Rapid international developments within this field justify a re-examination of the merits of invasive chimpanzee experimentation. Such a reappraisal is most applicable to the US. Although US animal research is governed by international, federal, and state laws, regulations, rules, guidelines, and standards [
50], contrary to the legislation of other key countries, the US
Animal Welfare Act 1966 (most recently amended in 1990) does not require the use of non-animal alternatives, even when scientifically validated alternatives exist. Unsurprisingly, therefore, US primate use is more than five times in excess of the number used in the entire European Union (approximately 58,000 vs. 11,000 annually; [
13]).
Advancements in biomedical knowledge?
When assessing the merits of invasive chimpanzee experimentation, a necessary first step is to obtain a definitive overview of the disciplines investigated by such research. Accordingly, I recently surveyed three major biomedical bibliographic databases and examined published studies conducted worldwide from 1995 – 2004 [
51].
I sought to assess the value of research on captive chimpanzees, particularly when invasive – that is, involving the entry of a needle, catheter or other instrument within the body, by puncture or incision – because such research incurs the greatest bioethical and social concerns. I included studies of captive chimpanzees or their tissues, and excluded studies of free-living populations, veterinary medical case reports of naturally-ill chimpanzees – whether or not in captivity, most genome studies, studies of skeletal anatomy – which frequently used museum specimens, and studies of cell lines (although I did include cell samples, such as peripheral blood mononuclear cells, obtained from captive chimpanzees).
749 studies of chimpanzees or their tissues were located that met my inclusion criteria, of which 48.5% (363/749) were biological experiments, and 41.5% (311/749) were virological experiments (Figure ).
Biological studies were conducted within nine broad disciplines (Figure ), of which the most common were cognition/neuroanatomy/neurology (36.6%, 133/363), and behavior/communication (20.7%, 75/363).
41.5% (311/749) of all chimpanzee experiments were virological studies. Thirty viruses were investigated, of which the most frequent were HCV and HIV (both 31.2%, 97/311) (Figure ).
The remaining experiments comprised therapeutic investigations (3.5%, 26/749) – namely, pharmacological, toxicological and anesthesiological investigations, and the testing of surgical techniques or prostheses; investigations of eight parasitic species (3.1%, 23/749) – of which the most frequent were the malaria protozoa Plasmodium falciparum and P. ovale (26.1%, 6/23), the roundworm Onchocerca volvulus (21.7%, 5/23), and the flatworm Schistosoma mansoni (17.4%, 4/23); and other diseases and miscellaneous experiments, which jointly comprised 3.5% (26/749) of all chimpanzee experiments.
On the face of it, these studies appear to have contributed toward a large array of biomedical disciplines. However, not all knowledge has significant value, nor is worth the bioethical, financial or other costs that may be incurred in gaining that knowledge. To gain a more critical assessment of the utility of invasive chimpanzee research in advancing biomedical knowledge, I randomly selected a statistically-significant subset of 95 experiments, and determined the frequency with which they were cited by papers subsequently published and included within these comprehensive bibliographic databases. 49.5% (47/95; 95% CI = 39.6 – 59.4%) were not cited by any subsequent papers (Figure ).
Given that almost all of these chimpanzee experiments would have been approved by at least one institutional ethics committee (Institutional Animal Care and Use Committee – IACUC – within the US), entrusted with ensuring that their welfare-related, bioethical and financial costs were reasonably likely to be exceeded by their expected benefits, it is disturbing that half of these randomly-selected experiments were not cited by any subsequent papers. The year of publication did not appear to substantially affect this outcome, as citation frequencies were similar across the decade, with more recent papers cited approximately as often as older papers.
Citation frequencies are not, of course, a definitive indication of the benefits or lack thereof, of scientific research. Uncited studies may also contribute to the advancement of biomedical knowledge, through a variety of mechanisms. However, citation frequencies do generally provide a quantifiable and reasonably objective approximation of utility, or lack thereof. Research that makes a significant contribution to a field – such as by confirming or refuting hypotheses – is very likely to be cited by future papers, as is research that produces interesting or controversial outcomes. On the other hand, research that is inconclusive, or of little interest or significance, is much less likely to be cited.
