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Introduction, conclusions, acknowledgments.

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A Brief History of Use of Animals in Biomedical Research and Perspective on Non-Animal Alternatives

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Lewis B Kinter, Ron DeHaven, David K Johnson, Joseph J DeGeorge, A Brief History of Use of Animals in Biomedical Research and Perspective on Non-Animal Alternatives, ILAR Journal , Volume 62, Issue 1-2, 2021, Pages 7–16, https://doi.org/10.1093/ilar/ilab020

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Animals have been closely observed by humans for at least 17 000 years to gain critical knowledge for human and later animal survival. Routine scientific observations of animals as human surrogates began in the late 19th century driven by increases in new compounds resulting from synthetic chemistry and requiring characterization for potential therapeutic utility and safety. Statistics collected by the United States Department of Agriculture’s Animal and Plant Health Inspection Service and United Kingdom Home Office show that animal usage in biomedical research and teaching activities peaked after the mid-20th century and thereafter fell precipitously until the early 21st century, when annual increases (in the UK) were again observed, this time driven by expansion of genetically modified animal technologies. The statistics also show a dramatic transfer of research burden in the 20th and 21st centuries away from traditional larger and more publicly sensitive species (dogs, cats, non-human primates, etc) towards smaller, less publicly sensitive mice, rats, and fish. These data show that new technology can produce multi-faceted outcomes to reduce and/or to increase annual animal usage and to redistribute species burden in biomedical research. From these data, it is estimated that annual total vertebrate animal usage in biomedical research and teaching in the United States was 15 to 25 million per year during 2001–2018. Finally, whereas identification and incorporation of non-animal alternatives are products of, but not an integral component of, the animal research cycle, they replace further use of animals for specific research and product development purposes and create their own scientific research cycles, but are not necessarily a substitute for animals or humans for discovery, acquisition, and application of new (eg, previously unknown and/or unsuspected) knowledge critical to further advance human and veterinary medicine and global species survival.

Human history is intertwined with the animal species sharing their environments, and throughout that history humans have gained critical knowledge for their survival, education, and health from observing both humans and animals with increasingly acumen and more powerful and sophisticated tools and techniques. The Lascaux Cave near the village of Montignac in southwestern France contains over 600 exquisite images of contemporary animals dating back 17 000 years ( Figure 1 ). Given this observational acumen, the same humans—when butchering these animals—must have noticed gross anatomical features, including bones, body cavities, musculature, and internal organs similar to their own, thereby establishing original knowledge of comparative anatomy. Over 10 000 years later, the Ebbers Papyrus (1536 BCE) describes more than 800 preparations from animal, mineral, and vegetable sources used to treat Egyptian maladies. 1 The first drug treatise from China (1st century CE) names 365 drugs with useful properties and parsed into 3 groups: considered non-toxic and supposedly useful, mildly toxic but with some efficacy to treat maladies, and toxic and effective to cure specific illnesses. 2 Neither Egyptian nor Chinese document describes who and/or how these remedies were discovered/developed, but observation and perhaps intentional “rudimentary experimentation” must have been primary tools. Later Egyptian, Greek, Arab, and Chinese literatures detail the use of humans and animals to explore and develop knowledge of anatomy and rudimentary surgical procedures as well as potions and theriacs—some of which continue to be used in traditional medicine and are being investigated for new medical treatments today. In Western experience, Aristotle (4th century BCE) is acknowledged as the first to perform “experiments” or to have added manipulation to observation of living animals. An early example of such scientific manipulation was by Galen (129–216 CE); in his “De theriaca ad Pisonem,” Galen describes assigning roosters to control and theriac treatments, exposing both groups to venomous snakes, and observing that whereas control roosters died immediately after a snake bite, theriac-treated roosters survived. 3 Ibn Zuhr (12th century CE) added manipulation when testing surgical procedures on animals before applying them to human patients. 4 , 5 Andreas Vesalius (1514–1564), John Hunter (1728–1793), and others demonstrated animal observation and manipulation by conducting animal dissections, surgical procedures, and rudimentary experiments as academic and public demonstrations through the 19th century. In reviewing this literature, Kinter and DeGeorge concluded that humans were the species most frequently used in ancient scientific inquiries, there was sparse evidence of animal use in medicinal discovery, and no evidence of animal use to evaluate safety; they concluded that lack of use of animals as human surrogates in medical investigations was due in part to sufficient availability and tractability of human subjects and insufficient concepts of allometric scaling (eg, dose/unit body weight or body surface area). 1

The relations between human observation and manipulation of animals sharing their environments. See text for details. Cave painting image courtesy of Prof Saxx—Public Domain, https://commons.wikimedia.org/w/index.php?curid=2846254 .

Closer to the modern era, advances in technology and economic growth fueled advances in scientific knowledge and welfare of both humans and animals. 6 Commenting on the human condition prior to the 18th century, English philosopher Thomas Hobbes (1588–1679) observed that human life was “solitary, poor, nasty, brutish, and short,” 7 and certainly the lives of animals were no better. The First Industrial Revolution (circa 1760–1840) unleashed unprecedented economic growth, technology, and improvements in living standards across Europe and North America. In addition to observations regarding basic anatomy and rudimentary surgical procedures, this period heralded advances in scientific knowledge, resulting in rudimentary explorations of the functions of body organs (medical physiology) using observation and increasingly sophisticated manipulations in both humans and animals: the monaural stethoscope and auscultation introduced in 1816 by René Laenne (1781–1826) 8 ; William Harvey’s (1578–1657) demonstrations of functions of the heart and circulation using both humans and animals 9 ; Stephen Hales’ (1677–1761) use of a column of water to measure arterial blood pressure in a horse 10 ; Robert Hooke’s (1635–1703) observations of oxygenation of the blood within the dog lung 5 , 11 ; and Antoine Lavoisier’s (1743–1794) observation using a guinea pig that respiration was a type of combustion. 5 , 12 Also notable for this period were the first social efforts to recognize and promote the more humane treatment of animals, including the founding of the British Society for the Prevention of Cruelty to Animals in Britain in 1824. 13

The Second Industrial Revolution (circa 1860–1914) brought new generations of technology and instrumentation with which to measure and record physiological functions, and new disciplines, including analytical, organic, and medicinal chemistry. August Waller (1856–1922) developed the first practical technology to record electrocardiograms using surface electrodes, conducting demonstrations using his pet bulldog dog “Jimmy”; arguably, Jimmy is the “poster dog” for use of canines in cardiovascular research. Willem Einthoven (1860–1927) showed that the electrocardiogram was useful in diagnoses heart conditions. 14 Adolf von Baeyer (1835–1917) synthetized malonylurea in 1864, initiating a century of synthetic barbiturate analgesic therapies, 15 , 16 and Paul Ehrlich (1854–1915) and Sahachiro Hata (1873–1938) synthesized arsenoxide and arsenobenzene derivatives of aminophenyl arsenic acid, making over 600 compounds before discovering dioxy-diamino-arsenobenzoldihydrochloride (“606”, arsphenamine), the first effective treatment for syphilis. 17 Notably, Ehrlich observed that most of the arsenicals he experimented with were toxic to mice and rabbits and therefore unsuitable for human testing, marking an early example of product safety evaluation using animals. Kinter and DeGeorge concluded that the explosion of new synthetic chemistry in the late 19th and early 20th centuries necessitated large-scale pharmacological testing using animals as human surrogates for identification and characterization of potentially useful pharmacological properties and determination of tolerability, thereby founding the modern disciplines of experimental pharmacology and toxicology. 1 Several professional organizations soon surfaced, including the American Physiological Society, founded in 1887; the American Society for Pharmacology and Experimental Therapeutics, founded in 1908 by John Jacob Abel of Johns Hopkins University; and the British Pharmacological Society in 1931. Notably, the first organizations dedicated to breeding and supplying animals explicitly for biomedical research were formed during this period, including Jackson Laboratories (1929), Harlan Laboratories (1931), Marshall BioResources (1939), and Charles River Laboratories (1947).

Additional significant events of this period included the 1902 US Biologics Control Act, the 1937 US Pure Food and Drug Act, and the 1962 Kefauver Amendment, heralding a new era of regulation of medical products for humans and routine animal safety testing of new drugs as a prerequisite for US clinical trials and marketing approvals. Notably, Marshall BioResources initiated raising beagle dogs for research in 1962 in response to the changes imposed by the US FDA for non-clinical testing of candidate drugs. 18 Other innovations occurring in this era included the electrical strain gauge by Edward E. Simmons and Arthur C. Ruge in 1938, enabling development of modern blood pressure and tissue contraction transducers. 19

The period following World War II thru the end of the 20th century, sometimes referred to as the Third Industrial Revolution, 6 witnessed the largest and most sustained advances in global economic growth and living standards, driven by some of the most remarkable advances and implementations of scientific knowledge and new technologies in human history. 1 During this period, in vivo animal and later in vitro bioassays using animal tissues proliferated and became the research “backbone” advancing the disciplines of physiology, pharmacology, pathology, endocrinology, toxicology, and others for exploration of biological properties, characterization and categorization of pharmacological and toxicological properties of new chemistry, and selections of new drugs for clinical trials and marketing authorizations. By the early 1980s, there were hundreds of individual bioassays for pharmacological activities using dogs, cats, rabbits, guinea pigs, swine, and smaller rodent species. 20 Technological advances in implantable catheters, sensors, and pumps, transducers, telemetry, and imaging technologies greatly expanded observational and manipulation assessments in animals. Additionally, this period witnessed development of conscious animal models acclimated to laboratory procedures to eliminate overlay of artifacts associated with stress and anesthesia. 21 , 22 Further, miniaturization of technologies permitted collection of experimental endpoints in rats and mice that were previously limited to larger species. 23 , 24 These advances were associated with the founding of the Society of Toxicology (1961), the British Society of Toxicology (1979), and the Safety Pharmacology Society (2000). However, despite these advances, uncertainty always remained as to whether and how results of animal studies would “predict” (or translate) to humans (eg, finding the “perfect animal model”).

Beginning in the 1970s and early 1980s, the primacy of observation/manipulation of animals in scientific research was challenged and progressively replaced by new concepts and technologies arising from new disciplines of cellular and molecular biology. The resulting paradigm shift—from phenomenological to mechanism-based characterizations of new chemistry and drug discovery based on specific interactions with human molecular targets (eg target-directed biology)—revolutionized both basic science and applied drug discovery disciplines. The impact was rapid replacement of the previous in vivo and in vitro animal model backbone of biomedical research with new cellular and molecular tools. This paradigm shift continues to evolve today with the use of stem cell models in cardiovascular risk assessment and in silico efforts to target specific mechanisms responsible for pharmacologic and toxic responses.

In a curious twist of history, a return to phenomenologically based animal observation and manipulation in the late 20th century was a result of perhaps the most transforming event of this period, Watson and Crick’s deciphering of the genetic code in the 1950s, leading to creation of genetically modified (GA) vertebrate organisms in the 1980s. 25 Following the seminal discoveries of Watson and Crick, sequencing of the human genome in 2001 and later sequencing of the genomes of animal species commonly used in research by the beginning of the 21st century revealed 80% or greater commonality (eg, common orthologs) of genetic sequences. 26 The genetic homologies confirmed prior centuries’ observational and phenomenological categorizations of relatedness of specific animal species and humans, for example, Linnaean taxonomy, 27 with chimpanzees and other non-human primates (NHPs) being the most similar. Collectively, the genomic sequences and prior practical experience confirm that no animal species is a “perfect model” for humans and supports the concept that GA technologies can produce better models. To paraphrase Professor George Box: “All animal models are wrong, but some are useful.” 28

Initially GA models (usually rodents) were applied to discovery and validation of new disease targets, 29 across disease areas from HTT protein and mouse models of Huntington’s disease to oncology targets. Later, GA models were successfully applied to reduce non-clinical safety testing in normal healthy animals with the adoption of GA P53 and rasH2 transgenic mouse models. 30–32 GA models have generally replaced the conduct of 2-year murine bioassays in non-clinical carcinogenicity testing with many fewer animals used. Likewise, functional defects observed in GA models also inform on potential safety risks from therapeutic interventions and thereby reduce animal safety testing. 33 Such approaches have been adopted into recent international regulatory guidance. 34 The impact has been the replacement of normal phenomenologically based animal, tissue, and cellular models to explore new biology and/or predict human responses with GA equivalents designed for the specific scientific purpose at hand.

This same period has witnessed the most pronounced global advances in animal welfare to date, beginning with the continuation of the concepts of Replacement, Refinement and Reduction (the 3Rs) 35 and the adoption of the first standards for appropriate animal welfare in biomedical research 36 and agriculture; 37 the United States Laboratory Animal Welfare Act in 1966, subsequently amended and expanded in scope; and culminating with efforts to replace animal experimentation with non-animal alternatives and technologies. 38 The period also witnessed global standardization for animal studies incorporating the principles of 3Rs and the attempt to eliminate unnecessary and/or duplicative studies (although sometimes at the expense of increasing animal usage in individual studies thru increasing the numbers and size of study groups), supporting global clinical trials and new product marketing authorizations. 39

Documentation of Animal Usage in Biomedical Research

Prior to the 20th century, there was no formal accounting of the numbers of animals used in scientific research activities. In the US regulations promulgated to implement the US Animal Welfare Act of 1966, the US Department of Agriculture (USDA) required annual reporting of numbers of specific species (cats, dogs, rabbits, guinea pigs, hamsters, NHPs, and farm species) used by every academic, industrial, and government organizations engaged in scientific research, beginning in 1973 ( Figure 2 ). The USDA data show that usage of these species peaked in the mid-1980s at over 2 million animals per year and, with 1 exception, the annual usage of all reported species has fallen by at least 50% since. Notably, these statistics are coincident with the paradigm shift away from phenomenological-based animal observation and manipulation to mechanism-based to cellular and molecular testing noted above as well as the international standardization of study requirements supporting clinical trials and new product registrations also noted above. The only exception in USDA statistics are NHPs, the least-used group of species in the 1970s but whose usage has approximately doubled since the 1980s. That growth has been driven by the perception based on phylogenetics and later comparative genomics that NHP species are more likely to mimic human responses, growth in development of new biopharmaceuticals and vaccines wherein NHPs are most appropriate species for non-clinical discovery and product development, 40 and implementation of primate GA models (eg, marmosets) in discovery research. 41

USDA/APHIS annual animal research data 1973–2019. Vertical axis: total numbers animals reported per year. Horizontal axis: years. (A) Total all reported species. (B) Totals individual reported species. The category of farm animals is a composite including pigs, goats, and sheep (1991–2007), after which pigs (including miniature pigs) and sheep were reported separately (2008–2018). 1973–2007 and 2019 data courtesy of USDA/APHIS staff; 2008–2018 data from USDA website. 51

A major deficiency of the USDA statistics is that only certain mammalian species (notably excluding mice and rats) are included, and all other vertebrate species, for example, birds, fish, and amphibians, are excluded. The National Survey of Laboratory Animal Facilities and Resources: Fiscal Year 1978 contains similar usage statistics for USDA-reported species and adds 13 413 813 mice, 4 358 766 rats, and 450 352 birds for total of 19 956 388 animals used in laboratory facilities. Health Designs Inc. (Rochester, NY) conducted a Survey and Estimates of Laboratory Animal Use in the United States in 1983, estimating in addition to USDA species 8 500 000 mice, 3 700 000 rats, 100 000 birds, 500 000 amphibians, and 4 000 000 fish for total of 18 581 875 animals in laboratory facilities. 42 Another recently published extrapolation concludes that between 2017 and 2018, over 100 000 000 mice and rats were used for research purposes in the United States. 43 These estimates suggest that the large decreases in usage of USDA-reported species ( Figure 2 ) were more than offset by increases in non-reported species in the late 20th and early 21st centuries.

The UK Home Office began reporting annual statistics on scientific procedures using living vertebrate animals (mammals, birds, reptiles, amphibians, and fish) in 1945, when total procedures were approximately 1 million per year ( Figure 3 ). The numbers of procedures performed annually in the United Kingdom increased steadily, peaked in the late 1960s to early 1970s at approximately 6 million per year, and then declined precipitously to approximately 3 million per year by 2001. Since 2001, mice, rats, and fish have accounted for 85% or more of total procedures, with all other individual species ≤8%. Sensitive species (dogs, cats, horses, and NHPs) have collectively accounted for <1% of procedures in the United Kingdom since 2001. 44

United Kingdom Home Office annual statistics of scientific procedures on living animals 1945–2019. Statistics are compiled from UK Home Office annual reports 2001–2019. Vertical axis: live animal procedures (millions/year). Horizontal axis: years. The disconnect between the 2 upper graphics (Experiments 1876 and 1986 Acts and Procedures 1986 Act, light and dark blue) reflect a recording difference occurring in 1987. 44 The middle graphics reflect total procedures filtered for creation, breeding, and usage of GA animals (purple) and normal animals (green) 2001–2019. The lower graphic (red) reflects UK usage of specific species approximate to those reported by USDA/APHIS 2001–2019 (see Figure 1 ).

After decades of decline, in the early 21st century, UK annual procedures began to increase, driven entirely by increased usage of mice, rats, and fish to generate GA animals ( Figure 3 ). A comparable increase in usage in the United States is not reflected in the USDA annual statistics ( Figure 2 ) because these do not include mice, fish, and rats. However, when the UK annual statistics are filtered for non-GA procedures, the same total downward trends are comparable in both the United States and United Kingdom. Additional insights provided by the UK statistics include: (1) use of genetically normal animals has continued to decrease in the 21st century; (2) use of GAs has increased and has accounted for approximately 50% of all reported procedures since 2012; and (3) the vast majority of reported GA procedures are for creation and breeding of GAs and the residual used in research programs. Enthusiasm for GA procedures is driven in part by the potential for inclusion of human response elements to improve efficacy, activity, and human translation of surrogate models for both therapeutic and safety endpoints, as noted above. The UK statistics demonstrate the substantial impact of a novel set of unanticipated transgenic and gene-editing technologies on usage of the traditional observation/manipulation animal research cycle, marking a fourth and current “Industrial Revolution” of genetic modification technologies in scientific research, product development, medicine, and animal welfare beginning in the first decade of the 21st century.

Filtering the 2001–2019 UK statistics for procedures with approximately the same species as reported in the 2001–2019 USDA statistics shows that UK procedures using these species has ranged from 70 000 to 280 000/year ( Figure 3 ), whereas US usage has ranged from 740 000 to 1 240 000 per year ( Figure 2 ). UK usage of these species was 7% to 16% of US usage during 2001–2013 and 27% to 36% during 2014–2018, reflecting an increase in UK and decrease in US usage during the latter interval. Between 2001 and 2019, procedures conducted in the United Kingdom using USDA-reported species ranged from approximately 2% to 7% of total reported procedures. Assuming that patterns and distributions of species usages in the United States and United Kingdom have been similar over this period, and USDA-reported species usage is approximately 5% of all vertebrate usage based on UK species procedure ratios during the same period, the estimated US annual usage (2001–2018) of all vertebrate species including fish has ranged from approximately 15 000 000 to 25 000 000/year ( Figure 4 ), roughly similar to previous estimates of the 1978 ILAR and 1983 Health Designs reports (anon. 1991). The difference (fivefold) between Carbone’s 2017–2018 estimate and that reported in this paper is that the Carbone estimate is based on a survey of mouse and rat usage by 16 large US institutions , 43 whereas the estimate in this paper is based on usage by all institutions of all vertebrate species by another country that is similar to the United States in scientific research activities.

Estimated US scientific usage of vertebrate species 2001–2019. Vertical axis: total estimated vertebrates/year. Horizontal axis: years. Analysis of UK Home Office statistics showing that specific species reported by USDA/APHIS 2001–2019 constitute approximately 5% of total UK scientific procedures on living animals during the period. See text for details.

Inferences to be drawn from the USDA and UK Home Office research animal statistics include:

Animals used in scientific research and product development increased progressively during the so-called third Industrial Revolution period, peaking between approximately 1970–1980 and likely reflecting the highest scientific annual use rates in US and UK history. Peak annual usage of all species in the United Kingdom was approximately 5 500 000 animals/year; peak annual usage for US AWA-reported species (eg excluding mice, rats, and all non-mammals) was approximately 2 000 000 animals/year, and undoubtedly many times more had all vertebrate species been included.

Animals used in scientific research and product development during the 20th century were predominantly normal or spontaneous mutants (eg, genetically hypertensive rats, immunodeficient mice) and used in primary physiological, pharmacological, and toxicological animal and animal tissue bioassays. Beginning in the late 1970s/early 1980s, primary animal and animal tissue bioassays were rapidly replaced by new molecular technologies that permitted target screening, target binding and activation, second messenger pathway activation, cellular pathways analyses, etc, or abandoned. The impact of the so-called “molecular revolution” is reflected in the dramatic decline (≥50%) in annual living animal procedures (UK) and usage of reported species (US) statistics into the 21st century.

Beginning in the early 21st century, the downward trend in the UK Home Office statistics unexpectedly reversed and over the following years rebounded to levels nearly as high as peak level procedures per year in the prior century. The rebound is almost entirely accounted for by mice, fish, and rats used for creating, breeding, and usage of GA animals. No rebound is apparent in the USDA statistics because the USDA-reported species have not generally been used for GA purposes. However, it is reasonable to surmise a similar pattern regarding GA species has occurred in the United States and that current levels of animal usage (all species) in the United States are also approaching/exceeding peak levels during the 20th century. This unanticipated increase in annual animal use in scientific research was the result of the uptake of unanticipated new technologies (eg, transgenics, gene editing/CRISPR-cas9). Notably, Russell and Birch predicted that advances in technology would create opportunities to enhance animal welfare thru the 3Rs, 35 and the USDA and UK Home Office statistics for the 20th century support their prediction. However, Russell and Birch apparently did not envision a potential impact of new and unanticipated technologies to rapidly generate new demands for animal usage in scientific research, for example, GAs. The UK Home Office statistics for the 21st century demonstrate the impact of new and unanticipated technologies driving new demand for animal usage in scientific research.

During the years of peak animal procedures (United Kingdom) and usage (United States) in the 20th century, the animal burden was shared by both rodent and non-rodent mammalian species, including mice, rats, dogs, cats, guinea pigs, rabbits, hamsters, and farm animals. In the current “Fourth Era,” the burden has shifted almost entirely towards species that reproduce rapidly, produce high numbers of offspring, and are subject to easy genetic manipulation, for example, mice, rats, and fish. In 2019 the UK Home Office reported 86% of experimental procedures used mice, fish, or rats; no other species accounted for >8%; dogs, cats, horses, and NHPs collectively <1%; and dogs and NHP usage was primarily for regulatory product testing. A similar conclusion was recently found for US dog and NHP usage using 2017 USDA statistics. 40 The USDA and UK Home Office statistics for the 21st century demonstrate the potential impact of new and unanticipated technologies to change the species distribution burden in scientific research. In addition, the shift in the discovery research paradigm away from animal models has enabled proliferation of both academic and venture capital biotechnology organizations to leverage new science for new potential therapies and to engage contract research organization for non-clinical development studies, contributing to increased animal usage and further underscoring the need to collect annual usage statistics for all species.

Non-animal Alternatives

Throughout history, humans—using their powers of observation and manipulation—have acquired critical knowledge leading to novel applications and thereby allowing survival and success of individuals and the species. Scientific research is just the most recent iteration of this observation/acquisition/application cycle ( Figure 5 ), and development of the scientific method-applied rigor, process, and new technologies has only facilitated generation of new knowledge leading to new applications. The iterative process also generates opportunities for the 3Rs (with another less-sentient species or tissues), opportunities for necessary animal research to achieve its goals. 35 However, replacement of animals and animal tissues with non-animal alternatives is highly sought and considered by some the ultimate goal. Non-animal replacements are applications derived from knowledge acquired through observation/manipulation using animals, and their utility is to replace for defined and specific purposes the necessity of further observations/manipulations using animals. Non-animal replacements offer greater efficiency, sensitivity, accuracy, cycle-time and productivity, and reduced cost for their specific purposes and should be identified, extracted, developed, and implemented whenever possible. However, non-animal replacements are products of, and not integral components of, the animal observation cycle, and although they will generate new knowledge within their alternative cycles, in the near term they are unlikely to replace the primacy of new observations using animals (including humans) to generate new previously unknown and unsuspected knowledge leading to new novel applications for clinical and veterinary healthcare and species survival. Consider the below examples of the animal observation/acquisition/application cycle leading to implementation of non-animal alternatives.

Depicts the modern relations between human observation and manipulation of animals for acquisition of new knowledge supporting new applications for benefit of clinical and veterinary medicine and species survival. See text for details.

Diabetes and Insulin

In 1889 Oskar Minkowski and Joseph von Mering performed manipulations and observed that pancreatectomized dogs developed diabetes mellitus whereas pancreatic duct ligation alone did not, thereby acquiring new knowledge of a hitherto unknown pancreatic function and establishing the dog as the primary animal model in early diabetes research. 45 , 46 Continuing the cycle, in 1920 Fredrick Banting and his student Charles Best prepared dog pancreas extracts and observed that upon injection into pancreatectomized dogs, the symptoms of diabetes mellitus (Type I) were relieved, thereby acquiring new knowledge that their pancreatic extract contained a hitherto unknown active substance or activity (they named “insletin”) critical for physiological glucose regulation. In 1921, Banting, Best, and their Department Chair John McLeod observed that the new knowledge acquired with canine insletin (renamed insulin) was reproduced in a Type I diabetic patient, thereby establishing cross-species translation of the therapeutic potential of insulin in Type I diabetes management. In retrospect, the dog model was fortuitous for human translation because diabetes Type I blood glucose regulation and pathophysiology are highly conserved between the 2 species and there is only 1 amino acid difference between canine and human insulins. 46 , 47

Recognizing that dog-sourced insulin was not logistically viable as a therapeutic for human diabetes, Best and David Scott developed procedures by which insulin could be isolated from commercial porcine and bovine sources, 48 thereby invoking 3Rs Reduction and Refinement principles in animal research by replacing use of a sensitive species with tissues obtained as a bi-product of agricultural processes. Eli Lilly & Co. then applied the new knowledge and commercialized bovine and porcine insulin extracts from 1923 to the end of the 20th century for human and veterinary diabetes therapy. In the 1980–1990s, recombinant DNA technology was applied for commercial manufacture of human insulin, creating a non-animal alternative (Replacement) for animal-sourced insulin in diabetes therapy.

McLeod and Banting (but not Best or Scott) were awarded the Nobel Prize in 1923 for their discovery of insulin—perhaps the most consequential Prize of the 20th century for its impact on diabetes management in human and veterinary medicine and for launching a century of advances in chemistry; the commercialization of insulin and other peptide hormones; and biology, pathophysiology, and therapeutics of diabetes and other endocrine disorders. The Prize has also been consequential many of the non-animal replacements for traditional animal sourcing of peptides and exploration (eg insulin, vasopressin, oxytocin, thyroid hormone, etc), identification and investigation of cellular and molecular diabetes mechanisms, and for identification of spontaneous, diet/nutrition, chemical and surgical induction, and genetically-altered (eg transgenic, knock-in, knock-out, etc.) animal models, diagnostic assays (eg glucose clamp, ELIZA), and therapeutic advances (eg feed-back controlled insulin pumps, synthetic hormone antagonists). 47 , 49 , 50

In summary, while the original discoveries of Banting, Best, Scott, and McLeod—following on observations of predecessors including Minkowski, von Mering, and others—laid the foundations for non–animal-sourced synthetic human insulin for diabetes management, they also laid the foundations for countless other observation cycles initially using animals for discovery, characterization, and therapeutic utilization of other peptide hormones and leading to new non-animal replacements for the detection, quantification, and production of said hormones and analogs for therapeutic applications. The research and discovery cycle is exemplary of so many current areas of biomedical research.

Endotoxin Detection

Parenterally administered drug formulations are routinely tested for presence of endotoxin, which can be inadvertently introduced through bacterial contamination during manufacture and packaging processes. Endotoxins (lipopolysaccharide complex [LPS], LPS A) are part of the outer membrane of the bacterial cell wall of Gram-negative pathogens such as Escherichia coli , Salmonella , Shigella , Pseudomonas , Neisseria , Haemophilus influenzae , Bordetella pertussis , and Vibrio cholerae . In humans, LPS binds to a lipid binding protein and triggers the signaling cascade for macrophage/endothelial cells to secrete pro-inflammatory cytokines, including IL-1 (“endogenous pyrogen”). IL-1 stimulates the hypothalamus to increase body temperature. The traditional method used to detect endotoxin is the rabbit pyrogen test (RPT), in which groups of rabbits are restrained and rectal probes inserted before intravenous test article administration; the primary experimental endpoint is rectal temperature change. Any agent that stimulates production of IL-1 or any other mechanism that stimulates hypothalamus to increase body temperature will be detected in the RPT. As late as the late 20th century, CROs specialized in performing RPTs and the RPT was probably second only to the Draize eye irritation test in generating pressure for a non-animal alternative method.

