Research Roundup: Combatting Zika virus, Understanding the brain, reprogramming skin cells, and more

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • A new model to study the transmission of Zika virus. Scientists at the National Institutes of Health (NIH) have developed a mouse model to study the transmission of Zika from males to females, as well as from females to their fetuses. Scientists from the National Institute of Allergy and Infectious Diseases (NIAID) devised a way to make the typically-difficult mouse model be a reliable Zika model. Mice naturally defend against Zika better than people because they have a stronger interferon response. The scientists discovered a way to suppress the interferon in these mice, called anti-interferon Rag (AIR) mice, which have prolonged virus infection in the testes — similar to Zika-infected men. AIR mice also exhibited vertical transmission of Zika from mother to fetus. Intriguingly, only some fetuses from each female were infected with Zika, suggesting that the placenta may be a crucial barrier in preventing the virus from reaching the fetus and thereby resulting in birth defects. The research was published in Scientific Reports and is freely available online.
  • Scientists at Ohio State University have used mice develop a new way to reprogram skin cells. This could represent a breakthrough in repairing injured or ageing tissue. The new technique, called tissue nanotransfection, is based on a tiny device that sits on the surface of the skin of a living body. An intense, focused electric field is applied, allowing it to deliver genes to the skin cells beneath it – turning them into different types of cells. The device was put on the skin of the mice with legs that had had their arteries cut, preventing blood flow through the limb. The team found that they were able to convert skin cells directly into vascular cells -with the effect extending deeper into the limb, in effect building a new network of blood vessels. “Seven days later we saw new vessels and 14 days later we saw [blood flow] through the whole leg,” said Dr. Chandan Sen, from the Ohio State University. Sen and colleagues say they are are hoping to develop the technique further, with plans to start clinical trials in humans next year. This research was published in Nature Nanotechnology.

  • Neuroscientists are trying to under how tangles of neurons produce complex behaviors. The brain is still largely unknown. Researchers hope to map out simple brains in hopes to see patterns that might be able to be applied to more complex brains.  Researchers at Howard Hughes Janelia Research Campus are studying the brains of fruit fly larvae. The brains of these animals are comprised of 15,000 neurons as compared to 86 billion in the human brain.  Researchers like Albert Cardona and Marta Zlatic‘s feel that a wiring diagram is an important step towards understanding how the central nervous system works.  The nematode’s (C. elegans) brain, at just 300 neurons, was mapped in the 1980’s but scientists question its applicability to larger brains so have sought the fruit fly because it exhibits more complex behaviors and thus more complex neural pathways and actions but there is still much unknown about simple brains. Animals being looked at include the gastric system of crabs, larval zebrafish and specific regions of the brain. Neuroscientists hope that mapping the brain will help to understand why some therapies work for one but not for others and how new therapies can be developed to treat many debilitating diseases.

  • Scientists destroy entire chromosome with CRISPR providing hope for future generations of individuals with aneuploidy, such as Down Syndrome –where an individual has an abnormal number of chromosomes. These researchers first, in vitro, used CRISPR-Cas 9 to induce numerous chromosomal breaks at the centromere on the long arm of the Y chromosome, effectively removing the chromosome from XY embryonic stem cells. Then, using male mice zygotes, in vivo, this team of researchers targeted 41 sites of the Y chromosome centromere, resulting in a 70% efficient removal of the Y chromosome. This research was published in the journal Molecular Therapy.
  • Gold particles increases the efficacy of drug treatments for cancer. Gold can be used as a catalyst in chemical reactions. Researchers from Edinburgh University, using zebrafish investigated whether gold would improve the efficacy of drugs, via catalysis, used to treat lung cancer. Here, gold nanoparticles were encased in a “chemical device”, and the activation of the structure as well as the subsequent release of therapeutics studied — which worked with good efficiency. The lead author, Dr. Unciti-Broceta states “We have discovered new properties of gold that were previously unknown and our findings suggest that the metal could be used to release drugs inside tumours very safely.” This research was published in the journal Angewandte Chemie (Applied Chemistry).

