The idea that animal research, especially that pertaining to pharmaceuticals and environmental agents, may not predict human reactions accurately is not a novel concept. For thousands of years, experts have cautioned against the use of animal models for research due to their unreliability. Alexander Pope’s dictum ‘the proper study of mankind is man’ and Abu Ali Sina’s belief that animal models fail to mimic human subjects are just some of the many warnings throughout history that cautioned against the use of animals when leading research for human treatments 1. Yet with a new era of medicine having recently entered the biomedical landscape through the revolutionary breakthroughs of drugs, animal testing is in full swing as companies push out thousands of experiments each year in an attempt to develop the new blockbuster drug of the decade. Animal research is viewed by many as the default and gold standard of preclinical testing yet its failure to predict human outcomes, its lacking regulations, and its usage of an immense amount of resources that could be going toward other research methods make it unworthy of such a title. More times than not, animal research results in confounded data made up of biases and false information that not only fails to help develop new drugs but also leads researchers down the wrong path. With such detrimental effects to the medical field, animal research has shown that it is no longer worthy of being a cornerstone of biomedical research, and if researchers continue to fail at conducting rigorous and accurate studies, then it may be time to leave animal research in the past instead of using it as a tool to pave the future of biomedicine.

For decades, the argument as to why animal research should remain a leader in biomedical research has always been that some results are better than no results. With the sheer number of tests conducted each year on animals, it is evident that some do indeed bear fruit. For example, thanks to testing done on mice, penicillin was found to help humans in fighting against staphylococcal infections 3, while research on primates led to the development of drugs that combat cancer, HIV/AIDS, hepatitis, and malaria 4. Yet even with these advancements, pharmacologists are insistent that there are major difficulties inherent in extrapolating drug data from animals to humans that significantly slow down biomedical advancements 2.  In many cases, drugs deemed suitable for animals turned out to fail in clinical trials and had devastating effects on human subjects. An experiment in 2006 had six men take a drug known as TGN1412 which had been previously tested on monkeys who had shown no ill effects when administered with the drug 5. Only minutes after taking in TGN1412, each human subject started showing disastrous side effects such as organ failure and brain swelling 5. In 2004, a similar disaster was caused by an anti inflammatory drug known as rofecoxib, which was pulled from the market after a reported 88,000-140,000 people suffered myocardial infarctions as a result of taking the drug 6. Rofexocib was not only deemed safe, but also protective in animal tests 6. TGN1412 and Rofexocib only make up a minute portion of the failures caused by animal research as most drugs are unable to even make it to clinical trials, something that can be attributed to the vast differences between animal and human models. One such example would be drugs designed to alleviate or cure Alzeihmer’s disease, which were announced to have reached an astounding 99.6% rate of attrition 7. Of the 244 compounds tested in clinical trials from 2002 to 2012, only one was approved 7. Noting that all 244 compounds fared well when tested with animals, Alzeihmer’s is just one of many diseases that has demonstrated animal research’s failure to reproduce adequate results when administered to humans 7. Similarly, despite decades of animal, human, and financial investment, stroke medicine has failed to advance as none of its experiments have yielded a possible treatment for humans even though many have been shown to work on animals 8. Even the drugs that do make it to clinical studies fail to yield successful results as according to a recent U.S. study, for every eight drugs that enter clinical trials, only one is approved, with the rest being completely abandoned 9. With drug companies getting so little return off of their experiments on animals, animal research seems to be less and less of a viable and efficient option in today’s biomedical world, signaling that animal research’s time as the gold standard for biomedical testing has passed. 

While animal testing failures stem in part from the vast differences between animal and human models, interspecies and intraspecies differences in behavior, genetics, and physiology also significantly limit the reliability of animal studies. Spinal cord injury, for example, is a field where researchers have found that different strains from a given species have yielded dramatically different results. In one study, 11 strains of mice were put through 12 different behavioral measures of pain sensitivity in an attempt to recreate different levels of spinal cord injuries 10. The results varied in every single subject, with no clear patterns allowing researchers to predict how each mouse would respond. On some mice, the drug worked efficiently, while on others, it failed to have an effect 10. Further exemplifying the importance of physiological differences amongst species is the way that varying gene configurations alter animals. Despite a high degree of genome conservation, species differ markedly in the order and function of their genes, so while the same genes are indeed expressed, their different orders result in different outcomes. Researchers have strived to surmount such barriers by focusing their attention on genetically modified animals, which are produced by inserting human genes into an animal host. While such a method results in animal models having the same genetic makeup as humans, the function of the human genes in the animal is altered considerably in the process. For example, when human genes are inserted into a mouse genome, one gets a transgenic mouse 11. An unintended consequence of such an action is that a crucial protein found in humans that controls blood sugar is nonexistent in mice, so, when the protein is expressed in the genetically altered mouse, it does the opposite of what it was conceived to do by causing a loss of blood sugar control in the animal 11. Genetically modified animals have failed to successfully model human diseases, with all reasons pointing to the fact that the humanized genes are still inside non human animals. With interspecies and intraspecies differences in genetics, behavior, and physiology preventing animal research from yielding reliable results and genetically modified animals failing to correct such issues, animal research seems to slow down biomedical developments more than it advances them, with no fix to the problem in sight. 

