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Do non-human primates make the “best” test subjects for medical research?  Why or why not?  Be sure to support your perspective with at least two pieces of scientific evidence from the two resources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC56361…

Excerpts from: Bailey, J. (2014). Monkey-based research on human disease: the implications of genetic differences. Alternatives to laboratory animals: ATLA, 42, 287-317. Jarrod Bailey New England Anti-Vivisection Society (NEAVS), Boston, MA, USA Summary Assertions that the use of monkeys to investigate human diseases is valid scientifically are frequently based on a reported 90–93% genetic similarity between the species. Critical analyses of the relevance of monkey studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for monkeys to constitute good models for research, and that monkey data do not translate well to progress in clinical practice for humans. Salient examples include the failure of new drugs in clinical trials, the highly different infectivity and pathology of SIV/HIV, and poor extrapolation of research on Alzheimer’s disease, Parkinson’s disease and stroke. The major molecular differences underlying these inter-species phenotypic disparities have been revealed by comparative genomics and molecular biology — there are key differences in all aspects of gene expression and protein function, from chromosome and chromatin structure to post-translational modification. The collective effects of these differences are striking, extensive and widespread, and they show that the superficial similarity between human and monkey genetic sequences is of little benefit for biomedical research. The extrapolation of biomedical data from monkeys to humans is therefore highly unreliable, and the use of monkeys must be considered of questionable value, particularly given the breadth and potential of alternative methods of enquiry that are currently available to scientists. Introduction Justification for the use of non-human animals in biomedical experimentation rests on the assumption that there exists sufficient general similarity between each experimental species and humans, to enable the reliable extrapolation of data from the former to the latter. It is widely assumed, and asserted by advocates of animal research, that those similarities that exist are most pronounced in non-human primates (NHPs) compared to other non-human animals, given their relatively recent evolutionary divergence from, and high degree of genetic identity to, humans. Therefore, they argue, NHPs must serve as the best models for researching human biology, in cases where human subjects cannot be used. However, in view of their high cognitive and emotional capacities, and the greater cost of their use in terms of ethics and resources, NHPs are used in much lower numbers than, for example, rats and mice. Indeed, the species with the greatest similarity to humans of all — chimpanzees— will cease to be used worldwide in invasive research in the very near future, as a result of ethical concerns coupled with a consensus that chimpanzee use is not scientifically necessary (1). Where NHPs continue to be used, it is claimed that their high degree of biological similarity to humans means that, in certain circumstances, there is simply no alternative, and that they are a last, but important, resort that offers significant scientific advantages where no other approach will suffice (e.g. 4, 5). Such advantages are, it is argued, conferred by a genetic similarity between NHPs and humans that is extremely high. Chimpanzees are superficially 98–99% genetically similar to humans, though more-stringent and more-comprehensive evaluations put the figure closer to 93% (6). Two of the monkey species most commonly used in research, the rhesus monkey/macaque (Macaca mulatta) and the cynomolgus monkey/macaque (Macaca fascicularis, also known as the longtailed or crab-eating macaque) are marginally more dissimilar to humans: some analyses suggest their similarity to humans is approximately 93%, though more rigorous comparisons put the figure at around 90% or even lower (7). While, at first sight, these similarity figures appear to be high, it is becoming increasingly evident that those genetic differences translate to profound biological differences that make these species unsuitable and poorly relevant models for humans, and/or which explain a number of observed empirical differences (see Discussion). These differences seem obvious when one considers the extraordinary diversity of the order of primates, which comprises 78 genera and 478 species, including humans, and for which 66 new species were identified in the past decade alone (8). It is estimated that the primate lineage is approximately 63 million years old; that chimpanzees and humans diverged 6–7.6 million years ago; that New World monkeys (NWMs), such as marmosets, tamarins, woolly monkeys and squirrel monkeys, diverged around 31 million years ago; and that Old World monkeys (OWMs), such as macaques, baboons, green and vervet monkeys, diverged from their common ancestor at least 14 million, though possibly up to 35 million, years ago (9–13). Consequently, lineagespecific differences, both in gene sequences and in gene regulation, have had plenty of time to occur and accrue. This may be evidenced, for example, by distinct phenotypic differences between species of monkey, even though they are closely related (such as the rhesus and long-tailed macaques): in fact, genetic variability among regional populations of cynomolgus macaques surpasses that even of rhesus macaques, meaning that they can “…differ from each other as much as some species and are not always appropriate for use as the same animal model” (14). Indeed, the difference between Indonesian and Mauritian cynomolgus macaques, in particular, is considered “remarkable”, leading them to “vary substantially” to the degree that they “…should not be included in the same experiments as models for heritable human diseases, because they may not be ideal for valid