American Psychological Association reaffirms support for animal research

The American Psychological Association (APA) represents its membership of 115,700 researchers, educators, clinicians, consultants and students working across the many subfields of psychology. The APA works to advance the creation, communication, and application of psychological knowledge to benefit society and improve people’s lives. On August 2nd, 2017, the organization reaffirmed its support for the careful use of animals in medical research. Speaking of Research welcome this clear statement of principles. We reproduce that statement below. 


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APA Reaffirms Support for Research with Nonhuman Animals

The American Psychological Association has reaffirmed its long-standing support for ethically sound and scientifically valid research with nonhuman animals and the scientists who conduct it, noting that the application of such research has “significantly improved the health and well-being of both human and nonhuman animals.”

“Historically, laboratory animal research has played a crucial role in the development of theory and research in virtually all sub-disciplines of psychology,” said APA President Antonio E. Puente, PhD, who is a neuropsychologist. “Knowledge gained through research with laboratory animals continues to provide answers to questions important to advancing the science of behavior and to improving the welfare of both humans and other animals.”

Understanding of such processes as learning, attention and cognition and disorders such as addictions, autism and depression has benefited from findings of nonhuman animal studies. Knowledge gained through research with nonhuman animals has also been critical to conservation efforts for various species, in various habitats across the world.

APA’s governing Council of Representatives passed a resolution on the subject Wednesday, reaffirming a resolution that was last adopted in 1990, and is reflected throughout the 125-year history of the organization. The resolution notes nonhuman animal research is foundational to scientific discoveries as is evidenced by the fact that most scientists support such research, and that such research is regulated by federal, state and local jurisdictions, as well as assessed for scientific merit by funding agencies and peer review. Additionally, the resolution asserts the responsibility of scientists themselves to ensure the humane care and treatment of laboratory animals.

The resolution recognizes that the public might not fully appreciate “the nature of nonhuman animal research and its benefits to society, due to overabundance of misinformation and simultaneous dearth of accurate information” in the public domain.

“Nonhuman animal research has proven invaluable for exploring the complexity of diverse behaviors across genetic, molecular, cellular/neuronal, circuit, network, cognitive and behavior levels,” the resolution states. “The assembly and application of findings from nonhuman animal research has contributed to numerous clinical applications that have significantly improved the health and well-being of both human and nonhuman animals.”

Studies that used animals have played a role in the prevention or treatment of conditions as diverse as tuberculosis, diabetes, polio, Parkinson’s disease, muscular dystrophy and high blood pressure — to name just a few benefits of this research. Although such research continues to provide important scientific data and insights, understanding and support of such research has declined in recent years among the American public. Moreover, some activist groups have spread misinformation about this research, have harassed psychologists and other scientists and have destroyed laboratories. APA’s reaffirmation of its position on nonhuman animal research is one step toward strengthening the public’s knowledge and support of this research and the scientists who conduct it, according to Puente.

“APA deplores the harassment of scientists, students and laboratory assistants who have been involved in animal research,” Puente said. “We join with other scholarly organizations in continuing to support ethically sound and scientifically valid research with nonhuman animals.”

APA’s Committee on Animal Research and Ethics, which was founded in 1925, developed and regularly updates its “Guidelines for Ethical Conduct in the Care and Use of Nonhuman Animals in Research.” These guidelines assist researchers in fulfilling their obligation for the humane care and treatment of nonhuman animals in research that is in the public’s interest.

Research Roundup: Chimpanzees with Alzheimer’s, mice with autism, the shrinking bat genome and more

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • Signs of Alzheimer’s found in chimpanzees for the first time.  Melissa Edler, of Northeast Ohio Medical University, and her colleagues, studied twenty brains of older chimpanzees and found more than 50% had beta-amyloid plaques and early forms of tau tangles similar to that seen  in humans with Alzheimers.  Another researcher, Mary Ann Raghanti of Kent State University, Ohio, whose lab in which the work was conducted, points out that the samples were not accompanied with cognitive data and there are no current examples of chimps with Alzheimers-like dementia.  This may show that although chimps demonstrate physiological aspects of the disease, they do not exhibit the cognitive decline as seen in humans. Raghanti says, “If we can identify those differences between the human and chimp brain then we might be able to pinpoint what is mediating the degeneration. That could be a target for drug treatment.”
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Chimpanzees at NCCC (not related to above study). Photo credit: Kathy West.