The disappointing citation rate of these chimpanzee studies is therefore cause for considerable concern. It is unreasonable to conclude that a large number of studies made a significant contribution, if none were cited by any future publication, as occurred for half of these randomly-selected chimpanzee studies.
Given that much research of lesser significance is not published, these published chimpanzee experiments can generally be assumed to be those with the greatest potential for advancing biomedical knowledge. Consequently, these results indicate that the majority of invasive chimpanzee studies generate data of questionable value, which makes little obvious contribution toward the advancement of biomedical knowledge.
Advancements in human healthcare?
Most would consider that the greatest justifications for invasive chimpanzee research involve attempts to advance human health. As stated, advocates of such research claim it has been of critical importance during our struggles against major human diseases [
48]. To critically assess such claims, I determined the frequency with which the statistically-significant subset of 95 randomly-selected chimpanzee studies had been cited by papers describing prophylactic, diagnostic or therapeutic methods efficacious in combating human diseases.
Only 14.7% (14/95; 95% CI = 8.9 – 23.4%) of all invasive chimpanzee studies were cited by a total of 27 papers describing well-developed diagnostic methods (5) or prophylactic and/or therapeutic methods (22) for combating human diseases (Figure ). Diseases examined included cancer (non-specific), chronic obstructive pulmonary disease, Epstein-Barr virus, hepatitis viruses A through G, hepatocellular carcinoma, HIV, malaria, organ transplant rejection, respiratory syncytial virus, rheumatoid arthritis, rhinovirus colds, systemic lupus erythematous, and transmissible spongiform encephalopathies.
As stated, citation rates are not a definitive indication of utility or lack thereof. Invasive chimpanzee studies may have contributed to medical advances through various indirect means, such as by stimulating investigation of certain lines of inquiry in humans – although it is unlikely that any medical papers subsequently published would not cite the chimpanzee studies that provided such inspiration. Alternatively, chimpanzee studies may have contributed to investigations of disease etiology, or to papers describing prophylactic, diagnostic or therapeutic methods for combating human diseases in early stages of development – although potential human benefits, in such cases, remain speculative.
However, it is reasonable to expect that if chimpanzee research had truly been of critical importance during struggles against major human diseases, as claimed by advocates, such chimpanzee studies would, in fact, be cited by papers describing methods efficacious in combating those diseases. The only alternative is that none of the struggles to which chimpanzee research purportedly made major contributions, resulted in effective, published solutions.
In fact, 27 papers describing well developed prophylactic, diagnostic or therapeutic methods for combating human diseases did cite chimpanzee studies. However, detailed examination of these medical papers revealed that in vitro studies, human clinical and epidemiological studies, molecular assays and methods, and genomic studies, contributed most to their development.
The randomly-selected chimpanzee studies proved to be of peripheral importance to most of these medical papers, for a variety of reasons. 63.0% (17/27) were, in fact, wide-ranging reviews of 26–300 (median 104) references, to which the cited chimpanzee study made a very small contribution.
In 12 cases the chimpanzee studies appeared redundant, as humans or human sera were studied concurrently, or because they served only to confirm previous human observations. In seven cases the method explored in the cited chimpanzee study was not developed further, sometimes because later clinical trials in humans failed to demonstrate safety or efficacy, contrary to positive chimpanzee results. In five cases the chimpanzee study examined a disease or method of only peripheral relevance to the medical method described. In three cases the chimpanzee study merely illustrated an historical finding, or was cited only during historical discussions of attempts to combat the disease in question. In another three cases the chimpanzee studies yielded results inconsistent with data from other NHP studies, and in two cases they yielded results inconsistent with human data. In two more cases only the human outcomes from human studies concurrently described within the cited chimpanzee studies were discussed. In one case the chimpanzee study may have helped establish the need for a new diagnostic method, but did not contribute further to its development.
In fact, none of these cited chimpanzee studies demonstrated an essential contribution, or – in most cases – a significant contribution of any kind, toward the development of the medical method described.