A candidate alternative method was limulus amoebocyte lysate (LAL), an in vitro test arising from observations that circulating blood cells in Atlantic horseshoe crabs ( Limulus polyphemus ) produce enzymes that bind and inactivate LPS from invading bacteria. The LAL test was accepted by the FDA as an alternative test method for endotoxin/LPS in 1983. It could be argued that the LAL test is not a true non-animal alternative because LAL is harvested from crabs, which originally did not survive the procedure; however, methods were quickly developed permitting the return of the crabs to the ocean unharmed following their blood donations. Today, LAL has almost completely replaced RPT and detects the presence of LPS by a mechanism entirely different from the RPT.

In the late 1990s, 2 authors (L.K. and D.J.) provided non-clinical support for the clinical development of a novel high-volume parenteral X-ray contrast agent. The formulation included a nanoparticulate encapsulated in egg-sourced lecithin-based liposomes. Clinical trials showed that volunteers receiving >100 mg of formulation experienced a febrile reaction, characteristic of LPS exposure. The formulation had been tested using LAL and was negative for LPS. Based on a finding from a non-rodent toxicology study that also suggested a febrile response, we evaluated the formulation using the RPT at a CRO; it was pyrogenic. We tested additional clinical formulations, all pyrogenic. We made a test formulation using the same nanoparticulate and synthetic lecithin liposomes, which tested negative for LPS in the LAL and was not pyrogenic in RPT. We concluded the following: (1) the febrile response observed in volunteers was due to LPS contamination of the test article, (2) the egg-sourced lecithin was the source of the LPS contamination, and (3) the liposome formulation effectively “masked” the LPS so that it was not detected in the LAL test. However, in the RPT, the liposomes were metabolized releasing the LPS, stimulating secretion of pro-inflammatory cytokines, including IL-1, and the pyrogenic response. Mechanisms matter, and tests based on different mechanisms may or may not provide congruent results, not because either test is “wrong” but because the tests measure different endpoints and/or use different conditions.

In summary, although non-animal replacements focusing on a specific mechanism do create their own “micro-cycles” in terms of new knowledge creation, these are separated from larger and more general endpoints and new knowledge opportunities associated with more mechanistically generalized animal research cycles.

Human ancestors recording their observations of animals as images on cave walls must have experienced a similar sense of accomplishment as modern scientists reporting their findings in peer-review journals or professional meetings; and we can surmise that the relationships between human observation and acquisition of knowledge leading to useful applications were as laborious, time-consuming, non-linear, and influenced by serendipity in ancient times as is for scientific research today. Yet despite that humans have benefited from observing and manipulating animals throughout their history, systematic use of animals as “human surrogates” in fundamental and applied scientific research is a modern phenomenon dating from the 19th century and reaching its peak in the latter half of the 20th century as documented by USDA and UK Home Office annual statistics. The dramatic decrease in annual animal usage for biomedical purposes in the latter 20th century was the result of multiple factors, most importantly discovery and implementation of new cellular- and molecular-based technologies that were more specific, analytic, efficient, productive, and cost-effective than then-current phenomenological-based animal and animal tissue bioassays. However, the UK Home Office annual statistics also show that implementation of new technology can be “multifaceted” and unpredictable. Implementation of new transgenics and gene-editing technologies in the early 21st century have been associated with sizable increases in annual animal usage to levels approaching or exceeding previous peak levels. The increases were largely due to necessary animal usage for creation and production of genetically modified animal constructs. The research burden imposed by GA animals has fallen almost exclusively on mice and fish, and to a lesser extent rats, demonstrating that redistribution of research burden is dependent on the new technology and is inherently unpredictable. Finally, whereas identifying and applying non-animal alternatives is a critical product of the observation/acquisition/application animal research cycle that replaces further use of animals for specific purposes, non-animal alternatives are generally not a substitute for animals or humans for future discovery, acquisition, and application of new knowledge critical to further advance human and veterinary medicine and global species survival.

The authors acknowledge the courtesy of Dr. Betty Goldentyer (Deputy Administrator, USDA/ APHIS, Animal Care) and members of the USDA/APHIS staff for providing 1973–2007 and 2019 summary statistics.

Potential conflicts of interest. All authors: No reported conflicts.

Kinter L , DeGeorge J . Scientific knowledge and technology, animal experimentation, and pharmaceutical development . ILAR J . 2016 ; 57 ( 2 ): 1 – 8 .

Google Scholar

Liu , Y. Poisonous medicine in ancient China. In Wexler P , ed. History of Toxicology and Environmental Health, Toxicology in Antiquity , Vol 2 , Chapter 9 . New York : Elsevier/Academic Press ; 2015.

Google Preview

Karamanou M , Androutsos G. Theriaca magna the glorious cure-all remedy. In: Wexler P , ed. History of Toxicology and Environmental Health: Toxicology in Antiquity Volume I . Kindle Edition. Waltham, MA : Academic Press ; 2014 .

Scutti S. Animal testing: a long, unpretty history . 2013 . Available at: https://www.medicaldaily.com/animal-testing-long-unpretty-history-247217 . Accessed April 22, 2021 .

West JB . Essays on the History of Respiratory Physiology . New York : Springer ; 2015 .

Patterson-Kane E , Golab G . Chapter 1: History, philosophies, and concepts of animal welfare. In: Bayne K , Turner P , eds. Laboratory Animal Welfare . New York : Elsevier ; 2014 . p. 1 – 6 .

Hobbes T . Leviathan ; 1651 . Chapter XIII .

Wade NJ , Deutsch D . Binaural hearing—before and after the stethophone . Acoustics Today . 2008 ; 2008 : 16 – 27 .

Ribatti D . William Harvey and the discovery of the circulation of the blood . Angiogenes Res . 2009 ; 2009 : 1:3 . Published online September 21, 2009 . doi: 10.1186/2040-2384-1-3 PMCID: PMC2776239, PMID: 19946411 .

Hoff HE , Geddes LA , McCrady JD . The contributions of the horse to knowledge of the heart and circulation. 1. Stephen Hales and the measurement of blood pressure . Conn Med . 1965 ; 29 ( 11 ): 795 – 800 5320322 .

West JB . High Life: A History of High Altitude Physiology and Medicine . New York, NY : Springer ; 1998 . p. 33 – 34 .

Lloyd E . A history of how scientists used animal testing to make medical advances . 2008. http://www . brighthub.com/science/medical/articles/16237.aspx . Accessed April 28, 2021.

Das S . The Age of Stagnation . New York, NY : Prometheus Books ; 2016 .

Burchell H . A Centennial note on Waler and the first human electrocardiogram . Am J Cardiology . 1987 ; 59 : 979 – 983 .

Lopes-Munoz F , Ucha-Udabe R , Alamo C . The history of barbiturates a century after their introduction . Neuropsych Dis Treat . 2005 ; 1 ( 4 ): 329 – 343 .

Dundee JW , McIlroy PDA . The history of the barbiturates . Anesthesia . 1982 ; 37 : 726 – 734 .

Frith J . Arsenic – the “Poison of Kings” and the “Saviour of Syphilis ”. J Milit Veterans’ Health . 2013 ; 2 ( 4 ): 11 – 17 .

Marshall BioResources . Available at: https://www.marshallbio.com/history . Accessed April 22, 2021.

Stein PK . A brief history of bonded resistance strain gages from conception to commercialization . Exp Tech . 1990 ; 14 ( 5 ): 13 – 19 .

Bass AS , Hombo T , Kasai C , et al.  A historical view and vision into the future of the field of safety pharmacology. In: Pugsley MK , Curtis MJ , eds. Handbook of Experimental Pharmacology 229: Principles of Safety Pharmacology . Berlin, Germany : Springer ; 2015 .

Goode TL , Kline HJ . Miniaturization: an overview of biotechnologies for monitoring the physiology and pathophysiology of rodent animal models . ILAR J . 2002 ; 43 ( 3 ): 136 – 146 .

Nolan TE , Klein HJ . Methods in vascular infusion biotechnology in research with rodents . ILAR J . 2002 ; 43 ( 3 ): 175 – 182 .

Kinter LB , Johnson DK . Remote monitoring of experimental endpoints in animals using radiotelemetry and bioimpedance technologies. In: Hendriksen CFM , Morton DB , eds. Proc. Intl. Conference on Humane Endpoints in Animal Experiments for Biomedical Research . London, UK : The Royal Society of Medicine Press Ltd ; 1999 . p. 58 – 65 .

Kramer K , Kinter LB . Evaluation and application of radiotelemetry in small laboratory animals . Physiol Genomics . 2003 ; 13 : 197 – 205 .

Costantini F , Lacy E . Introduction of a rabbit beta-globin gene into the mouse germ line . Nature . 1981 ; 294 : 92 – 94 1981 .

Pennisi E . The human genome . Science . 2001 ; 291 ( 5507 ): 1177 – 1180 . doi: 10.1126/science.291.5507.1177 . PMID 11233420. S2CID 38355565.

Linnæus C . Systema naturæ per regna tria naturæ, secundum classes, ordines, genera, species, cum characteribus, differentiis, synonymis locis . In: Tomus I Editio decima, reformata . Holmiæ. (Salvius); 1758. p. 1–4, 1–824.

Box GEP . Science and statistics . J Am Stat Assoc . 1976 ; 71 ( 356 ): 791 – 799 .

Rudman DG , Durham SK . Use of genetically altered animals in the pharmaceutical industry . Tox path . 1999 ; 27 ( 12 ): 111 – 114 . doi: https://doi.org/10.1177/01926233990200121 .

Anon. FDA Guidance for Industry: S1B Testing for Carcinogenicity of Pharmaceuticals (ICH S1B) . 1997. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s1b-testing-carcinogenicity-pharmaceuticals . Accessed April 22, 2021.

Jackson J , Lozano G . The mutant p53 mouse as a pre-clinical model . Oncogene . 2013 ; 32 , 4325 – 4330 . Available at: https://doi.org/10.1038/onc.2012.610 . Accessed April 22, 2021.

Tamaoki N . The rasH2 transgenic mouse: nature of the model and mechanistic studies on tumorigenesis. Toxicol Pathol . 2001 ; 29 ( Suppl ): 81 – 89 .

Poulet FM , Wolf JJ , Herzyk DJ , et al.  An evaluation of the impact of PD-1 pathway blockade on reproductive safety of therapeutic PD-1 inhibitors . Birth Defects Research (Part B) . 2016 ; 107 : 108 – 119 .

Anon . International Council for Harmonization of Technical Requirements For Pharmaceuticals For Human Use. Draft ICH Harmonized Guideline: Detection of Toxicity to Reproduction for Human Pharmaceuticals S5(R3) Current Step 1 . Draft version dated July 5, 2017 . Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/s5r3-detection-toxicity-reproduction . Accessed April 22, 2021.

Russell WMS , Burch RL . The Principles of Humane Experimental Technique . London, UK : Methuen and Co.; [Reissued: 1992, Universities Federation for Animal Welfare, Herts, UK ; 1959 .

Animal Care Panel . Guide for Laboratory Animal Facilities and Care . Washington, DC : U.S. Government Printing Office ; 1963. Available at: http://dels.nas.edu/resources/static-assets/ilar/miscellaneous/GUIDE1963.pdf

Brambell R . Report of the Technical Committee to Enquire into the Welfare of Animals Kept Under Intensive Livestock Husbandry Systems, Cmd. (Great Britain. Parliament), H.M. Stationery . Office . 1965 ; 1 – 84 .

Anestidou L , Kinter LB , Patterson-Kane E . Broader perspectives on laboratory animal welfare advancing animal welfare in the 21st century . OIE (World Organization for Animal Health) . 2017 ; 2017 ( 1 ): 101 – 104 . Available at: http://dx.doi.org/10.20506/bull.2017.1.2598 .

Van der Laan JW , DeGeorge JD . Global approach in safety testing ICH guidelines explained. In: DJA Crommelin and RA Lipper, series eds. AAPS Advances in Pharmaceutical Sciences Series 5 . Berlin, Germany : Springer ; 2013 .

Anon . National Academies of Sciences Engineering and Medicine Consensus Study Report: Necessity, care, and use of laboratory dogs at the U.S. Department of Veterans Affairs, Appendix B . Washington DC : The National Academies Press ; 2020. p. 143–148. Available at: https://www.nap.edu/catalog/25772/necessity-use-and-care-of-laboratory-dogs-at-the-us-department-of-veterans-affairs . Accessed April 22, 2021

Park JE , Sasaki E . Assisted reproductive techniques and genetic manipulation in the common marmoset . ILAR J . 2021 ; ilab002. doi: 10.1093/ilar/ilab002 . Online ahead of print.

Anon . Important laboratory animal resources: selection criteria and funding mechanisms for their preservation . ILAR News . 1990 ; 32 ( 4 ): A9 .

Carbone , L . Estimating mouse and rat use in American laboratories by extrapolation from Animal Welfare Act-regulated species. Nature Research/Scientific Reports 11/493 . 2021. Available at: https://doi.org/10.1038/s41598-020-79961-0 . Accessed April 22, 2021

UK Home Office Statistics of Scientific Procedures on Living Animals. 2001-2019 . Available at: https://www.gov.uk/government/collections/statistics-of-scientific-procedures-on-living-animals . Accessed April 20, 2021.

von Mering J , Minkowski O . Diabetes mellitus nach Pankreas extirpation . Arch f exper Path u Pharmakol . 1889 ; 26 : 371 .

Karamanou M , Protogerou A , Tsoucalas G , et al.  Milestones in the history of diabetes mellitus: the main contributors . World J Diabetes . 2016 ; 7 ( 1 ): 1 – 7 . Published online Jan 10, 2016 . doi: 10.4239/wjd.v7.i1.1 . PMCID: PMC4707300 PMID: 26788261 .

Anon . National Academies of Sciences Engineering and Medicine Consensus Study Report: Necessity, Care, and Use of Laboratory Dogs at the U.S. Department of Veterans Affairs . Washington DC : The National Academies Press ; 2020. p. 49–51. Available at: https://www.nap.edu/catalog/25772/necessity-use-and-care-of-laboratory-dogs-at-the-us-department-of-veterans-affairs . Accessed April 22, 2021.

Best CH , Scott DA . The preparation of insulin . J Biol Chem . 1923 ; 57 : 709 – 723 .

Leiter EH , Lee C-H . Mouse models and the genetics of diabetes, is there evidence for genetic overlap between type 1 and type 2 diabetes? Diabetes . 2005 ; 54 ( suppl 2 ): S151 – S158 .

Srinivasan K , Ramarao P . Animal models of type 2 diabetes research . Indian J Med Res . 2007 ; 125 : 451 – 472 .

USDA/APHIS website . Available at: https://www.aphis.usda.gov/aphis/ourfocus/animalwelfare/sa_obtain_research_facility_annual_report/ct_research_facility_annual_summary_reports . Accessed April 26, 2021.

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Extending Animal Cruelty Protections to Scientific Research

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Photo by Sandy Millar on Unsplash

INTRODUCTION

On November 25, 2019, the federal law H.R. 724 – the Preventing Animal Cruelty and Torture Act (PACT) prohibiting the intentional harm of “living non-human mammals, birds, reptiles, or amphibians” was signed. [1] This law was a notable step in extending protections, rights, and respect to animals. While many similar state laws existed, the passing of a federal law signaled a new shift in public tone. PACT is a declaration of growing societal sentiments that uphold the necessity to shield our fellow creatures from undue harm. Protecting animals from the harm of citizens is undoubtedly important, but PACT does nothing to protect animals from state-sanctioned harm, particularly in the form of research, which causes death and cruelty. It is time to extend and expand protections for animals used in research.

There is a long history of animal experimentation in the US, but no meaningful ethical protections of animals emerged until the 20 th century. Proscription of human experimentation and dissection led to animals bearing the brunt of harm for scientific and medical progress. For instance, English physician William Harvey discovered the heart did not continuously produce blood but instead recirculated it; he made this discovery by dissecting and bleeding out living dogs without anesthesia. [2] Experiments like this were considered ethically tenable for hundreds of years. Philosophers like Immanuel Kant, Thomas Aquinas, and Rene Descartes held that humans have no primary moral obligations to animals and that one should be concerned about the treatment of an animal only because it could indicate how one would treat a human. [3] During the 20 th century, as agriculture became more industrialized and government funding for animal research increased, the social demand for ethical regulations finally began to shift. In 1966, the Animal Welfare Act (Public Law 89-544) marked the first American federal legislation to protect laboratory animals, setting standards for use of animals in research. [4]

There has been progress in the field of animal research ethics since Harvey’s experiments, but much work remains. In the US alone, there are an estimated 20 million mice, fish, birds, and invertebrates used for animal research each year that are not regulated by the Animal Welfare Act. [5] Instead, the “3Rs Alternatives” approach (“reduce, replace, and refine”) [6] is one framework used to guide ethical treatment of animals not covered by federal protections. Unfortunately, unpacking the meaning and details of this approach only leads to ambiguity and minimal actionable guidance. For instance, an experimenter could reduce the number of animals used in research but subsequently increase the number of experiments conducted on the remaining animals. Replace could be used in the context of replacing one species with another. Refining is creating “any decrease in the severity of inhumane procedures applied to those animals, which still have to be used.” [7] The vague “ any ” implies that even a negligible minimization would be ethically acceptable. [8] An experimenter could technically follow each of the “3Rs” with minimal to no reduction in harm to the animals. One must also consider whether it is coherent to refer to guidelines as ethical when they inevitably produce pain, suffering, and death as consequences of research participation.

Other ethical guides like Humane Endpoints for Laboratory Animals Used in Regulatory Testing [9] encourage researchers to euthanize animals that undergo intractable pain or distress. This is a fate that an estimated one million animals face yearly in the US. [10] However, to use the word “humane” in this context contradicts the traditional meaning and undermines the integrity of the word. Taking living creatures, forcing them to experience intractable pain and suffering for human benefit, and killing them is the antithesis of what it means to be humane. During one of my Animal Ethics classes as a graduate student, our cohort visited an animal research facility to help inform our opinions on animal research. We observed one of the euthanasia chambers for lab mice – an enclosed metal lab bench with a sign above describing methods for euthanasia if CO 2 asphyxiation were to fail. The methods included decapitation, removal of vital organs, opening of the chest cavity, incision of major blood vessels, and cervical dislocation. [11] Behind us were rows and rows of see-through shoebox-sized containers housing five mice in each little box. Thousands of mice were packed together in this room for the sole purpose of breeding. If the mice were not the correct “type” for research, then they were “humanely” euthanized. “Humane,” in this context, has been deprived of its true meaning.

One can acknowledge that animal research was historically necessary for scientific progress, but those that currently claim these practices are still required must show empirically and undoubtedly this is true. As of now, this is not a settled issue. In the scientific community, there is contention about whether current animal research is actually applicable to humans. [12] Many drug researchers even view animal testing as a tedious barrier to development as it may be wholly irrelevant to the drug or medical device being tested. Since 1962, the FDA has required preclinical testing in animals; it is time to question whether this is necessary or helpful for drug development.

The scientific community should stop viewing animal testing as an unavoidable evil in the search for medical and technological innovation. PACT should be amended and extended to all animals and the FDA should modify the requirement for preclinical animal testing of all drugs and medical devices. It is time to encourage the scientific community to find alternative research methods that do not sacrifice our fellow animals. We use animals as test subjects because, in some sense, they resemble humans. But, if they are indeed like humans, they should receive similar protections. Science builds a better world for humans, but perhaps it is time for science to be more inclusive and build a better world for all creatures.

[1] Theodore E. Deutch, “Text - H.R.724 - 116th Congress (2019-2020): Preventing Animal Cruelty and Torture Act,” legislation, November 25, 2019, 2019/2020, https://www.congress.gov/bill/116th-congress/house-bill/724/text.

[2] Anita Guerrini, “Experiments, Causation, and the Uses of Vivisection in the First Half of the Seventeenth Century,” Journal of the History of Biology 46, no. 2 (2013): 227–54.

[3] Bernard E. Rollin, “The Regulation of Animal Research and the Emergence of Animal Ethics: A Conceptual History,” Theoretical Medicine and Bioethics 27, no. 4 (September 28, 2006): 285–304, https://doi.org/10.1007/s11017-006-9007-8; Darian M Ibrahim, “A Return to Descartes: Property, Profit, and the Corporate Ownership of Animals,” LAW AND CONTEMPORARY PROBLEMS 70 (n.d.): 28.

[4] Benjamin Adams and Jean Larson, “Legislative History of the Animal Welfare Act: Introduction | Animal Welfare Information Center| NAL | USDA,” accessed November 3, 2021, https://www.nal.usda.gov/awic/legislative-history-animal-welfare-act-introduction.

[5] National Research Council (US) and Institute of Medicine (US) Committee on the Use of Laboratory Animals in Biomedical and Behavioral Research, Patterns of Animal Use , Use of Laboratory Animals in Biomedical and Behavioral Research (National Academies Press (US), 1988), https://www.ncbi.nlm.nih.gov/books/NBK218261/.

[6] Robert C. Hubrecht and Elizabeth Carter, “The 3Rs and Humane Experimental Technique: Implementing Change,” Animals: An Open Access Journal from MDPI 9, no. 10 (September 30, 2019): 754, https://doi.org/10.3390/ani9100754.

[7] Hubrecht and Carter.

[8] Hubrecht and Carter.                           

[9] William S. Stokes, “Humane Endpoints for Laboratory Animals Used in Regulatory Testing,” ILAR Journal 43, no. Suppl_1 (January 1, 2002): S31–38, https://doi.org/10.1093/ilar.43.Suppl_1.S31.

[10] Stokes.

[11] “Euthanasia of Research Animals,” accessed April 21, 2022, https://services-web.research.uci.edu/compliance/animalcare-use/research-policies-and-guidance/euthanasia.html.

[12] Neal D. Barnard and Stephen R. Kaufman, “Animal Research Is Wasteful and Misleading,” Scientific American 276, no. 2 (1997): 80–82.

Chad Childers

MS Bioethics Candidate Harvard Medical School Center for Bioethics

Article Details

This work is licensed under a Creative Commons Attribution 4.0 International License .

• History of animal research

The use of animals in scientific experiments in the UK can be traced back at least as far as the 17th Century with Harvey’s experiments on numerous animal species aiming to demonstrate blood circulation. Across Europe, the use of animals in scientific research began to expand over the 19th Century, in part supported by the development of anaesthetics which had previously made animal research impossible. In 1876, parliament passed the Cruelty to Animals Act, the first legislation aimed at regulating animal experiments. Over the late 19th and the 20th centuries, the expansion of medical science meant that the numbers of animals used in research expanded steadily, accelerated by the Medicines Act, 1968, which provided a clearer guide to the use of animals in safety testing in the wake of the Thalidomide tragedy. The number of animals used rose  to over 5.5 million in 1970 after which point the numbers began to decline rapidly. This large expansion reflected a growing medical field; animals had played a part in most medical advances of the 20th century including insulin, the polio vaccine, penicillin and the elimination of smallpox. In 1986 the Animals (Scientific Procedures) Act was passed, which ensured higher animal welfare standards in laboratories across the UK. In 2010, EU Directive 2010/63 was passed. This regulation harmonises European animal laboratory standards, improving animal welfare across the EU, and is currently being transposed into the laws of the member countries. It passed into UK law on 1st January 2013.

Animal Research in Medicine: 100 Years of Politics, Protests and Progress (John Illman) provides a history of animal research legislation and the context in which they were developed.  - Illman, J., 2008. Aninmal Research in Medicine: 100 years of Politics, Protests and Progress. The Story of the Research Defence Society. London: Research Defence Society. A Guinea Pig’s History of Biology (Jim Endersby) tells the story of modern biology through the stories of the animals and plants that made it possible.  - Endersby, J., 2007. A Guinea Pig’s History of Biology. Heinemann.

Online resources

Medical Advances and Animal Research (RDS & CMP) is an excellent booklet outlining the role of animals in many of the medical developments we see around us. It provides full references to the scientific literature it mentions throughout.  - Research Defence Society & Coalition for Medical Progress, 2007. Medical Advances and Animal Research: The Contribution of Animal Science to the Medical Revolution: Some Case Histories. London: RDS. Available from our document library here . The Animal Research Timeline (AR.info) provides an outline of many of the major medical discoveries since 1881, as well as explaining the role of animals in each of these developments.  - AnimalResearch.Info. Timeline. Available at:  http://www.animalresearch.info/en/medical-advances/timeline/ Animal Research Info: Nobel Prizes (AR.info) provides a breakdown of all the Nobel Prizes in Physiology and Medicine since 1901 and includes how animals were involved in the discoveries.  - AnimalResearch.Info. Nobel Prizes. Available at:  http://www.animalresearch.info/en/medical-advances/nobel-prizes/ Pro-Test: Tackling Animal Rights (SR) is an essay following the battle over the building of the Oxford University Biomedical Facility from 2005-2008. It covers the rise of the animal rights group SPEAK, and the student counter-movement, Pro-Test. It also covers some of the issues which helped change public opinion from 2006.  - Speaking of Research, 2008. Pro-Test Tackling Animal Rights in the UK. Available at:  http://speakingofresearch.com/about/the-uk-experience/ Click on one of the links below to see other topics on animal research

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Animal experiments in biomedical research: a historical perspective.

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1. introduction, 2. from antiquity to the renaissance, 3. seventeenth century and the dawn of the enlightenment.

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4. Eighteenth Century and the Rise of Moral Consideration for Animals

5. the nineteenth-century medical revolution and the upsurge of the antivivisection societies.

This surgeon’s spring course of experimental physiology commenced in the beginning of April. I seldom fail of “assisting” at his murders. At his first lecture, a basketful of live rabbits, 8 glass receivers full of frogs, two pigeons, an owl, several tortoises and a pup were the victims ready to lay down their lives for the good of science! His discourse was to explain the function of the fifth pair of nerves. The facility was very striking with which the professor could cut the nerve at its origin, by introducing a sharp instrument through the cranium, immediately behind and below the eye. M. Magendie drew the attention of the class to several rabbits in which the fifth pair of nerves had been divided several days before. They were all blind of one eye, a deposition of lymph having taken place in the comes, from inflammation of the eye always following the operation alluded to, although the eye is by this section deprived of all its sensibility. Monsieur M. has not only lost all feeling for the victims he tortures, but he really likes his business. When the animal squeaks a little, the operator grins; when loud screams are uttered, he sometimes laughs outright. The professor has a most mild, gentle and amiable expression of countenance, and is in the habit of smoothing, fondling and patting his victim whilst occupied with preliminary remarks, and the rabbit either looks him in the face or ‘licks the hand just raised to shed his blood. During another lecture, in demonstrating the functions of the motive and sensitive fibers of the spinal nerves, he laid bare the spinal cord in a young pup, and cut one bundle after another of nerves. (…) Living dissection is as effectual a mode of teaching as it is revolting, and in many cases the experiments are unnecessarily cruel and too frequently reiterated; but so long as the thing is going on, I shall not fail to profit by it, although I never wish to see such experiments repeated. cit in Olmsted, 1944 [ 101 ]

No hesitation is possible, the science of life can be established only by experiment, and we can save living beings from death only by sacrificing others. Experiments must be made either on man or on animals. Now I think physicians already make too many dangerous experiments on man, before carefully studying them on animals. I do not admit that it is moral to try more or less dangerous or active remedies on patients, without first experimenting with them on dogs; for I shall prove, further on, that results obtained on animals may all be conclusive for man when we know how to experiment properly. If it is immoral, then, to make an experiment on man when it is dangerous to him, even though the result may be useful to others, it is essentially moral to do experiments on an animal, even though painful and dangerous to him, if they may be useful to man.

6. The Twentieth-Century Triumph of Science-Based Medicine

7. animal liberation and the pathway for a more humane science, 8. conclusion, acknowledgments, conflict of interest, references and notes.