On top of inter and intraspecies differences, laboratory procedures and conditions exert considerable influences on animals’ physiology and behaviors that can ultimately impact research outcomes, making animal research an even more unreliable source of data. Captivity and the array of common biomedical laboratory features such as artificial lighting, human-produced noises, and restricted housing environments have all been found to prevent species-typical behaviors, causing distress and abnormal conduct in animals 12. Among the types of laboratory-generated distress is a phenomenon known as contagious anxiety 13. In monkeys, cortisone levels rise as they watch their companions being restrained for blood collection, while in rats, blood pressure and heart rates elevate as they watch other rats go through pain 14. Routine laboratory procedures, such as catching an animal and removing them from the cage can also cause significant and prolonged elevations in animals’ stress markers. It has also been observed that the social isolation experienced by testing animals is extremely harmful and alters both physiological and behavioral characteristics in the subjects 15. These stress-related changes in physiological parameters can have significant effects on test results. According to a study done by a group of Chinese researchers, stressed rats were found to develop chronic inflammatory conditions and intestinal leakage, extra variables that could potentially affect data 16. But inflammation and intestinal leakage are just the tip of the iceberg. Neurochemistry, genetic expression, and nerve regeneration were all been found to be altered by laboratory environments. In one study, mice were genetically altered to develop aortic defects, but when the mice were housed in larger cages, the defects almost completely disappeared 17. Consequently, man made noises in laboratories were found to damage blood vessels in animals and even the type of flooring on which animals were tested for spinal cord injury experiments affected whether a drug was beneficial or not 17. Researchers have tried throughout the years to iron out the differences in laboratory experiments in order to eliminate potential confounders in the data, but such efforts have proved fruitless. One notable effort was made by Crabbe et al. who investigated the possible impact that laboratory environments had on six mouse behaviors commonly studied for neuromedicine 18. They conducted experiments in three laboratories simultaneously, taking extreme care to equate testing apparatus, protocols, and all other aspects of animal husbandry in each facility 18. To their dismay, the data recorded proved to be systematically different and different mouse strains varied markedly in all behavioral tests 18. With confounding data still arising from laboratories operating virtually synonymously, the results suggest that there remain important influences exerted by environmental conditions and procedures specific to individual laboratories that cannot be eliminated by equating procedures and protocols in each laboratory. With no solution to such a problem, animal research has a serious flaw in its data collection, making results unpredictable and impeding the extrapolation of such research to humans. 

Not only does animal research lack the bases needed for it to produce consistent results, but the poor quality and reporting of these experiments makes animal findings tenuous at best. The first guidelines on reporting animal research emerged in 1985, followed closely by an updated checklist in 1997 19. Over the years, a number of collaborative efforts have focused on minimum information reporting requirements to improve the quality of research on animals. Such guidelines have been put in place in order to promote efficient and humane animal-based research by addressing ethical concerns, minimizing waste, particularly of animal lives, and enabling extraction and subsequent reporting of useful information 19. In 2009, a research group reported that only 53% of journals publishing research involving animal experiments had an editorial policy or any sort of guidelines on reporting 19. The guidelines that were present usually only contained the word animal or requested that research conform to legal standards 19. The lack of guidelines stems in part from the absence of systematic reviews, which ensure that each research group conducts experiments efficiently and humanely. A research group led by Korevaar and colleagues kept track of systematic reviews carried out through a span of 5 years 20. Reviews were shown to double every three years and as the number of systematic reviews increased, the poor quality of preclinical animal research became more and more apparent 20. Evidence suggested that many of the studied animal testings failed to address threats to internal and external validity, making results hardly reliable 20. Additionally, a group of researchers in 2013 assessed whether there was evidence for excess statistical significance (biases) in results of animal studies on neurological disorders 21. By studying the data from meta-analyses of interventions deposited in Collaborative Approach to Meta-Analysis and Review of Animal Data in Experimental Studies (CAMARADES), the group compared the number of statistically significant results that were reported to the expected number and found staggering disparities (919 were expected versus the 1719 that were observed) 21. Overall, the research showed that there were just too many animal studies with statistically significant results in the literature of neurological disorders in order for all of them to be real, suggesting that researchers were implementing exaggerated or false results in order to boost their findings 21. Consequently, these biases affect the domain of biomedicine as a whole as the industry finds itself filled with false  leads 21. With guidelines for animal testing being so scarce and hardly enforced, researchers are free to do as they wish, and until further regulations are implimented, will continue to lead biomedicine down the wrong path. 