Limitations on the medical utility of chimpanzee models
These results suggest a lack of utility of chimpanzees as experimental models for studying human diseases. On the face of it, this appears counter-intuitive, given the genetic similarities of chimpanzees and humans. Our two species shared a common ancestor just 5–7 million years ago [
52] – a very short period in phylogenetic terms.
A 2005 draft of the chimpanzee genome confirmed it to be 98.77% identical to the mean human genome in terms of base pairs [
53]. When considering only the most functional DNA – that is, bases that cannot be altered without a consequent change in the amino acid coded for by the gene, as distinct from bases that may be altered without such changes, or so-called 'junk' DNA outside coding regions – Wildman and colleagues [
33] found a 99.4% correlation between chimpanzees and humans. However insertions, deletions and consequent misalignments raise the total estimated difference to around 4–5% [
54,
55].
While a minority of these genetic differences lie within structural genes, most are now known to lie within the regulatory regions of our DNA. By controlling the activities of structural genes, regulatory genes can exert an 'avalanche' effect upon hundreds of other genes. Consequently, a small difference may have profound effects [
56]. Striking differences have been found in the levels of gene expression between chimpanzees and humans, within the brain and liver, for example [
57]. Although chimpanzees and humans differ in only 4–5% of their DNA, that difference is sufficiently important to result in a difference of around 80% in protein expression [
58], yielding marked phenotypic differences between the species.
Additionally, systemic responses to disease agents and test chemotherapeutics within laboratory chimpanzees may be distorted by the neurological, endocrinological and immunological abnormalities that may result from a variety of experienced stressors. Although when between studies chimpanzees may be housed within social groups, with access to enlarged, environmentally-enriched enclosures, during study participation laboratory housing may be small, barren and standardized, and chimpanzees may experience isolation, trauma, chronic boredom, and a variety of stressful laboratory procedures [
59].
The substantial differences in protein expression between chimpanzees and humans, and the further distortions of normal physiology that may result from stressful laboratory environments and procedures, confer differences in the susceptibility to, etiology and progression of various diseases; differing absorption, tissue distribution, metabolism and excretion of chemotherapeutic agents; and differences in the toxicity and efficacy of pharmaceuticals.
Whilst it is true that interspecies differences in response may sometimes be illuminating – for example, during elucidation of disease mechanisms – it is generally more desirable that experimental models mimic human responses as accurately as possible, within experiments aimed toward the development of prophylactic, diagnostic, or therapeutic methods for combating human diseases. The lack of fidelity, or accurate reproduction, of key human characteristics and responses, is the most likely cause of the demonstrable lack of utility of chimpanzee models during the development of methods efficacious in combating human diseases.
Bioethically-relevant chimpanzee characteristics
Chimpanzees possess a range of advanced sensory, psychological and social characteristics, which may enhance their potential for suffering, and are therefore morally relevant when considering the ethics of subjecting them to invasive experimentation.
Pain perception
Whilst chimpanzees lack some of the most advanced human neurological and cognitive capacities [
60], it nevertheless remains true that they possess well-developed neuroanatomical mechanisms common to vertebrates – including nerve endings ('nociceptors') and peripheral and central neuroanatomical architecture – that confer the ability to detect and perceive as painful a variety of noxious stimuli, including mechanical, chemical and thermal insults. Such mechanisms evolved partly to encourage avoidance of natural agents capable of causing tissue damage. These same mechanisms may result in pain perception when chimpanzees are exposed to invasive procedures, noxious stimuli, or tissue damage secondary to artificially-inflicted diseases or toxic agents.
Most – if not all – invasive experiments result in at least mild physical discomfort, for example, during restraint and venipuncture, and some may result in marked discomfort or pain. Whilst analgesic provision is adequate in some cases, it is less so in others, partly due to concerns – well-founded or otherwise – that experimental outcomes may be altered by drug use. Whilst anaesthetic and analgesic use undoubtedly alters normal physiology, claims that such alterations are sufficiently important to hypotheses under investigation, to warrant their exclusion, require careful scrutiny. Despite increasing recognition [
61,
62] that pain relief improves both animal welfare and research quality – via minimization of pain-related physiological, psychological, behavioural or other animal model distortion – pain monitoring and analgesic provision remains less than optimal within many animal research protocols [
63,
64].