• von Staden, H. Herophilus: The Art of Medicine in Early Alexandria ; Cambridge University Press: Cambridge, UK, 1989. [ Google Scholar ]
• Court, W.E. Pharmacy from the ancient world to 1100 AD. In Making Medicines: A Brief History of Pharmacy and Pharmaceuticals ; Anderson, S., Ed.; Pharmaceutical Press: London, UK, 2005. [ Google Scholar ]
• Maehle, A.-H.; Tröhler, U. Animal experimentation from antiquity to the end of the eighteenth century: Attitudes and arguments. In Vivisection in Historical Perspective ; Rupke, N.A., Ed.; Croom Helm: London, UK, 1987. [ Google Scholar ]
• Geller, M.J. Phlegm and breath—Babylonian contributions to hippocratic medicine. In Disease in Babylonia ; Finkel, I.L., Geller, M.J., Eds.; Brill: Leiden, The Netherlands, 2007. [ Google Scholar ]
• Guerrini, A. Experimenting with Humans and Animals: From Galen to Animal Rights ; Johns Hopkins University Press: Baltimore, MD, USA, 2003. [ Google Scholar ]
• O’Malley, C.D. Andreas Vesalius of Brussels ; University of California Press: Berkeley, CA, USA, 1964. [ Google Scholar ]
• Regan, T.; Singer, P. Animal Rights and Human Obligations , 2nd ed.; Prentice Hall: Upper Saddle River, NJ, USA, 1989. [ Google Scholar ]
• Prioreschi, P. A History of Medicine, Volume 3: Roman Medicine ; Horatius Press: Omaha, NE, USA, 1998. [ Google Scholar ]
• Prioreschi, P. A History of Medicine, Volume 2: Greek Medicine , 2nd ed.; Horatius Press: Omaha, NE, USA, 1996. [ Google Scholar ]
• Prioreschi, P. Experimentation and scientific method in the classical world: Their rise and decline. Med. Hypoth. 1994 , 42 , 135–148. [ Google Scholar ] [ CrossRef ]
• Prioreschi, P. A History of Medicine, Volume 5: Medieval Medicine , 2nd ed.; Edwin Mellen Press: Lewiston, NY, USA, 1996. [ Google Scholar ]
• Bacon, F. The second book of francis bacon on the proficience and advancement of learning, divine and human (originally published in 1605). In The Works of Francis Bacon: Baron of Verulam, Viscount St. Albans, and Lord High Chancellor of England ; Montague, B., Ed.; Carey and Hart: Philadelphia, PA, USA, 1842. [ Google Scholar ]
• Descartes, R. Animals are machines. In Animal Rights and Human Obligations , 2nd ed.; Regan, T., Singer, P., Eds.; Prentice Hall: Upper Saddle River, NJ, USA, 1989; pp. 13–19. [ Google Scholar ]
• Rupke, N.A. Vivisection in Historical Perspective ; Croom Helm: London, UK, 1987. [ Google Scholar ]
• Boden, M.E. Mind as Machine: A History of Cognitive Science ; Oxford University Press: Oxford, UK, 2006; Volume 1. [ Google Scholar ]
• Allen, C. Animal consciousness. In The Stanford Encyclopedia of Philosophy , Summer 2011 ed.; Zalta, E.N., Ed.; Center for the Study of Language and Information, Stanford University: Stanford, CA, USA, 2011. [ Google Scholar ]
• Cottingham, J. A brute to the brutes—Descartes’ treatment of animals. In Rene Descartes: Critical Assessments ; Moya, G.J.D., Ed.; Routledge: London, UK, 1991. [ Google Scholar ]
• Harrison, P. Descartes on animals. Philosoph. Quart. 1992 , 42 , 219–227. [ Google Scholar ]
• Leiber, J. Descartes: The smear and related misconstruals. J. Theory Soc. Behav. 2011 , 41 , 365–376. [ Google Scholar ] [ CrossRef ]
• Dennett, D.C. Animal consciousness: What matters and why. Soc. Res. 1995 , 62 , 691–710. [ Google Scholar ]
• Steiner, G. Descartes on the moral status of animals. Arch. für Geschichte der Philosophie 1998 , 80 , 268–291. [ Google Scholar ]
• Steintrager, J.A. Science and insensibility. In Cruel Delight: Enlightenment Culture and the Inhuman ; Steintrager, J.A., Ed.; Indiana University Press: Bloomington, IN, USA, 2004. [ Google Scholar ]
• Bayon, H.P. René Descartes, 1596–1650. A short note on his part in the history of medicine. Proc. Roy. Soc. Med. 1950 , 43 , 783–785. [ Google Scholar ]
• Bitbol-Hespériès, A. Cartesian physiology. In Descartes’ Natural Philosophy ; Gaukroger, S., Schuster, J., Sutton, J., Eds.; Routledge: London, UK, 2000. [ Google Scholar ]
• Steiner, G. Anthropocentrism and its Discontents: The Moral Status of Animals in the History of Western Philosophy ; University of Pittsburgh Press: Pittsburgh, PA, USA, 2010. [ Google Scholar ]
• Spinoza, B. The Ethics ; Echo Library: Teddington, Middlesex, UK, 2006. [ Google Scholar ]
• Locke, J. Some Thoughts Concerning Education ; Walker: Dublin, Ireland, 1778. [ Google Scholar ]
• Kant, I. Lectures on Ethics ; Schneewind, J.B., Ed.; Cambridge University Press: Cambridge, UK, 1997. [ Google Scholar ]
• Broadie, A.; Pybus, E.M. Kant’s treatment of animals. Philosophy 1974 , 49 , 375–383. [ Google Scholar ] [ CrossRef ]
• Linzey, A. The Link between Animal Abuse and Human Violence ; Sussex Academic Press: Eastbourne, UK, 2009. [ Google Scholar ]
• Gregory, A. Harvey’s Heart: The Discovery of Blood Circulation ; Icon Books Ltd.: Cambridge, UK, 2001. [ Google Scholar ]
• Wear, A. Early Modern Europe, 1500–1700. In The Western Medical Tradition: 800 BC–1800 AD ; Conrad, L.I., Neve, M., Nutton, V., Porter, R., Wear, A., Eds.; Cambridge University Press: Cambridge, UK, 1995. [ Google Scholar ]
• Shackelford, J. William Harvey and the Mechanics of the Heart ; Oxford University Press: New York, NY, USA, 2003. [ Google Scholar ]
• McMullen, E. Anatomy of a physiological discovery: William Harvey and the circulation of the blood. J. Roy. Soc. Med. 1995 , 88 , 491–498. [ Google Scholar ]
• Cohen, I.B. Scientific revolution. In Interactions: Some Contacts between the Natural Sciences and Social Sciences ; MIT Press: Cambridge, UK, 1994. [ Google Scholar ]
• Beard, D.A.; Bassingthwaighte, J.B.; Greene, A.S. Computational modeling of physiological systems. Physiol. Genom. 2005 , 23 , 1–3. [ Google Scholar ] [ CrossRef ]
• Grene, M.G.; Depew, D.J. Descartes, Harvey, and the emergence of modern mechanism. In The Philosophy of Biology: An Episodic History ; Cambridge University Press: Cambridge, UK, 2004; pp. 35–63. [ Google Scholar ]
• Weil, E. The Echo of Harvey’s de Motu Cordis (1628) 1628 to 1657. J. History Med. Allied Sci. 1957 , XII , 167–174. [ Google Scholar ] [ CrossRef ]
• Martins e Silva, J. From the discovery of the circulation of the blood to the first steps in hemorheology: Part 2. Revista Portuguesa de Cardiologia 2009 , 28 , 1405–1439. [ Google Scholar ]
• Grene, M.G. Descartes and the heart beat: A conservative innovation. In Wrong for the Right Reasons (Archimedes-New Studies in the History and Phylosophy of Science and Technology) ; Buchwald, J.Z., Franklin, A., Eds.; Springer: Berlin/Heidelberg, Germany, 2005; Volume 11, pp. 91–97. [ Google Scholar ]
• Gorham, G. Mind-body dualism and the Harvey-Descartes controversy. J. History Ideas 1994 , 55 , 211–234. [ Google Scholar ] [ CrossRef ]
• Frank, R.G. Harvey and the Oxford Physiologists: Scientific Ideas and Social Interaction ; University of California Press: Berkeley, CA, USA, 1980. [ Google Scholar ]
• Wooley, C.F. Palpitation: Brain, heart, and ‘spirits’ in the seventeenth century. J. Roy. Soc. Med. 1998 , 91 , 157–160. [ Google Scholar ]
• Felts, J.H. Richard Lower: Anatomist and physiologist. Ann. Int. Med. 2000 , 132 , 420–423. [ Google Scholar ]
• Wootton, D. Bad Medicine: Doctors Doing Harm Since Hippocrates ; Oxford University Press: New York, NY, USA, 2006. [ Google Scholar ]
• Dear, P. The meanings of experience. In The Cambridge History of Science, Volume 3: Early Modern Science ; Park, K., Daston, L., Eds.; Cambridge University Press: Cambridge, UK, 2006. [ Google Scholar ]
• French, R.K. William Harvey’s Natural Philosophy ; Cambridge University Press: Cambridge, UK, 1994. [ Google Scholar ]
• Van der Worp, H.B.; Howells, D.W.; Sena, E.S.; Porritt, M.J.; Rewell, S.; O’Collins, V.; Macleod, M.R. Can animal models of disease reliably inform human studies? PLoS Med. 2010 , 7 . [ Google Scholar ] [ CrossRef ]
• Maehle, A.-H. Opium: Explorations of an ambiguous drug-ethical aspects. In Drugs on Trial: Experimental Pharmacology and Therapeutic Innovation in the Eighteenth Century ; Editions Rodopi: Amsterdam, The Netherlands, 1999; pp. 193–195. [ Google Scholar ]
• Boyle, R. New Experiments Physico-Mechanicall, Touching the Spring of the Air, and its Effects (Made in a New Pneumatical Engine): Written by Way of Letter to the Right Honorable Charles, Lord Vicount of Dungarvan, Eldest Son to the Earl of Corke/by the Honorable Robert Boyle, Esq. ; Printed by H. Hall: Oxford, UK, 1660. [ Google Scholar ]
• West, J.B. Robert Boyle’s landmark book of 1660 with the first experiments on rarified air. J. Appl. Physiol. 2005 , 98 , 31–39. [ Google Scholar ] [ CrossRef ]
• West, J.B. Stephen Hales: Neglected respiratory physiologist. J. Appl. Physiol. 1984 , 57 , 635–639. [ Google Scholar ]
• Smith, I.B. The impact of Stephen Hales on medicine. J. Roy. Soc. Med. 1993 , 86 , 349–352. [ Google Scholar ]
• Clark-Kennedy, A.E. Stephen Hales, DD, FRS. Br. Med. J. 1977 , 2 , 1656–1658. [ Google Scholar ] [ CrossRef ]
• Porter, R. The eighteenth century. In The Western Medical Tradition: 800 BC-1800 AD ; Conrad, L.I., Neve, M., Nutton, V., Porter, R., Wear, A., Eds.; Cambridge University Press: Cambridge, UK, 1995. [ Google Scholar ]
• Frixione, E. Albrecht Von Haller (1708–1777). J. Neurol. 2006 , 253 , 265–266. [ Google Scholar ] [ CrossRef ]
• Duffin, J. Interrogating life: History of physiology. In History of Medicine: A Scandalously Short Introduction , 2nd ed.; University of Toronto Press: Toronto, Canada, 2010; p. 40. [ Google Scholar ]
• Buess, H. William Harvey and the foundation of modern haemodynamics by Albrecht Von Haller. Med. Hist. 1970 , 14 , 175–182. [ Google Scholar ] [ CrossRef ]
• Fye, W.B. Albrecht von Haller. Clin. Cardiol. 1995 , 18 , 291–292. [ Google Scholar ] [ CrossRef ]
• Bay, J.C. Albrecht Von Haller medical encyclopedist. Bull. Med. Library Assoc. 1960 , 48 , 393–403. [ Google Scholar ]
• Festing, S. Animal experiments: The long debate. New Sci. 1989 , 121 , 51–54. [ Google Scholar ]
• Maehle, A.H. Literary responses to animal experimentation in seventeenth- and eighteenth-century britain. Med. Hist. 1990 , 34 , 27–51. [ Google Scholar ] [ CrossRef ]
• Maehle, A.-H. Drugs on Trial: Experimental Pharmacology and Therapeutic Innovation in the Eighteenth Century ; Editions Rodopi: Amsterdam, The Netherlands, 1999. [ Google Scholar ]
• Cajavilca, C.; Varon, J.; Sternbach, G.L. Luigi Galvani and the foundations of electrophysiology. Resuscitation 2009 , 80 , 159–162. [ Google Scholar ] [ CrossRef ]
• Piccolino, M. Luigi Galvani and animal electricity: Two centuries after the foundation of electrophysiology. Trends Neurosci. 1997 , 20 , 443–448. [ Google Scholar ] [ CrossRef ]
• Roe, S.A. Matter, Life, and Generation: Eighteenth-Century Embryology and the Haller-Wolff Debate ; Cambridge University Press: Cambridge, UK, 1981. [ Google Scholar ]
• Nuffield Council on Bioethics, The context of animal research: Past and present. In The Ethics of Research Involving Animals ; Nuffield Council on Bioethics: London, UK, 2005.
• Voltaire, F.M.A. Animals. In Philosophical Dictionary ; Penguin Books: London, UK, 2004. [ Google Scholar ]
• Schopenhauer, A. On the Basis of Morality ; Swan Sonnenschein & Co., Ltd.: London, UK, 1903. [ Google Scholar ]
• Rousseau, J.-J. Discourse on the Origin of Inequality ; Filiquarian Publishing, LLC: Minneapolis, MN, USA, 2007. [ Google Scholar ]
• Bentham, J. An Introduction to the Principles of Morals and Legislation ; W. Pickering: London, UK, 1823. [ Google Scholar ]
• Bentham, J. Anarchical fallacies: Being an examination of the declarations of rights issued during the french revolution. In The Works of Jeremy Bentham ; Bowring, J., Ed.; William Tate: London, UK, 1843. [ Google Scholar ]
• Boralevi, L.C. Bentham and the Oppressed ; W. de Gruyter: Berlin, Germany, 1984. [ Google Scholar ]
• Jacyna, L.S. The localization of disease. In Medicine Transformed: Health, Disease and Society in Europe, 1800–1930 ; Brunton, D., Ed.; Manchester University Press: Manchester, UK, 2004. [ Google Scholar ]
• Thomas, L. Biomedical science and human health. Yale J. Biol. Med. 1978 , 51 , 133–142. [ Google Scholar ]
• Duffin, J. First do no harm: History of treatment, pharmacology and pharmaceuticals. In History of Medicine: A Scandalously Short Introduction , 2nd ed.; University of Toronto Press: Toronto, Canada, 2010; p. 98. [ Google Scholar ]
• Bynum, W.F. Conclusion: Did science matter? In Science and the Practice of Medicine in the Nineteenth Century ; Cambridge University Press: Cambridge, UK, 1994; pp. 218–226. [ Google Scholar ]
• Lesch, J.E. The Paris Academy of Medicine and Experimental Science. In The Investigative Enterprise: Experimental Physiology in Nineteenth-Century Medicine ; Coleman, W., Holmes, F.L., Eds.; University of California Press: Berkeley, CA, USA, 1988. [ Google Scholar ]
• Elliot, P. Vivisection and the emergence of experimental physiology in nineteenth-century France. In Vivisection in Historical Perspective ; Rupke, N.A., Ed.; Croom Helm: London, UK, 1987; p. 125. [ Google Scholar ]
• LaFollette, H.; Shanks, N. Animal experimentation: The legacy of Claude Bernard. Int. Stud. Philos. Sci. 1994 , 8 , 195–210. [ Google Scholar ]
• Orlans, B. History and ethical regulation of animal experimentation: An international perspective. In A Companion to Bioethics ; Kuhse, H., Singer, P., Eds.; Blackwell Publishing: Oxford, UK, 1998. [ Google Scholar ]
• Tubbs, R.S.; Loukas, M.; Shoja, M.M.; Shokouhi, G.; Oakes, W.J. François Magendie (1783–1855) and his contributions to the foundations of neuroscience and neurosurgery. J. Neurosurg. 2008 , 108 , 1038–1042. [ Google Scholar ]
• Schiller, J. Physiology’s struggle for independence in the first half of the nineteenth century. Hist. Sci. 1968 , 7 , 64–89. [ Google Scholar ]
• Monamy, V. Animal Experimentation: A Guide to the Issues ; Cambridge University Press: Cambridge, UK, 2000. [ Google Scholar ]
• Ryder, R.D. Victorian consolidation. In Animal Revolution: Changing Attitudes Toward Speciesism ; Berg: Oxford, UK, 2000; pp. 95–120. [ Google Scholar ]
• Bloch, H. Francois Magendie, Claude Bernard, and the interrelation of science, history, and philosophy. South. Med. J. 1989 , 82 , 1259–1261. [ Google Scholar ] [ CrossRef ]
• Normandin, S. Claude Bernard and an introduction to the study of experimental medicine: “Physical vitalism”, dialectic, and epistemology. J. Hist. Med. Allied Sci. 2007 , 62 , 495–528. [ Google Scholar ] [ CrossRef ]
• Rudacille, D. Viruses, vaccines and vivisection. In The Scalpel and the Butterfly: The Conflict between Animal Research and Animal Protection ; University of California Press: Berkeley, CA, USA, 2001; pp. 17–29. [ Google Scholar ]
• Bernard, C. An Introduction to the Study of Experimental Medicine ; Macmillan: New York, NY, USA, 1927. [ Google Scholar ]
• Berkowitz, C. Disputed discovery: Vivisection and experiment in the 19th century. Endeavour 2006 , 30 , 98–102. [ Google Scholar ]
• Bynum, W.F. Medicine in the laboratory. In Science and the Practice of Medicine in the Nineteenth Century ; Press Syndicate of the University of Cambridge: Cambridge, UK, 1994. [ Google Scholar ]
• Zimmer, H.G. Carl Ludwig: The man, his time, his influence. Pflügers Archiv-Eur. J. Physiol. 1996 , 432 , R9–R22. [ Google Scholar ]
• Lenoir, T. Science for the clinic: Science policy and the formation of Carl Ludwig’s institute in leipzig. In The Investigative Enterprise: Experimental Physiology in Nineteenth-Century Medicine ; Coleman, W., Holmes, F.L., Eds.; University of California Press: Berkeley, CA, USA, 1988. [ Google Scholar ]
• Cahan, D. Hermann von Helmholtz and the Foundations of Nineteenth-Century Science ; University of California Press: Berkeley, CA, USA, 1993. [ Google Scholar ]
• Otis, L. Johannes Peter Müller (1801–1858). The Virtual Laboratory ; Max Planck Institute for the History of Science: Berlin, Germany, 2004. Available online: http://vlp.mpiwg-berlin.mpg.de/essays/data/enc22 (accessed on 13 March 2013).
• Coleman, W.; Holmes, F.L. The Investigative Enterprise: Experimental Physiology in Nineteenth-Century Medicine ; University of California Press: Berkeley, CA, USA, 1988. [ Google Scholar ]
• O’Malley, C.D. The History of Medical Education ; University of California Press: Los Angeles, CA, USA, 1970. [ Google Scholar ]
• Manuel, D. Marshall Hall (1790–1857): Vivisection and the development of experimental physiology. In Vivisection in Historical Perspective ; Rupke, N.A., Ed.; Croom Helm: London, UK, 1987; p. 78. [ Google Scholar ]
• Preece, R. The history of animal ethics in western culture. In The Psychology of the Human-Animal Bond: A Resource for Clinicians and Researchers ; Blazina, C., Boyra, G., Shen-Miller, D., Eds.; Springer: New York, NY, USA, 2011; pp. 45–62. [ Google Scholar ]
• Guerrini, A. Animal experiments and antivivisection debates in the 1820s. In Frankenstein’s Science: Experimentation and Discovery in Romantic Culture, 1780–1830 ; King, C.K., Goodall, J.R., Eds.; Ashgate: Burlington, Canada, 2008. [ Google Scholar ]
• Olmsted, J.M.D. François Magendie ; Arno Press: New York, NY, USA, 1944. [ Google Scholar ]
• Gross, C.G. Claude Bernard and the constancy of the internal environment. The Neuroscientist 1998 , 4 , 380–385. [ Google Scholar ] [ CrossRef ]
• Broennle, A.M. Lectures on anesthetics and on asphyxia (book review). Anesth. Analg. 1991 , 72 , 132. [ Google Scholar ] [ CrossRef ]
• Lee, J.A. Claude Bernard (1813–1878). Anaesthesia 1978 , 33 , 741–747. [ Google Scholar ] [ CrossRef ]
• Davis, N.K. The moral aspects of vivisection. North Am. Rev. 1885 , 140 , 203–220. [ Google Scholar ]
• Inoue, T.; Kodama, Y. Future Alternatives in “3Rs”: Learning from History. In Proceedings of the 6th World Congress on Alternatives & Animal Use in the Life Sciences, Tokyo, Japan, 21–25 August 2007; pp. 257–260.
• Debré, P. Louis Pasteur ; Johns Hopkins University Press: Baltimore, MD, USA, 2000. [ Google Scholar ]
• Rey, R. The History of Pain ; Harvard University Press: Cambridge, MA, USA, 1998. [ Google Scholar ]
• Snow, S.J. Blessed Days of Anaesthesia: How Anaesthetics Changed the World ; Oxford University Press: New York, NY, USA, 2008. [ Google Scholar ]
• Richards, S. Anaesthetics, ethics and aesthetics: Vivisection in the late nineteenth-century british laboratory. In The Laboratory Revolution in Medicine ; Cunningham, A., Williams, P., Eds.; Cambridge University Press: Cambridge, UK, 1992; pp. 142–169. [ Google Scholar ]
• Feller, D.A. Dog fight: Darwin as animal advocate in the antivivisection controversy of 1875. Stud. Hist. Philos. Sci. Part C: Stud. Hist. Philos. Biol. Biomed. Sci. 2009 , 40 , 265–271. [ Google Scholar ] [ CrossRef ]
• Tait, L. The Uselessness of Vivisection upon Animals as a Method of Scientific Research ; The Herald Press: Birmingham, West Midlands, UK, 1882; Volume II. [ Google Scholar ]
• Elliot, C.W.; Walker, F.A.; Paddock, F.K. Vivisection—A statement in behalf of science. Science 1896 , 3 , 421–426. [ Google Scholar ]
• Johnson, E.M. Charles Darwin and the vivisection outrage. The Primate Diaries. Scientific American, 2011. Available online: http://blogs.scientificamerican.com/primate-diaries/2011/10/06/vivisection-outrage/ (accessed on 13 March 2013).
• Darwin, C. Darwin on vivisection—Experiments on living animals necessary to the progress of physiological study. The New York Times 1881 . [ Google Scholar ]
• Gaw, J.L. “A Time to Heal”: The Diffusion of Listerism in Victorian Britain ; American Philosophical Society: Philadelphia, PA, USA, 1999. [ Google Scholar ]
• Richards, S. Drawing the life-blood of physiology: Vivisection and the physiologists’ dilemma, 1870–1900. Ann. Sci. 1986 , 43 , 27–56. [ Google Scholar ] [ CrossRef ]
• Dolan, K. The coming of the law on laboratory animals. In Laboratory Animal Law: Legal Control of the Use of Animals in Research , 2nd ed.; Blackwell Publisher: Oxford, UK, 2007. [ Google Scholar ]
• Connor, J.T. Cruel knives? Vivisection and biomedical research in Victorian English Canada. Can. Bull. Med. Hist. 1997 , 14 , 37–64. [ Google Scholar ]
• Semmelweis, I. Etiology, Concept and Prophylaxis of Childbed Fever ; University of Wisconsin Press: Madison, WI, USA, 1983. [ Google Scholar ]
• Flack, H.D. Louis Pasteur’s discovery of molecular chirality and spontaneous resolution in 1848, together with a complete review of his crystallographic and chemical work. Acta Crystallogr. Sec. A 2009 , 65 , 371–389. [ Google Scholar ] [ CrossRef ]
• Bazin, H. The swine erypselas vaccine: 1883. In Vaccination—A History: From Lady Montagu to Genetic Engineering ; John Libbey Eurotext Ltd.: Montrouge, France, 2011. [ Google Scholar ]
• Hansen, B. America’s first medical breakthrough: How popular excitement about a french rabies cure in 1885 raised new expectations for medical progress. Am. Hist. Rev. 1998 , 103 , 373–418. [ Google Scholar ] [ CrossRef ]
• Schwartz, M. The life and works of Louis Pasteur. J. Appl. Microbiol. 2001 , 91 , 597–601. [ Google Scholar ] [ CrossRef ]
• Morton, D.B. Humane endpoints in animal experimentation for biomedical research. In Humane Endpoints in Animals Experiments for Biomedical Research ; Hendriksen, C.F.M., Morton, D.B., Eds.; Royal Society of Medicine Press: London, UK, 1999; pp. 5–12. [ Google Scholar ]
• Rosenau, M.J. The pasteur prophylactic treatment. In Preventive Medicine and Hygiene , 2nd ed.; D. Appleton and Co.: New York, NY, USA, 1916; pp. 45–53. [ Google Scholar ]
• Vallery-Radot, R. The Life of Pasteur ; Doubleday: Garden City, NY, USA, 1911. [ Google Scholar ]
• Vallery-Radot, R. Louis Pasteur—His Life and Labours ; D. Appleton and Company: New York, NY, USA, 1886. [ Google Scholar ]
• Howard-Jones, N. Robert Koch and the cholera vibrio: A centenary. Br. Med. J. 1984 , 288 , 379–381. [ Google Scholar ] [ CrossRef ]
• Ullmann, A. Pasteur–Koch: Distinctive ways of thinking about infectious diseases. Microbe 2007 , 2 , 383–387. [ Google Scholar ]
• Brock, T.D. Robert Koch: A Life in Medicine and Bacteriology ; ASM Press: Washington, DC, USA, 1988. [ Google Scholar ]
• Bosch, F.; Rosich, L. The contributions of Paul Ehrlich to pharmacology: A tribute on the occasion of the centenary of his Nobel Prize. Pharmacology 2008 , 82 , 171–179. [ Google Scholar ] [ CrossRef ]
• Silverstein, A.M. The standardization of toxins and antitoxins. In Paul Ehrlich’s Receptor Immunology: The Magnificent Obsession ; Elsevier Science: Amsterdam, The Netherlands, 2001; pp. 41–54. [ Google Scholar ]
• Kantha, S.S. A centennial review: The 1890 tetanus antitoxin paper of von Behring and Kitasato and the related developments. Keio J. Med. 1991 , 40 , 35–39. [ Google Scholar ] [ CrossRef ]
• Linton, D.S. From immunization to serum therapy. In Emil von Behring: Infectious Disease, Immunology, Serum Therapy ; American Philosophical Society: Philadelphia, PA, USA, 2005. [ Google Scholar ]
• Pearce, R.M. Research in medicine. II. The development of laboratories for the medical sciences. Popul. Sci. Month. 1912 , 80 , 548–562. [ Google Scholar ]
• Davis, N. History of medical progress during the last half of the nineteenth century completed. The present status of medical investigations and progress, and the indications of further advancement. In History of Medicine ; Cleveland Press: Chicago, IL, USA, 1903. [ Google Scholar ]
• Ernst, H.C. Animal Experimentation; A Series of Statements Indicating its Value to Biological and Medical Science ; Little, Brown, and Company: Boston, MA, USA, 1902. [ Google Scholar ]
• Romano, T.M. Part III. The medical sciences: Critics and allies. In Making Medicine Scientific: John Burdon Sanderson and the Culture of Victorian Science ; Johns Hopkins University Press: Baltimore, MD, USA, 2002. [ Google Scholar ]
• Warner, J.H. Ideals of science and their discontents in late nineteenth-century American medicine. Isis 1991 , 82 , 454–478. [ Google Scholar ]
• Warner, J.H. The fall and rise of professional mystery. In The Laboratory Revolution in Medicine ; Cunningham, A., Williams, P., Eds.; Cambridge University Press: Cambridge, UK, 1992; pp. 110–141. [ Google Scholar ]
• Research Defence SocietyUnderstanding Animal ResearchCoalition for Medical Progress Medical Advances and Animal Research—The Contribution of Animal Science to the Medical Revolution: Some Case Histories ; Understanding Animal Research: London, UK, 2007.
• Foundation for Biomedical Research. Available online: http://www.fbresearch.org/nobelprize/ (accessed on 12 March 2013).
• Kirkwood, T.B.L. A systematic look at an old problem. Nature 2008 , 451 , 644–647. [ Google Scholar ] [ CrossRef ]
• Kinsella, K.; He, W. An Aging World: 2008; U.S. Census Bureau, International Population Reports, P95/09-1 ; U.S. Government Printing Office: Washington, DC, USA, 2009. [ Google Scholar ]
• Oeppen, J.; Vaupel, J.W. Broken limits to life expectancy. Science 2002 , 296 , 1029–1031. [ Google Scholar ] [ CrossRef ]
• Rudacille, D. The dogs of war. In The Scalpel and the Butterfly: The Conflict between Animal Research and Animal Protection ; University of California Press: Berkeley, CA, USA, 2001; pp. 55–79. [ Google Scholar ]
• Preece, R. Animal sensibilities in the Shavian era. In Animal Sensibility and Inclusive Justice in the Age of Bernard Shaw ; University of British Columbia Press: Vancouver, Canada, 2011; pp. 93–143. [ Google Scholar ]
• Liddick, D. History and philosophy of the animal rights movement. In Eco-Terrorism: Radical Environmental and Animal Liberation Movements ; Praeger: Westport, CT, USA, 2006. [ Google Scholar ]
• Lederer, S.E. Political animals. The shaping of biomedical research literature in twentieth-century america. Isis 1992 , 83 , 61–79. [ Google Scholar ]
• Baumans, V. The welfare of laboratory mice. In The Welfare of Laboratory Animals ; Kaliste, E., Ed.; Springer: Dordrecht, The Netherlands, 2007; Volume 2, pp. 119–152. [ Google Scholar ]
• Kaliste, E.; Mering, S. The welfare of laboratory rats. In The Welfare of Laboratory Animals ; Kaliste, E., Ed.; Springer: Dordrecht, The Netherlands, 2007; Volume 2, pp. 153–180. [ Google Scholar ]
• Lindsey, J.R.; Baker, H.J. Historical foundations. In The Laboratory Rat ; Suckow, M.A., Weisbroth, S.H., Franklin, C.L., Eds.; Elsevier: Amsterdam, The Netherlands, 2006. [ Google Scholar ]
• Hedrich, H.J. The history and development of the rat as a laboratory animal model. In The Laboratory Rat ; Krinke, G., Ed.; Academic: Waltham, MA, USA, 2000; pp. 3–16. [ Google Scholar ]
• Henig, R.M. The Monk in the Garden: The Lost and Found Genius of Gregor Mendel, the Father of Genetics ; Houghton Mifflin: Boston, MA, USA, 2001. [ Google Scholar ]
• Gordon, J.W.; Ruddle, F.H. Integration and stable germ line transmission of genes injected into mouse pronuclei. Science 1981 , 214 , 1244–1246. [ Google Scholar ]
• Morse, H.C. Building a better mouse: One hundred years of genetics and biology. In The Mouse in Biomedical Research: History, Wild Mice, and Genetics ; Fox, J.G., Ed.; Academic Press: Waltham, MA, USA, 2007. [ Google Scholar ]
• Davisson, M.T.; Linder, C.C. History of mouse genetics and research with the laboratory mouse. In The Laboratory Mouse ; Hedrich, H.J., Bullock, G.R., Eds.; Elsevier Academic Press: Oxford, UK, 2004; pp. 16–20. [ Google Scholar ]
• Sixth Report on the Statistics on the Number of Animals Used for Experimental and Other Scientific Purposes in the Member States of the European Union ; European Commission: Brussels, Belgium, 2010.
• Singer, P. Animal liberation at 30. The New York Review of Books 2003 . [ Google Scholar ]
• Ryder, R.D. Speciesism. In Animal Revolution: Changing Attitudes toward Speciesism ; Berg: Oxford, UK, 2000; pp. 223–250. [ Google Scholar ]
• Singer, P. Animal Liberation ; HarperCollins Publishers: New York, NY, USA, 2001. [ Google Scholar ]
• Singer, P. About ethics. In Practical Ethics ; Cambridge University Press: Cambridge, UK, 2011; pp. 1–15. [ Google Scholar ]
• Singer, P. Equality for animals? In Practical Ethics ; Cambridge University Press: Cambridge, UK, 2011; pp. 48–70. [ Google Scholar ]
• Singer, P. Setting limits on animal testing. The Sunday Times 2006 . [ Google Scholar ]
• Regan, T. The case for animal rights. In Animal Rights and Human Obligations , 2nd ed.; Regan, T., Singer, P., Eds.; Prentice Hall: Upper Saddle River, NJ, USA, 1989. [ Google Scholar ]
• Orlans, F.B. In the Name of Science: Issues in Responsible Animal Experimentation ; Oxford University Press: Cary, NC, USA, 1996. [ Google Scholar ]
• Cohen, C.; Regan, T. The Animal Rights Debate ; Rowman & Littlefield Publishers: Lanham, MD, USA, 2001. [ Google Scholar ]
• Conn, P.M.; Parker, J.V. The Animal Research War ; Palgrave Macmillan: New York, NY, USA, 2008. [ Google Scholar ]
• Liddick, D. Eco-Terrorism: Radical Environmental and Animal Liberation Movements ; Praeger: Westport, CT, USA, 2006. [ Google Scholar ]
• Regan, T.; Masson, J.M. Empty Cages: Facing the Challenge of Animal Rights ; Rowman & Littlefield Publishers: Lanham, MD, USA, 2005. [ Google Scholar ]
• Goodwin, F.K.; Morrison, A.R. Scientists in bunkers: How appeasement of “animal rights” activism has failed. In Cerebrum: The Dana Forum on Brain Science ; Donway, W., Ed.; Diane Publishing Company: Darby, PA, USA, 1999; Volume 1, pp. 50–62. [ Google Scholar ]
• Birke, L.; Michael, M. Views from behind the barricade. New Sci. 1992 , 134 , 29–32. [ Google Scholar ]
• Cressey, D. Battle scars. Nature 2011 , 470 , 452–453. [ Google Scholar ] [ CrossRef ]
• Rollin, B.E. The ethics of animal research. Talking point on the use of animals in scientific research. EMBO Rep. 2007 , 8 , 521–525. [ Google Scholar ] [ CrossRef ]
• Aldhous, P.; Coghlan, A.; Copley, J. Animal experiments: Let the people speak. New Sci. 1999 , 162 , 26–31. [ Google Scholar ]
• Crettaz von Roten, F. Public perceptions of animal experimentation across Europe. Public Underst. Sci. 2012 . [ Google Scholar ] [ CrossRef ]
• Singer, P. Ethics into Action: Henry Spira and the Animal Rights Movement ; Rowman & Littlefield Publishers: Lanham, MD, USA, 2000. [ Google Scholar ]
• Russell, W.M. The three Rs: Past, present and future. Anim. Welf. 2005 , 14 , 279–286. [ Google Scholar ]
• Balls, M. Professor W.M.S. Russell (1925–2006): Doyen of the three Rs. In Proceedings of the 6th World Congress on Alternatives & Animal Use in the Life Sciences, Tokyo, Japan, 21–25 August 2007; pp. 1–7.
• Stephens, M.L.; Goldberg, A.M.; Rowan, A.N. The first forty years of the alternatives approach: Refining, reducing, and replacing the use of laboratory animals. In The STate of the Animals: 2001 ; Salem, D.J., Rowan, A.N., Eds.; Humane Society Press: Washington, DC, USA, 2001; pp. 121–135. [ Google Scholar ]
• Russell, W.M.S.; Burch, R.L. The Principles of Humane Experimental Technique ; Methuen & Co. Ltd.: London, UK, 1959. [ Google Scholar ]
• Balls, M. Alternatives to animal experiments: Serving in the middle ground. AATEX 2005 , 11 , 4–14. [ Google Scholar ]
• Smyth, D.H. Alternatives to Animal Experiments ; Scolar Press [for] the Research Defence Society: London, UK, 1978. [ Google Scholar ]
• Olsson, I.A.S.; Robinson, P.; Sandøe, P. Ethics of animal research. In Handbook of Laboratory Animal Science-Volume I: Essential Principles and Practices , 3rd ed.; Hau, J., Schapiro, S.J., Eds.; CRC Press: Boca Raton, FL, USA, 2011. [ Google Scholar ]
• Frey, R.G. Utilitarianism and animals. In The Oxford Handbook of Animal Ethics ; Beauchamp, T.L., Frey, R.G., Eds.; Oxford University Press: New York, NY, USA, 2011; pp. 172–197. [ Google Scholar ]
• Sztybel, D. Animal rights law: Fundamentalism versus pragmatism. J. Crit. Anim. Stud. 2007 , 5 , 1–37. [ Google Scholar ]
• Rollin, B.E. Reasonable partiality and animal ethics. Ethical Theory Moral Pract. 2005 , 8 , 105–121. [ Google Scholar ] [ CrossRef ]
• Francione, G.L. Rain without Thunder: The Ideology of the Animal Rights Movement ; Temple University Press: Philadelphia, PA, USA, 1996. [ Google Scholar ]
• Francione, G.L. Animal rights theory and utilitarianism: Relative normative guidance. Between the Species . 2003. Available online: http://digitalcommons.calpoly.edu/cgi/viewcontent.cgi?article=1054&context=bts (accessed on 13 March 2013).
• Burch, R.L. The progress of humane experimental technique since 1959: A personal view. Altern. Lab. Anim. 1995 , 23 , 776–783. [ Google Scholar ]
• Stephens, M.L. Pursuing Medawar’s challenge for full replacement. ALTEX Proc. 2012 , 1 , 23–26. [ Google Scholar ]
• Mukerjee, M. Trends in animal research. Sci. Am. 1997 , 276 , 86–93. [ Google Scholar ] [ CrossRef ]
• Carlsson, H.-E.; Hagelin, J.; Hau, J. Implementation of the ‘three Rs’ in biomedical research. Vet. Record 2004 , 154 , 467–470. [ Google Scholar ] [ CrossRef ]
• Kulpa-Eddy, J.; Snyder, M.; Stokes, W. A review of trends in animal use in the united states (1972–2006). In Proceedings of the 6th World Congress on Alternatives & Animal Use in the Life Sciences, Tokyo, Japan, 21–25 August 2007; Volume 14, pp. 163–165.
• Rowan, A.N. A brief history of the animal research debate and the place of alternatives. AATEX 2007 , 12 , 203–211. [ Google Scholar ]
• Taylor, K.; Gordon, N.; Langley, G.; Higgins, W. Estimates for worldwide laboratory animal use in 2005. ATLA 2008 , 36 , 327–342. [ Google Scholar ]
• Ormandy, E.H.; Schuppli, C.A.; Weary, D.M. Worldwide trends in the use of animals in research: The contribution of genetically-modified animal models. Altern. Lab. Anim. 2009 , 37 , 63–68. [ Google Scholar ]
• Festing, S.; Wilkinson, R. The ethics of animal research—Talking point on the use of animals in scientific research. EMBO Rep. 2007 , 8 , 526–530. [ Google Scholar ] [ CrossRef ]
• Executive Committee of the Congress. Background to the three Rs declaration of bologna, as adopted by the 3rd world congress on alternatives and animal use in the life sciences, bologna, italy, on 31 august 1999. Altern. Lab. Anim. 2009 , 37 , 286–289.
• Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the Protection of Animals Used for Scientific Purposes ; European Commission: Brussels, Belgium, 2010.
• Basel Declaration Society. Position paper: 3R in research—how can the concept of 3Rs best be implemented in the context of fundamental research? Adopted on 17 October 2011. Available online: http://www.basel-declaration.org/basel-declaration/the-3rs/ (accessed on 13 March 2013).
• Basel Declaration Society. Basel declaration: A call for more trust, transparency and communication on animal research. Adopted on 29 November 2010. Available online: http://www.basel-declaration.org/basel-declaration/ (accessed on 13 March 2013).
• Louhimies, S. Eu Directive 2010/63/EU: “Implementing the three Rs through policy”. ALTEX Proc. 2012 , 1 , 27–33. [ Google Scholar ]