  • Human embryos edited to stop diseases using CRISPR. In a massive collaborative effort, researchers in the USA and Korea, have for the first time “freed embryos of a piece of faulty DNA that causes deadly heart disease to run in families.” Hypertrophic cardiomyopathy, is a common heart disorder, affecting approximately one in every 500 people, and can lead to cardiac arrest. In this study, “sperm from a man with hypertrophic cardiomyopathy was injected into healthy donated eggs alongside Crispr technology to correct the defect” — and in 72% of the embryos the disease-causing mutation was removed. Safety and efficacy evaluation of the CRISPR technique is still under scrutiny, and this evaluation owes much to animal research as we have previously highlighted in our research roundups. This research was published in the journal Nature.

  • ‘Autistic’ mice affect the behaviour of their littermates. Researchers at Cardiff University, led by Dr Stéphane Baudouin, genetically altered mice to exhibit symptoms of autistic spectrum disorder and found that other unaltered mice became less social. The mice altered mice had the neurolignin-3 gene turned off, changing their behaviour. Wild-type mice in the same cage ceased to be interested in the smells of the urine of other mice – a standard test for social behaviour in mice. When the Neurolignin-3 gene was turned back on, both the altered mice and the wild-type in the cage returned to their ordinary behaviours. Dr Badouin also found that the ‘autistic’ tendencies of the mice were worse when the mice where housed with wild-type mice compared with housed with other altered mice. This study was published in eNeuro.
  • Genome elasticity and shrinking found in bats. The size of genomes are known to vary across the animal kingdom: hummingbird — 1.11 billion base pairs (bp); human — 3.42 bill. bp; leaf insect — 7.82 bill. bp. These sizes are typically maintained across millions of years, but when they do change it is usually an increase in size from the addition of transposons. Transposons are classically referred to as “jumping genes” and partly drive genetic evolution. Researchers at the University of Utah recently studied size change of genomes and transposons in the common little brown bat (Myotis lucifugus) and found something interesting. Around 40 – 50 million years ago, the genome had gained 400 million transposons and shrunk in size — over a small amount of time (in evolutionary terms) the genome dramatically changed. Because genomes serve as the raw materials to living life, this is a huge finding. Furthermore, mammalian genomes are widely recognized as monotonous — rarely changing in size over time and rarely gaining many transposons, however it now appears the little brown bat is an anomaly. Further research on these bats and other mammals will help us better understand the relationship between genes and evolution.
  • A less invasive form of swabbing is being investigated as a means of refinement aiming to improve the welfare of zebrafish. Zebrafish use continues to increase, because of their utility as a model organism for investigating both basic and applied biological mechanisms related to health and disease. Previously, the collection of DNA from zebrafish was done via fin clipping — a fairly invasive procedure performed without anesthesia. With funding from the NC3Rs, researchers at the University of Leicester’s Department of Neuroscience, Psychology and Behaviour are systematically exploring a new technique. Here, “researchers gently stroke a swab along the flank of a netted fish and takes just a few seconds to complete. Previous research by this team has already shown that this technique collects ample material for DNA analysis.” This two year project will investigate the potential benefit to the animals’ wellbeing by comparing the standard method to the newly proposed one.

Animal Research Statistics in Austria, Hungary and Slovenia

Speaking of Research try to keep on top of the latest statistics coming from governments around the world. This post will look at three countries which have recently published their 2016 statistics. All three are regulated by EU Directive 2010/63 which requires countries to produce national statistics on their animal use.

Austria

Austria reported 236,459 procedures on animals in 2016, a 4% rise on the previous year.

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Procedures on animals in Austria for research in 2016. Click to Enlarge

The rise in animal experiments appears to be mainly due to large increases in the number of birds (mainly chickens) used (up 116%), other mammals (up 89%; mainly pigs) and rats (up 23%).

