the poor contribution of chimpanc© experiments to -

REDVET. Revista electrónica de Veterinaria 1695-7504 2008 Vol. IX Nº 10B

The poor contribution of chimpancé experiments to biomedical progress http://www.veterinaria.org/revistas/redvet/n101008B/BA024.pdf

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REDVET Rev. electrón. vet. http://www.veterinaria.org/revistas/redvet Vol. IX, Nº 10B, Octubre/2008– http://www.veterinaria.org/revistas/redvet/n101008B.html

The poor contribution of chimpancé experiments to biomedical progress

Andrew Knight BSc. BVMS, CertAW, MRCVS Animal Consultants International 91 Vanbrugh Ct. incott St. London SE11 4NR UK Ph: +44-(0)7876436631 www.AnimalConsultants.org

REDVET: 2008. Vol. IX Nº 10B

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Summary Biomedical research on captive chimpanzees incurs substantial animal welfare, bioethical and financial costs, which advocates claim results in substantial advancements in biomedical knowledge. However, of 95 experiments randomly selected from a population of 749 published worldwide between 1995 and 2004, 49.5% (47/95) were not cited by any subsequent papers, demonstrating minimal contribution towards the advancement of biomedical knowledge generally. 35.8% (34/95) were cited by 116 papers that clearly did not describe well developed methods for combating human diseases. Only 14.7% (14/95) were cited by 27 papers that abstracts indicated described well developed methods for combating human diseases. 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. 63.0% (17/27) were wide-ranging reviews of 26-300 (median 104) references, to which the cited chimpanzee study made a very small contribution. Duplication of human outcomes, inconsistency with other human or primate data, and other causes resulted in the absence of any chimpanzee study able to demonstrate an essential contribution, or, in most cases, a significant contribution of any kind, towards the development of the medical method described. Almost all of these chimpanzee experiments would have been approved by an institutional ethics committee required by legislation to approve only those experiments likely to result in substantial benefits, in light of their substantial costs. Consequently, this demonstrates a widespread failure of the ethics committee system. The demonstrable lack of benefit of chimpanzee experimentation and its profound animal welfare and bioethical costs indicate that a ban is warranted in those remaining countries—notably the US—that continue to conduct it. Key Words: Animal experiment, animal research, chimpanzee, bonobo, Pan troglodytes, Pan paniscus.



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Introduction Chimpanzees are the species most closely related to humans, and consequently, the species most likely to be predictive of human outcomes when used in biomedical research. Hence, some advocate their use as models of humans in toxicity testing and research procedures it would be unethical to perform on people. The use of non-human primates (NHPs) such as chimpanzees is advocated for studies of virology, haematology, immunology and pharmacology (Herodin et al. 2005), neurotoxicology (Evans 1990), and of potential bioterrorism agents such as Lassa virus, Ebola virus, the plague and anthrax (Patterson & Carrion 2005). Chimpanzees are postulated to predict human pharmacokinetics—the time course of absorption, distribution, metabolism and excretion of drugs—more accurately than other laboratory species, such as rats, dogs and other NHPs, making them the test model of choice for human toxicity testing and drug development (Wong et al. 2004). Even their human-like ageing phenotypes are said to make NHPs such as chimpanzees ideal animal models when studying aging and related degenerative diseases (Roth et al. 2004). In a recent, prominent plea in Nature for increased funding for biomedical research on chimpanzees, Vandeberg et al. (2005) stated that such research has been of critical importance during our struggles against major human diseases. Similarly, British scientists recently called for the right to conduct such research on chimpanzees, contrary to the existing UK ban, in rare scenarios, such as the investigation of dangerous emerging infectious diseases (Jha 2006). However, the similarities between humans and chimpanzees, when combined with the particularly high costs of their procurement and maintenance, also raise exceptional animal welfare, ethical and financial concerns when these highly sentient creatures are experimented on in laboratories (Sauer 2000; Thew 2002). Some postulate that it is precisely the genetic similarities of chimpanzees to humans which are claimed to make them so useful as experimental models that also confers upon them a similar ability to suffer (e.g., Goodall 1986, de Waal, 1982, 1996), making it unethical to confine and experiment upon them as a result (Goodall & Bekoff 2002, Sauer 2000, Thew 2002). Additionally, the high costs of chimpanzee research present an increasing problem as competition for scarce research funds intensifies. The first step in assessing the merits or otherwise of biomedical research on captive chimpanzees must be to obtain a clear picture of the disciplines examined by such research. The US conducts more research on primates than any other country in the world, using in excess of five times the number used in the entire European Union (approximately 58,000 vs. 11,000; Conlee et al. 2004). Over 2,200 chimpanzees were believed to be used in laboratories worldwide in 1993, over 75% of which were used in the US (Stephens 1995). Although the numbers had substantially fallen, 1,171 remained available for research in US laboratories by 2005 (VandeBerg et al. 2005). To provide a recent assessment, Conlee et al. (2004) surveyed the Computer Retrieval of Information on Scientific Projects (CRISP) database, which contains US federally funded extramural biomedical research projects, and PubMed (www.PubMed.com), a biomedical literature portal containing Medline, the US National Library of Medicine's premier bibliographic database, and related papers and citations. Based on 184 grant abstracts filed in CRISP and 89 biomedical journal articles cited in PubMed, some initial indications were gained of the disciplines investigated by US chimpanzee research. A much larger survey, however, is required for definitiveness. Carlsson et al. (2004) surveyed 2,937 articles published in 2001 describing 4,411 NHP studies that used over 41,000 animals worldwide; however, only a small minority of these used chimpanzees. In order to gain a clear overview of the biomedical disciplines investigated via research on captive chimpanzees or chimpanzee tissues, I surveyed three major biomedical bibliographic databases and examined published studies conducted around the world from 1995-2004. I focused specifically on research on captive chimpanzees, particularly when invasive, because such research has raised the most concerns. To assess the utility of such research in advancing biomedical knowledge in general, I randomly selected a subset of chimpanzee experiments from the worldwide population, and