comparisons”, and that “combining information on quantitative risk factors for disease from different populations of cynomolgus macaques could obscure risk factor–disease associations or create spurious or artificial associations that are biologically irrelevant” (14, 15). Even within species, there are significant differences: six rhesus macaque subspecies have been noted, displaying a variety of morphological, physiological, and behavioural characteristics (16). Geographical differences are also of major importance, affecting macaque populations worldwide, from Sumatra, Mauritius, Singapore, Cambodia and the Philippines (14), and impacting susceptibility to malarial parasites, SIV infection and pathology, and xenobiotic metabolism via cytochrome P450 (CYP) differences, for example (see Results). It is these differences, and many others, that this review collates and explains in the context of genetics. Historically, genetic inter-species comparisons have been difficult, and therefore rare, due to the lack of knowledge of NHP genomes, and more recently they have been hampered by the poor quality of NHP genome assemblies (17). Nevertheless, knowledge of NHP genomes, in particular of the species used most commonly in biomedical research and testing — the rhesus and cynomolgus macaques (7) — has become sufficiently adequate to enable a number of studies, including the critical comparative analysis presented in this paper. These burgeoning data are increasingly underlining and substantiating King and Wilson’s 1975 hypothesis (see 18) that variable gene regulation is the key to species differences, rather than variable gene sequences — a theory that becomes even more compelling when the effects of the inherent stress associated with laboratory life and experimentation on gene expression in those laboratory animals are considered. The consequences of genetic differences: Translation of data from NHP research to humans Given the extent of NHP use in research and testing, as well as its ethical and financial costs, surprisingly little critical analysis of its worth has been conducted to date. It must be concluded that the use of NHPs rests on an assumption, perhaps based on anecdotal evidence, that it is predictive of human biology and translates well. However, this can only be assessed, and established, by comprehensive and critical scientific inquiry. What investigation has been done, however, is far from supportive of the value of NHP use, or of its necessity in the future. Much of the following evidence is monkey specific, but more has been collated against the use of apes, primarily chimpanzees (131, 132, 137–139), and notably also considers the genetic basis of the failures of chimpanzee research in the same manner as this paper does for monkeys (6). Toxicology and drug testing With regard to NHP use in toxicology and drug testing, no data categorically demonstrate the predictive nature of NHP tests for human toxicity. In fact, evidence has shown that: a) the primate tests for hepatic, renal and respiratory toxicities yielded high rates of false positive results when compared with subsequent human data (147); b) results from NHPs in developmental toxicity testing correlate with known human teratogens only 50% of the time, less even than results from more evolutionarily distant species such as rats, hamsters and ferrets (148–150); d) an analysis of the prediction of drug-induced liver injury (DILI) by animal models revealed that NHPs were less predictive than rodents —which themselves failed to predict up to 51% of effects in humans (152); and e) since their commercial introduction in the early 1980s, many non-steroidal anti-inflammatory drugs (NSAIDs) have been clinical failures. For example, having been found safe in year-long studies in rhesus monkeys, benoxaprofen caused thousands of serious adverse events and dozens of deaths within three months of its approval and marketing (153). Biomedical research The evidence against NHP research is not confined to drug development and testing. In biomedical research, a wide range of evidence specific to monkey use has been published: • In HIV/AIDS research, the use of macaques is widely considered to lead to failure and to be of questionable human relevance (157–164). Many, if not all, of some 100 different types of HIV vaccines were tested in monkeys with positive results, yet none provided protection or therapeutic benefit in humans, due to major differences in SIV-infected macaques compared to HIV-infected humans (157, 158, 162, 165–167). • With regard to Alzheimer’s disease (AD), many scientists have spent years trying to create an AD animal model with significant human relevance, but have failed (168–171), and havemade very little progress in understanding its various pathologies. For example, plaques and tangles in the brain are the hallmark of AD in humans, but not in NHPs (172). The once much-vaunted AD ‘vaccine’, AN-1792, dramatically slowed brain damage in an AD mouse model, and “was well tolerated when tested in several animal species, including monkeys” in experiments prior to clinical trials (175, 176). Despite the encouraging NHP data, clinical trials were suspended following CNS-inflammation and ischaemic strokes in 15 participants (177). • In stroke research, significant species-specific and even strain-specific differences in response to ischaemic injury exist (178). Decades of research have resulted in thousands of publications reporting more than 1,300 successful stroke interventions in animals (including NHPs), including more than 700 for acute ischaemic stroke, none of which has led to human benefit (179, 180). Some experts have labelled stroke animal models a failed paradigm: they have argued convincingly for human-based research (181, 182); lamented that animal models of stroke could not be translated to humans (183); and stated that “The repeated failures of laboratory-proven stroke therapies in humans can be due only to the inapplicability of animal models to human cerebral vascular disease” (184) • Parkinson’s disease (PD) has been studied using neurotoxic