Emotional capacity
The potential suffering of laboratory chimpanzees is compounded by their relatively advanced emotional capabilities. They appear able to experience a range of emotions, similar to those we label as happiness and sadness, fear and anxiety, irritation, rage and despair [
65-
67], and appear able to suffer emotional, as well as physical, pain [
59]. Psychological stress is likely to result both from aversive experiences directly, and from the inability of laboratory chimpanzees to escape them. Such considerations are of greatest concern where pain or discomfort are substantial or prolonged.
Psychological abilities
The relatively advanced capacities of chimpanzees to understand and remember that certain people, tools or procedures are likely to cause pain and distress, and their ability to anticipate future aversive experiences, is likely to compound the distress such events may cause. Chimpanzees have some capacity to anticipate and understand the intentions and psychological states of others [
68-
71], and have long memories [
67,
72-
75]. The psychological abilities of chimpanzees may encompass abstract reasoning [
76], self-awareness (although mirror self-recognition may decline with age) [
66,
77,
78], and simple problem solving [
67,
79]. These relatively advanced abilities most probably evolved to enable chimpanzees to cope with their complex natural environments and social structures [
66].
Social characteristics
Chimpanzees are highly social animals, and the disruption of social networks when animals are captured from the wild – as many older research chimpanzees once were – or when subjected to confinement or translocation during biomedical research, may add to their suffering. The social relationships of chimpanzees appear to encompass prolonged rearing of offspring, close and affectionate family bonds, friendship, and mourning behavior following the deaths of companions [
66]. Anecdotal accounts of consolation of victims of aggression, and solicitous treatment of injured individuals, suggest that chimpanzees feel empathy [
80,
81]. Chimpanzees plan for the future and interact in a variety of cooperative activities, including territorial patrols, coalitionary aggression, cooperative hunting, food sharing and joint mate guarding [
72,
73,
81].
Chimpanzees possess well-developed communicative skills. Facial expressions [
82] and sophisticated vocalizations [
83-
85] convey information, for example, about identity [
83], emotional states [
82] and social status [
84]. Chimpanzees kiss, hold hands, pat one another on the back, embrace, tickle, punch and swagger [
66], with gestural dialects varying between communities [
86].
Although chimpanzees appear to lack the ability to explicitly teach [
60], they have some ability to learn through observation, emulation and practice [
87], although limitations on learning capacity have been recorded [
88]. At least 39 behavior patterns, including courtship, grooming, tool manufacturing and use, essentially comprising discreet 'cultures,' are passed from generation to generation through such learning. As with human cultures and customs, these have been shown to vary substantially between chimpanzee communities [
8,
89], in ways that cannot be attributed solely to ecological or genetic variation [
90].
De Waal [
91,
92] asserted that the social sophistication of chimpanzees is similar to that of humans, and that reciprocity among them is influenced by a similar sense of moral 'rightness' and justice. Chimpanzees may reject exchanges in which they value potential gains less than potential losses, for example, but, as with humans, there is no evidence that they are averse to interactions from which they benefit [
81].
Despite the relatively advanced sensory, psychological and social sophistication of chimpanzees, certain morally-relevant dissimilarities with humans do exist. Recent research suggests that human altruistic behavior – that is, a willingness to incur costs to assist genetically-unrelated strangers, in the absence of any personal gain ('other-regarding preferences') – provides a key example. In contrast, assistance offered by chimpanzees and other NHPs appears mainly limited to biologically-related or reciprocating individuals, and is rarely extended to unfamiliar individuals [
81,
93], although such behavior has been observed in common marmoset monkeys (
Callithrix jacchus) [
94].