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Franco, N.H. Animal Experiments in Biomedical Research: A Historical Perspective. Animals 2013 , 3 , 238-273. https://doi.org/10.3390/ani3010238

Franco NH. Animal Experiments in Biomedical Research: A Historical Perspective. Animals . 2013; 3(1):238-273. https://doi.org/10.3390/ani3010238

Franco, Nuno Henrique. 2013. "Animal Experiments in Biomedical Research: A Historical Perspective" Animals 3, no. 1: 238-273. https://doi.org/10.3390/ani3010238

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• Corpus ID: 10208025

HISTORY OF ANIMAL EXPERIMENTS RESEARCH TESTING

• Dr. R. I Sharpe
• Published 2013

16 References

An introduction to the study of experimental medicine, animals and alternatives in toxicity testing, the contribution of acute toxicity testing to the evaluation of pharmaceuticals, risk-benefit analysis in drug research, related papers.

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Animal Experimentation

There are many opinions about the pros and cons of using animals in scientific research. Read the overview below to gain a balanced understanding of the issue and explore the previews of opinion articles that highlight many perspectives on animal testing.

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Animal experimentation topic overview.

"Animal Experimentation." Opposing Viewpoints Online Collection , Gale, 2021.

Animal experimentation, also called animal testing , has contributed to many important scientific and medical discoveries. Breakthroughs include the development of many antibiotics, insulin therapy for diabetes, modern anesthesia, vaccines for whooping cough and other diseases, the use of lithium in mental health treatments, and the discovery of hormones. Studies using animals have also led to the development of new surgical techniques and medical devices. Scientists use animals for testing the safety of chemical products, known as toxicology testing , and for evaluating the effects of radiation and biological and chemical processes. Unlike field research, which involves observing animals in their natural habitats, animal experimentation takes place at laboratories in universities, medical schools, government facilities, and commercial facilities such as those run by pharmaceutical and cosmetics manufacturers. Experiments on animals can involve testing drugs and other substances as well as performing behavioral tests such as those conducted on dogs by Russian physiologist Ivan Pavlov in the early twentieth century.

Many people object to the use of animals in scientific studies because the animals are denied their freedom and often suffer serious injury and discomfort. Other people identify certain practices used in animal studies as cruel while still recognizing the benefits of using live animals when no alternative is available. Proponents of animal experimentation maintain that these studies provide benefits to humans that cannot be achieved through other means. Conversely, critics of using animals to learn more about humans contend that the differences between humans and nonhuman species are too great for such studies to produce meaningful results. In response, proponents note that humans are not the only beneficiaries of this type of research. Many experiments are carried out to further veterinary treatments and services, improve environmental protection efforts, and better understand diseases that affect nonhuman animals and plants.

• Scientists have often used animals to learn about biology, test new surgical techniques, and observe the effects of different products on living things to determine the products' safety.
• Because humans and other animals respond differently when exposed to different substances, critics of animal experimentation have questioned the scientific value of using animals to test products intended for humans.
• Some opponents of animal experimentation contend that no scientific discovery can justify the conditions endured by animal test subjects.
• Researchers in the United States have faced difficulty obtaining lab monkeys, as several countries that previously supplied to US labs have enacted bans on such exports. A worldwide decrease in the supply of primates used in research coincided with increased demand during research for a vaccine for COVID-19 .
• The US Department of Agriculture enforces the Animal Welfare Act, which establishes regulations for the treatment of some animals used in research. While the law protects a range of species, it does not cover many of the species most commonly used in research, such as mice and fish.
• Vivisection refers to surgical experiments performed on living specimens, while dissection refers to experiments performed on dead specimens. Many companies, research institutes, and schools are exploring alternatives to such practices.
• Researchers have developed microdevices that use cell cultures to determine how different products would affect human physiology. In some cases, these devices can provide more useful and precise information than that gathered from experiments conducted on animals.

Regulations on Animal Test Subjects

Congress has enacted several pieces of legislation to regulate animal experimentation and prevent animal abuse, including the Animal Welfare Act (AWA), first passed as the Laboratory Animal Welfare Act in 1966; the Improved Standards for Laboratory Animals Act (ISLAA), passed as part of the Food Security Act of 1985; and the Health Research Extension Act of 1985, which tasks the National Institutes of Health (NIH) with establishing research standards. The AWA requires research facilities that use animals to establish an institutional committee, including at least one veterinarian and one person otherwise unaffiliated with the organization, to ensure compliance with the law. Established in 2000 as part of the NIH, the Office of Laboratory Animal Welfare (OLAW) implements federal policy and provides guidance to institutions receiving federal support.

As reported by the US Department of Agriculture (USDA), 780,070 animals were used in experiments at USDA-registered facilities in fiscal year 2018. The total includes only animals protected by the AWA and omits amphibians, birds, fish, mice, rats, and reptiles, which combined account for the majority of animals used in scientific studies. Of the animals monitored by the USDA, the most commonly used in laboratories is the guinea pig, which has been widely used for experimentation since the eighteenth century, leading it to become synonymous with a subject of any experiment. Guinea pigs, rabbits, and hamsters account for more than half of the animals in the totals reported by the USDA. The other reported test subjects include nonhuman primates, dogs, pigs, cats, and sheep.

Laboratories obtain animals for their experiments through three types of dealers: those licensed by the USDA as Class A dealers, those licensed as Class B dealers, or those not licensed at all. Class A dealers breed and raise animals for specific purposes in a closed, regulated environment. Class B dealers are less regulated and purchase or obtain animals to resell. The USDA excuses some breeders and dealers from licensing because of the type, amount, or intended use of the animals. Some states require research facilities to purchase solely from Class A dealers. Class B dealers often acquire animals from animal shelters and then sell them to research facilities.

Investigations in the 1990s revealed that some Class B dealers abducted family pets. This phenomenon led lawmakers to introduce the Pet Safety and Protection Act as an amendment to the AWA in 1996. The provision would have banned research facilities from using any dog or cat that was not obtained from a legal source. The amendment was not adopted, nor was it adopted when reintroduced in nearly every subsequent session of Congress, most recently in 2019. Despite the amendment repeatedly failing to become law, the National Institutes of Health (NIH) adopted rules in 2012 and 2014 that ended NIH funding for research involving cats and dogs from Class B or unlicensed dealers. Likewise, a provision to the Consolidated Appropriations Act of 2016 prevents the USDA from using any funds appropriated by the act to provide or renew licenses for Class B dealers. The law has effectively made it impossible for Class B dealers to obtain licenses to sell cats or dogs for research purposes. Some critics have questioned the need for the Pet Safety and Protection Act, noting that cats and dogs make up only a small portion of the animals used in experiments.

In 2017 Representative Martha McSally (R-AZ) introduced the Humane Cosmetics Act, which aims to phase out the use of animal testing in the cosmetics industry. In 2018 Representatives Mike Bishop (R-MI) and Jimmy Panetta (D-CA) followed by Senator Jeff Merkley (D-OR) introduced the Kittens in Traumatic Testing Ends Now (KITTEN) Act, which would ban the use of cats in any painful or stressful experiment, to their respective chambers of Congress. No action was taken on either the Humane Cosmetics Act or the KITTEN Act in 2019, so lawmakers reintroduced similar pieces of legislation in the subsequent session of Congress. Subsequently, in April 2019, USDA announced it would stop using cats in research. Also in 2019, lawmakers introduced the Humane and Existing Alternatives in Research and Testing Sciences (HEARTS) Act, which would prioritize federal funding for research that substituted animal subjects with alternatives. As of 2021, however, none of these bills had received a vote.

Scientists in certain fields have favored using nonhuman primates in experiments because they closely resemble humans in physiology. The National Aeronautics and Space Administration (NASA), for example, sent several nonhuman primates into space before sending astronaut Alan Shepard in 1961. Many laboratories worked with chimpanzees throughout the twentieth century. Animal behaviorists, noting the chimpanzee's intelligence and capacity for emotion, raised concerns that the use of chimpanzees in experiments amounted to torture. The Institute of Medicine deemed the use of chimpanzees in scientific research unnecessary in a 2011 report commissioned by the NIH. This report was followed by a proposal by the United States Fish and Wildlife Service (USFWS) to include captive chimpanzees, such as those used in research facilities, on the list of animals protected by the Endangered Species Act; chimpanzees in the wild had already been protected by the act since 1990. In 2013 the NIH announced its intentions to stop providing funding or granting research requests for experiments involving chimpanzees, and the USFWS proposal was finalized in 2015. Many NIH chimpanzees have since been moved to federal sanctuaries. However, scientists have chosen not to resettle many older research chimpanzees in sanctuaries because of concerns the move would worsen their health.

Though researchers have largely stopped using chimpanzees, other nonhuman primates continue to serve as research subjects. However, the policies of other countries have limited their availability. Since 2013, for example, India has banned foreign monkey exports, forcing several organizations to find new suppliers or limit their experiments. Obtaining research monkeys became increasingly difficult in 2020 when China, which had supplied more than 60 percent of research monkeys imported into the United States, instituted a ban on wildlife sales. The ban came in response to concerns that wildlife sales had contributed to the novel coronavirus disease (COVID-19) outbreak that originated in Wuhan, China, and was declared a worldwide pandemic in March 2020 by the World Health Organization (WHO). Though many animal rights activists and public health officials applauded China's decision, the ban had the unintended effect of reducing the supply of lab monkeys at a time when demand significantly increased as medical researchers and pharmaceutical companies sought to develop a vaccine for COVID-19. Like vaccines for other diseases, the COVID-19 vaccines available in the United States as of March 2021 were approved for emergency use based in part on results of experiments on animals including mice, rats, hamsters, and monkeys.

Alternatives to Animal Testing

Animal rights advocates and members of the scientific community have pushed for the use of alternatives to animal experimentation. The pursuit of alternatives has largely centered on concepts first introduced in 1959 by British zoologists W. M. S. Russell and R. L. Burch in The Principles of Humane Experimental Technique . Russell and Burch framed their proposal around three Rs. They suggested that experimentation should replace animal subjects with something else, such as nonsentient material or less sentient animals; reduce the number of animal subjects used experimentally while increasing the amount of data obtained; and refine living conditions and experimental procedures for animal subjects to reduce pain and discomfort.

The NIH established the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) in 2000 as part of the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) to promote and regulate alternatives to animal testing. In addition to government programs, animal rights advocacy groups such as People for the Ethical Treatment of Animals (PETA) and the American Fund for Alternatives to Animal Research (AFAAR) also contribute funding to develop alternative research methods. AAALAC International, formerly known as the Association for Assessment and Accreditation of Laboratory Animal Care, distributes up to four $5,000 prizes each year to researchers that make significant contributions to improving the nature of animal research. The awards are a component of the organization's Global 3Rs Awards program, named for the principles put forth by Russell and Burch.

Companies and research facilities, however, can be slow to adopt alternatives. In 2009, for example, the Organisation for Economic Cooperation and Development (OECD) approved two alternatives to the Draize test, a research method that involves applying chemicals directly to the eyes or skin of animals, typically rabbits. The test is widely condemned by animal rights activists. In 2020 university researchers in the United Kingdom announced a method that they determined to be both cheaper and more ethical than the Draize test, as flatworms served as a substitute for rabbits. As of 2021, despite the availability of these alternatives, scientists continue to perform the Draize test, arguing that no single test has proven able to replicate the full benefits of the Draize test.

Technological advances have enabled scientists to perform many experiments without using live animals. Invasive animal experimentation that involves performing surgery on a living animal can be referred to as vivisection , as opposed to dissection , which is surgery performed on a deceased animal. The term vivisection, however, is typically used by opponents of animal experimentation and avoided by scientists. Researchers have developed ways to obtain data without using live specimens by experimenting on cells and tissues rather than the entire living organism; these procedures are referred to as in vitro experiments. In many in vitro experiments, human cells and tissues can be used. Proponents argue that this method produces data that is more relevant to human safety. Critics of in vitro methods argue that operating on a live animal provides more accurate data because the effects on the entire organism can be observed.

US schools began incorporating dissection into biology instruction in the 1920s, with the practice becoming widespread by the 1960s. A 2014 survey conducted by the National Association of Biology Teachers (NABT) found that 84 percent of biology teachers and 76 percent of biology students were using dissection in the classroom. Many of the responding teachers, however, reported that their schools were shifting away from dissection and pursuing alternatives such as virtual dissection programs, 3D models, and videos, largely in response to student requests. Educators also reported using these alternatives alongside traditional hands-on dissection. In 2019 the NABT reaffirmed its belief that students should have access to living and formerly living specimens and that nonanimal alternatives may not provide students with the most comprehensive understanding of life science. However, the NABT stresses the importance of teachers educating students about maintaining professional and ethical standards in animal research.

In the early 2000s, researchers began developing microdevices referred to as organs-on-a-chip (OOCs), which use cell cultures to imitate a human organ and determine how that organ would respond to different chemicals and other stimuli. OOCs are approximately the size of a deck of playing cards and have been developed to imitate lungs, hearts, kidneys, skin, eyes, and entire organ systems. In 2018 researchers successfully tested OOCs that imitated interconnected organ systems and could produce data for twenty-eight days, indicating that a microdevice could likely support an entire "human on a chip." In some cases, computer models can simulate the effects of diseases and medicines on the human body with greater accuracy than animal subjects. Research methods that substitute computer models for live animals are referred to as in silico experiments.

Critical Thinking Questions

• In your opinion, why have federal lawmakers delayed holding votes on legislation introduced in the late 2010s that would have expanded protections for animals used in research?
• Would you support a ban on the use of dissection in high school biology classrooms? Why or why not?
• Under what conditions, if any, do you think scientists should be allowed to use animal subjects in their research? Explain your answer.

Extremist Activism

Despite efforts to reduce the number of animals used in scientific studies and minimize the pain and distress that animal subjects experience, some animal rights activists believe that the benefits of animal experimentation do not justify the cruelties involved. Some extremist groups of activists calling for an end to all animal testing have engaged in criminal activity to prevent animals from being used in experiments. In the late 1970s, radical animal rights groups began targeting companies and research facilities, using terrorist strategies to disrupt these industries and promote their extremist platform. These activists were sometimes called "ecoterrorists" by federal authorities and included members of radical groups such as the Animal Liberation Front (ALF) and Stop Huntingdon Animal Cruelty (SHAC).

To protect research companies and other commercial enterprises vulnerable to animal rights violence, Congress passed the Animal Enterprise Protection Act of 1992 and the Animal Enterprise Terrorism Act of 2006. Critics of these laws note that both bills received support from biomedical and agribusiness lobbying groups. Additionally, critics note that both laws include language that criminalizes activities protected by the First Amendment, such as picketing and leading boycotts, if they interfere with a company's ability to make money. In 2015 two animal rights activists, Kevin Johnson and Tyler Lang, challenged the constitutionality of the Animal Enterprise Terrorism Act after they were charged with violating the act for vandalizing a mink farm and setting hundreds of animals free in 2013. However, the United States Court of Appeals for the Seventh Circuit ruled that the law was constitutional in November 2017. By April 2021, this type of extreme action to stop animal experimentation has become rare, with no major events reported in the United States since 2013.

More Articles

Government regulations will encourage alternatives to animal experimentation.

“There was a time when dosing and contaminating animals with often toxic levels of chemicals was horrible for them but imperative for human health and safety.”

The Times Editorial Board determines the perspectives and positions of the news organization.

In the following viewpoint, the authors contend that the recent overhaul of the Toxic Substances Control Act will lead to a reduction in the number of animals subjected to experimentation. Revisions to the law, the authors maintain, will encourage companies to employ alternative methods for gathering data and work with other companies to reduce instances of duplicated experiments. The authors argue that advances in technology and a new willingness among companies to cooperate with one another have eliminated the need to test products on animals to ensure they are safe for humans to use.

Using Monkeys for Research Is Justified—It’s Enabling Treatments that Would Be Otherwise Impossible

“I am confident that the next 50 years will see wonderful progress in treatments for these terrible disorders and primate research will be central to this effort.”

Stuart Baker is a professor of movement neuroscience at Newcastle University in the United Kingdom.

In the following viewpoint, Baker argues that the expanded use of primates and other animals in experiments is necessary to find a cure to challenging diseases like neurological disorders among the elderly. Baker refutes the argument of critics that animals used in research are subjected to extreme suffering and contends that researchers follow state-of-the-art surgical procedures commonly used on humans. As a researcher himself, Baker maintains that the primates he used in his experiments willingly cooperated and did not exhibit any signs of stress. For the author, the use of animals in scientific pursuits is essential for alleviating suffering among human beings.

The Grim Good of Animal Research

"Experimenting with animals before testing on people is a crucial human rights protection required by the famous Nuremberg Code."

In the following viewpoint, Wesley J. Smith argues that research on animals has been indispensable in developing ways to treat human disease. No one likes the idea of experimenting on animals, he says, and efforts are being made to reduce it to a minimum; however, there is no other way to do the necessary research and check the safety of new drugs. Medical treatments have to be tested on living organisms; if not on animals, then on humans, which in Smith's opinion would be an atrocity. Smith is a senior fellow for the Discovery Institute's program on human exceptionalism. He also consults with the Patients Rights Council and the Center for Bioethics and Culture.

Results from Research on Animals Are Not Valid When Applied to Humans

"Animal advocates, as well as many scientists, are increasingly questioning the scientific validity and reliability of animal experimentation."

In the following viewpoint, the American Anti-Vivisection Society (AAVS) declares that experimentation on animals is not a valid means of testing treatments for human disease. The AAVS maintains that animal studies do not reliably predict human outcomes, that most drugs that appear promising in animal studies go on to fail in human clinical trials, and that reliance on animal experimentation can delay discovery. In the opinion of the AAVS, animals are used in medical research more from tradition than from evidence of scientific value. The AAVS is a nonprofit animal advocacy organization dedicated to ending experimentation on animals in research, testing, and education.