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determined the frequency with which they were cited by papers subsequently published and included within these bibliographic databases. Additionally, I determined the species and biomedical disciplines that were the focus of these citing papers. To assess the utility of chimpanzee research in combating human diseases in particular, I determined the frequency with these randomly selected chimpanzee studies had been cited by papers describing human prophylactic, diagnostic or therapeutic methods efficacious in combating human diseases. Materials and Methods Three bibliographic biomedical databases were searched for published papers describing research conducted on living chimpanzees or chimpanzee tissues from 1995 to 2004 inclusive: CAB Abstracts, the most comprehensive bibliographic database covering the applied life sciences, containing over 4.5 million records (Anon. n.d. a, b); EMBASE, the Excerpta Medica database, which is a biomedical and pharmacological database containing over 10 million records (Anon. n.d. c); and Medline, the leading medical and allied health profession database, containing over 12 million records (Anon. 2005). Jointly these databases included over 6,000 biomedical journals and thousands of other scientific documents sourced from over 140 countries. One of my key objectives was to determine the frequency with which chimpanzee research was cited by papers describing methods efficacious in combating human diseases; hence my survey was limited to these major biomedical bibliographic databases likely to contain human medical papers. Primate-specific databases such as Primate Lit were excluded. All titles, abstracts, and associated fields were searched for the terms ‘chimpanzee,’ ‘bonobo,’ ‘Pan troglodytes,’ and ‘Pan paniscus,’ and the search was limited to documents with abstracts. To focus on research on captive chimpanzees, particularly when invasive, the following papers were included:

studies of captive chimpanzees; studies of biometric information taken from captive chimpanzees, such as MRI scans; studies of fresh or preserved chimpanzee tissues, other than those specified below.

Excluded were:

studies of free-living chimpanzees; veterinary medical case reports of the diagnosis, treatment or post-mortem

examination of naturally-ill chimpanzees, whether or not in captivity; genome studies, other than of experimentally infected chimpanzees; studies of skeletal anatomy (which frequently used museum specimens); studies of cell lines (although I did include cell samples, such as peripheral blood

mononuclear cells (PBMCs), obtained from captive chimpanzees); studies of primate blood where the sources or species used were unspecified; secondary analyses of data obtained in primary studies.

749 chimpanzee studies were located that met these inclusion criteria. Resource constraints prevented detailed examination of all of these studies; hence an appropriate sample size was required to estimate the proportion of chimpanzee studies subsequently cited by other published papers. When calculating the sample size required, the relatively small population of 749 chimpanzee studies necessitated the use of the more accurate normal approximation to the hypergeometric distribution, rather than the normal approximation to the binomial distribution commonly used for large populations (Morris n.d., Green 1982). The hypergeometric formula used was: Minimum sample size n = Nz2pq (Morris, n.d., Guenther 1973, Green 1982) (E2(N-1)+z2pq)