chemicals to induce superficial PD-like symptoms, predominantly in marmosets and macaques. Fundamental differences in theonset, type and persistence of symptoms exist in all the models, in addition to physiological differences such as the absence of Lewy bodies in NHPs. Species differences are known to play a role in the clinical expression, as well as in the cellular specificity of the lesions. For example,striatal degeneration in humans is frequently associated with dyskinesia, whereas striatal excitotoxic lesions alone are not sufficient to induce dyskinesia or chorea in NHPs. Also, the time-course of nerve cell degeneration, which normally evolves over several years in neurodegenerative diseases in humans, is for practical reasons replaced by a much shorter period of time in NHP models (187). Deep-brain stimulation of PD patients, often claimed to have been developed through NHP experiments, was actually discovered serendipitously in a human patient and arguably owes nothing to NHPs for its advancement (188, 189). The Ethical Argument Though not the focus of this review, it would be remiss not to include some salient considerations of suffering, given that the scientific worth of NHP use in science cannot be used in isolation as an argument to defend it, and because the inherent stress and distress directly affect experimental results via modulation of gene expression. While it is obvious that NHPs are able to suffer, considerable empirical evidence of sentience and capacity to suffer supports this common-sense view. Rhesus macaques, for instance, can perform rudimentary arithmetic, think using symbols (211), possess an essential component of ‘theory of mind’ (the ability to deduce what others perceive on the basis of where they are looking; 212), refuse to take food when this means other individuals would receive electric shocks (213), have a social system with rules for specific relationships and social behaviour, often developing lifetime social bonds (214), and show highly innovative behaviour, which is only surpassed by Pan, Pongo, and Cebus (215). Experimentation itself causes harm. The Organisation for Economic Co-operation and Development (OECD; 216) and the Nuffield Council on Bioethics (217) list many conditions and clinical signs that may occur during chronic toxicity and carcinogenicity tests, which indicate an animal is experiencing pain and/or distress. Drugs to relieve pain and distress may be withheld, over concerns that they might alter the toxicity profile of the chemical being tested (218). Neurological and vision experiments often cause significant suffering,as they involve craniotomies, head stereotaxy via bars implanted into the skull and/or ears, coils implanted into the eyes to monitor eye movements, and often deprivation of food or water for many hours prior to the experiments, to motivate the animals to perform visual tasks. NHPs are known to have been kept, instrumented, in single caging for two years, while being used and re-used in vision research (219). In Parkinson’s disease research, neurotoxins such as MPTP might be injected directly into monkeys’ brains to damage them, causing them to experience severely restricted mobility, including an inability to feed or groom themselves (220, 221). In stroke research, head and neck arteries are blocked, which involves craniotomy, and sometimes removing an eye and cutting the optic nerve to access the brain via drilling through the eye socket (222, 223). Sometimes related procedures are carried out whilst the monkeys are awake and restrained in primate chairs to avoid the effects of anaesthesia (224). Suffering may be psychological, as well as physical, evidenced by many macaques kept in standard laboratory cages exhibiting stereotypical behaviour (225). One study noted that 89% of singly-housed rhesus macaques exhibited at least one abnormal behaviour (226), while another showed that self-injurious behaviour occurred in 10% of NHPs (227). The use of primate restraint chairs causes immense psychological stress and extreme distress, associated with physical problems such as inguinal hernia (a protrusion of abdominal-cavity contents through the inguinal canal), and rectal prolapse (228). NHPs also suffer due to their anticipation of painful procedures based on past experiences (229, 230), as well as due to laboratory confinement (231) and the resulting lack of agency and social interactions (232,233). Furthermore, it is now well-known that even routine procedures that monkeys and other animals undergo in laboratories, such as simple handling, blood collection and drug administration, cause significant physiological stress (234). Transportation, change of environment and exposure to new laboratory staff and procedures induce changes in body weight, hormone levels, heart rate and blood pressure, all of which are indicators of stress (235, 236). Marmosets are well-known for avoidance behaviour during attempts at capture, and often become stressed and violent, even toward themselves; indeed, cage-capture of various NHP species is associated with signs of stress and distress (237). These ethical considerations are directly linked to scientific concerns. Stress-related elevations of heart rate, blood pressure and a variety of hormone levels (including cortisol) influence the nervous and immune systems, and affect scientific data obtained from animals in laboratories (238–241) — far from helpful when researching new drugs and infectious agents (234). Handling has been shown to interfere with immunity (and therefore, for example, tumour growth and susceptibility to infectious disease; 242, 243), and this effect varies with regard to species, strain, age and sex. This all has important methodological implications (243). Indeed, warnings have been issued about the consequences of disregarding the effects of stress due to laboratory routines (239–241), yet this remains under-reported, or not reported at all, in scientific studies (244). **References cited can be found in full copy of article (available upon request)

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