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• History of Animal Testing

Animals are used to develop medical treatments, determine the toxicity of medications, check the safety of products destined for human use, and other biomedical , commercial, and health care uses. Research on living animals has been practiced since at least 500 BC. [ 2 ]

Early History

Descriptions of the dissection of live animals have been found in ancient Greek writings from as early as circa 500 BC. Physician-scientists such as Aristotle , Herophilus , and Erasistratus performed the experiments to discover the functions of living organisms. Vivisection (dissection of a living organism) was practiced on human criminals in ancient Rome and Alexandria, but prohibitions against mutilation of the human body in ancient Greece led to a reliance on animal subjects. Aristotle believed that animals lacked intelligence, and so the notions of justice and injustice did not apply to them. Theophrastus , a successor to Aristotle, disagreed, objecting to the vivisection of animals on the grounds that, like humans, they can feel pain, and causing pain to animals was an affront to the gods. [ 79 ] [ 80 ]

Roman physician and philosopher Galen (130-200 AD), whose theories of medicine were influential throughout Europe for fifteen centuries, engaged in the public dissection of animals (including an elephant), which was a popular form of entertainment at the time. Galen also engaged in animal vivisection in order to develop theories on human anatomy, physiology, pathology, and pharmacology. In one of his experiments, he demonstrated that arteries, which were believed by earlier physicians to contain air, actually contained blood. Galen believed that animal physiology was very similar to that of human beings, but despite this similarity he had little sympathy for the animals on which he experimented. Galen recommended that his students vivisect animals “without pity or compassion” and warned that the “unpleasing expression of the ape when it is being vivisected” was to be expected. [ 80 ] [ 82 ] [ 81 ]

French philosopher René Descartes (1596-1650), who occasionally experimented on live animals, including at least one rabbit, as well as eels and fish, believed that animals were “automata” who could not experience pain or suffer the way that humans do. Descartes recognized that animals could feel, but because they could not think, he argued, they were unable to consciously experience those feelings. [ 66 ] [ 83 ]

English Physician William Harvey (1578-1657) discovered that the heart, and not the lungs, circulated blood throughout the body as a result of his experiments on living animals. [ 84 ] [ 85 ]

Animal Testing in the 1800s and Early 1900s

There was little public objection to animal experimentation until the 19th Century, when the increased adoption of domestic pets fueled interest in an anti-vivisection movement, primarily in England. This trend culminated in the founding of the Society for the Protection of Animals Liable to Vivisection in 1875, followed by the formation of similar groups. [ 79 ] [ 87 ]

One of the first proponents of animal testing to respond to the growing anti-testing movement was French physiologist Claude Bernard in his Introduction to the Study of Experimental Medicine (1865). Bernard argued that experimenting on animals was ethical because of the benefits to medicine and the extension of human life. [ 79 ]

Queen Victoria was an early opponent of animal testing in England, according to a letter written by her private secretary in 1875: “The Queen has been dreadfully shocked at the details of some of these [animal research] practices, and is most anxious to put a stop to them.” Soon the anti-vivisection campaign became strong enough to pressure lawmakers into establishing the first laws controlling the use of animals for research: Great Britain’s Cruelty to Animals Act of 1876 . [ 15 ] [ 88 ]

Russian physiologist Ivan Pavlov (1849-1936) demonstrated the “conditioned reflex” by training dogs to salivate upon hearing the sound of a bell or electric buzzer. In order to measure “the intensity of the salivary reflex,” wrote Pavlov, the dogs were subjected to a “minor operation, which consists in the transplantation of the opening of the salivary duct from its natural place on the mucous membrane of the mouth to the outside skin.” A “small glass funnel” was then attached to the salivary duct opening with a “special cement.” [ 86 ] [ 75 ]

In 1959, The Principles of Humane Experimental Technique by zoologist William Russell and microbiologist Rex Burch was published in England. The book laid out the principle of the “Three Rs” for using animals in research humanely: Replacement (replacing the use of animals with alternative research methods), Reduction (minimizing the use of animals whenever possible), and Refinement (reducing suffering and improving animals’ living conditions). The “Three Rs” were incorporated into the AWA and have formed the basis of many international animal welfare laws. [ 89 ] [ 90 ] [ 91 ]

Animals in Space and the Military

Since as early as 1948, animals have been used by the US space program for testing such aspects of space travel as the effects of prolonged weightlessness. After several monkeys died in unmanned space flights carried out during the 1940s, the first monkey to survive a space flight was Yorick, recovered from an Aerobee missile flight on Sep. 20, 1951. However, Yorick died several hours after landing, possibly due to heat stress. The first living creature to orbit the Earth was Laika , a stray dog sent into space on the Soviet spacecraft Sputnik 2 in Nov. 1957. Laika died of “overheating and panic” early in the mission, according to the BBC. The record for the most animals sent into space was set Apr. 17, 1998, when more than two thousand animals, including rats, mice, fish, crickets, and snails, were launched into space on the shuttle Columbia (along with the seven-member human crew) for neurological testing. [ 7 [ 8 ] [ 92 ] [ 116 ]

Since the Vietnam war , animals have also been used by the US military. The US Department of Defense used 488,237 animals for research and combat trauma training (“live tissue training”) in fiscal year 2007 (the latest year for which data are available), which included subjecting anesthetized goats and pigs to gunshot wounds, burns, and amputations for the training of military medics. In February 2013, after an escalation of opposition by animal rights groups such as People for the Ethical Treatments of Animals (PETA), Congress ordered the Pentagon to present a written plan to phase out live tissue training. The US Coast Guard, however, which was at the center of a 2012 scandal involving videotaped footage of goats being mutilated as part of its live tissue training program, said in May 2013 that the program will continue. [ 6 ] [ 93 ] [ 94 ] [ 95 ]

Regulations

A public outcry over animal testing and the treatment of animals in general broke out in the United States in the mid-1960s, leading to the passage of the AWA. An article in the November 29, 1965 issue of Sports Illustrated about Pepper, a farmer’s pet Dalmatian that was kidnapped and sold into experimentation, is believed to have been the initial catalyst for the rise in anti-testing sentiment. Pepper died after researchers attempted to implant an experimental cardiac pacemaker in her body. [ 74 ] [ 75 ]

Animal testing in the United States is regulated by the federal Animal Welfare Act (AWA), passed in 1966 and amended in 1970, 1976, and 1985. The AWA defines “animal” as “any live or dead dog, cat, monkey (nonhuman primate mammal), guinea pig, hamster, rabbit, or such other warm blooded animal.” The AWA excludes birds, rats and mice bred for research, cold-blooded animals, and farm animals used for food and other purposes. [ 3 ] [ 27 ]

The AWA requires that each research facility develop an internal Institutional Animal Committee (more commonly known as an Institutional Animal Care and Use Committee, or IACUC) to “represent society’s concerns regarding the welfare of animal subjects.” The Committee must be comprised of at least three members. One member must be a veterinarian and one must be unaffiliated with the institution. [ 3 ] [ 27 ]

While the AWA regulates the housing and transportation of animals used for research, it does not regulate the experiments themselves. The U.S. Congress Conference Committee stated at the time of the bill’s passage that it wanted “to provide protection for the researcher… by exempting from regulations all animals during actual research and experimentation… It is not the intention of the committee to interfere in any way with research or experimentation.” [ 66 ]

Animal studies funded by US Public Health Service (PHS) agencies, including the National Institutes of Health (NIH), are further regulated by the Public Health Service Policy on Humane Care and Use of Laboratory Animals. [ 27 ] All PHS funded institutions must base their animal care standards on the AWA and the Guide for the Care and Use of Laboratory Animals (also known as “the Guide “), prepared by the Institute for Laboratory Animal Research at the National Research Council. Unlike the AWA, the Policy on Humane Care and Use of Laboratory Animals and the Guide cover all vertebrate animals used for research, including birds, rats and mice. The Guide “establishes the minimum ethical, practice, and care standards for researchers and their institutions,” including environment and housing standards and required veterinary care. The Guide stipulates that “the avoidance or minimization of discomfort, distress, and pain when consistent with sound scientific practices, is imperative.” [ 71 ]

The US Department of Agriculture (USDA) Animal and Plant Health Inspection Service (APHIS) reports the number of animals used for research each year, though it excludes animals not covered by the AWA. For fiscal year 2010 (the latest year for which data are available as of Oct. 11, 2013), 1,134,693 animals were reported. Since the data excludes cold-blooded animals, farm animals used for food, and birds, rats, and mice bred for use in research, the total number of animals used for testing is unknown. Estimates of the number of animals not counted by APHIS range from 85%-96% of the total of all animals used for testing. [ 1 ] [ 2 ] [ 26 ] [ 65 ] [ 72 ]

The USDA breaks down its data by three categories of pain type: animals that experience pain during their use in research but are given drugs to alleviate it; animals who experience pain and are not given drugs; and animals who do not experience pain and are not given drugs. [ 26 ]

The U.S. Food and Drug Administration (FDA), which regulates the development of new medications, states that “At the preclinical stage, the FDA will generally ask, at a minimum, that sponsors… determine the acute toxicity of the drug in at least two species of animals.” [ 73 ]

On Dec. 29, 2022, President Joe Biden signed the FDA Modernization Act 2.0. Sponsored by Senator Rand Paul (R-KY), the law updates the U.S. Federal Food, Drug, and Cosmetic Act by eliminating the requirement that pharmaceutical companies test new drugs on animals before human trials. The amendment does not prevent companies from performing animals tests, but makes the tests the choice of the company. [ 151 ]

The Modern Debate

The 1975 publication of Animal Liberation by Australian philosopher Peter Singer galvanized the animal rights and anti-testing movements by popularizing the notion of “speciesism” as being analogous to racism, sexism, and other forms of prejudice. Addressing animal testing specifically, Singer predicted that “one day… our children’s children, reading about what was done in laboratories in the twentieth century, will feel the same sense of horror and incredulity… that we now feel when we read about the atrocities of the Roman gladiatorial arenas or the eighteenth-century slave trade.” [ 66 ]

In 1981, an early victory by then-fledgling animal rights group People for the Ethical Treatment of Animals (PETA) served to revitalize the anti-testing movement once again. A PETA activist working undercover at the Institute for Biological Research in Silver Spring, MD took photographs of monkeys in the facility that had engaged in self-mutilation due to stress. The laboratory’s director, Edward Taub, was charged with more than a dozen animal cruelty offenses, and an especially notorious photo of a monkey in a harness with all four limbs restrained became a symbolic image for the animal rights movement. [ 96 ]

In 2001, controversy erupted over animal experiments undertaken by a veterinarian at Ohio State University. Dr. Michael Podell infected cats with the feline AIDS virus in order to study why methamphetamine users deteriorate more quickly from the symptoms of AIDS. After receiving several death threats, Dr. Podell abandoned his academic career. Over 60% of biomedical scientists polled by Nature magazine say “animal-rights activists present a real threat to essential biomedical research.” [ 35 ] [ 97 ]

A 2007 report by the National Research Council of the National Academy of Sciences called for a reduction in the use of animal testing, recommending instead the increased use of in vitro methods using human cells. Though the report touted new technologies that could eventually eliminate the need for animal testing altogether, the authors acknowledged that “For the foreseeable future… targeted tests in animals would need to be used to complement the in vitro tests, because current methods cannot yet adequately mirror the metabolism of a whole animal.” [ 104 ]

In Mar. 2013, the European Union banned the import and sale of cosmetic products that use ingredients tested on animals. Some proponents of animal testing objected, arguing that some animal tests had no non-animal equivalents. A spokesman for the trade association Cosmetics Europe stated it is likely “that consumers in Europe won’t have access to new products because we can’t ensure that some ingredients will be safe without access to suitable and adequate testing.” India and Israel have also banned animal testing for cosmetic products, while the United States has no such ban in place. [ 98 ] [ 99 ]

China is the only major market where testing all cosmetics on animals is required by law, and foreign companies distributing their products to China must also have them tested on animals. China announced that its animal testing requirement will be waived for shampoo, perfume, and other so-called “non-special use cosmetics” manufactured by Chinese companies after June 2014. “Special use cosmetics,” including hair regrowth, hair removal, dye and permanent wave products, antiperspirant, and sunscreen, will continue to warrant mandatory animal testing. China’s National Medical Products Administration announced that animal testing for “ordinary” cosmetics (those that do not make claims such as “anti-aging”) will no longer be required as of May 2021. [ 43 ] [ 65 ] [ 114 ] [ 149 ]

After ceasing to breed chimpanzees for research in May 2007, the US National Institutes of Health announced in June 2013 that it would retire most of its chimpanzees (310 in total) over the next several years. While the decision was welcomed by animal rights groups, opponents said the decision would have a negative impact on the development of critical vaccines and treatments. The Texas Biomedical Research Institute released a statement claiming that the number of chimps to be retained (up to 50) was “not sufficient to enable the rapid development of better preventions and cures for hepatitis B and C, which kill a million people every year.” On Nov. 18, 2015 the US National Institutes of Health announced that its remaining 50 research chimpanzees will be retired to the Federal Chimpanzee Sanctuary System. Gabon remains the only country in the world that still experiments on chimpanzees. [ 4 ] [ 100 ] [ 117 ]

The Environmental Protection Agency (EPA) released a plan on Sep. 10, 2019 to reduce studies using mammal testing by 30% by 2025 and to eliminate the mammal testing altogether by 2035. In Nov. 2019, the FDA enacted a policy allowing some lab animals used for animal testing to be sent to shelters and sanctuaries for adoption. The National Institutes of Health (NIH) adopted a similar policy in Aug. 2019 and the Department of Veterans Affairs (VA) did so in 2018. [ 131 ] [ 146 ]

On Sep. 2, 2021, Mexico became the 41st country and first in North America to ban cosmetics testing on animals, according to the Humane Society International. [ 150 ]

Animal Testing and COVID-19

The COVID-19 (coronavirus) global pandemic brought attention to the debate about animal testing as researchers sought to develop a vaccine for the virus as quickly as possible. Vaccines are traditionally tested on animals to ensure their safety and effectiveness. News broke in Mar. 2020 that there was a shortage of the genetically modified mice that were needed to test coronavirus vaccines. [ 133 ]

Meanwhile, other companies tried new development techniques that allowed them to skip animal testing and start with human trials. Moderna Therapeutics used a synthetic copy of the virus genetic code instead of a weakened form of the virus. The FDA approved an application for Moderna to begin clinical trials on a coronavirus vaccine on Mar. 4, 2020, and the first participant was dosed on Mar. 16, 2020. [ 143 ] [ 147 ]

A shortage of monkeys, including pink-faced rhesus macaques, threatened vaccine development at the beginning of the pandemic and as variants of COVID-19 were found. The monkeys were previously flown in from China, but a ban on wildlife imports from China forced researchers to look elsewhere, a difficult task as China previously supplied over 60% of research monkeys in the United States. [ 148 ]

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History and Evolution of Animal Testing Research Paper

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This research paper explores the multifaceted history and intricate evolution of animal testing, delving into its origins in ancient civilizations, its pivotal role during the Scientific Revolution, and its expansion in modern science. It critically examines the ethical concerns that have arisen alongside its development, tracing the formation of regulations and the emergence of alternative testing methods. Through a global lens, it investigates varying international perspectives on animal testing practices and regulations. Finally, this paper offers insights into the future of animal testing, contemplating its continued relevance in scientific endeavors while acknowledging the ever-evolving landscape of ethical considerations and technological advancements. In doing so, it provides a comprehensive overview of a contentious and evolving practice that continues to shape the boundaries of scientific inquiry.

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Animal testing has been a fundamental component of scientific research for centuries, playing an indispensable role in advancing our understanding of biology, medicine, and numerous other fields. From the early experiments of ancient civilizations to the contemporary investigations in laboratories worldwide, the use of animals as research subjects has been a topic of enduring debate and ethical scrutiny. This research paper seeks to trace the history and evolution of animal testing, shedding light on its roots, pivotal moments, and contemporary relevance. It is imperative to recognize that animal testing is an intricate and multifaceted subject with far-reaching implications, encompassing ethical considerations, regulatory frameworks, and scientific progress. This paper endeavors to address the overarching question: How has animal testing evolved over time, and what are its ethical, scientific, and regulatory dimensions in the modern era? To elucidate this question, we will embark on a journey through history, exploring its historical roots, the Scientific Revolution’s influence, modern ethical concerns, and the emergence of alternative testing methods. By the end of this exploration, it is our aim to provide a comprehensive understanding of the complexities surrounding animal testing and its place in contemporary scientific inquiry. In doing so, this paper will not only unveil the historical tapestry of animal testing but also set the stage for an in-depth examination of its current landscape and future prospects.

II. Historical Roots of Animal Testing

The practice of animal testing, with its origins deeply rooted in the annals of history, has undergone a dynamic evolution over time, reflecting the ever-evolving relationship between humans and animals in the realm of scientific inquiry.

The earliest recorded instances of animal testing can be traced to ancient civilizations, where curiosity and the pursuit of knowledge led to experiments on animals. In the renowned Ebers Papyrus, dating back to 1550 BCE, ancient Egypt stands as one of the earliest civilizations to document experiments involving animals, marking an early interest in understanding physiological and medical phenomena (Ebers Papyrus, 1550 BCE). Ancient Greece, a cradle of intellectual development, made significant contributions to the early history of animal experimentation. The works of Greek luminaries such as Aristotle and Hippocrates included references to experiments conducted on animals, signifying the Greeks’ recognition of animals as valuable research subjects (Aristotle, “Historia Animalium,” 350 BCE). Similarly, ancient Rome engaged in animal experimentation, employing animals like dogs and pigs in medical inquiries (Galen, “On the Natural Faculties,” 2nd century CE).

The medieval and Renaissance periods ushered in a resurgence of scientific exploration and innovation, which further advanced the use of animals in experiments. Medieval Islamic scholars, notably Al-Razi and Ibn al-Nafis, contributed to the development of animal experimentation by conducting vivisections and animal dissections, expanding knowledge in the realms of anatomy and physiology (Al-Razi, “Kitab al-Hawi,” 9th century CE). The Renaissance, characterized as an era of scientific renaissance, witnessed the pioneering work of Andreas Vesalius, who conducted extensive dissections on animals to challenge the inaccuracies prevalent in ancient texts and lay the foundation for modern anatomical understanding (Vesalius, “De humani corporis fabrica,” 1543). These historical epochs collectively served as crucibles for the evolution of animal testing, not only establishing its historical roots but also fostering an environment of empirical investigation that would become the hallmark of the Scientific Revolution’s transformative influence on the practice.

III. Animal Testing in the Scientific Revolution and Beyond

The Scientific Revolution marked a pivotal juncture in the history of animal testing, as it catalyzed a profound shift in scientific inquiry, laying the groundwork for modern experimental methods while giving rise to ethical and scientific debates that continue to resonate.

The Scientific Revolution, spanning the 16th to the 18th centuries, revolutionized scientific thought and methodology. Animal testing assumed a central role during this era as researchers began to embrace empirical experimentation. Notably, Andreas Vesalius, a pioneering anatomist of the Renaissance, utilized animal dissections to challenge long-standing anatomical dogma. His magnum opus, “De humani corporis fabrica” (1543), featured detailed illustrations derived from animal dissections, offering a more accurate representation of human anatomy and fundamentally altering the field of anatomy (Vesalius, “De humani corporis fabrica,” 1543).

While Vesalius contributed to the advancement of animal testing, William Harvey, in the 17th century, revolutionized our understanding of circulation by conducting meticulous experiments on animals, particularly through vivisections of mammals. His groundbreaking work, “De Motu Cordis” (1628), not only demonstrated the role of the heart in circulation but also highlighted the scientific utility of animal experimentation (Harvey, “De Motu Cordis,” 1628).

However, the adoption of animal testing during the Scientific Revolution was not without ethical and scientific debates. Prominent ancient physician Galen’s theories, which had dominated medical thought for over a millennium, were based on animal dissections. This continuity posed ethical questions about the justifiability of continuing to use animals in experiments when such practices were rooted in centuries-old beliefs (Galen, “On the Natural Faculties,” 2nd century CE). The burgeoning debates questioned the moral implications of vivisection and fueled inquiries into the treatment and welfare of animals used in experimentation.

The Scientific Revolution thus established animal testing as an integral component of empirical science, paving the way for modern scientific inquiry. It was a period when the roles of key figures like Galen, Vesalius, and Harvey in shaping the practice became evident, yet it also generated ethical and scientific dialogues that continue to shape the contours of animal testing in the contemporary world.

IV. The Rise of Modern Animal Testing

The 19th and early 20th centuries witnessed the meteoric rise of animal testing as a prominent fixture in scientific research, marked by its expanded scope, the emergence of ethical concerns, and notable scientific breakthroughs that hinged on this practice.

During the 19th century, the utilization of animals in experiments became increasingly prevalent across various scientific disciplines. Physiologists like Claude Bernard championed the use of animals in their investigations, solidifying the practice’s importance in advancing knowledge about the functioning of living organisms (Bernard, “Introduction à l’Étude de la Médecine Expérimentale,” 1865). Concurrently, Charles Darwin’s groundbreaking work on evolution, “On the Origin of Species” (1859), was significantly informed by his studies on domesticated animals, further highlighting the critical role of animals in scientific exploration (Darwin, “On the Origin of Species,” 1859).

This period also saw the emergence of early animal rights movements and regulatory efforts aimed at mitigating the ethical concerns surrounding animal testing. Activists like Frances Power Cobbe and Henry Bergh advocated for the humane treatment of animals used in experiments and the development of ethical guidelines (Cobbe, “The Scientific Spirit of the Age,” 1888). These nascent movements laid the foundation for future regulatory frameworks, eventually leading to the formation of organizations like the American Society for the Prevention of Cruelty to Animals (ASPCA) in 1866.

Significant scientific breakthroughs and discoveries during this era heavily relied on animal experimentation. The development of the smallpox vaccine by Edward Jenner in 1796, which paved the way for modern vaccination, involved testing on animals (Jenner, “An Inquiry into the Causes and Effects of the Variolae Vaccinae,” 1798). Similarly, Louis Pasteur’s work on rabies and the germ theory of disease depended on animal experimentation, forever altering the landscape of medical science (Pasteur, “Sur la rage,” 1885).

As animal testing gained prominence in the 19th and early 20th centuries, it became entwined with both scientific progress and ethical dilemmas. This period marked a critical juncture in the history of animal testing, setting the stage for continued advancements, heightened ethical scrutiny, and the eventual development of regulatory frameworks aimed at balancing scientific innovation with the welfare of research animals.

V. Ethical Concerns and Regulations

The evolution of animal testing brought forth a host of ethical concerns that prompted introspection, advocacy, and the establishment of regulatory frameworks. This section delves into the ethical dilemmas associated with animal testing, the formulation of animal welfare and ethical guidelines, and the enactment of landmark regulations and laws governing this practice.

Ethical dilemmas have been a persistent companion of animal testing since its inception. Central to these concerns is the moral status of animals and the question of whether their use in scientific experiments is justifiable. Philosophers like Peter Singer, in “Animal Liberation” (1975), and Tom Regan, in “The Case for Animal Rights” (1983), challenged the ethical foundations of animal testing, advocating for the recognition of animals’ intrinsic worth and their right to be free from unnecessary suffering. The use of animals in potentially harmful experiments raised questions about the moral boundaries of scientific inquiry and human responsibility toward sentient beings.

In response to these ethical dilemmas, the scientific community and governments worldwide began to formulate animal welfare and ethical guidelines. The development of the “Three Rs” principle by William Russell and Rex Burch in “The Principles of Humane Experimental Technique” (1959) marked a significant milestone. This framework emphasizes the Reduction, Refinement, and Replacement of animal use in experiments, seeking to minimize harm to animals and promote more humane research practices (Russell & Burch, “The Principles of Humane Experimental Technique,” 1959).

Landmark regulations and laws governing animal testing emerged as a result of growing ethical concerns and advocacy efforts. The United States passed the Animal Welfare Act in 1966, establishing minimum standards for the humane treatment of research animals and oversight by the Animal and Plant Health Inspection Service (APHIS). Similarly, the European Union implemented the Directive 2010/63/EU in 2010, setting strict guidelines for the use of animals in scientific research and prioritizing the refinement and reduction of animal use.

The ethical quandaries surrounding animal testing and the subsequent formulation of ethical guidelines and regulations reflect a continual struggle to balance scientific progress with the welfare and ethical treatment of animals. These efforts represent pivotal steps in the ongoing evolution of animal testing, aiming to ensure that scientific exploration occurs within a framework of compassion and ethical responsibility.

VI. Alternatives to Animal Testing

As ethical concerns surrounding animal testing have grown, so too has the development of alternative testing methods that aim to reduce or replace the use of animals in scientific research. This section examines the evolution of alternative testing methods, including in vitro and computer modeling approaches, discusses their advantages and limitations, and highlights ongoing efforts to reduce and replace animal testing.

The development of alternative testing methods has been driven by the desire to minimize animal suffering and ethical concerns while still advancing scientific knowledge. In vitro methods, which involve testing on isolated cells, tissues, or organs outside the living organism, have gained prominence. These methods include cell cultures, tissue engineering, and organ-on-a-chip technologies (Hartung et al., “Food for Thought…On Alternative Methods for Chemical Safety Testing,” 2004). Additionally, computer modeling and simulations have become increasingly sophisticated, offering virtual platforms to predict the effects of substances on biological systems (Kleinstreuer et al., “In vitro to in vivo Extrapolation for High Throughput Prioritization and Decision Making,” 2011).

The advantages of alternative testing methods are manifold. They allow for more precise control over experimental conditions, reducing variability and enhancing reproducibility. In vitro and computer models can provide rapid results, accelerating the pace of research and drug development. Moreover, these methods often obviate the need for animal testing, aligning research practices with ethical considerations (Basketter et al., “A Roadmap for the Development of Alternative (Non-Animal) Methods for Systemic Toxicity Testing,” 2012).

However, alternative testing methods also have limitations. While they can mimic certain aspects of biological systems, they may not fully replicate the complexity of whole organisms, potentially limiting their predictive accuracy (Hartung, “Food for Thought…On Mapping the Human Toxome,” 2009). Furthermore, the validation and acceptance of these methods by regulatory agencies can be a lengthy and challenging process (Leist et al., “Consensus Report on the Future of Animal-Free Systemic Toxicity Testing,” 2014).

Current efforts to reduce and replace animal testing are gaining momentum. The “Toxicology in the 21st Century” initiative, led by the U.S. Environmental Protection Agency (EPA), seeks to shift toxicity testing toward more efficient and humane methods, including computational models and high-throughput in vitro assays (Kavlock et al., “Update on EPA’s ToxCast Program: Providing High Throughput Decision Support Tools for Chemical Risk Management,” 2012). Similarly, the European Union’s REACH program encourages the use of alternative methods to assess chemical safety (ECHA, “REACH Regulation: Guidance on Information Requirements and Chemical Safety Assessment,” 2020).

In summary, the development of alternative testing methods represents a critical step in the ongoing evolution of animal testing. These methods offer advantages in terms of precision, speed, and ethical considerations but must contend with limitations and regulatory challenges. Current efforts are focused on integrating these alternatives into regulatory frameworks and promoting a future where animal testing is minimized or replaced altogether.

VII. Contemporary Trends and Debates

In the contemporary landscape, animal testing remains a topic of intense scrutiny, replete with complex trends, debates, and ethical dilemmas. This section delves into the current state of animal testing across diverse fields, including pharmaceuticals, cosmetics, and medical research, highlights recent controversies and high-profile cases, and engages with the ongoing debates concerning the necessity and ethics of animal experimentation.

The Current State of Animal Testing Across Fields

Pharmaceuticals.

Animal testing continues to be a linchpin in pharmaceutical research. Medicines, vaccines, and therapeutic treatments undergo rigorous preclinical testing on animals to assess their safety and efficacy before human trials (Mak et al., “Animal Models of Disease and the Development of a Human Vaccine Against West Nile Virus,” 2004). Regulatory agencies, such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), require extensive animal testing data as part of the drug approval process (FDA, “Animal Testing & Cosmetics,” 2021). Despite advances in alternative methods, animal testing remains integral to pharmaceutical development due to its role in assessing complex physiological responses.

The cosmetics industry has faced increasing pressure to reduce or eliminate animal testing, particularly for product safety assessments. Several countries, including the European Union and Israel, have banned or heavily regulated cosmetic testing on animals (EC, “Cosmetics,” 2013). The industry has responded by adopting alternative methods such as in vitro testing and computer modeling to assess product safety (Pfuhler et al., “The Cosmetic Ingredient Review Program—Expert Safety Assessments for Sensitive Skin,” 2008). However, challenges persist, as some markets, including China, still require animal testing for certain cosmetic products (Regulation (EC) No 1223/2009, 2009).