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where: N = population size = 749. z specifies the desired confidence interval (CI). z = 1.96 for a 95% CI. p and q are population proportions, which are initially unknown, and which were both set to 0.5 to yield the most conservative possible outcomes. E = the desired accuracy of the sample proportions for the confidence interval chosen. For an accuracy of +/- 10%, E = 0.1. Hence, the minimum sample size required to achieve 95% confidence intervals with an accuracy of at least plus or minus 10%, for the sample proportions derived, was 86. An increased accuracy of plus or minus 5%, for example, would have been preferable; however, this would have required a sample size of 255, and detailed examination of a sample of this size was not possible due to resource constraints. To select at least 86 viable chimpanzee studies for examination from the population of 749, the 'Research Randomizer' random number generator (www.randomizer.org) was used to generate a sample of 100 chimpanzee studies. For four of these studies, citing papers were not available through the bibliographic databases used, and one additional study was cited only by a paper for which no abstract was available. Resource constraints precluded examination of papers lacking abstracts, hence these studies were removed from further consideration, leaving 95 chimpanzee studies in the sample. These 95 studies were examined to determine the proportion that were subsequently cited by papers of any kind at all, and also by medical papers in particular, that were published and included within these bibliographic databases by January 2006. 95% confidence intervals were then calculated for these proportions via the modified Wald method, available through the online statistical calculators at http://www.graphpad.com/quickcalcs/index.cfm, which is described in The American Statistician as providing more accurate results than the so-called “exact” method commonly used (Agresti & Coull 1998). The species and biomedical disciplines that were the focus of these citing papers were also ascertained. Where abstracts of citing papers indicated the existence of prophylactic, diagnostic or therapeutic methods with clear potential for combating human diseases, the complete medical papers were obtained and reviewed in detail to determine the contribution of the cited chimpanzee study to the development of the medical method described, in comparison with other cited sources of knowledge. Results Disciplines investigated in chimpanzee studies Bibliographic databases are constantly updated. As of 28th Aug. 2005, however, 2400 abstracts were located using the specified search terms. Upon examination of the abstracts, 749 of these were found to be studies of captive chimpanzees or chimpanzee tissues that met the inclusion criteria, of which 48.5% (363/749) were biological experiments, and 41.5% (311/749) were virological experiments (Figure 1).



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Figure 1: Chimpanzee experiments 1995-2004 (total 749)

363

311

26

23 14

12

26

BiologyDiseases: virologyTherapeutic investigationsDiseases: parasitologyMiscellaneousDiseases: other

Biological investigations were conducted in nine disciplines, of which the most frequent were cognition/neuroanatomy/neurology (36.6%, 133/363) and behaviour/communication (20.7%, 75/363) (Figure 2).

Figure 2: Biology experiments (363 of 749)

133

75

3734

27

25

20

9

3

32

Cognition/Neuroanatomy/NeurologyBehaviour/Communication

Immunology

Biochemistry

Reproduction/EndocrinologyGenetics

Anatomy/Histology

Physiology

Microbiology

Virological investigations were conducted in 30 disciplines, of which the most frequent were hepatitis C virus (HCV) and human immunodeficiency virus (HIV), which both comprised 31.2% (97/311) of all virology experiments (Figure 3).



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Figure 3: Virology experiments (311 of 749)

97

97

29 12 11 98

7

7

6

4

2

2

2

2

2

1

1

1

1

1

1

1

1

1

1

1

1

1

1

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HCVHIVHBVRSVHEVSTLVHIV & SIVSIVTTVFVHAVGBV - BHIV & HVIVPIVNoroviusesBacteriophagesDengue v.Ebola v.HCMVHGVHMPVH/S TLV LCVPapillomavirusesRV2RhinovirusVZVWMHBVUnspecified

HCV = hepatitis C v., HIV = human immunodeficiency v., HBV = hepatitis B v., RSV = respiratory syncytial v., HEV = hepatitis E v., STLV = simian T-cell lymphotropic v., SIV = simian immunodeficiency v., TTV = transfusion-transmitted v., FV = foamy v (human and simian FV), HAV = hepatitis A v., GBV-B = GB virus B, HV = herpes v., IV = influenza v., PIV = parainfluenza v., HCMV = human cytomegalovirus, HGV = hepatitis G v., HMPV = human metapneumovirus, H/S TLV = human/simian T-cell leukemia v., LCV = lymphocryptoviruses, RV2 = rhadinovirus (or gamma-2-herpesvirus) genogroup 2, VZV = varicella-zoster v., WMHBV = woolly monkey hepatitis B v.



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Therapeutic investigations comprised 3.5% (26/749) of all chimpanzee experiments, of which 61.5% (16/26) investigated the pharmacological properties of various compounds. Other experiments included the testing of surgical techniques or prostheses, anaesthesiological and toxicological investigations (Figure 4).

Figure 4: Therapeutic investigations (26 of 749)

16

4

3

3

PharmacologySurgical techniques\ProsthesesAnesthesiologyToxicology

Parasitology experiments comprised 3.1% (23/749) of all chimpanzee experiments. Eight parasitic species were investigated, 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) (Figure 5).

Figure 5: Parasitology experiments (23 of 749)

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5

4

3

2

1

1

1

Plasmodium falciparum,P. ovale (malaria)Onchocerca volvulus(roundworm)Schistosoma mansoni(flatworm)Enterobius vermicularis,E. gregorii (pinworm)Plasmodium vivax

Balantodium coli

Mycoplasma spp.