Bioethical considerations
During study participation chimpanzees may be individually confined within small, relatively barren, standardized cages [
67], on the assumption that these facilitate cage cleaning, minimize infection risks, and facilitate ease of access, such as for blood sampling. They may be housed in buildings lacking windows, without access to natural lighting [
66]. They may be involuntarily subjected to potentially harmful experiments, including the artificial induction of diseases, and tests of the toxicity and efficacy of chemotherapeutic agents.
It is reasonable to expect that the relatively advanced sensory, psychological and social characteristics of chimpanzees may enhance their capacity for suffering during involuntary participation within invasive research protocols – and particularly, overtly harmful research. In the opinion of some experts, such chimpanzee characteristics render it impossible to provide laboratory environments that satisfactorily meet their minimum physiological and behavioral requirements [
8,
95].
Unanswered questions about the precise psychological abilities of chimpanzees inevitably result in a degree of uncertainty about the nature and magnitude of the suffering likely to result from such protocols and procedures. However, where such doubt exists, it seems reasonable to apply a precautionary principle – assuming that suffering may occur, and considering restrictions on procedures likely to cause such suffering – until proven otherwise. Such precautionary principles are, after all, enshrined within other fundamental social institutions, because they are considered to be rational, reasonable and humane. The Western legal system, for example, generally assumes innocence until guilt is proven beyond reasonable doubt. Where such doubt remains, judicial punishment is withheld.
Conversely, however, a precautionary principle might also be applied in favor of human patients or consumers that may potentially benefit from laboratory animal experimentation: where healthcare advances or other human utility may result, perhaps such experiments should proceed, until lack of potential benefit is proven beyond reasonable doubt.
When applied in isolation, each of these viewpoints represents a diametrically opposite position, consistent with ideological viewpoints that consider the interests of animals, or people, respectively, as overwhelmingly more important than those of each other. Such viewpoints are but two of a diverse range of religious, cultural and philosophical viewpoints about our moral duties toward animals and people that could be applied [
96-
98].
It is the opinion of this author, however, along with various philosophers [
98,
99], that achieving a reasonable and rational balance between the interests of people and those of laboratory animals requires balanced consideration of the interests of both groups: primarily, the likely benefits accruing to humans, and the probable costs incurred by animal experimental subjects. Such a 'utilitarian' position aims to achieve the 'greatest good for the greatest number,' and considers the interests of all affected, whether human, or other creatures likely to be capable of experiencing states as 'good,' or less desirable.
Fortunately, in the case of invasive chimpanzee experimentation, it is possible to achieve a reasonable weighting of interests, because concrete evidence about the likely human benefits, and costs to chimpanzees, does exist. Invasive chimpanzee experimentation allows investigation of a virtually limitless number of scientific questions. However, as previously demonstrated, the majority of such experiments appear to generate data of questionable value, which makes little obvious contribution toward the advancement of biomedical knowledge. Additionally, such studies rarely – if ever – make significant contributions toward the development of methods efficacious in combating human diseases [
51]. The resource and financial burdens incurred by such research are also considerable – issues of no small importance, within a climate of ever-increasing competition for scarce research resources.
The costs to chimpanzees enrolled in such experiments include involuntary confinement within laboratory settings, social disruption, and participation within potentially-harmful research protocols. Recent studies have established beyond any reasonable doubt that the effects of laboratory confinement and procedures, especially long-term, can be severe. Many captive great apes show gross behavioral abnormalities, such as stereotypies, self-mutilation or other self-injurious behavior, inappropriate aggression, fear or withdrawal [
100,
101], including among chimpanzees recently retired from US laboratories [
102]. It is increasingly acknowledged that such abnormal behaviors resemble symptoms associated with human psychiatric disorders, such as depression, anxiety disorders, eating disorders, and post-traumatic stress disorder, and that pharmacological treatment modalities similar to those applied to human patients may be appropriate, and indeed, morally compelled, for severely disturbed animal patients [
100,
103]. Long-term therapeutic combination with positive reinforcement training, environmental enrichment, and social and environmental modification may be necessary in severe cases [
101].