Medical Research

In medical research, animal testing remains crucial for studying disease mechanisms, developing treatments, and advancing surgical techniques (Ratcliffe, “Animal Models of Heart Failure: A Scientific Statement From the American Heart Association,” 2017). For instance, animal models have played a pivotal role in cancer research, neuroscience, and cardiovascular studies. These models enable researchers to investigate the biological complexities of diseases and evaluate potential interventions (National Cancer Institute, “Mouse Models of Human Cancers Consortium,” 2020). Nevertheless, the use of animals in such research is a contentious issue, with ongoing efforts to refine experimental methods and minimize animal suffering.

Recent Controversies and High-Profile Cases

• Cosmetic Testing: One of the most notable controversies in recent years centers on cosmetic testing. The debate was ignited when multinational beauty corporations, such as L’Oréal and Procter & Gamble, announced their commitments to eliminate animal testing from their product development processes. Simultaneously, the demand for cruelty-free cosmetics surged, prompting consumers to seek products bearing cruelty-free certifications (Dwyer, “Cruelty-Free Cosmetics Sales in the United States: Who Cares, Who Pays?”, 2016). The contrasting regulatory requirements across different regions have posed a challenge for companies operating in global markets, leading to debates about harmonizing standards (European Parliament, “Harmonising Cosmetic Safety Assessment: A Rational Approach to Cosmetic Regulation in the EU,” 2012).
• Animal Welfare in Research: High-profile cases of animal welfare violations have spurred public outrage and heightened scrutiny of research institutions. Notable incidents, such as the exposure of unethical animal experimentation practices in laboratories, have prompted calls for greater transparency, accountability, and adherence to ethical guidelines (Casey et al., “A Time for Transparency,” 2015). These controversies have underscored the importance of robust oversight and the enforcement of ethical standards in animal research.

Ongoing Debates Surrounding Necessity and Ethics

Debates surrounding the necessity and ethics of animal experimentation persist in academic, scientific, and ethical circles. Key points of contention include:

• Scientific Validity: Critics argue that animal models may not always accurately replicate human responses and that alternative methods, such as human cell-based assays and organoids, may offer more relevant insights (Shanks et al., “The Need for a New Approach to the Use of Nonhuman Animals in Scientific Research,” 2009). Proponents, on the other hand, contend that carefully chosen animal models remain indispensable for understanding complex biological processes and assessing the safety and efficacy of treatments (Balls et al., “Replacement of Animal Procedures: Alternatives in Research, Education, and Testing,” 1990).
• Ethical Considerations: Ethical debates revolve around whether the potential benefits of animal testing justify the ethical costs. Critics argue that the ethical treatment of animals necessitates minimizing their use and suffering, while proponents assert that the pursuit of scientific knowledge and medical advancements can, in some cases, ethically outweigh the harm caused to animals (Rollin, “The Use of Animals in Research: A Philosophical Problem,” 1989).
• Regulatory Reform: Advocacy groups and policymakers continue to push for regulatory reforms aimed at reducing animal testing and promoting alternative methods (Seidle et al., “Banning Animal Testing in Cosmetics: A Global Perspective,” 2010). This has led to discussions about the adequacy of existing regulations, the harmonization of international standards, and the allocation of resources for the development and validation of alternative testing approaches.

In conclusion, the contemporary landscape of animal testing is marked by a dynamic interplay of scientific, ethical, and regulatory considerations. It continues to be an essential tool in pharmaceuticals, medical research, and other fields, yet faces persistent challenges and controversies related to its ethical implications and scientific validity. The ongoing debates surrounding the necessity and ethics of animal experimentation underscore the need for a nuanced and balanced approach that respects both scientific progress and ethical considerations.

VIII. International Perspectives on Animal Testing

The practice of animal testing is subject to varying approaches, practices, and regulations across different countries and regions. This section aims to compare and contrast animal testing practices and regulations in select countries, highlighting notable differences and commonalities. Additionally, it delves into global initiatives and collaborative efforts aimed at standardizing and harmonizing animal testing practices on an international scale.

Comparing and Contrasting Animal Testing Practices and Regulations

• United States: In the United States, animal testing is conducted across a range of sectors, including pharmaceuticals, cosmetics, and biomedical research. The regulatory framework is primarily governed by agencies such as the U.S. Food and Drug Administration (FDA) and the National Institutes of Health (NIH). The Animal Welfare Act, enforced by the U.S. Department of Agriculture (USDA), sets standards for the humane treatment of research animals (Animal Welfare Act, 1966). Despite these regulations, the U.S. has faced criticism for relatively permissive standards regarding animal testing in cosmetics compared to some European countries.
• European Union: The European Union (EU) has taken a more stringent approach to animal testing, particularly in the cosmetics industry. Since 2009, the EU has banned animal testing for cosmetic products and ingredients, including imports (Regulation (EC) No 1223/2009, 2009). Additionally, the EU’s REACH (Registration, Evaluation, Authorization, and Restriction of Chemicals) regulation encourages the use of alternative testing methods and restricts the use of animals for testing chemical safety (ECHA, “REACH Regulation: Guidance on Information Requirements and Chemical Safety Assessment,” 2020). These measures reflect a commitment to minimizing the use of animals in cosmetic and chemical testing.
• China: China presents a unique perspective on animal testing, especially in the cosmetics sector. The country requires animal testing for certain cosmetic products as part of its regulatory framework (Regulation on Hygiene Supervision over Cosmetics, 2013). However, there have been encouraging signs, as China has made progress toward accepting non-animal methods for cosmetics safety assessment, aligning with global trends towards alternative testing (CFDA, “Cosmetic Safety and Technical Standards,” 2015).

Global Initiatives and Collaborations

International initiatives and collaborations have emerged to standardize and harmonize animal testing practices, recognizing the importance of consistent standards in a globalized world.

• OECD (Organisation for Economic Co-operation and Development): The OECD plays a pivotal role in developing guidelines for the testing of chemicals, including those involving animals. The Test Guidelines Program of the OECD is instrumental in harmonizing testing protocols and promoting the use of alternative methods (OECD, “Test Guidelines for Chemicals,” 2021).
• ICCVAM (Interagency Coordinating Committee on the Validation of Alternative Methods): In the United States, ICCVAM facilitates the evaluation and validation of alternative methods to animal testing. It promotes the adoption of scientifically validated alternatives and collaborates with regulatory agencies (ICCVAM, “About ICCVAM,” 2021).
• International Collaboration on Alternative Test Methods (ICATM): ICATM is a global network of organizations and regulatory bodies committed to advancing alternative test methods. It fosters international cooperation, information exchange, and the development of alternative methods (ICATM, “About ICATM,” 2021).
• EPAA (European Partnership for Alternative Approaches to Animal Testing): EPAA brings together industry, regulatory authorities, and animal welfare organizations in Europe to promote the development and use of alternative methods in chemical safety testing (EPAA, “About EPAA,” 2021).

These initiatives and collaborations are instrumental in facilitating the sharing of knowledge, resources, and best practices on a global scale. They underscore the collective commitment to reducing and refining animal testing practices while ensuring the safety and efficacy of products and chemicals worldwide.

In conclusion, international perspectives on animal testing demonstrate a diverse range of approaches and regulations, often shaped by historical, cultural, and regulatory factors. However, global initiatives and collaborative efforts are working toward standardization and harmonization, recognizing the need for consistent practices that balance scientific inquiry with ethical considerations across borders.

IX. The Future of Animal Testing

The future of animal testing is poised for significant advancements and transformations, driven by emerging technologies and evolving ethical considerations. This section explores potential changes in the field of animal testing, the role of cutting-edge technologies, and the ethical considerations that will shape its trajectory.

Advancements in Animal Testing

• Advanced In Vitro Models: The development and refinement of in vitro models are expected to accelerate. These models will become increasingly sophisticated, enabling researchers to simulate complex physiological systems with greater accuracy (Leist et al., “Human-based in vitro models of non-communicable diseases,” 2020). Microphysiological systems, also known as “organs-on-a-chip,” will play a pivotal role in mimicking the functions of organs and tissues, reducing the reliance on whole animals for testing (Huh et al., “Reconstituting Organ-Level Lung Functions on a Chip,” 2010).
• Artificial Intelligence and Machine Learning: The integration of artificial intelligence (AI) and machine learning algorithms will revolutionize data analysis and prediction in toxicology and drug development. These technologies will enhance researchers’ ability to extrapolate results from in vitro and in silico experiments to human contexts, reducing the need for animal models (Low et al., “Artificial Intelligence in Drug Development: Present Status and Future Prospects,” 2020).
• Humanized Animal Models: Humanized animal models, including genetically modified animals with humanized immune systems or organs, will become increasingly prevalent. These models aim to replicate human responses more accurately, further reducing the need for traditional animal models (Shultz et al., “Humanized Mouse Models of Immunological Diseases and Precision Medicine,” 2018).

Emerging Technologies Shaping the Future

• Organoids and 3D Bioprinting: Organoids, miniature 3D structures resembling human organs, and 3D bioprinting technologies will enable the creation of customized, patient-specific models for drug testing and disease research. These approaches hold immense potential for personalized medicine and reducing reliance on animal models (Lancaster et al., “Cerebral organoids model human brain development and microcephaly,” 2013).
• Organ Chips and Microfluidics: The continued development of organ chips and microfluidics platforms will replicate the dynamic microenvironments of human organs. These technologies will facilitate real-time monitoring and testing of drugs, toxins, and disease mechanisms (Esch et al., “On Chip, Human Organ Mimics for Drug Safety Screening,” 2011).

Ethical Considerations and the Future of Animal Testing

• Ethical Frameworks: Ethical considerations will continue to drive changes in animal testing. The principle of the “Three Rs” (Reduction, Refinement, Replacement) will guide research practices, emphasizing the reduction of animal use, refinement of experiments to minimize suffering, and replacement of animals with alternative methods (Russell & Burch, “The Principles of Humane Experimental Technique,” 1959).
• Public Awareness and Pressure: Heightened public awareness and advocacy for animal welfare will influence corporate and regulatory decisions. Consumer demand for cruelty-free products and transparency in research practices will incentivize industries to seek alternative testing methods (Dombrowski et al., “Consumer Behavior in Animal Testing: A Review,” 2020).
• Regulatory Changes: Regulatory agencies worldwide will continue to revise and adapt their guidelines to encourage the use of alternative testing methods while ensuring product safety. Collaborative efforts between regulators, industry stakeholders, and animal welfare organizations will shape the regulatory landscape (Hartung et al., “Food for Thought…On Alternative Methods for Chemical Safety Testing,” 2004).

In conclusion, the future of animal testing is poised for a profound transformation. Emerging technologies, such as advanced in vitro models and AI, will enable more accurate, efficient, and humane methods for scientific inquiry and product safety assessment. Ethical considerations and evolving public attitudes will drive regulatory changes, incentivizing industries to adopt alternative testing methods. While traditional animal testing will not be entirely eliminated in the near term, its role is expected to diminish significantly as the scientific community and society at large prioritize the development and implementation of alternatives that align with both scientific rigor and ethical responsibility.

X. Conclusion

This comprehensive exploration of the history, practices, and future of animal testing has shed light on a multifaceted and evolving subject. As we conclude this research paper, we summarize key findings and insights, restate the research question and its significance, and offer concluding remarks on the evolution and future prospects of animal testing.

Throughout this paper, we embarked on a journey through time, tracing the historical roots of animal testing from ancient civilizations to the Scientific Revolution and its subsequent expansion in the 19th and 20th centuries. We examined the ethical dilemmas that have arisen alongside its development, leading to the formulation of animal welfare guidelines and regulations. Additionally, we explored the emergence of alternative testing methods and their potential to reshape the landscape of scientific research. Contemporary trends and debates were analyzed, considering the current state of animal testing in various fields, recent controversies, and ongoing ethical discussions. We also examined international perspectives and collaborative initiatives aimed at standardizing animal testing practices.

The overarching research question that guided this inquiry was: How has animal testing evolved over time, and what are its ethical, scientific, and regulatory dimensions in the modern era? This question is significant as it delves into the intricate tapestry of a practice that has been pivotal in advancing human knowledge while raising profound ethical concerns about the treatment of sentient beings.

In conclusion, the evolution of animal testing reflects a complex interplay between scientific progress, ethical considerations, and regulatory frameworks. While the practice remains integral to certain scientific endeavors, its future is poised for transformation. Advanced technologies, including in vitro models and artificial intelligence, are rapidly reducing the reliance on traditional animal testing. Ethical considerations and public awareness are driving changes in research practices and regulatory guidelines. Although traditional animal testing may not disappear entirely in the near term, it is undergoing a profound reevaluation, with a growing emphasis on humane and scientifically rigorous alternatives.

As we navigate the path forward, it is imperative that we continue to strike a balance between scientific inquiry and ethical responsibility. The future of animal testing lies in a landscape where the welfare of animals and the pursuit of scientific knowledge coexist harmoniously, where technological advancements and ethical considerations shape a research paradigm that respects the rights and dignity of all living beings involved in the quest for knowledge and progress.

Bibliography

• Animal Welfare Act. (1966). Retrieved from https://www.aphis.usda.gov/animal_welfare/downloads/awa/awa.pdf
• (350 BCE). Historia Animalium.
• Balls, M., et al. (1990). Replacement of Animal Procedures: Alternatives in Research, Education, and Testing. ATLA – Alternatives to Laboratory Animals, 18(4), 312-334.
• Casey, W., et al. (2015). A Time for Transparency. Science, 348(6235), 1422-1423.
• CFDA (China Food and Drug Administration). (2015). Cosmetic Safety and Technical Standards.
• Cobbe, F. P. (1888). The Scientific Spirit of the Age.
• Darwin, C. (1859). On the Origin of Species.
• Dombrowski, A. M., et al. (2020). Consumer Behavior in Animal Testing: A Review. Animals, 10(3), 542.
• EC (European Commission). (2013). Cosmetics. Retrieved from https://ec.europa.eu/growth/sectors/cosmetics_en
• ECHA (European Chemicals Agency). (2020). REACH Regulation: Guidance on Information Requirements and Chemical Safety Assessment.
• EPAA (European Partnership for Alternative Approaches to Animal Testing). (2021). About EPAA. Retrieved from http://ecvam-dbalm.jrc.ec.europa.eu/index.php/about-epaa
• Esch, E. W., et al. (2011). On Chip, Human Organ Mimics for Drug Safety Screening. Microfluidics and Nanofluidics, 12(4), 513-525.
• FDA (U.S. Food and Drug Administration). (2021). Animal Testing & Cosmetics. Retrieved from https://www.fda.gov/cosmetics/cosmetics-laws-regulations/animal-testing-cosmetics
• (2nd century CE). On the Natural Faculties.
• Hartung, T., et al. (2004). Food for Thought…On Alternative Methods for Chemical Safety Testing. Toxicology and Applied Pharmacology, 195(2), 170-180.
• Harvey, W. (1628). De Motu Cordis.
• Huh, D., et al. (2010). Reconstituting Organ-Level Lung Functions on a Chip. Science, 328(5986), 1662-1668.
• ICATM (International Collaboration on Alternative Test Methods). (2021). About ICATM. Retrieved from https://www.icatm.com/about-icatm/
• ICCVAM (Interagency Coordinating Committee on the Validation of Alternative Methods). (2021). About ICCVAM. Retrieved from https://ntp.niehs.nih.gov/iccvam/about/index.html
• Jenner, E. (1798). An Inquiry into the Causes and Effects of the Variolae Vaccinae.
• Kavlock, R., et al. (2012). Update on EPA’s ToxCast Program: Providing High Throughput Decision Support Tools for Chemical Risk Management. Chemical Research in Toxicology, 25(7), 1287-1302.
• Kleinstreuer, N. C., et al. (2011). In vitro to in vivo Extrapolation for High Throughput Prioritization and Decision Making. Toxicology and Applied Pharmacology, 259(2), 270-277.
• Lancaster, M. A., et al. (2013). Cerebral organoids model human brain development and microcephaly. Nature, 501(7467), 373-379.
• Leist, M., et al. (2014). Consensus Report on the Future of Animal-Free Systemic Toxicity Testing. ALTEX – Alternatives to Animal Experimentation, 31(3), 341-356.
• Leist, M., et al. (2020). Human-based in vitro models of non-communicable diseases. Nature Reviews Drug Discovery, 19(8), 529-542.
• Low, Y., et al. (2020). Artificial Intelligence in Drug Development: Present Status and Future Prospects. Drug Discovery Today, 25(1), 51-58.
• Mak, T. W., et al. (2004). Animal Models of Disease and the Development of a Human Vaccine Against West Nile Virus. European Journal of Immunology, 34(10), 2387-2390.
• National Cancer Institute. (2020). Mouse Models of Human Cancers Consortium. Retrieved from https://www.cancer.gov/research/infrastructure/cancer-models/mmhc
• OECD (Organisation for Economic Co-operation and Development). (2021). Test Guidelines for Chemicals. Retrieved from http://www.oecd.org/chemicalsafety/testing/oecdguidelinesforthetestingofchemicals.htm
• Pasteur, L. (1885). Sur la rage.
• Pfuhler, S., et al. (2008). The Cosmetic Ingredient Review Program—Expert Safety Assessments for Sensitive Skin. Toxicology Letters, 180(3), 194-200.
• Ratcliffe, M. J. (2017). Animal Models of Heart Failure: A Scientific Statement From the American Heart Association. Circulation Research, 121(11), e63-e86.
• Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on Cosmetic Products. (2009). Official Journal of the European Union, L 342/59. Retrieved from https://eur-lex.europa.eu/legal-content/EN/ALL/?uri=CELEX%3A32009R1223
• Rollin, B. E. (1989). The Use of Animals in Research: A Philosophical Problem. American Scientist, 77(4), 362-367.
• Russell, W. M. S., & Burch, R. L. (1959). The Principles of Humane Experimental Technique.
• Shanks, N., et al. (2009). The Need for a New Approach to the Use of Nonhuman Animals in Scientific Research. ATLA – Alternatives to Laboratory Animals, 37(Supplement 2), 409-414.
• Shultz, L. D., et al. (2018). Humanized Mouse Models of Immunological Diseases and Precision Medicine. Mammalian Genome, 29(7-8), 130-143.
• Singer, P. (1975). Animal Liberation.
• USDA (U.S. Department of Agriculture). (2021). Animal Welfare Act. Retrieved from https://www.aphis.usda.gov/animal_welfare/downloads/awa/awa.pdf

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A Century of Suffering: 10 Gruesome Experiments on Animals From the Last 100 Years

Mice, rats, dogs, monkeys, rabbits, and other animals have been suffering in experiments for more than a century. During the last 100 years, sensitive animals trapped in laboratories have been burned, shocked, poisoned, forcibly impregnated, decapitated, locked away in isolation from other members of their species, and made to endure countless other atrocities. Below, you can learn more about the sordid history of animal testing — including the landmark investigation that launched PETA more than 40 years ago.

The History of Animal Testing — 10 Shocking Experiments on Animals From the Last Century

1. maryland psychologist severed spinal cords, repeatedly shocked monkeys (1958–1981).

At the Institute for Behavioral Research in Silver Spring, Maryland, psychologist and animal experimenter Edward Taub—a man with no medical or veterinary training—kept 17 monkeys in cramped wire cages that were caked with feces. The animals were subjected to debilitating surgeries in which their spinal nerves were severed, rendering one or more of their limbs useless. They were then forced to try to regain function in their impaired limbs through cruel methods such as electric shocks and pinches with pliers.

PETA’s groundbreaking investigation into this hellhole led to the nation’s first arrest and criminal conviction of an animal experimenter for cruelty to animals, the first confiscation of abused animals from a laboratory, and the first U.S. Supreme Court victory for animals used in experiments.

2. Pfizer Injects Horses With Snake Venom (1961–Present)

In Pfizer laboratories, snake venom has been repeatedly injected into 111 horses and large quantities of their blood have been drawn. These painful procedures can cause horses to fall ill, lose weight, and become anemic, and no pain relief is provided.

3. Government Experimenter Inflicts Permanent Brain Damage on Monkeys (1983–Present)

The National Institutes of Health’s Elisabeth Murray carves out a section of monkeys’ skulls and then injects toxins into the brain or suctions out portions of it, causing permanent and traumatic damage. The monkeys are then held alone in a small metal cage. A guillotine-like door at the front of the cage is suddenly raised, revealing realistic-looking fake spiders or snakes, which are inherently frightening to monkeys. The animals endure this same torture repeatedly. When Murray has finished with them, they may be killed or recycled into other experiments to be further tormented.

4. Sensory-Deprivation Experiments on Baby Monkeys (1983–Present)

Margaret Livingstone, a Harvard University experimenter, has spent her entire 40-year career tormenting animals, including by tearing baby monkeys away from their mothers and sewing their eyes shut—or making sure they never see a human or monkey face in other ways—just to see how badly it damages their brain and visual development. Livingstone calls it science. We call it psychosis. Harvard must shut down her lab permanently and have her head examined.

Figure 1 in Triggers for Mother Love | Margaret S. Livingstone | CC BY-NC-ND

5. Oregon Experimenter Killed and Cut Open Pregnant Monkeys (1997–2017)

Kevin Grove at the Oregon National Primate Research Center confined female monkeys to cramped cages and fed them unhealthy, high-fat diets until they became obese. He then artificially inseminated them. Some of these pregnant monkeys were killed and cut open, and their brains and fetuses were removed and examined. Those who weren’t killed gave birth, and their newborns were taken away from them almost immediately, traumatizing both mother and baby.

6. Columbia Experimenters Cut Baboons’ Eyes Out, Induced Strokes (2001–2011)

In experiments conducted at Columbia University, baboons’ eyes were cut out, sometimes while they were conscious, and the arteries to their brains were clamped in a crude procedure intended to induce strokes.

7. Animals Beheaded With Kitchen Scissors in UNC Experiments (2001–2003)

At the University of North Carolina, animals were used in alcohol, dopamine, and nicotine experiments. Mice and rats who had been inadequately gassed or undergone improper cervical dislocation (neck-breaking) were still alive in a cooler used to store dead animals. An experimenter admitted that he was not numbing young rats with ice before cutting their heads off with scissors and removing their brains.

8. Johns Hopkins Experimenter Cuts Into Owls’ Skulls, Implants Electrodes in Brains (2005–Present)

Shreesh Mysore, an experimenter at Johns Hopkins University, cuts into owls’ skulls to expose their brains and then screws and glues metal devices to their heads. These birds—nocturnal hunters who would fly great distances in their natural habitat—are forced into plastic tubes so small that they can’t even move their wings. Then, Mysore bombards them with lights and sounds. He pokes electrodes around in their brains while they’re conscious, mutilating the tissue so severely that they become “unusable” to him—at which point he kills them.

9. University Experimenter Traps Birds, Wounds Them Without Painkillers (2008–Present)

At Tufts and Yale universities, experimenter Christine Lattin injected sparrows and other birds with chemicals to destroy their adrenal glands, used a biopsy punch to inflict painful wounds on birds’ legs, and fed sparrows food that was laced with crude oil.

Now at Louisiana State University (LSU), she’s begun a new round of pointless experiments on birds. House sparrows breeding in nest boxes at the LSU College of Agriculture will be captured, banded, and fitted with digital ID transmitters. At the end of the breeding season, Lattin will recapture and then kill all the birds— and their chicks —before removing their brains for analysis.

10. Liberty Research Workers Drilled Holes Into Young Beagles’ Skulls (2016–2017)

A 2017 PETA eyewitness investigation showed that workers at Liberty Research, Inc.—a laboratory in New York—drilled holes into the skulls of young beagles so that distemper virus could be injected directly into their brains. Some dogs blinked and even whimpered during the painful procedure—indicating that they were not adequately anesthetized—and woke up moaning. Likely in severe pain, some banged their heads on cage walls, causing blood to spurt from their wounds. Some foamed at the mouth, and others had seizures. They were left to suffer without any apparent treatment and were killed at the end of the study.

Want to Learn More About the History of Animal Testing?

Be sure to check out PETA’s interactive online timeline, “Without Consent.” It explores the troubled history of animal testing and challenges what we’ve been told for decades is normal.

It’s speciesist to believe that animals in laboratories don’t feel emotions or experience pain. Animals used in experiments are no different from the cats and dogs with whom many people lovingly share their homes, yet they are afforded few—if any—of the same protections or considerations. As a result, more than 100 million animals suffer and die in the U.S. every year in cruel chemical, drug, food, and cosmetics tests as well as in  medical training exercises  and curiosity-driven  medical experiments at universities .

What You Can Do for These Animals

Now that you’ve learned more about the history of animal testing, discover what you can do for animals in the present day. PETA makes it easy to take action for animals suffering in cruel and useless experiments like the ones described above. It only takes a minute using your phone or computer, so what are you waiting for?

From PETA and executive producer Bill Maher, the new docuseries ‘The Failed Experiment’ exposes what most people don’t know about experiments on animals.

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Semester after semester, undergraduate students at Utah State University (USU) who are enrolled in a course called Advanced Analysis of Behavior (PSY 3400) are required to lock rats inside barren metal boxes where the animals are trained to push a lever to receive food pellets, all while being bombarded with random bursts of bright light.

In a newly published paper, PETA scientists lay bare a solid plan for ending two of the pharmaceutical industry’s most cruel and pointless experiments on animals.

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“Almost all of us grew up eating meat, wearing leather, and going to circuses and zoos. We never considered the impact of these actions on the animals involved. For whatever reason, you are now asking the question: Why should animals have rights?” READ MORE

— Ingrid E. Newkirk, PETA President and co-author of Animalkind

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Is this the end of animal testing?

Researchers are increasingly turning to organ-on-a-chip technology for drug testing and other applications.

• Harriet Brown archive page

In a clean room in his lab, Sean Moore peers through a microscope at a bit of intestine, its dark squiggles and rounded structures standing out against a light gray background. This sample is not part of an actual intestine; rather, it’s human intestinal cells on a tiny plastic rectangle, one of 24 so-called “organs on chips” his lab bought three years ago.

Moore, a pediatric gastroenterologist at the University of Virginia School of Medicine, hopes the chips will offer answers to a particularly thorny research problem. He studies rotavirus, a common infection that causes severe diarrhea, vomiting, dehydration, and even death in young children. In the US and other rich nations, up to 98% of the children who are vaccinated against rotavirus develop lifelong immunity. But in low-income countries, only about a third of vaccinated children become immune. Moore wants to know why.

His lab uses mice for some protocols, but animal studies are notoriously bad at identifying human treatments. Around 95% of the drugs developed through animal research fail in people. Researchers have documented this translation gap since at least 1962 . “All these pharmaceutical companies know the animal models stink,” says Don Ingber, founder of the Wyss Institute for Biologically Inspired Engineering at Harvard and a leading advocate for organs on chips. “The FDA knows they stink.” 

But until recently there was no other option. Research questions like Moore’s can’t ethically or practically be addressed with a randomized, double-blinded study in humans. Now these organs on chips, also known as microphysiological systems, may offer a truly viable alternative. They look remarkably prosaic: flexible polymer rectangles about the size of a thumb drive. In reality they’re triumphs of bioengineering, intricate constructions furrowed with tiny channels that are lined with living human tissues. These tissues expand and contract with the flow of fluid and air, mimicking key organ functions like breathing, blood flow, and peristalsis, the muscular contractions of the digestive system.

More than 60 companies now produce organs on chips commercially, focusing on five major organs: liver, kidney, lung, intestines, and brain. They’re already being used to understand diseases, discover and test new drugs, and explore personalized approaches to treatment.

As they continue to be refined, they could solve one of the biggest problems in medicine today. “You need to do three things when you’re making a drug,” says Lorna Ewart, a pharmacologist and chief scientific officer of Emulate, a biotech company based in Boston. “You need to show it’s safe. You need to show it works. You need to be able to make it.” 

All new compounds have to pass through a preclinical phase, where they’re tested for safety and effectiveness before moving to clinical trials in humans. Until recently, those tests had to run in at least two animal species —usually rats and dogs—before the drugs were tried on people. 

But in December 2022, President Biden signed the FDA Modernization Act , which amended the original FDA Act of 1938 . With a few small word changes, the act opened the door for non-animal-based testing in preclinical trials. Anything that makes it faster and easier for pharmaceutical companies to identify safe and effective drugs means better, potentially cheaper treatments for all of us. 

Moore, for one, is banking on it, hoping the chips help him and his colleagues shed light on the rotavirus vaccine responses that confound them. “If you could figure out the answer,” he says, “you could save a lot of kids’ lives.”

While many teams have worked on organ chips over the last 30 years, the OG in the field is generally acknowledged to be Michael Shuler, a professor emeritus of chemical engineering at Cornell. In the 1980s, Shuler was a math and engineering guy who imagined an " animal on a chip ," a cell culture base seeded with a variety of human cells that could be used for testing drugs. He wanted to position a handful of different organ cells on the same chip, linked to one another, which could mimic the chemical communication between organs and the way drugs move through the body. “This was science fiction,” says Gordana Vunjak-Novakovic, a professor of biomedical engineering at Columbia University whose lab works with cardiac tissue on chips. “There was no body on a chip. There is still no body on a chip. God knows if there will ever be a body on a chip.”