Other

Other diseases and miscellaneous experiments together comprised 3.5% (26/749) of all chimpanzee experiments. The most frequent were investigations of laboratory/husbandry techniques (42.3%, 11/26) and endotoxemia (30.8%, 8/26). Radiation studies were also conducted, and four other diseases were investigated, namely benign prostatic hyperplasia, Creutzfeldt-Jakob disease, gastrointestinal bacteriology (Bacillus thuringiensis) and tuberculosis (Mycobacterium tuberculosis) (Figure 6).



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Figure 6: Other diseases and miscellaneous experiments (26 of 749)

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8 3

1

1

1

1

Laboratory/HusbandryTechniquesEndotoxaemia

Radiation studies

Benign prostatic hyperplasia

Creutzfeldt-Jakob dis.

Gastrointestinal bacteriology(Bacillus thuringiensis)Mycobacterium tuberculosis

Citations of chimpanzee studies Ninety five chimpanzee studies were randomly selected from the population of 749 published between 1995-2004 (Appendix 1). Of these, 49.5% (47/95; 95% CI = 39.6 – 59.4%) were not cited by any subsequent papers (Figure 7).

Figure 7: Citations of 95 randomly selected published chimpanzee studies

47

34

14

05

101520253035404550

Notsubsequently

cited

Cited by otherpaper

Cited bymedical paper

The remaining 48 cited chimpanzee experiments were distributed fairly evenly across the decade (Figure 8).



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Figure 8: Chronological distribution of 48 cited chimpanzee studies

54

76

34

65

3

5

012345678

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

These 48 chimpanzee studies were cited by 143 papers with abstracts, and by 17 additional papers that lacked them. Examination of these abstracts indicated that 35.8% (34/95; 95% CI = 26.9 – 45.8%) of all chimpanzee studies were cited by 116 papers that clearly did not describe well developed prophylactic, diagnostic or therapeutic methods for combating human diseases (Figure 7). Some of these citing papers focused on humans only, or on humans in combination with other species, namely: Asian elephants (Elephas maximus), bacteria (Escherichia coli), birds (pigeons: Columba livia), bottlenose dolphins (Tursiops truncatus), dogs (Canis familiaris), mice (natural or genetically-modified), pigs, and, unsurprisingly, a very large variety of primate species: African green monkeys (Chlorocebus aethiops), chimpanzees (Pan troglodytes or Pan paniscus), common marmosets (Callithrix jacchus), cotton top tamarins (Saguinus oedipus), cynomologus macaques (Macaca fascicularis), gorillas (Gorilla gorilla), Japanese macaques (Macaca fuscata), olive baboons (Papio anubis), orang-utans (Pongo abelii and Pongo pygmaeus), rhesus macaques (Macaca mulatta), squirrel monkeys (Saimiri sciureus) and tufted capuchin monkeys (Cebus apella) (Table 1).

Table 1: Species and disciplines investigated in 143 studies citing 48 chimpanzee experiments

Species Discipline Asian elephants (Elephas maximus) behaviour

bacteria: Escherichia coli lab techniques (cDNA microarray interpretation)

birds: pigeons (Columba livia) cognition bottlenose dolphins (Tursiops truncatus) cognition dogs BPH

humans

asthma, autism, BPH, cancer (HCC), cancer (leukaemia), cancer (unspecified), cognition, COPD, CVB3, EBV, genetics, hepatitis viruses: A-G, HIV, HPIV-3, immunology, KD, laboratory techniques: gene expression profiling, malaria, neuroanatomy, neurology, organ transplantation, RSV, rheumatoid arthritis, rhinovirus colds, SLE, toxicity: arsenic, TSE, TTV

mammals: non-specific HCV, HEV, malaria (Plasmodium sp.)

non-species specific

cognition, HCV, HEV, lab techniques (cDNA microarray interpretation), psychology, virology



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pigs HEV primates: African green monkeys (Chlorocebus aethiops)

laboratory techniques: gene expression profiling

primates: bonobos (Pan paniscus), chimpanzees (Pan troglodytes)

behaviour, cognition, HCV, HIV, immunology, neuroanatomy, pathology (clinical), psychology, SIV

primates: capuchin monkeys (Cebus apella) cognition, toxicity: arsenic primates: common marmoset (Callithrix jacchus) neurology, psychology primates: cotton top tamarins (Saguinus oedipus) cognition

primates: cynomolgus monkeys (Macaca Fascicularis)

laboratory techniques: gene expression profiling, neuroanatomy, rheumatoid arthritis, SIV, surgical techniques: allografts (cardiac),

primates: gorillas (Gorilla gorilla) cognition primates: olive baboons (Papio anubis) cognition primates: orang-utans (Pongo abelii and Pongo pygmaeus) cognition, psychology

primates: rhesus macaques (Macaca mulatta) cognition, HIV, laboratory techniques: gene expression profiling, neurology, SHIV, SIV

primates: squirrel monkeys (Saimiri sciureus) cognition primates: tufted capuchin monkeys (Cebus apella) cognition primates: unspecified immunology rodents: mice HBV, HIV, immunology, PYNL, MHV-68 rodents: mice (genetically-modified) immunology rodents: rats cancer