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The vast majority of research was conducted on mice (81.2%), with rabbits (6.2%) and fish (4.4%) the next most common species. It is interesting that Austria, rabbits are the second most common species, a fact not seen anywhere else in Europe, though neighbouring Germany also has a relatively high number (4% of total). No primates were used in Austria in 2016 (or the previous two years) and dogs and cats accounted for less than 0.08% of all animals used despite the rises in the number of procedures for the former.

Trend over time in animal experiments in Austria. Click to Enlarge.

From historical statistics, we can see that while there has been an overall decline of almost 50% since 1990, the numbers have been edging upwards since their nadir in 1999. These numbers tend to reflect changing science funding environments within the country.

This year was the third year where there were retrospective assessment and reporting of severity (i.e. reporting how much an animal actually suffered rather than how much it was predicted to suffer prior to the study). Reassuringly the proportions in each severity banding were similar to previous years, suggesting the system has been well understood. The report showed that 2.5% as non-recovery (4% in 2015) , 63% of procedures were classed as mild (60% in 2015), 27.5% as moderate (24% in 2015), and 7.3% as severe (down from 12% in 2015).

Finally the statistics note that 41.4% of procedures involved genetically altered animals. These were mainly mice and zebrafish, but also included rats and other fish.

See previous reports:

Hungary

Hungary reported 170,075 procedures on animals in 2016, a 7.9% fall on the previous year.

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Procedures on animals in Hungary for research in 2016. Click to Enlarge

The fall in animal experiments appears to be mainly due to falls in the number of procedures on birds (down 5%), rats (down 9%), reptiles and amphibians (down 25%) and fish (down 72%).

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Together, mice, rats and birds account for 84% of all procedures in Hungary, this figure rises to over 95% when fish, reptiles, amphibians and guinea pigs are included. The use of primates went from 3 in 2015, down to 0 in 2016 (presumably after a specific study ended). Dogs and cats accounted for less than 0.4% of all animals used.

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Trend over time in animal experiments in Hungary. Click to Enlarge.

Using the trend graph we can see how – bar an anomalous year in 2013 – there has been a steady downward trend in animal procedures in Hungary from over 300,000 in 2007, to less than 175,000 in 2016. Perhaps coincidentally the 2013 high point coincides with the implementation of the EU Directive (and its rules around counting procedures), meaning it is possible that this figure is a statistical error caused by incorrect data from the first year under a new counting regime.

This year was the third year where there were retrospective assessment and reporting of severity (i.e. reporting how much an animal actually suffered rather than how much it was predicted to suffer prior to the study). The report showed that 19% as non-recovery (8% in 2015) , 49% of procedures were classed as mild (71% in 2015), 24% as moderate (15% in 2015), and 8.2% as severe (up from 6% in 2015).

Lastly, of note, only 4.7% of animal procedures were on genetically altered animal (up from 2.8% in 2015) – a much lower proportion than, say, the UK, where almost half of procedures were the breeding of a genetically altered animal.

See previous reports:

Slovenia

Slovenia reported 6,819 procedures on animals in 2016, a 25% fall on the previous year.

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Procedures on animals in Sloevnia for research in 2016. Click to Enlarge

The main changes was a 24% fall in the use of mice. This is particularly noteworthy given the 22% fall between 2014 and 2015. Neither fish nor horses were used in 2016 (there were 57 and 2 procedures respectively). The only rise was in pigs which went from 8 procedures to 32 in 2016.

As is the case in many smaller countries (but not all), most of the research was animal testing for regulatory purposes (66%), followed by translational and applied research (26%) and basic research (6%).

See previous reports:

That’s all for today but we will endeavor to provide the latest statistics as they are published by national governments. All our statistics can be found on the Statistics Overview page.

Research Roundup: Lupus protein identified, vaccine for Type 1 diabetes, new chronic pain treatment, and more!

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • A protein that may cause Lupus has been identified.Lupus is a chronic inflammatory disease that occurs when your body’s immune system attacks its own tissues and organs. An estimated 1.5 million Americans, and at least 5 million people worldwide, have a form of lupus. Previous research has implicated the gene PRDM1 as a risk factor for lupus. Scientists looking at Blimp-1, a protein that is encoded by the PRDM1 gene, have found in mice thatthat a low level of or no Blimp-1 in a particular cell type led to an increase in the protein cathepsin S (CTSS) which caused the immune system to identify healthy cells as something to attack — particularly in females.” These results are particularly striking as women have an increased risk for lupus compared to men. While this work needs to be replicated and validated, this research provides some valuable insight into the etiology and treatment of lupus. This research was published in the journal Nature Immunology.
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Mice from the Lupus study. Source: AJP Renal Physiology.