As years of animal research have gone by and return on investment has lagged significantly, funding bodies have become overly aware of the unreliable state that animal experiments find themselves in, leading to a significant drop in animal research investment. In the UK, public and charitable funding directed toward animal experiments decreased from 68.3% in 2005 to 59.4% in 2010 22. With the growing belief that animal research fails to bring promising results paired with studies suggesting that clinical rather than animal research has the most effect on patient care, investment in the animal research sector has seen a significant drop in the United Kingdom. This lack of investment is already starting to bear its marks as from 2016 to 2017, the country saw a 3.7% decrease in the total animals tested (down from 3.94 to 3.79 million) 23. Procedures on non human primates fell to 2,960, while dogs fell to 3,847, a new low for the two species in the last 40 years 23. The overall pain the animals had to experience during said experiments decreased on all levels. 14.5% of studies had the animals experience moderate pain (down from 16%), while 3.6% of studies had the animals experience severe pain (down from 3.9%) 23. While the United Kingdom has seen strong cutbacks and improvements to animal research, reports released by the United States Department of Agriculture’s (USDA) Animal and Plant Health Inspection Service show that the United States is still lagging in making significant change to the way animal research is carried out. While the overall number of animals being used as test subjects has indeed decreased in America, the amount of pain that they are put through has remained stagnant throughout the years 24. This can be attributed to the lack of guidelines and reviews in the U.S. which allows researchers to carry out their experiments on animals freely. With investment and research on the decline, animal experiments are beginning to feel like a tool of the past more than a tool of the future, marking the beginning of the end for animal research. 

For decades, the argument as to why animal research should remain a leader in biomedical research has always been that some results are better than no results. This thesis, however, fails to take into account how misleading information is often worse than no information at all. The use of inconsistent animal experiments not only causes human suffering by producing misleading safety and efficacy data but also draws resources away from more effective testing methods. Imprecise results from animal research have lead to biologically faulty substances being used in clinical trials, exposing patients to unnecessary risk and wasting key research resources 25. TGN1412 and rofecoxib, two examples examined above, caused harm to human subjects because investigators were misled by the safety and efficacy of a drug based on inconsistent animal studies. Volunteers stepped into clinical trials with a false sense of security that was derived from the misguided confidence that researchers put into their results, resulting in the suffering and death of many. But animal research has also harmed humans in other ways. A more indirect source of human suffering that stems from animal research is the abandonment of promising drugs due to their inability to work on animals. Candidate drugs proceed down the development pipeline and enter clinical trials if they successfully work on animals, meaning that certain drugs that could have been very helpful to humans are ruled out because of misleading animal tests 26. It is difficult to pinpoint the number of missed opportunities due to animal experiments, however, of the thousands of potential drugs tested on animals, only about a few proceed to clinical trials, leaving ample room for potentially successful drugs to be ruled out 27.  For example, a drug known as cyclosporine which showed to be a tremendous help in treating autoimmune disorders and preventing organ transplant rejection was delayed significantly due to its failure to work on animals 28. Its effects differed so markedly from species to species that researchers deemed it unusable on humans for some time before eventually pushing it to clinical trials 28. Providing further proof, revolutionary drugs such as aripiprazole (Abilify) and esomeprazole (Nexium) had little success working on animals and would not be available on the market today if animal research were the sole way that drugs were tested 29. In addition to causing the abandonment of useful drugs, animal testing also leads to a collosal waste of time and investment. The costs of continuing to fund unreliable animal tests impedes the development of more accurate testing methods such as organs on chips, 3D printing of human tissue, human organs grown in labs, and computer models 30. These testing methods, unlike animal testing, are based on human biology, omitting many of the errors tied to animal research. While these methods are gaining momentum, they are still in early stages of use and require prioritization over animal research in order to make significant progress 30. With animal research not only producing misleading data but also taking funding away from other forms of research that show more promise, animal testing seems to be more of an anchor keeping biomedicine from advancing rather than the great blockbuster that it has been painted to be. 

When looking at animal research from a medical point of view, it becomes obvious that it is not the cornerstone of biomedical research that it shines as today but rather an obstruction in the advancement of medicine. While animals and humans may be similar on a psychological level, differences in their physiology, genetics and biological makeup make it virtually impossible to extrapolate data from animal experiments and use it to further human treatments. On top of the vast differences between animal and human models, the limited enforcement of animal research guidelines leaves researchers free of restrictions, leading to poorly conducted experiments and biases in results. The unreliability of animal research that has been uncovered over the past few years not only undermines the longstanding claims that animal experiments are vital for human advancement but also shows the harms and costs that result from such research. With so many resources going towards a form of research that seems more harmful than beneficial to humans, it raises questions about the ethical justifiability of animal research. In the end, one should ask themselves if depriving people of resources, opportunity, and potentially their lives by investing in an inconsistent research method is just. 

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