BPH = benign prostatic hyperplasia, HCC = hepatocellular carcinoma, COPD = chronic obstructive pulmonary disease, CVB3 = coxasackievirus B3, EBV = Epstein-Barr v., HIV = human immunodeficiency v., HPIV-3 = human parainfluenza virus type 3, KD = Kawasaki disease, RSV = respiratory syncytial v., RA = rheumatoid arthritis, SLE = systemic lupus erythematosus, TSE = transmissible spongiform encephalopathy, TTV = transfusion transmissible v., HCV = hepatitis C v., HEV = hepatitis E v., SIV = simian immunodeficiency v., SHIV = simian human immunodeficiency v., HBV = hepatitis B v., PYNL = malaria (Plasmodium yoelii) non-lethal strain, MHV-68 = murine [gamma] herpesvirus. A variety of biological disciplines were investigated in these citing studies. Hepatitis viruses, cognition and HIV featured most prominently, in that order. Others included: asthma, autism, behaviour, benign prostatic hyperplasia, cancer, chronic obstructive pulmonary disease (COPD), coxsackievirus B3, Epstein-Barr virus (EBV), genetic studies, human parainfluenza virus type 3, immunology, Kawasaki disease, laboratory techniques including gene expression profiling and cDNA microarray interpretation, leukaemia, malaria, neuroanatomy, neurology, organ transplantation, pathology (clinical), psychology, respiratory syncytial virus (RSV), rheumatoid arthritis (RA), rhinovirus colds, simian immunodeficiency virus, systemic lupus erythematosus (SLE), surgical techniques: cardiac allografts, toxicity: arsenic, transmissible spongiform encephalopathies (TSE), and virology: non-specific (Table 1). Citing studies in this set that focused on humans as a primary subject examined a variety of disciplines other than pathology, or the aetiological or other aspects of human diseases. In a few cases potential prophylactic, diagnostic or therapeutic methods for combating human diseases were mentioned, however, all fell well short of being sufficiently developed for human use. Citing medical papers 14.7% (14/95; 95% CI = 8.9 – 23.4%) of all chimpanzee studies were cited by a total of 27 papers describing diagnostic methods (5) or describing prophylactic and/or therapeutic methods (22) for combating human diseases, that abstracts indicated were fully developed for human use, or in the latter stages of development (Figure 7). Diseases examined included



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cancer (non-specific), COPD, EBV, hepatitis viruses A through G (HAV through HGV), hepatocellular carcinoma (HCC), HIV, malaria, organ transplant rejection, RSV, RA, rhinovirus colds, SLE and TSEs (Table 2).

Table 2: Twenty seven medical papers citing chimpanzee studies Human

disease investigated

Medical approach:

prophylactic, diagnostic, therapeutic

Citing medical paper

Paper type

Review refs

Cited chimpanzee study

1 Cancer (non-specific)

Ther Tong & Stone. (2003). Cancer Gene Ther. 10(1),1-13.

review 155 Brams et al. (2001). Intnl Immunopharmacol. 1(2),277-294.

2 COPD Prophy Suzuki et al. (2001). Chest 120(3),730-733.

research Huguenel et al. (1997). Amer J Resp Crit Care Med. 155(4),1206-1210.

3 EBV Prophy Khanna et al. (1999). Immunol Rev. 170,49-64.

review 112 Bertoni et al. (1998). J Immunol. 161(8),4447-4455.

4 HAV & HBV Prophy Koff. (2002). Digestive Dis Sci. 47(6),1183-1194.

review 85 Ogata et al. (1999). Hepatol. 30(3),779-786.

5 HAV - HGV Prophy, Ther Regev & Schiff. (1999). Curr Op Gastroenterol. 15(3),234-239.

review 71 Mast et al. (1998). Hepatol. 27(3),857-861.

6 HBV Prophy McMahon et al. (2005). Ann Internal Med. 142(5),333-341.

research Ogata et al. (1999). Hepatol. 30(3),779-786.

7 HBV Prophy, Ther Karayiannis. (2003). J Antimicrob Chemother. 51(4),761-785.

review 300 Pancholi et al. (2001). Hepatol. 33(2),448-454.

