to flashy, sensationalized, and emotion-evoking campaigns.  Simplistic approaches to this issue are not useful and do a disservice to all of us.

From our perspective, it is both disappointing and frustrating to find that understanding of the process by which science moves from idea, to the conducting of the study, to the dissemination of the findings, to the evaluation of those findings receives far less attention than would be needed in order to rationally discuss the research.  Why?  Because the reality of how science is actually conducted is centrally relevant to conversations about science.  And while this is an obvious statement, it is also clear from many portrayals of science by opposing groups that the basics of scientific process and conduct are often missed in the discussion.

In the case of laboratory animal research, the starting point of many opponents is an absolutist position in which the conditions for animals, the ultimate outcome of the research, and its benefits, are irrelevant. They are irrelevant because the starting assumption is that the use of animals is morally unacceptable. For those who hold this view, there is no benefit that would justify the animal use.  There are others who hold a less absolute view and, like us, believe that the use of animals in research begins with moral and ethical consideration that requires thoughtful, fact-based weighing of both relative harm and benefit.  One major part of this evaluation is identifying whether alternatives exist to meet the same goal.  Another is identifying as closely as possible what harm may be incurred, the probability and extent of benefits. Each of these considerations is integral to regulation of animal research in the U.S. and elsewhere. They are also considerations that are so integral to the scientific process that they operate far beyond those stages typically identified as the “checks” for ethical and humane conduct of animal research (e.g., IACUC review, federal oversight).

long haul slide

How scientific research moves from idea stage, to conducting a study, to success or failure, to critical review, to dissemination and use of findings is a process that can appear somewhat opaque to public view.  The pieces of information required to construct the general pathways are publicly available.  Putting them together, however, is not necessarily straightforward for those without immediate interest, expertise, or engagement.  So while the information is neither hidden nor made secret, it is of the type that can be easily misunderstood or misrepresented.

Should this gap in basic understanding and perspectives on how scientists’ ideas move from thinking to reality concern us?  The answer is yes.  Among other reasons, the gap serves as an impediment to an informed evaluation of science.  It also weighs heavily against productive dialogue about core issues of public interest.

How does an animal research project move from scientist’s idea to finished study?

In general, the process looks like this:  Scientists generate ideas that are based in careful study of what is known, what is not known, what methods already exist, what facts we have.  They next critically evaluate and review relevant previous literature and data–  often soliciting others’ expert knowledge–  to determine whether the idea is novel (has not already been tested),  of potential importance or significance, and feasible.

Thus, while some may have the impression that scientists roll out of bed in the morning, or have an aha-moment- then  move straight to the lab to conduct whatever study occurred to them via dream – this is not the way it typically works.

As illustrated, deciding on whether an idea is worth pursuing or not is driven by many factors. If the resulting data would have little potential benefit, few scientists are likely to pursue it. Why?  Because scientists have a lot of ideas and it makes no sense to expend energy on one that won’t be useful in terms of providing significant new knowledge or understanding.  It is also true that such ideas are unlikely to compete successfully in the different arenas of expert scientific review, including review for funding, publication, and citation.

research process

If a scientist judges his/her idea worth pursuing, the next step is likely to decide whether the study is feasible or practical. What does this mean?  In short, this is a question that revolves around ethical, economic, and practical issues.  On the ethical side, for animal research the scientist will consider animal welfare and treatment, any potential for harm.  Next, on the financial and practical sides, the scientist will consider how much the study will cost and whether the necessary work can even be done. During this initial stage the scientist will also critically evaluate whether the existing literature and facts provide adequate and strong platforms for the proposed study, or whether more basic and background data are needed to guide decisions before moving forward.

For that fraction of studies that survive the scientist’s own critical examination—and likely that of his/her collaborative group and colleagues—the scientist may decide to pursue the work. If so, for animal research the next step will be to write a proposal to the Institutional Animal Care and Use Committee (IACUC) in order to conduct a study.  In the U.S., IACUSs are among the main venues for thorough review of animal studies.  We have written previously about IACUCs and there is more information here.