  • Vaccine for virus induced Type 1 diabetes successful in mice. Coxsackie B viruses are the most common enteroviruses and are believed to be associated with the development of Type 1 diabetes. Type 1 diabetes is  a common human disease defined by a decrease in the production of insulin, which is a hormone that allows blood glucose (sugar) to enter energy producing cells. Thus, without insulin your body cannot effectively produce energy. This week, a team of Finnish researchers published a preclinical evaluation of a Coxsackie B1 vaccine using mice and found that the vaccine successfully protected the mouse after administering the Coxsackie B1 virus. Pre-clinical trials in humans are the next logical step for this vaccine, and the researchers believe that this research will aid in the development of vaccines for other disease caused by enteroviruses such as; hand-foot-and-mouth disease, meningitis, and myocarditis. This research was published in the journal Vaccine.
  • High iron levels in brain linked to progression of Alzheimer’s. Alzheimer’s is a degenerative neurological disease that causes dementia in humans. Previous research has linked Alzheimer’s to the buildup of amyloid protein in the brain, but research on drugs that reduce amyloid levels have not successfully slowed the progression of the disease. New research from the University of Melbourne however, discovered that humans with high levels of iron and amyloid were suffering from rapid dementia, while those with just high levels of amyloid protein were stable. This finding will fuel a five year trial on whether an anti-iron drug can slow the progression of the disease. This research was published the journal Brain.
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Brain MRI using Quantitative Susceptibility Mapping (QSM). Source: University of Melbourne.

  • Compound protects macaques from simian HIV. Research being presented this week at the National AIDS Treatment Advocacy Project (NATAP) Conference on HIV Pathogenesis Treatment and Prevention in Paris shows that weekly administration of a compound called MK-8591 repeatedly protected 8 of 8 macaques from simian HIV (SHIV) 6 days after treatment. Researchers from the Aaron Diamond AIDS Research Center in New York, Merck, and the Tulane National Primate Research Center studies 16 male macaques, 8 of which received weekly treatments of MK-8591 for up to 14 weeks, the other 8 of which received a placebo. MK-8591 is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that thwarts HIV. All 8 monkeys treated with MK-8591 remained SHIV-free even after 12 challenges with SHIV, to the end of the 168-day study. In contrast, the monkeys not treated with the drug all became infected with SHIV. The researchers noted that protective intracellular active MK-8591 concentrations can be attained in humans at low drug doses. These new findings support the potential use of MK-8591 as a prophylactic treatment for high-risk individuals.
  • New drug acting at two opioid receptors shows promise to treat chronic pain without the adverse effects of morphine. An epidemic of opioid abuse is killing people by the hundred of thousands in the United States, becoming the main cause of death for people under 40. The epidemic has been traced to the prescription of new opioid analgesics like Oxycontin over the last years, which has led people to become addicted to it and then to harder drugs like heroin. A group of scientist followed the strategy of creating drugs that bind not only to the receptor for morphine in the brain, the mu-opioid receptor, but also to a new opioid receptor called the nociceptin FQ receptor. The new drug, BU08028, was shown to reduce pain responses in rats as effectively as morphine. Now the drug is being tested in rhesus monkeys, where it also decreased pain. Importantly, the monkeys showed no desire to self-administer BU08028, an indication that the drug is not addictive.
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Male rhesus macaque. Source: Kathy West.

  • Computer-designed opioid drug may decrease pain without producing respiratory arrest. People dying during the current opioid epidemic do so because the drugs inhibit the centers in the brain that drive breathing, leading to suffocation. Scientists proposed that the pain-relieving and breathing-suppressive effects of the opioids depend on different interactions of these drugs with the mu-opioid receptor, and set up to produce a compound that would suppress pain but not breathing. To do that, they modeled the drug binding site at the receptor using computers. After testing millions of compounds in the computer, they found a drug, PZM21, that showed promise. Then they tested PZM21 in mice and found that it suppressed pain but not breathing. They also found that PZM21 did not show the rewarding effect that typically lead to addiction. This demonstrates how even when new drugs are designed using computer models, animal studies are still needed to evaluate their effects.