Shuler had hoped to develop a computer model of a multi-organ system, but there were too many unknowns. The living cell culture system he dreamed up was his bid to fill in the blanks. For a while he played with the concept, but the materials simply weren’t good enough to build what he imagined. 

“You can force mice to menstruate, but it’s not really menstruation. You need the human being.” Linda Griffith, founding professor of biological engineering at MIT and a 2006 recipient of a MacArthur “genius grant”

He wasn’t the only one working on the problem. Linda Griffith, a founding professor of biological engineering at MIT and a 2006 recipient of a MacArthur “genius grant,” designed a crude early version of a liver chip in the late 1990s: a flat silicon chip, just a few hundred micrometers tall, with endothelial cells, oxygen and liquid flowing in and out via pumps, silicone tubing, and a polymer membrane with microscopic holes. She put liver cells from rats on the chip, and those cells organized themselves into three-dimensional tissue. It wasn’t a liver, but it modeled a few of the things a functioning human liver could do. It was a start.

Griffith, who rides a motorcycle for fun and speaks with a soft Southern accent, suffers from endometriosis, an inflammatory condition where cells from the lining of the uterus grow throughout the abdomen. She’s endured decades of nausea, pain, blood loss, and repeated surgeries. She never took medical leaves, instead loading up on Percocet, Advil, and margaritas, keeping a heating pad and couch in her office—a strategy of necessity, as she saw no other choice for a working scientist. Especially a woman. 

And as a scientist, Griffith understood that the chronic diseases affecting women tend to be under-researched , underfunded , and poorly treated. She realized that decades of work with animals hadn’t done a damn thing to make life better for women like her. “We’ve got all this data, but most of that data does not lead to treatments for human diseases,” she says. “You can force mice to menstruate, but it’s not really menstruation. You need the human being.” 

Or, at least, the human cells. Shuler and Griffith, and other scientists in Europe, worked on some of those early chips, but things really kicked off around 2009, when Don Ingber’s lab in Cambridge, Massachusetts, created the first fully functioning organ on a chip. That “lung on a chip” was made from flexible silicone rubber, lined with human lung cells and capillary blood vessel cells that “breathed” like the alveoli—tiny air sacs—in a human lung. A few years later Ingber, an MD-PhD with the tidy good looks of a younger Michael Douglas, founded Emulate, one of the earliest biotech companies making microphysiological systems. Since then he’s become a kind of unofficial ambassador for in vitro technologies in general and organs on chips in particular, giving hundreds of talks, scoring millions in grant money, repping the field with scientists and laypeople. Stephen Colbert once ragged on him after the New York Times quoted him as describing a chip that “walks, talks, and quacks like a human vagina,” a quote Ingber says was taken out of context.

Ingber began his career working on cancer. But he struggled with the required animal research. “I really didn’t want to work with them anymore, because I love animals,” he says. “It was a conscious decision to focus on in vitro models.” He’s not alone; a growing number of young scientists are speaking up about the distress they feel when research protocols cause pain, trauma, injury, and death to lab animals. “I’m a master’s degree student in neuroscience and I think about this constantly. I’ve done such unspeakable, horrible things to mice all in the name of scientific progress, and I feel guilty about this every day,” wrote one anonymous student on Reddit . (Full disclosure: I switched out of a psychology major in college because I didn’t want to cause harm to animals.)

Taking an undergraduate art class led Ingber to an epiphany: mechanical forces are just as important as chemicals and genes in determining the way living creatures work. On a shelf in his office he still displays a model he built in that art class, a simple construction of sticks and fishing line, which helped him realize that cells pull and twist against each other. That realization foreshadowed his current work and helped him design dynamic microfluidic devices that incorporated shear and flow. 

Ingber coauthored a 2022 paper that’s sometimes cited as a watershed in the world of organs on chips. Researchers used Emulate’s liver chips to reevaluate 27 drugs that had previously made it through animal testing and had then gone on to kill 242 people and necessitate more than 60 liver transplants. The liver chips correctly flagged problems with 22 of the 27 drugs, an 87% success rate compared with a 0% success rate for animal testing. It was the first time organs on chips had been directly pitted against animal models, and the results got a lot of attention from the pharmaceutical industry. Dan Tagle, director of the Office of Special Initiatives for the National Center for Advancing Translational Sciences (NCATS), estimates that drug failures cost around $2.6 billion globally each year. The earlier in the process failing compounds can be weeded out, the more room there is for other drugs to succeed.

“The capacity we have to test drugs is more or less fixed in this country,” says Shuler, whose company, Hesperos, also manufactures organs on chips. “There are only so many clinical trials you can do. So if you put a loser into the system, that means something that could have won didn’t get into the system. We want to change the success rate from clinical trials to a much higher number.”

In 2011, the National Institutes of Health established NCATS and started investing in organs on chips and other in vitro technologies. Other government funders, like the Defense Advanced Research Projects Agency and the Food and Drug Administration, have followed suit. For instance, NIH recently funded NASA scientists to send heart tissue on chips into space . Six months in low gravity ages the cardiovascular system 10 years, so this experiment lets researchers study some of the effects of aging without harming animals or humans. 

Scientists have made liver chips, brain chips, heart chips, kidney chips, intestine chips, and even a female reproductive system on a chip (with cells from ovaries, fallopian tubes, and uteruses that release hormones and mimic an actual 28-day menstrual cycle). Each of these chips exhibits some of the specific functions of the organs in question. Cardiac chips, for instance, contain heart cells that beat just like heart muscle, making it possible for researchers to model disorders like cardiomyopathy. 

Shuler thinks organs on chips will revolutionize the world of research for rare diseases. “It is a very good model when you don’t have enough patients for normal clinical trials and you don’t have a good animal model,” he says. “So it’s a way to get drugs to people that couldn’t be developed in our current pharmaceutical model.” Shuler’s own biotech company used organs on chips to test a potential drug for myasthenia gravis, a rare neurological disorder. In 2022,the FDA approved the drug for clinical trials based on that data—one of six Hesperos drugs that have so far made it to that stage. 

Each chip starts with a physiologically based pharmacokinetic model, known as a PBPK model—a mathematical expression of how a chemical compound behaves in a human body. “We try and build a physical replica of the mathematical model of what really occurs in the body,” explains Shuler. That model guides the way the chip is designed, re-creating the amount of time a fluid or chemical stays in that particular organ—what’s known as the residence time. “As long as you have the same residence time, you should get the same response in terms of chemical conversion,” he says.

Tiny channels on each chip, each between 10 and 100 microns in diameter, help bring fluids and oxygen to the cells. “When you get down to less than one micron, you can’t use normal fluid dynamics,” says Shuler. And fluid dynamics matters, because if the fluid moves through the device too quickly, the cells might die; too slowly, and the cells won’t react normally. 

Chip technology, while sophisticated, has some downsides. One of them is user friendliness. “We need to get rid of all this tubing and pumps and make something that’s as simple as a well plate for culturing cells,” says Vunjak-Novakovic. Her lab and others are working on simplifying the design and function of such chips so they’re easier to operate and are compatible with robots, which do repetitive tasks like pipetting in many labs. 

Cost and sourcing can also be challenging. Emulate’s base model, which looks like a simple rectangular box from the outside,starts at around $100,000 and rises steeply from there. Most human cells come from commercial suppliers that arrange for donations from hospital patients. During the pandemic, when people had fewer elective surgeries, many of those sources dried up. As microphysiological systems become more mainstream, finding reliable sources of human cells will be critical.

“As your confidence in using the chips grows, you might say, Okay, we don’t need two animals anymore— we could go with chip plus one animal.” Lorna Ewart, Chief Scientific Officer, Emulate

Another challenge is that every company producing organs on chips uses its own proprietary methods and technologies. Ingber compares the landscape to the early days of personal computing, when every company developed its own hardware and software, and none of them meshed well. For instance, the microfluidic systems in Emulate’s intestine chips are fueled by micropumps, while those made by Mimetas, another biotech company, use an electronic rocker and gravity to circulate fluids and air. “This is not an academic lab type of challenge,” emphasizes Ingber. “It’s a commercial challenge. There’s no way you can get the same results anywhere in the world with individual academics making [organs on chips], so you have to have commercialization.”

Namandje Bumpus, the FDA’s chief scientist, agrees. “You can find differences [in outcomes] depending even on what types of reagents you’re using,” she says. Those differences mean research can’t be easily reproduced, which diminishes its validity and usefulness. “It would be great to have some standardization,” she adds.

On the plus side, the chip technology could help researchers address some of the most deeply entrenched health inequities in science. Clinical trials have historically recruited white men, underrepresenting people of color, women (especially pregnant and lactating women), the elderly, and other groups. And treatments derived from those trials all too often fail in members of those underrepresented groups, as in Moore’s rotavirus vaccine mystery. “With organs on a chip, you may be able to create systems by which you are very, very thoughtful—where you spread the net wider than has ever been done before,” says Moore.

Another advantage is that chips will eventually reduce the need for animals in the lab even as they lead to better human outcomes. “There are aspects of animal research that make all of us uncomfortable, even people that do it,” acknowledges Moore. “The same values that make us uncomfortable about animal research are also the same values that make us uncomfortable with seeing human beings suffer with diseases that we don’t have cures for yet. So we always sort of balance that desire to reduce suffering in all the forms that we see it.”

Lorna Ewart, who spent 20 years at the pharma giant AstraZeneca before joining Emulate, thinks we’re entering a kind of transition time in research, in which scientists use in vitro technologies like organs on chips alongside traditional cell culture methods and animals. “As your confidence in using the chips grows, you might say, Okay, we don’t need two animals anymore—we could go with chip plus one animal,” she says. 

In the meantime, Sean Moore is excited about incorporating intestine chips more and more deeply into his research. His lab has been funded by the Gates Foundation to do what he laughingly describes as a bake-off between intestine chips made by Emulate and Mimetas. They’re infecting the chips with different strains of rotavirus to try to identify the pros and cons of each company’s design. It’s too early for any substantive results, but Moore says he does have data showing that organ chips are a viable model for studying rotavirus infection. That could ultimately be a real game-changer in his lab and in labs around the world.

“There’s more players in the space right now,” says Moore. “And that competition is going to be a healthy thing.” 

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How Science Went to the Dogs (and Cats)

Pets were once dismissed as trivial scientific subjects. Today, companion animal science is hot.

Max, a 2-year-old German shepherd, Belgian Malinois and husky mix, was photographed in Greenlake Park in Seattle this month. A stray who was rescued in an emaciated condition, Max is a participant in Darwin’s Ark, a community science initiative that investigates animal genetics and behavior. Credit... M. Scott Brauer for The New York Times

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By Emily Anthes

Emily Anthes, who has both a dog and a cat, has been writing about canine genetics since 2004.

• June 30, 2024

This article is part of our Pets special section on scientists’ growing interest in our animal companions.

Every dog has its day, and July 14, 2004, belonged to a boxer named Tasha. On that date, the National Institutes of Health announced that the barrel-chested, generously jowled canine had become the first dog to have her complete genome sequenced. “And everything has kind of exploded since then,” said Elaine Ostrander, a canine genomics expert at the National Human Genome Research Institute, who was part of the research team.

In the 20 years since, geneticists have fallen hard for our canine companions, sequencing thousands upon thousands of dogs, including pedigreed purebreds, mysterious mutts, highly trained working dogs, free-ranging village dogs and even ancient canine remains.

Research on canine cognition and behavior has taken off, too. “Now dog posters are taking up half of an animal behavior conference,” said Monique Udell, who directs the human-animal interaction lab at Oregon State University. “And we’re starting to see cat research following that same trend.”

Just a few decades ago, many researchers considered pets to be deeply unserious subjects. (“I didn’t want to study dogs,” said Alexandra Horowitz, who has since become a prominent researcher in the field of canine cognition.) Today, companion animals are absolutely in vogue. Scientists around the world are peering deep into the bodies and minds of cats and dogs, hoping to learn more about how they wriggled their way into our lives, how they experience the world and how to keep them living in it longer. It’s a shift that some experts say is long overdue.

“We have a responsibility to deeply understand these animals if we’re going to live with them,” Dr. Udell said. “We also have this great potential to learn a lot about them and a lot about ourselves in the process.”

Pet projects

For geneticists, dogs and cats are both rich subjects , given their long, close history with humans and their susceptibility to many of the same diseases, from cancer to diabetes.

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The Flaws and Human Harms of Animal Experimentation

Nonhuman animal (“animal”) experimentation is typically defended by arguments that it is reliable, that animals provide sufficiently good models of human biology and diseases to yield relevant information, and that, consequently, its use provides major human health benefits. I demonstrate that a growing body of scientific literature critically assessing the validity of animal experimentation generally (and animal modeling specifically) raises important concerns about its reliability and predictive value for human outcomes and for understanding human physiology. The unreliability of animal experimentation across a wide range of areas undermines scientific arguments in favor of the practice. Additionally, I show how animal experimentation often significantly harms humans through misleading safety studies, potential abandonment of effective therapeutics, and direction of resources away from more effective testing methods. The resulting evidence suggests that the collective harms and costs to humans from animal experimentation outweigh potential benefits and that resources would be better invested in developing human-based testing methods.

Introduction

Annually, more than 115 million animals are used worldwide in experimentation or to supply the biomedical industry. 1 Nonhuman animal (hereafter “animal”) experimentation falls under two categories: basic (i.e., investigation of basic biology and human disease) and applied (i.e., drug research and development and toxicity and safety testing). Regardless of its categorization, animal experimentation is intended to inform human biology and health sciences and to promote the safety and efficacy of potential treatments. Despite its use of immense resources, the animal suffering involved, and its impact on human health, the question of animal experimentation’s efficacy has been subjected to little systematic scrutiny. 2

Although it is widely accepted that medicine should be evidence based , animal experimentation as a means of informing human health has generally not been held, in practice, to this standard. This fact makes it surprising that animal experimentation is typically viewed as the default and gold standard of preclinical testing and is generally supported without critical examination of its validity. A survey published in 2008 of anecdotal cases and statements given in support of animal experimentation demonstrates how it has not and could not be validated as a necessary step in biomedical research, and the survey casts doubt on its predictive value. 3 I show that animal experimentation is poorly predictive of human outcomes, 4 that it is unreliable across a wide category of disease areas, 5 and that existing literature demonstrates the unreliability of animal experimentation, thereby undermining scientific arguments in its favor. I further show that the collective harms that result from an unreliable practice tip the ethical scale of harms and benefits against continuation in much, if not all, of experimentation involving animals. 6

Problems of Successful Translation to Humans of Data from Animal Experimentation

Although the unreliability and limitations of animal experimentation have increasingly been acknowledged, there remains a general confidence within much of the biomedical community that they can be overcome. 7 However, three major conditions undermine this confidence and explain why animal experimentation, regardless of the disease category studied, fails to reliably inform human health: (1) the effects of the laboratory environment and other variables on study outcomes, (2) disparities between animal models of disease and human diseases, and (3) species differences in physiology and genetics. I argue for the critical importance of each of these conditions.

The Influence of Laboratory Procedures and Environments on Experimental Results

Laboratory procedures and conditions exert influences on animals’ physiology and behaviors that are difficult to control and that can ultimately impact research outcomes. Animals in laboratories are involuntarily placed in artificial environments, usually in windowless rooms, for the duration of their lives. Captivity and the common features of biomedical laboratories—such as artificial lighting, human-produced noises, and restricted housing environments—can prevent species-typical behaviors, causing distress and abnormal behaviors among animals. 8 Among the types of laboratory-generated distress is the phenomenon of contagious anxiety. 9 Cortisone levels rise in monkeys watching other monkeys being restrained for blood collection. 10 Blood pressure and heart rates elevate in rats watching other rats being decapitated. 11 Routine laboratory procedures, such as catching an animal and removing him or her from the cage, in addition to the experimental procedures, cause significant and prolonged elevations in animals’ stress markers. 12 These stress-related changes in physiological parameters caused by the laboratory procedures and environments can have significant effects on test results. 13 Stressed rats, for example, develop chronic inflammatory conditions and intestinal leakage, which add variables that can confound data. 14

A variety of conditions in the laboratory cause changes in neurochemistry, genetic expression, and nerve regeneration. 15 In one study, for example, mice were genetically altered to develop aortic defects. Yet, when the mice were housed in larger cages, those defects almost completely disappeared. 16 Providing further examples, typical noise levels in laboratories can damage blood vessels in animals, and even the type of flooring on which animals are tested in spinal cord injury experiments can affect whether a drug shows a benefit. 17

In order to control for potential confounders, some investigators have called for standardization of laboratory settings and procedures. 18 One notable effort was made by Crabbe et al. in their investigation of the potential confounding influences of the laboratory environment on six mouse behaviors that are commonly studied in neurobehavioral experiments. Despite their “extraordinary lengths to equate test apparatus, testing protocols, and all possible features of animal husbandry” across three laboratories, there were systematic differences in test results in these labs. 19 Additionally, different mouse strains varied markedly in all behavioral tests, and for some tests the magnitude of genetic differences depended on the specific testing laboratory. The results suggest that there are important influences of environmental conditions and procedures specific to individual laboratories that can be difficult—perhaps even impossible—to eliminate. These influences can confound research results and impede extrapolation to humans.

The Discordance between Human Diseases and Animal Models of Diseases

The lack of sufficient congruence between animal models and human diseases is another significant obstacle to translational reliability. Human diseases are typically artificially induced in animals, but the enormous difficulty of reproducing anything approaching the complexity of human diseases in animal models limits their usefulness. 20 Even if the design and conduct of an animal experiment are sound and standardized, the translation of its results to the clinic may fail because of disparities between the animal experimental model and the human condition. 21

Stroke research presents one salient example of the difficulties in modeling human diseases in animals. Stroke is relatively well understood in its underlying pathology. Yet accurately modeling the disease in animals has proven to be an exercise in futility. To address the inability to replicate human stroke in animals, many assert the need to use more standardized animal study design protocols. This includes the use of animals who represent both genders and wide age ranges, who have comorbidities and preexisting conditions that occur naturally in humans, and who are consequently given medications that are indicated for human patients. 22 In fact, a set of guidelines, named STAIR, was implemented by a stroke roundtable in 1999 (and updated in 2009) to standardize protocols, limit the discrepancies, and improve the applicability of animal stroke experiments to humans. 23 One of the most promising stroke treatments later to emerge was NXY-059, which proved effective in animal experiments. However, the drug failed in clinical trials, despite the fact that the set of animal experiments on this drug was considered the poster child for the new experimental standards. 24 Despite such vigorous efforts, the development of STAIR and other criteria has yet to make a recognizable impact in clinical translation. 25

Under closer scrutiny, it is not difficult to surmise why animal stroke experiments fail to successfully translate to humans even with new guidelines. Standard stroke medications will likely affect different species differently. There is little evidence to suggest that a female rat, dog, or monkey sufficiently reproduces the physiology of a human female. Perhaps most importantly, reproducing the preexisting conditions of stroke in animals proves just as difficult as reproducing stroke pathology and outcomes. For example, most animals don’t naturally develop significant atherosclerosis, a leading contributor to ischemic stroke. In order to reproduce the effects of atherosclerosis in animals, researchers clamp their blood vessels or artificially insert blood clots. These interventions, however, do not replicate the elaborate pathology of atherosclerosis and its underlying causes. Reproducing human diseases in animals requires reproducing the predisposing diseases, also a formidable challenge. The inability to reproduce the disease in animals so that it is congruent in relevant respects with human stroke has contributed to a high failure rate in drug development. More than 114 potential therapies initially tested in animals failed in human trials. 26

Further examples of repeated failures based on animal models include drug development in cancer, amyotrophic lateral sclerosis (ALS), traumatic brain injury (TBI), Alzheimer’s disease (AD), and inflammatory conditions. Animal cancer models in which tumors are artificially induced have been the basic translational model used to study key physiological and biochemical properties in cancer onset and propagation and to evaluate novel treatments. Nevertheless, significant limitations exist in the models’ ability to faithfully mirror the complex process of human carcinogenesis. 27 These limitations are evidenced by the high (among the highest of any disease category) clinical failure rate of cancer drugs. 28 Analyses of common mice ALS models demonstrate significant differences from human ALS. 29 The inability of animal ALS models to predict beneficial effects in humans with ALS is recognized. 30 More than twenty drugs have failed in clinical trials, and the only U.S. Food and Drug Administration (FDA)–approved drug to treat ALS is Riluzole, which shows notably marginal benefit on patient survival. 31 Animal models have also been unable to reproduce the complexities of human TBI. 32 In 2010, Maas et al. reported on 27 large Phase 3 clinical trials and 6 unpublished trials in TBI that all failed to show human benefit after showing benefit in animals. 33 Additionally, even after success in animals, around 172 and 150 drug development failures have been identified in the treatment of human AD 34 and inflammatory diseases, 35 respectively.

The high clinical failure rate in drug development across all disease categories is based, at least in part, on the inability to adequately model human diseases in animals and the poor predictability of animal models. 36 A notable systematic review, published in 2007, compared animal experimentation results with clinical trial findings across interventions aimed at the treatment of head injury, respiratory distress syndrome, osteoporosis, stroke, and hemorrhage. 37 The study found that the human and animal results were in accordance only half of the time. In other words, the animal experiments were no more likely than a flip of the coin to predict whether those interventions would benefit humans.

In 2004, the FDA estimated that 92 percent of drugs that pass preclinical tests, including “pivotal” animal tests, fail to proceed to the market. 38 More recent analysis suggests that, despite efforts to improve the predictability of animal testing, the failure rate has actually increased and is now closer to 96 percent. 39 The main causes of failure are lack of effectiveness and safety problems that were not predicted by animal tests. 40

Usually, when an animal model is found wanting, various reasons are proffered to explain what went wrong—poor methodology, publication bias, lack of preexisting disease and medications, wrong gender or age, and so on. These factors certainly require consideration, and recognition of each potential difference between the animal model and the human disease motivates renewed efforts to eliminate these differences. As a result, scientific progress is sometimes made by such efforts. However, the high failure rate in drug testing and development, despite attempts to improve animal testing, suggests that these efforts remain insufficient to overcome the obstacles to successful translation that are inherent to the use of animals. Too often ignored is the well-substantiated idea that these models are, for reasons summarized here, intrinsically lacking in relevance to, and thus highly unlikely to yield useful information about, human diseases. 41

Interspecies Differences in Physiology and Genetics

Ultimately, even if considerable congruence were shown between an animal model and its corresponding human disease, interspecies differences in physiology, behavior, pharmacokinetics, and genetics would significantly limit the reliability of animal studies, even after a substantial investment to improve such studies. In spinal cord injury, for example, drug testing results vary according to which species and even which strain within a species is used, because of numerous interspecies and interstrain differences in neurophysiology, anatomy, and behavior. 42 The micropathology of spinal cord injury, injury repair mechanisms, and recovery from injury varies greatly among different strains of rats and mice. A systematic review found that even among the most standardized and methodologically superior animal experiments, testing results assessing the effectiveness of methylprednisolone for spinal cord injury treatment varied considerably among species. 43 This suggests that factors inherent to the use of animals account for some of the major differences in results.

Even rats from the same strain but purchased from different suppliers produce different test results. 44 In one study, responses to 12 different behavioral measures of pain sensitivity, which are important markers of spinal cord injury, varied among 11 strains of mice, with no clear-cut patterns that allowed prediction of how each strain would respond. 45 These differences influenced how the animals responded to the injury and to experimental therapies. A drug might be shown to help one strain of mice recover but not another. Despite decades of using animal models, not a single neuroprotective agent that ameliorated spinal cord injury in animal tests has proven efficacious in clinical trials to date. 46

Further exemplifying the importance of physiological differences among species, a 2013 study reported that the mouse models used extensively to study human inflammatory diseases (in sepsis, burns, infection, and trauma) have been misleading. The study found that mice differ greatly from humans in their responses to inflammatory conditions. Mice differed from humans in what genes were turned on and off and in the timing and duration of gene expression. The mouse models even differed from one another in their responses. The investigators concluded that “our study supports higher priority to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory disease.” 47 The different genetic responses between mice and humans are likely responsible, at least in part, for the high drug failure rate. The authors stated that every one of almost 150 clinical trials that tested candidate agents’ ability to block inflammatory responses in critically ill patients failed.

Wide differences have also become apparent in the regulation of the same genes, a point that is readily seen when observing differences between human and mouse livers. 48 Consistent phenotypes (observable physical or biochemical characteristics) are rarely obtained by modification of the same gene, even among different strains of mice. 49 Gene regulation can substantially differ among species and may be as important as the presence or absence of a specific gene. Despite the high degree of genome conservation, there are critical differences in the order and function of genes among species. To use an analogy: as pianos have the same keys, humans and other animals share (largely) the same genes. Where we mostly differ is in the way the genes or keys are expressed. For example, if we play the keys in a certain order, we hear Chopin; in a different order, we hear Ray Charles; and in yet a different order, it’s Jerry Lee Lewis. In other words, the same keys or genes are expressed, but their different orders result in markedly different outcomes.

Recognizing the inherent genetic differences among species as a barrier to translation, researches have expressed considerable enthusiasm for genetically modified (GM) animals, including transgenic mice models, wherein human genes are inserted into the mouse genome. However, if a human gene is expressed in mice, it will likely function differently from the way it functions in humans, being affected by physiological mechanisms that are unique in mice. For example, a crucial protein that controls blood sugar in humans is missing in mice. 50 When the human gene that makes this protein was expressed in genetically altered mice, it had the opposite effect from that in humans: it caused loss of blood sugar control in mice. Use of GM mice has failed to successfully model human diseases and to translate into clinical benefit across many disease categories. 51 Perhaps the primary reason why GM animals are unlikely to be much more successful than other animal models in translational medicine is the fact that the “humanized” or altered genes are still in nonhuman animals.

In many instances, nonhuman primates (NHPs) are used instead of mice or other animals, with the expectation that NHPs will better mimic human results. However, there have been sufficient failures in translation to undermine this optimism. For example, NHP models have failed to reproduce key features of Parkinson’s disease, both in function and in pathology. 52 Several therapies that appeared promising in both NHPs and rat models of Parkinson’s disease showed disappointing results in humans. 53 The campaign to prescribe hormone replacement therapy (HRT) in millions of women to prevent cardiovascular disease was based in large part on experiments on NHPs. HRT is now known to increase the risk of these diseases in women. 54

HIV/AIDS vaccine research using NHPs represents one of the most notable failures in animal experimentation translation. Immense resources and decades of time have been devoted to creating NHP (including chimpanzee) models of HIV. Yet all of about 90 HIV vaccines that succeeded in animals failed in humans. 55 After HIV vaccine gp120 failed in clinical trials, despite positive outcomes in chimpanzees, a BMJ article commented that important differences between NHPs and humans with HIV misled researchers, taking them down unproductive experimental paths. 56 Gp120 failed to neutralize HIV grown and tested in cell culture. However, because the serum protected chimpanzees from HIV infection, two Phase 3 clinical trials were undertaken 57 —a clear example of how expectations that NHP data are more predictive than data from other (in this case, cell culture) testing methods are unproductive and harmful. Despite the repeated failures, NHPs (though not chimpanzees or other great apes) remain widely used for HIV research.

The implicit assumption that NHP (and indeed any animal) data are reliable has also led to significant and unjustifiable human suffering. For example, clinical trial volunteers for gp120 were placed at unnecessary risk of harm because of unfounded confidence in NHP experiments. Two landmark studies involving thousands of menopausal women being treated with HRT were terminated early because of increased stroke and breast cancer risk. 58 In 2003, Elan Pharmaceuticals was forced to prematurely terminate a Phase 2 clinical trial when an investigational AD vaccine was found to cause brain swelling in human subjects. No significant adverse effects were detected in GM mice or NHPs. 59

In another example of human suffering resulting from animal experimentation, six human volunteers were injected with an immunomodulatory drug, TGN 1412, in 2006. 60 Within minutes of receiving the experimental drug, all volunteers suffered a severe adverse reaction resulting from a life-threatening cytokine storm that led to catastrophic systemic organ failure. The compound was designed to dampen the immune system, but it had the opposite effect in humans. Prior to this first human trial, TGN 1412 was tested in mice, rabbits, rats, and NHPs with no ill effects. NHPs also underwent repeat-dose toxicity studies and were given 500 times the human dose for at least four consecutive weeks. 61 None of the NHPs manifested the ill effects that humans showed almost immediately after receiving minute amounts of the test drug. Cynomolgus and rhesus monkeys were specifically chosen because their CD28 receptors demonstrated similar affinity to TGN 1412 as human CD28 receptors. Based on such data as these, it was confidently concluded that results obtained from these NHPs would most reliably predict drug responses in humans—a conclusion that proved devastatingly wrong.