8 HCV Diag Hussy et al. (1997). J Hepatol. 26(6),1179-1186.

research Wang et al. (1996). J Infect Dis. 173(4),808-821.

9 HCV Ther Feld & Hoofnagle. (2005). Nature 436(7053),967-972.

review 91 Bigger et al. (2001). J Virol. 75(15),7059-7066.

10 HCV Ther Nakano et al. (1999). J Hepatol. 30(6),1014-1022.

research Wang et al. (1996). J Infect Dis. 173(4),808-821.

11 HEV Prophy Worm & Wirnsberger. (2004). Drugs. 64(14):1517-1531.

review 133 Mast et al. (1998). Hepatol. 27(3),857-861.

12 HEV Diag Obriadina et al. (2002). J Gastroenterol Hepatol. 17(Suppl3),S360-S364.

research Mast et al. (1998). Hepatol. 27(3),857-861.

13 HCC Diag Kim & Wang. (2003). Carcinogenesis.

review 81 Bigger et al. (2001). J Virol.



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24(3),363-369. 75(15),7059-7066. 14 HIV Prophy, Ther Armbruster et al.

(2002). AIDS. 16(2),227-233.

research Conley et al. (1996). J Virol. 70(10),6751-6758.

15 HIV Prophy, Ther Armbruster et al. (2004). J Antimicrob Chemother. 54(5),915-920.


16 HIV Prophy, Ther Bardsley-Elliot & Perry. (2000). Paediatric Drugs. 2(5),373-407.

review 130 Grob et al. (1997). Nature Med. 3(6),665-670.

17 HIV Prophy Hone et al. (2002). J Human Virol. 5(1),17-23.

review 108 Conley et al. (1996). J Virol. 70(10),6751-6758.

18 HIV Prophy, Ther Sleasman & Goodenow.(2003). J Allergy Clin Immunol. 111(2 Suppl iii):S582-S592.

review 93 Conley et al. (1996). J Virol. 70(10),6751-6758.

19 HIV Diag Yang et al.(1998). J AIDS Human Retrovirol. 17(1):27-34.


20 HIV Ther Gallo. (2002). Immunol Rev. 185:236–265.

review 258 Goh et al. (1998). Nature Med. 4(1),65-71.

21 Malaria Prophy Moore & Hill. (2004). Immunol Rev.199(1),126-143.

review 104 Pancholi et al. (2001). Hepatol. 33(2),448-454.

22 Organ transplant rejection

Ther Matthews et al. (2003). J Viral Hepatitis. 3(7),794-803.

review 87 Newman et al. (2001). Clin Immunol. 98(2),164-174.

23 RSV Prophy Kneyber & Kimpen. (2002). Pediatric Infect Dis. 21(7),685-696.

review 150 Crowe et al. (1999). Virus Res. 59(1),13-22.

24 RA Ther Hepburn et al. (2003). Rheumatol. 42(1),54-61.

research Newman et al. (2001). Clin Immunol. 98(2),164-174.

25 Rhinoviral colds

Prophy Turner et al. (1999). JAMA. 281(19),1797-1804.

research Huguenel et al. (1997). Amer J Resp Crit Care Med. 155(4),1206-1210.

26 SLE Ther Gescuk & Davis. (2002). Curr Opinion Rheumatol. 14(5),515-521.

review 77 Brams et al. (2001). Intnl Immunopharmacol. 1(2),277-294.

27 TSE Diag Brown. (2005). Vox Sanguinis. 89(2):63-70.

review 26 Cervenakova et al. (2003). Electrophoresis. 24(5):853-859.

COPD = chronic obstructive pulmonary disease, EBV = Epstein-Barr virus, HAV – HGV = hepatitis viruses A through G, HCC = hepatocellular carcinoma, HIV = human



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immunodeficiency virus, RSV = respiratory syncytial virus, RA = rheumatoid arthritis, SLE = systemic lupus erythematosus, TSE = transmissible spongiform encephalopathy. Sources contributing to human medical papers Each of these 27 medical papers was obtained and examined in detail. Methods that featured very frequently in the development of the medical methods described included in vitro studies, human clinical and epidemiological studies, molecular assays and methods, and genomic studies. Methods that featured particularly prominently in specific papers included:

In vitro studies such as of human T-cells, HeLa cells, human respiratory epithelium (embryonic lung fibroblasts), human adenoid explants, lymphoblastoid and rodent cells lines, were used in at least 18 studies.

Human clinical and epidemiological studies were used in at least 15 and six medical

papers respectively.

Molecular methods such as immune electron microscopy, radioimmunoassay, polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), Western blot, and several assays designed for the diagnosis of TSEs: a combination of competitive antibody capture and capillary electrophoresis, conformation-dependent immunoassay, screening for intensely fluorescent targets, and an immuno-PCR assay, were used in at least eight medical papers.