The analogous legal scenario is once again illuminating. Although these highly sentient creatures are in no way responsible for any human grievance, such as the serious diseases we attempt to induce in them, we sometimes subject chimpanzees to conditions that would cause widespread social outrage if used to punish the most heinous of human criminals – for years on end, and in some cases, for decades. Bradshaw and colleagues [
102] observed that:
"The costs of laboratory-caused trauma are immeasurable in their life-long psychological impact on, and consequent suffering of, chimpanzees." As stated, humans are not usually punished until proven guilty beyond reasonable doubt. It is not altogether unreasonable to assert that the lack of humanity highlighted by this difference in standards applies less to chimpanzees, than to ourselves.
The logic of Bradshaw and colleagues' corollary is elementary, yet compelling: "In human traumatology, the first step in treatment is to arrest its causes. This implies that prevention and treatment of chimpanzee psychopathology entails considering the factors and institutions that have brought chimpanzees to the point of irreversible distress: in simple terms, desisting from using apes as biomedical subjects in lieu of humans is compelled if trauma is not to be perpetuated."
The unique biological characteristics of chimpanzees – which are rare in their own right – and their advanced sensory, psychological and social characteristics – which have some similarities with those of humans – all create a strong ethical basis for acknowledging the necessity of respecting at least the most basic and essential interests of chimpanzees, such as their interests in avoiding death, pain, suffering and captivity [
104,
105]. When according due consideration to the interests of both humans and chimpanzees, it cannot be concluded that invasive chimpanzee experimentation is generally ethically justifiable.
Acceptable chimpanzee research?
Potential chimpanzee research protocols range from field studies of free-living (wild) populations, through non-invasive behavioral or psychological studies of sanctuary or laboratory populations, to mildly-harmful invasive experimentation, more-harmful experimentation, and finally, to include research protocols resulting in major harm or death. According due respect to chimpanzee characteristics and associated bioethical considerations does not require the termination of all chimpanzee research. Bioethical concerns are minimized within non-invasive observational, behavioral or psychological studies of free-living or sanctuary populations.
It is precisely the advanced psychological abilities of chimpanzees that may incur marked welfare-related and bioethical burdens during biomedical experimentation, that also place chimpanzees at risk of boredom and associated pathology within sanctuary settings, unless highly enriched. Offering such chimpanzees the choice to participate within behavioral or psychological studies, may, in fact, constitute a valuable form of environmental enrichment [
106]. Whilst participation remains truly voluntary, rather than coerced through conditional provision of essential needs, such as sufficient food, water, or social contact with compatible conspecifics, bioethical concerns are minimized. As stated, such studies are consistent with existing bans on great ape experimentation in countries such as Sweden, and consistent with the US
Chimp Haven is Home Act 2007, which prohibits further research on chimpanzees retired to federal sanctuaries, other than non-invasive behavioral studies [
44].
Limiting chimpanzee experimentation to non-invasive observational, behavioral or psychological studies of free-living or sanctuary populations would inevitably restrict the range of scientific questions that might be investigated. It would, however, strike the correct ethical balance between satisfying the interests of chimpanzees, and those of human beings.
Ecological considerations
Alarming declines in wild chimpanzee populations [
107] have led some to call for the maintenance of experimental chimpanzee populations for conservation reasons. However, chimpanzees maintained in captive environments other than very expansive, naturalistic settings, are unlikely to retain the full range of abilities, characteristics and behaviors demonstrated by wild chimpanzees. It is not only the physical characteristics of chimpanzees that are of scientific interest, or worthy of preservation, after all. For reasons such as these, the ultimate objective of genuine conservation programs is the maintenance or re-establishment of wild populations. Unfortunately, the capacity of chimpanzees to recover from disturbance is limited, and the reinforcement of wild populations with captive-born individuals is rarely a realistic option [
108]. Conservation efforts are therefore most appropriately directed toward addressing the factors responsible for declining wild chimpanzee populations – particularly, habit destruction, hunting and the spread of Ebola haemorrhagic fever – through aggressive investments in law enforcement, protected area management and Ebola prevention [
107].
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