In brief, the IACUC is comprised of individuals with veterinary and scientific expertise, as well as a public representative.  Animal studies do not proceed until the IACUC has reviewed and approved a proposal.  What do these protocols contain?  You can see some here, this site contains links to protocol forms from a range of institutions.  Although institutions vary in the format of applications, among other things, they include: information about what the study is designed to test, why it should be conducted, the literature review and strategies used to ensure that it is not unnecessarily duplicative, that alternatives do not exist, the number of animals proposed and justification for both the number and the species,  detailed description of all procedures,  and other details about the animals’ care and treatment.  In other words, the full range of information that the review committee will need in order to evaluate whether the study meets standards.

Is the IACUC process perfect in evaluating study protocols? No.  It is, however, the current system mandated by federal law and it is one that generally functions well to protect animal welfare.  It is also an evolving system, with scientists, veterinarians, federal agencies, science and animal welfare advocates engaged in its ongoing evaluation and improvement. Some of the criticisms of the existing system, however, neglect consideration of the larger context, the process by which research unfolds. For example, critics point to the fact that IACUCs approve the majority of studies put before them as evidence that “almost anything” a scientist could dream up receives approval.  In reality, IACUCs only review proposals that scientists write and submit. This means that the IACUC only sees study proposals that have already received some critical evaluation and that likely already fall within the constraints of current guidelines, practices, and norms.  Scientists, like others involved in animal research, take part in training and education about the range of issues related to animal welfare, humane treatment, and regulatory requirements.  As a result, they are generally not likely to write protocols that diverge from acceptable practices.

Following IACUC approval, the scientist may then begin conducting the study. It is often the case however, that IACUC approval is not the final step between idea and study.  Instead, for a new project, the scientist must also write a proposal to a funding agency in order to secure financial support for the research. In many cases in academic research, funding for these studies comes from federal agencies such as the National Institutes of Health or the National Science Foundation.  Competition for these funds is high and the majority of applications are not successful.  Those proposals that are funded have undergone rigorous review by a panel of scientists whose expertise is within the area of the proposal.  The criteria for review vary by agencies, but include very close examination of the significance of the research question, evaluation of its potential for success, scrutiny of the methods, expertise of the investigator, and quality of the facilities in which the research will be conducted.  The appropriateness of the animals chosen for study, their number, and their treatment are also subject to critical evaluation and discussion.  In sum, beyond IACUC review, many animal studies—including all of those funded by NIH, NSF, and other agencies— undergo another level of external expert scientific review.

Take-home message?  The evaluative process between a scientific idea, the conduct of a study, the results, and their evaluation, use, and further discovery is one with many steps and significant consideration.  The potential harm and benefit of each study receives review at each stage as well, both within and outside.

Research aimed at addressing basic, translational, or clinical questions relevant to advancing our scientific understanding and medical progress for humans and other animals is ultimately all aimed at questions with significance to many.  At the same time, it is also absolutely true that the benefits of research are not always directly or immediately apparent.  We simply do not know the answers before we conduct the work.  Furthermore, we can be confident—drawing from real conclusions from the history of science – that important, meaningful, generative breakthroughs are not entirely predictable.  As a result, it is no easy task to construct a metric by which to evaluate the potential benefit of research and to weigh that against any harm incurred during its conduct.

Considered carefully, the history of animal research and animal welfare are quite clear with respect to how the accomplishments of research and consideration of mutual interests in animal welfare provide the basis for progress in ethical and humanely-conducted animal research.   Public interests are served by dialogue based in fact and in clear accurate articulation of ethical frameworks from which animal research is considered.  Understanding the multiple levels at which research projects are evaluated from scientific and ethical perspectives is an integral starting point for this discussion.  Science doesn’t occur through simple processes or via a single stage of evaluation; nor should public dialogue about this complex issue.

Allyson J. Bennett