Genomic techniques such as serial analysis of gene expression and microarray analysis

e.g. of viral genomes, suppression subtractive hybridisation, representational difference analysis, and differential display, featured more prominently in four medical papers.

Several viral studies used E. coli and baculoviruses in conjunction with Sf9 insect cells

as vectors for viral delivery and expression. Chimpanzee studies were, of course, cited by all of the medical papers. Additional

animal models were cited more prominently in five medical papers, including: transgenic and natural mice, rats, hamsters, guinea pigs, sheep, goats, cows, mink, woodchucks and NHPs (baboons, orang-utans, cynomolgous monkeys and rhesus macaques). Several of these species were only cited in one paper Brown (2005) that described diagnostic methods for combating TSEs, either as sources or recipients of TSE-infected tissues.

A detailed examination of the contributions or otherwise of various animal models other than chimpanzees is beyond the scope of this study. However, as Brown (2005) aptly put it, “… it is always problematic to what extent such models reflect the human situation.” Contributions made by chimpanzee studies The randomly selected chimpanzee studies proved to be incidental to most of these medical papers for a variety of reasons. 63.0% (17/27) of these medical papers were wide-ranging reviews of 26-300 (median 104) studies, to which the cited chimpanzee study made a very small contribution. In nine cases (Table 1: papers 5,9,11-13,16,20,24-25) the chimpanzee studies appeared to be redundant, as humans or human sera were studied concurrently, or because they served only to confirm previous human observations. In six cases (Table 1: papers 2,22-26) 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 four cases (Table 1: papers 4,13,21,25) the chimpanzee study examined a disease or method that was peripheral to the medical method described. In three cases (Table 1: papers 2,17,19) the chimpanzee study merely illustrated an historical finding, or was cited only during historical discussions of attempts to



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combat the disease in question. In three cases (Table 1: papers 1,8,10) only the human outcomes from concurrent human studies described within the cited chimpanzee studies were discussed. In three cases (Table 1: papers 7,17,26) the chimpanzee studies yielded results inconsistent with data from other NHP studies, and in two cases (Table 1: papers 18,24) they yielded results inconsistent with human data. In one case (Table 1: paper 12) the chimpanzee study may have helped establish the need for a new diagnostic method, but did not contribute further to its development. Five chimpanzee studies were cited by more than one medical paper. Bigger et al.’s 2001 paper on the effects of HCV in chimpanzees was peripheral to Kim & Wang’s 2003 paper describing a diagnostic method for the detection of HCC (Table 1: paper 13), and served only to confirm what had already been observed in earlier human studies cited by Feld & Hoofnagle’s 2005 paper on therapeutic methods for combating HCV (Table 1: paper 9). Conley et al.’s 1996 study of the prophylactic use of human monoclonal antibodies (hMAbs) in chimpanzees challenged with HIV-1 was cited by five medical papers. In two studies of prophylactic and therapeutic methods for combating HIV (Armbruster et al. 2002 & 2004), positive prior results in the cited chimpanzee study suggested a potential field of further development with respect to hMAb choices used in combination prophylactic and therapeutic regimes (Table 1: papers 14-15). The cited chimpanzee study did not, however, play an integral role in the citing studies by Armbruster et al., the purpose of which was to examine the safety, immunogenicity and pharmacokinetics of hMAb protocols in clinically healthy HIV-1-infected human volunteers. In papers by Yang et al. (1998) and Hone et al. (2002) describing the development of vaccines and a diagnostic method, respectively, for combating HIV, the cited chimpanzee study served only to demonstrate that effective HIV antibodies can indeed neutralise HIV in chimpanzees, to varying degrees, although conflicting results were observed in six other NHP studies cited by Hone et al (Table 1: paper 17 & 19). Other than through such very peripheral means, the cited chimpanzee study did not contribute to the development of these prophylactic and diagnostic methods. The contribution of this study towards the development of prophylactic and therapeutic methods for combating HIV reviewed by Sleasman & Goodenow (2003) was similarly limited by inconsistency with other cited human data (Table 1: paper 18). Mast et al.’s 1998 paper describing the poor sensitivity, concordance and variable efficiency of previously-available HEV assays in chimpanzees, particularly against different HEV strains, was cited by Regev et al.’s 1999 review of prophylactic and therapeutic options for combating HAV, HBV, HCV, HEV, HGV and TTV (Table 1: paper 5), as well as by Obriadina et al.’s 2002 paper describing the development of a diagnostic technique for the detection of HEV (Table 1: paper 12). The chimpanzees in this study were used as both positive and negative controls. However, their use in both roles was redundant, for more relevant positive and negative human controls in the form of human sera were concurrently available. Additionally, one of Mast et al.’s key outcomes was the highly discrepant existing HEV assay results from US blood donors which were presumed HEV negative, necessitating great caution when interpreting positive assay results. This outcome relied exclusively on human results. Newman et al.’s 2001 paper demonstrating the safety and efficacy of Keliximab, a primatized IgG1 anti-CD4 mAb, in modulating T-cell receptor responsiveness in chimpanzees, was cited by two medical papers. In Matthews et al.’s 2003 review of therapeutic strategies designed to combat organ transplant rejection, it was hoped that the targeting of cell-surface receptors might result in T-cell inactivation, thereby delaying allograft rejection, because T-cell activation is central to the inflammation and tissue damage that results in allograft rejection (Table 1: paper 22). Hepburn et al. (2003) also described their clinical trial of Clenoliximab, an anti-CD4 mAb proposed for the treatment of RA (Table 1: paper 24). However, a later Phase II human clinical trial of an analogue drug (Zanolimumab) failed to demonstrate efficacy at combating RA, resulting in discontinuation of the development of this drug for RA patients, and also casting doubts upon the efficacy of anti-CD4 mAbs generally in combating allograft rejection.