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.

 

 

Research Roundup: Brain circuits for dominance, new HepC rodent model, eye repair in zebrafish and more

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • Brain circuits for social dominance discovered. For humans and most other animals, a previous history of winning dictates continued social dominance. In a study recently published in Science, Zhou et al. may have found a neurological explanation for this “winner effect”. They show, using mice, that the dorsomedial prefrontal cortex (dmPFC) mediates behavior in a social conflict. Using optogenetic methods, researchers stimulated the dmPFC using light and found that this was sufficient to induce “winning” in mice tested on a task used to measure social dominance. Interestingly, this also worked in mice that were previously shown to be a “loser” when paired with another mouse in the task. If an analogous mechanism present in humans, this study could be of major importance in understanding various relevant psychiatric conditions associated with social behavior. This research was published in the journal Science.

  • New animal models for hepatitis C could pave the way for a vaccine. This discovery is a stepping stone towards the development of a vaccine for Hepatitis C which affects nearly 71 million people worldwide. Although there is now a cure for Hepatitis C, most people go undiagnosed leading to damage of the liver. Until now, an animal model was not available for vaccine development because hepatitis C is highly specific affecting only humans and chimpanzees. This breakthrough comes as a result of a collaborative effort with Ian Lipkin, a researcher at Columbia University, who was studying pathogens of common rats in New York City. He found a rat version of the hepatitis virus and after sharing his work with Dr. Charlie Rice, a researcher in virology at The Rockefeller University, they found a way to infect mice with the rat version of the virus. There are differences between the primate and rodent version of the virus but there is hope that “this research will help unravel mechanisms of liver infection, virus clearance, and disease mechanisms, which should prove valuable as we work to develop and test hepatitis C vaccines that can help to finally eradicate the disease around the world.” This study was published in Science.
  • A study in zebrafish found that the immune system controlled its ability to regenerate eye tissue. Researchers at John Hopkins are studying the ability of zebrafish to repair damaged eye retinal tissue using the regenerative response of Müller glia Having found that microglia, a type of cell involved in immune response, were the only cells able to penetrate the blood-retinal barrier, they prevented these cells from functioning, resulting in almost no regeneration from the Müller glia cells. A better understanding of this process could help scientists unlock human eye regeneration. Dr Jeffrey Mumm noted, “humans still have the genetic machinery needed to regenerate retinal tissue, if we can activate and control it.” This study was published in PNAS.
  • Early disruption of gut microbiota shapes later health. The gut microbiome plays an important role for health in humans and all living animals. In a recent study published in Nature Communications, researchers discovered that disruption of gut bacteria in frogs during the tadpole stage of maturation had negative effects on how adult frogs dealt with parasites. This effect may also be present in humans. Wherein, early-life disruption of human microbiota may stimulate the development of an under-reactive immune response to infections in adulthood.

  • Potential treatment for infants exposed to alcohol in utero identified. In the United States 1-5 percent of children are diagnosed with fetal alcohol spectrum disorder, which impairs learning, is linked to later-life behavioral problems, cardiovascular problems, and delayed development. In efforts to reverse these negative effects, scientists at Northwestern University treated rat pups, exposed to alcohol in utero, thyroxin or metaformin. Thyroxin is a hormone that is reduced in pregnant women that consume alcohol, and also in infants with fetal alcohol spectrum disorder. Metaformin is an insulin sensitizing drug that is found at higher concentrations in alcoholics. Both drugs reversed memory deficits, independently, as a consequence of in utero alcohol exposure. “We’ve shown you can interfere after the damage from alcohol is done. That’s huge,” said lead investigator and senior author Eva Redei. “We have identified a potential treatment for alcohol spectrum disorder. Currently, there is none.”The researchers are now looking for funding for clinical trials. This study was published in Molecular Psychiatry.