As exemplified by the study of HIV/AIDS, TGN 1412, and other experiences, 62 experiments with NHPs are not necessarily any more predictive of human responses than experiments with other animals. The repeated failures in translation from studies with NHPs belie arguments favoring use of any nonhuman species to study human physiology and diseases and to test potential treatments. If experimentation using chimpanzees and other NHPs, our closest genetic cousins, are unreliable, how can we expect research using other animals to be reliable? The bottom line is that animal experiments, no matter the species used or the type of disease research undertaken, are highly unreliable—and they have too little predictive value to justify the resultant risks of harms for humans, for reasons I now explain.

The Collective Harms That Result from Misleading Animal Experiments

As medical research has explored the complexities and subtle nuances of biological systems, problems have arisen because the differences among species along these subtler biological dimensions far outweigh the similarities , as a growing body of evidence attests. These profoundly important—and often undetected—differences are likely one of the main reasons human clinical trials fail. 63

“Appreciation of differences” and “caution” about extrapolating results from animals to humans are now almost universally recommended. But, in practice, how does one take into account differences in drug metabolism, genetics, expression of diseases, anatomy, influences of laboratory environments, and species- and strain-specific physiologic mechanisms—and, in view of these differences, discern what is applicable to humans and what is not? If we cannot determine which physiological mechanisms in which species and strains of species are applicable to humans (even setting aside the complicating factors of different caging systems and types of flooring), the usefulness of the experiments must be questioned.

It has been argued that some information obtained from animal experiments is better than no information. 64 This thesis neglects how misleading information can be worse than no information from animal tests. The use of nonpredictive animal experiments can cause human suffering in at least two ways: (1) by producing misleading safety and efficacy data and (2) by causing potential abandonment of useful medical treatments and misdirecting resources away from more effective testing methods.

Humans are harmed because of misleading animal testing results. Imprecise results from animal experiments may result in clinical trials of biologically faulty or even harmful substances, thereby exposing patients to unnecessary risk and wasting scarce research resources. 65 Animal toxicity studies are poor predictors of toxic effects of drugs in humans. 66 As seen in some of the preceding examples (in particular, stroke, HRT, and TGN1412), humans have been significantly harmed because investigators were misled by the safety and efficacy profile of a new drug based on animal experiments. 67 Clinical trial volunteers are thus provided with raised hopes and a false sense of security because of a misguided confidence in efficacy and safety testing using animals.

An equal if indirect source of human suffering is the opportunity cost of abandoning promising drugs because of misleading animal tests. 68 As candidate drugs generally proceed down the development pipeline and to human testing based largely on successful results in animals 69 (i.e., positive efficacy and negative adverse effects), drugs are sometimes not further developed due to unsuccessful results in animals (i.e., negative efficacy and/or positive adverse effects). Because much pharmaceutical company preclinical data are proprietary and thus publicly unavailable, it is difficult to know the number of missed opportunities due to misleading animal experiments. However, of every 5,000–10,000 potential drugs investigated, only about 5 proceed to Phase 1 clinical trials. 70 Potential therapeutics may be abandoned because of results in animal tests that do not apply to humans. 71 Treatments that fail to work or show some adverse effect in animals because of species-specific influences may be abandoned in preclinical testing even if they may have proved effective and safe in humans if allowed to continue through the drug development pipeline.

An editorial in Nature Reviews Drug Discovery describes cases involving two drugs in which animal test results from species-specific influences could have derailed their development. In particular, it describes how tamoxifen, one of the most effective drugs for certain types of breast cancer, “would most certainly have been withdrawn from the pipeline” if its propensity to cause liver tumor in rats had been discovered in preclinical testing rather than after the drug had been on the market for years. 72 Gleevec provides another example of effective drugs that could have been abandoned based on misleading animal tests: this drug, which is used to treat chronic myelogenous leukemia (CML), showed serious adverse effects in at least five species tested, including severe liver damage in dogs. However, liver toxicity was not detected in human cell assays, and clinical trials proceeded, which confirmed the absence of significant liver toxicity in humans. 73 Fortunately for CML patients, Gleevec is a success story of predictive human-based testing. Many useful drugs that have safely been used by humans for decades, such as aspirin and penicillin, may not have been available today if the current animal testing regulatory requirements were in practice during their development. 74

A further example of near-missed opportunities is provided by experiments on animals that delayed the acceptance of cyclosporine, a drug widely and successfully used to treat autoimmune disorders and prevent organ transplant rejection. 75 Its immunosuppressive effects differed so markedly among species that researchers judged that the animal results limited any direct inferences that could be made to humans. Providing further examples, PharmaInformatic released a report describing how several blockbuster drugs, including aripiprazole (Abilify) and esomeprazole (Nexium), showed low oral bioavailability in animals. They would likely not be available on the market today if animal tests were solely relied on. Understanding the implications of its findings for drug development in general, PharmaInformatic asked, “Which other blockbuster drugs would be on the market today, if animal trials would have not been used to preselect compounds and drug-candidates for further development?” 76 These near-missed opportunities and the overall 96 percent failure rate in clinical drug testing strongly suggest the unsoundness of animal testing as a precondition of human clinical trials and provide powerful evidence for the need for a new, human-based paradigm in medical research and drug development.

In addition to potentially causing abandonment of useful treatments, use of an invalid animal disease model can lead researchers and the industry in the wrong research direction, wasting time and significant investment. 77 Repeatedly, researchers have been lured down the wrong line of investigation because of information gleaned from animal experiments that later proved to be inaccurate, irrelevant, or discordant with human biology. Some claim that we do not know which benefits animal experiments, particularly in basic research, may provide down the road. Yet human lives remain in the balance, waiting for effective therapies. Funding must be strategically invested in the research areas that offer the most promise.

The opportunity costs of continuing to fund unreliable animal tests may impede development of more accurate testing methods. Human organs grown in the lab, human organs on a chip, cognitive computing technologies, 3D printing of human living tissues, and the Human Toxome Project are examples of new human-based technologies that are garnering widespread enthusiasm. The benefit of using these testing methods in the preclinical setting over animal experiments is that they are based on human biology. Thus their use eliminates much of the guesswork required when attempting to extrapolate physiological data from other species to humans. Additionally, these tests offer whole-systems biology, in contrast to traditional in vitro techniques. Although they are gaining momentum, these human-based tests are still in their relative infancy, and funding must be prioritized for their further development. The recent advancements made in the development of more predictive, human-based systems and biological approaches in chemical toxicological testing are an example of how newer and improved tests have been developed because of a shift in prioritization. 78 Apart from toxicology, though, financial investment in the development of human-based technologies generally falls far short of investment in animal experimentation. 79

The unreliability of applying animal experimental results to human biology and diseases is increasingly recognized. Animals are in many respects biologically and psychologically similar to humans, perhaps most notably in the shared characteristics of pain, fear, and suffering. 80 In contrast, evidence demonstrates that critically important physiological and genetic differences between humans and other animals can invalidate the use of animals to study human diseases, treatments, pharmaceuticals, and the like. In significant measure, animal models specifically, and animal experimentation generally, are inadequate bases for predicting clinical outcomes in human beings in the great bulk of biomedical science. As a result, humans can be subject to significant and avoidable harm.

The data showing the unreliability of animal experimentation and the resultant harms to humans (and nonhumans) undermine long-standing claims that animal experimentation is necessary to enhance human health and therefore ethically justified. Rather, they demonstrate that animal experimentation poses significant costs and harms to human beings. It is possible—as I have argued elsewhere—that animal research is more costly and harmful, on the whole, than it is beneficial to human health. 81 When considering the ethical justifiability of animal experiments, we should ask if it is ethically acceptable to deprive humans of resources, opportunity, hope, and even their lives by seeking answers in what may be the wrong place. In my view, it would be better to direct resources away from animal experimentation and into developing more accurate, human-based technologies.

Aysha Akhtar , M.D., M.P.H., is a neurologist and preventive medicine specialist and Fellow at the Oxford Centre for Animal Ethics, Oxford, United Kingdom.

1. Taylor K, Gordon N, Langley G, Higgins W. Estimates for worldwide laboratory animal use in 2005 . Alternatives to Laboratory Animals 2008; 36 :327–42. [ PubMed ] [ Google Scholar ]

2. Systematic reviews that have been conducted generally reveal the unreliability and poor predictability of animal tests. See Perel P, Roberts I, Sena E, Wheble P, Briscoe C, Sandercock P, et al. Comparison of treatment effects between animal experiments and clinical trials: Systematic review. BMJ 2007;334:197. See also Pound P, Bracken MB. Is animal research sufficiently evidence based to be a cornerstone of biomedical research? BMJ 2014;348:g3387. See Godlee F. How predictive and productive is animal research? BMJ 2014;348:g3719. See Benatar M. Lost in translation: Treatment trials in the SOD 1 mouse and in human ALS. Neurobiology Disease 2007; 26 :1–13 [ PubMed ] [ Google Scholar ] . And see Akhtar AZ, Pippin JJ, Sandusky CB. Animal studies in spinal cord injury: A systematic review of methylprednisolone . Alternatives to Laboratory Animals 2009; 37 :43–62. [ PubMed ] [ Google Scholar ]

3. Mathews RAJ. Medical progress depends on animal models—doesn’t it? Journal of the Royal Society of Medicine 2008; 101 :95–8. [ PMC free article ] [ PubMed ] [ Google Scholar ]

4. See Shanks N, Greek R, Greek J. Are animal models predictive for humans? Philosophy, Ethics, and Humanities in Medicine 2009; 4 :2 [ PMC free article ] [ PubMed ] [ Google Scholar ] . See also Wall RJ, Shani M. Are animal models as good as we think? Theriogenology 2008; 69 :2–9. [ PubMed ] [ Google Scholar ]

5. See note 3, Mathews 2008. See also Hartung T, Zurlo J. Food for thought… alternative approaches for medical countermeasures to biological and chemical terrorism and warfare . ALTEX 2012; 29 :251–60 [ PubMed ] [ Google Scholar ] . See Leist M, Hartung T. Inflammatory findings on species extrapolations: Humans are definitely no 70-kg mice . Archives in Toxicology 2013; 87 :563–7 [ PMC free article ] [ PubMed ] [ Google Scholar ] . See Mak IWY, Evaniew N, Ghert M. Lost in translation: Animal models and clinical trials in cancer treatment . American Journal in Translational Research 2014; 6 :114–18 [ PMC free article ] [ PubMed ] [ Google Scholar ] . And see Pippin J. Animal research in medical sciences: Seeking a convergence of science, medicine, and animal law . South Texas Law Review 2013; 54 :469–511. [ Google Scholar ]

6. For an overview of the harms-versus-benefits argument, see LaFollette H. Animal experimentation in biomedical research In: Beauchamp TL, Frey RG, eds. The Oxford Handbook of Animal Ethics . Oxford: Oxford University Press; 2011:812–18. [ Google Scholar ]

7. See Jucker M. The benefits and limitations of animal models for translational research in neurodegenerative diseases . Nature Medicine 2010; 16 :1210–14 [ PubMed ] [ Google Scholar ] . See Institute of Medicine. Improving the Utility and Translation of Animal Models for Nervous System Disorders: Workshop Summary. Washington, DC: The National Academies Press; 2013. And see Degryse AL, Lawson WE. Progress towards improving animal models for IPF . American Journal of Medical Science 2011; 341 :444–9. [ PMC free article ] [ PubMed ] [ Google Scholar ]

8. See Morgan KN, Tromborg CT. Sources of stress in captivity . Applied Animal Behaviour Science 2007; 102 :262–302 [ Google Scholar ] . See Hart PC, Bergner CL, Dufour BD, Smolinsky AN, Egan RJ, LaPorte L, et al. Analysis of abnormal repetitive behaviors in experimental animal models In Warrick JE, Kauleff AV, eds. Translational Neuroscience and Its Advancement of Animal Research Ethics . New York: Nova Science; 2009:71–82 [ Google Scholar ] . See Lutz C, Well A, Novak M. Stereotypic and self-injurious behavior in rhesus macaques: A survey and retrospective analysis of environment and early experience . American Journal of Primatology 2003; 60 :1–15 [ PubMed ] [ Google Scholar ] . And see Balcombe JP, Barnard ND, Sandusky C. Laboratory routines cause animal stress . Contemporary Topics in Laboratory Animal Science 2004; 43 :42–51. [ PubMed ] [ Google Scholar ]

9. Suckow MA, Weisbroth SH, Franklin CL. The Laboratory Rat . 2nd ed. Burlington, MA: Elsevier Academic Press; 2006, at 323.

10. Flow BL, Jaques JT. Effect of room arrangement and blood sample collection sequence on serum thyroid hormone and cortisol concentrations in cynomolgus macaques ( Macaca fascicularis ). Contemporary Topics in Laboratory Animal Science 1997;36:65–8.

11. See note 8, Balcombe et al. 2004.

12. See note 8, Balcombe et al. 2004.

13. Baldwin A, Bekoff M. Too stressed to work. New Scientist 2007;194:24.

14. See note 13, Baldwin, Bekoff 2007.

15. Akhtar A, Pippin JJ, Sandusky CB. Animal models in spinal cord injury: A review . Reviews in the Neurosciences 2008; 19 :47–60. [ PubMed ] [ Google Scholar ]

16. See note 13, Baldwin, Bekoff 2007.

17. See note 15, Akhtar et al. 2008.

18. See Macleod MR, O’Collins T, Howells DW, Donnan GA. Pooling of animal experimental data reveals influence of study design and publication bias . Stroke 2004; 35 :1203–8 [ PubMed ] [ Google Scholar ] . See also O’ Neil BJ, Kline JA, Burkhart K, Younger J. Research fundamentals: V. The use of laboratory animal models in research. Academic Emergency Medicine 1999;6:75–82.

19. Crabbe JC, Wahlsten D, Dudek BC. Genetics of mouse behavior: Interactions with laboratory environment . Science 1999; 284 :1670–2, at 1670. [ PubMed ] [ Google Scholar ]

20. See Curry SH. Why have so many drugs with stellar results in laboratory stroke models failed in clinical trials? A theory based on allometric relationships. Annals of the New York Academy of Sciences 2003;993:69–74. See also Dirnagl U. Bench to bedside: The quest for quality in experimental stroke research . Journal of Cerebral Blood Flow & Metabolism 2006; 26 :1465–78 [ PubMed ] [ Google Scholar ] .

21. van der Worp HB, Howells DW, Sena ES, Poritt MJ, Rewell S, O’Collins V, et al. Can animal models of disease reliably inform human studies? PLoS Medicine 2010; 7 :e1000245. [ PMC free article ] [ PubMed ] [ Google Scholar ] .

22. See note 20, Dirnagl 2006. See also Sena E, van der Worp B, Howells D, Macleod M. How can we improve the pre-clinical development of drugs for stroke? Trends in Neurosciences 2007; 30 :433–9. [ PubMed ] [ Google Scholar ]

23. See Gawrylewski A. The trouble with animal models: Why did human trials fail? The Scientist 2007;21:44. See also Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, et al. Update of the stroke therapy academic industry roundtable preclinical recommendations . Stroke 2009; 40 :2244–50. [ PMC free article ] [ PubMed ] [ Google Scholar ]

24. See note 23, Gawrylewski 2007. There is some dispute as to how vigorously investigators adhered to the suggested criteria. Nevertheless, NXY-059 animal studies were considered an example of preclinical studies that most faithfully adhered to the STAIR criteria. For further discussion see also Wang MM, Guohua X, Keep RF. Should the STAIR criteria be modified for preconditioning studies? Translational Stroke Research 2013; 4 :3–14 [ PMC free article ] [ PubMed ] [ Google Scholar ] .

25. See note 24, Wang et al. 2013.

26. O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke . Annals of Neurology 2006; 59 :467–7 [ PubMed ] [ Google Scholar ] .

27. See note 5, Mak et al. 2014.

28. See note 5, Mak et al. 2014.

29. See Perrin S. Preclinical research: Make mouse studies work . Nature 2014; 507 :423–5 [ PubMed ] [ Google Scholar ] . See also, generally, Wilkins HM, Bouchard RJ, Lorenzon NM, Linseman DA. Poor correlation between drug efficacies in the mutant SOD1 mouse mode versus clinical trials of ALS necessitates the development of novel animal models for sporadic motor neuron disease. In: Costa A, Villalba E, eds. Horizons in Neuroscience Research. Vol. 5. Hauppauge, NY: Nova Science; 2011:1–39.

30. Traynor BJ, Bruijn L, Conwit R, Beal F, O’Neill G, Fagan SC, et al. Neuroprotective agents for clinical trials in ALS: A systematic assessment . Neurology 2006; 67 :20–7 [ PubMed ] [ Google Scholar ] .

31. Sinha G. Another blow for ALS . Nature Biotechnology 2013; 31 :185 [ Google Scholar ] . See also note 30, Traynor et al. 2006.

32. See Morales DM, Marklund N, Lebold D, Thompson HJ, Pitkanen A, Maxwell WL, et al. Experimental models of traumatic brain injury: Do we really need a better mousetrap? Neuroscience 2005; 136 :971–89 [ PubMed ] [ Google Scholar ] . See also Xiong YE, Mahmood A, Chopp M. Animal models of traumatic brain injury . Nature Reviews Neuroscience 2013; 14 :128–42 [ PMC free article ] [ PubMed ] [ Google Scholar ] . And see commentary by Farber: Farber N. Drug development in brain injury. International Brain Injury Association ; available at http://www.internationalbrain.org/articles/drug-development-in-traumatic-brain-injury/ (last accessed 7 Dec 2014).

33. Maas AI, Roozenbeek B, Manley GT. Clinical trials in traumatic brain injury: Past experience and current developments . Neurotherapeutics 2010; 7 :115–26. [ PMC free article ] [ PubMed ] [ Google Scholar ]

34. Schneider LS, Mangialasche F, Andreasen N, Feldman H, Giacobini E, Jones R, et al. Clinical trials and late-stage drug development in Alzheimer’s disease: An appraisal from 1984 to 2014 . Journal of Internal Medicine 2014; 275 :251–83 [ PMC free article ] [ PubMed ] [ Google Scholar ] .

35. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV, Xu W, et al. Genomic responses in mouse models poorly mimic human inflammatory diseases . Proceedings of the National Academy of Sciences USA 2013; 110 :3507–12. [ PMC free article ] [ PubMed ] [ Google Scholar ]

36. Palfreyman MG, Charles V, Blander J. The importance of using human-based models in gene and drug discovery . Drug Discovery World 2002. Fall:33–40 [ Google Scholar ] .

37. See note 2, Perel et al. 2007.

38. Harding A. More compounds failing phase I. The Scientist 2004 Sept 13; available at http://www.the-scientist.com/?articles.view/articleNo/23003/title/More-compounds-failing-Phase-I/ (last accessed 2 June 2014).

39. See note 5, Pippin 2013.

40. See note 5, Hartung, Zurlo 2012.

41. Wiebers DO, Adams HP, Whisnant JP. Animal models of stroke: Are they relevant to human disease? Stroke 1990; 21 :1–3. [ PubMed ] [ Google Scholar ]

42. See note 15, Akhtar et al. 2008.

43. See note 2, Akhtar et al. 2009.

44. Lonjon N, Prieto M, Haton H, Brøchner CB, Bauchet L, Costalat V, et al. Minimum information about animal experiments: Supplier is also important . Journal of Neuroscience Research 2009; 87 :403–7. [ PubMed ] [ Google Scholar ]

45. Mogil JS, Wilson SG, Bon K, Lee SE, Chung K, Raber P, et al. Heritability of nociception I: Responses of 11 inbred mouse strains on 12 measures of nociception . Pain 1999; 80 :67–82. [ PubMed ] [ Google Scholar ]

46. Tator H, Hashimoto R, Raich A, Norvell D, Fehling MG, Harrop JS, et al. Translational potential of preclinical trials of neuroprotection through pharmacotherapy for spinal cord injury . Journal of Neurosurgery: Spine 2012; 17 :157–229. [ PubMed ] [ Google Scholar ]

47. See note 35, Seok et al. 2013, at 3507.

48. Odom DT, Dowell RD, Jacobsen ES, Gordon W, Danford TW, MacIsaac KD, et al. Tissue-specific transcriptional regulation has diverged significantly between human and mouse . Nature Genetics 2007; 39 :730–2 [ PMC free article ] [ PubMed ] [ Google Scholar ] .

49. Horrobin DF. Modern biomedical research: An internally self-consistent universe with little contact with medical reality? Nature Reviews Drug Discovery 2003; 2 :151–4. [ PubMed ] [ Google Scholar ]

50. Vassilopoulous S, Esk C, Hoshino S, Funke BH, Chen CY, Plocik AM, et al. A role for the CHC22 clathrin heavy-chain isoform in human glucose metabolism . Science 2009; 324 :1192–6. [ PMC free article ] [ PubMed ] [ Google Scholar ]

51. See Guttman-Yassky E, Krueger JG. Psoriasis: Evolution of pathogenic concepts and new therapies through phases of translational research . British Journal of Dermatology 2007; 157 :1103–15 [ PubMed ] [ Google Scholar ] . See also The mouse model: Less than perfect, still invaluable. Johns Hopkins Medicine ; available at http://www.hopkinsmedicine.org/institute_basic_biomedical_sciences/news_events/articles_and_stories/model_organisms/201010_mouse_model.html (last accessed 10 Dec 2014). See note 23, Gawrylewski 2007. See note 2, Benatar 2007. See note 29, Perrin 2014 and Wilkins et al. 2011. See Cavanaugh S, Pippin J, Barnard N. Animal models of Alzheimer disease: Historical pitfalls and a path forward. ALTEX online first; 2014 Apr 10. And see Woodroofe A, Coleman RA. ServiceNote: Human tissue research for drug discovery . Genetic Engineering and Biotechnology News 2007; 27 :18 [ Google Scholar ] .

52. Lane E, Dunnett S. Animal models of Parkinson’s disease and L-dopa induced dyskinesia: How close are we to the clinic? Psychopharmacology 2008; 199 :303–12. [ PubMed ] [ Google Scholar ]

53. See note 52, Lane, Dunnett 2008.

54. See note 5, Pippin 2013.

55. Bailey J. An assessment of the role of chimpanzees in AIDS vaccine research . Alternatives to Laboratory Animals 2008; 36 :381–428. [ PubMed ] [ Google Scholar ]

56. Tonks A. The quest for the AIDs vaccine . BMJ 2007; 334 :1346–8 [ PMC free article ] [ PubMed ] [ Google Scholar ] .

57. Johnston MI, Fauci AS. An HIV vaccine—evolving concepts . New England Journal of Medicine 2007; 356 :2073–81. [ PubMed ] [ Google Scholar ]

58. See Rossouw JE, Andersen GL, Prentice RL, LaCroix AZ, Kooperberf C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy menopausal women: Principle results from the Women’s Health Initiative randomized controlled trial . JAMA 2002; 288 :321–33 [ PubMed ] [ Google Scholar ] . See also Andersen GL, Limacher A, Assaf AR, Bassford T, Beresford SA, Black H, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: The Women’s Health Initiative randomized controlled trial . JAMA 2004; 291 :1701–12 [ PubMed ] [ Google Scholar ] .

59. Lemere CA. Developing novel immunogens for a safe and effective Alzheimer’s disease vaccine . Progress in Brain Research 2009; 175 :83. [ PMC free article ] [ PubMed ] [ Google Scholar ] .

60. Allen A. Of mice and men: The problems with animal testing. Slate 2006 June 1; available at http://www.slate.com/articles/health_and_science/medical_examiner/2006/06/of_mice_or_men.html (last accessed 10 Dec 2014).

61. Attarwala H. TGN1412: From discovery to disaster . Journal of Young Pharmacists 2010; 2 :332–6 [ PMC free article ] [ PubMed ] [ Google Scholar ] .

62. See Hogan RJ. Are nonhuman primates good models for SARS? PLoS Medicine 2006; 3 :1656–7 [ PMC free article ] [ PubMed ] [ Google Scholar ] . See also Bailey J. Non-human primates in medical research and drug development: A critical review . Biogenic Amines 2005; 19 :235–55. [ Google Scholar ]

63. See note 4, Wall, Shani 2008.

64. Lemon R, Dunnett SB. Surveying the literature from animal experiments: Critical reviews may be helpful—not systematic ones . BMJ 2005; 330 :977–8. [ PMC free article ] [ PubMed ] [ Google Scholar ]

65. Roberts I, Kwan I, Evans P, Haig S. Does animal experimentation inform human health care? Observations from a systematic review of international animal experiments on fluid resuscitation . BMJ 2002; 324 :474–6 [ PMC free article ] [ PubMed ] [ Google Scholar ] .

66. See note 60,Allen 2006. See also Heywood R. Target organ toxicity . Toxicology Letters 1981; 8 :349–58 [ PubMed ] [ Google Scholar ] . See Fletcher AP. Drug safety tests and subsequent clinical experience . Journal of the Royal Society of Medicine 1978; 71 :693–6. [ PMC free article ] [ PubMed ] [ Google Scholar ]

67. See note 60, Allen 2006. See note 5, Pippin 2013. See also Greek R, Greek J. Animal research and human disease . JAMA 2000; 283 :743–4 [ PubMed ] [ Google Scholar ] .

68. See note 60, Allen 2006. See also note 5, Leist, Hartung 2013.

69. Food and Drug Administration. Development & approval process (drugs); available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ (last accessed 7 Dec 2014). See also http://www.fda.gov/drugs/resourcesforyou/consumers/ucm143534.htm (last accessed 7 Dec 2014).

70. Drug discovery pipeline. IRSF; available at http://www.rettsyndrome.org/research-programs/programmatic-overview/drug-discovery-pipeline (last accessed 24 Sept 2014).

71. See note 60, Allen 2006.

72. Follow the yellow brick road. Nature Reviews Drug Discovery 2003;2:167, at 167.

73. See note 5, Pippin 2013.

74. For data on aspirin, see Hartung T. Per aspirin as astra … Alternatives to Laboratory Animals 2009; 37 (Suppl 2 ):45–7 [ PubMed ] [ Google Scholar ] . See also note 5, Pippin 2013. For data on penicillin, see Koppanyi T, Avery MA. Species differences and the clinical trial of new drugs: A review . Clinical Pharmacology and Therapeutics 1966; 7 :250–70 [ PubMed ] [ Google Scholar ] . See also Schneierson SS, Perlman E. Toxicity of penicillin for the Syrian hamster . Proceedings of the Society for Experimental Biology and Medicine 1956; 91 :229–30. [ PubMed ] [ Google Scholar ]

75. See note 67, Greek, Greek 2000.

76. Oral bioavailability of blockbuster drugs in humans and animals. PharmaInformatic . available at http://www.pharmainformatic.com/html/blockbuster_drugs.html (last accessed 19 Sept 2014).

77. Sams-Dodd F. Strategies to optimize the validity of disease models in the drug discovery process . Drug Discovery Today 2006; 11 :355–63 [ PubMed ] [ Google Scholar ] .

78. Zurlo J. No animals harmed: Toward a paradigm shift in toxicity testing . Hastings Center Report 2012;42. Suppl:s23–6 [ PubMed ] [ Google Scholar ] .

79. There is no direct analysis of the amount of money spent on animal testing versus alternatives across all categories; however, in 2008 the Chronicle of Higher Education reported that funding of research involving animals (under basic research) of the National Institute of Health (NIH) remained steady at about 42 percent since 1990. See Monastersky R. Protesters fail to slow animal research. Chronicle of Higher Education 2008:54. In 2012, NIH director Francis Collins noted that the NIH’s support for basic research has held steady at 54 percent of the agency’s budget for decades. The remainder of the NIH’s budget is heavily funded toward clinical research, suggesting that preclinical human-based testing methods are much less funded. See also Wadman M. NIH director grilled over translational research centre. Nature News Blog 2012 Mar 20. Available at http://blogs.nature.com/news/2012/03/nih-director-grilled-over-translational-research-center.html (last accessed 5 Mar 2015). There is no data that suggests that the NIH’s funding of animal experimentation has decreased. A 2010 analysis estimates that at least 50 percent of the NIH’s extramural funding is directed into animal research; see Greek R, Greek J. Is the use of sentient animals in basic research justifiable? Philosophy, Ethics, and Humanities in Medicine 2010; 5 :14 [ PMC free article ] [ PubMed ] [ Google Scholar ] .

80. For a helpful discussion on animal pain, fear, and suffering, see DeGrazia D. Taking Animals Seriously: Mental Lives and Moral Status . New York: Cambridge University Press; 1996:116–23. [ Google Scholar ]

81. See Akhtar A. Animals and Public Health: Why Treating Animals Better Is Critical to Human Welfare . Hampshire, UK: Palgrave Macmillan; 2012:chap. 5.