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A paper describing chimpanzee studies of DNA-based vaccines (Pancholi et al. 2001) was cited both by Karayiannis’s 2003 review of the prophylactic and therapeutic options available for combating HBV (Table 1: paper 7), and by Moore & Hill’s 2004 review of strategies for the development of a malaria vaccine (Table 1: paper 21). In the former case inconsistency with other chimpanzee and NHP results limited the utility of the cited chimpanzee study, while in the latter case the disease and vaccination strategies explored were too distant from those investigated in the cited chimpanzee study to accord it more than tenous relevance. Wang et al.’s 1996 study of the reactivity of humans and chimpanzees to various epitopes of HCV H strain structural proteins was cited by both Hüssy et al.’s 1997 paper investigating a diagnostic method for HCV (Table 1: paper 8), and by Nakano et al.’s 1999 paper investigating therapeutic options for HCV (Table 1: paper 10). However, in both cases only the human outcomes concurrently described within this chimpanzee study contributed to the citing medical paper. In fact, the cited chimpanzee study really served only to highlight differences in the immune response of humans and chimpanzees to HCV. Several authors of human medical papers or cited chimpanzee studies identified potential problems with attempts to extrapolate chimpanzee results to human outcomes. Wang et al. (1996), for example, identified key differences between the immune response of humans and chimpanzees to HCV infection. In their study of prophylactic methods for combating EBV, Khanna et al. (1999) stated that: “It would be a mistake to assume that experimental results obtained in these … primate models had direct relevance to vaccine formulations that might offer protection against infectious mononucleosis [one of the main targets for a vaccine].” When commenting on the failure of a test drug to demonstrate efficacy at combating (T-cell dependent) RA in a phase II clinical trial, despite prior efficacy of an analogue drug in modulating T-cell receptor responsiveness in chimpanzees, Newman et al. (2001) stated that: “…results to date illustrate the profound difficulties in translating animal model success to the clinical arena.” Development of this test drug for RA patients was discontinued. In his review of prophylactic methods for combating HAV & HBV, Koff (2002) described the cited chimpanzee study as potentially complicating our understanding of escape viruses. Human utility of medical papers citing chimpanzee studies Unfortunately, contrary to hopes arising from initial examination of their abstracts, on detailed examination the great majority of these 27 medical papers were not found to describe prophylactic, diagnostic or therapeutic methods for combating human diseases that were sufficiently developed for routine human use, and efficacious in a sizeable proportion of human patients. In at least three cases (Table 1: papers 2,24-25) no further progression of test drugs towards the marketplace was apparent after initial animal or human trials, which usually indicates that safety or efficacy concerns have arisen. In three cases (Table 1: papers 12,19,27) the diagnostic assays under development were some way short of being sufficiently developed for routine medical use, while in one other case (Table 1: paper 8) the sensitivity of the assay did not equal that of the assay traditionally used. Most of the putative vaccination strategies described remained far from completion and implementation. One combination chemotherapeutic protocol for HCV did not achieve sustained viral clearance in half of chronically-infected patients treated (Table 1: paper 9). When describing the development of vaccines against RSV, which have been explored using many animal studies over a substantial number of years, Kneyber et al. (2002, Table 1: paper 23) stated that “it will probably be at least another 5 to 10 years before any routine vaccination against RSV becomes daily practice.” In one case a single vaccine candidate for the prevention of HEV had passed a phase I clinical trial was being field tested in Nepal (Table 1: paper 11), however, further tests were considered necessary to determine long-term efficacy. A few reviews, however, described vaccines that have been successfully used for many years, e.g. the combination HAV and HBV vaccine Twinrix (Table 1: paper 4), and others described



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similarly well-established therapeutic methods, e.g., the use of rIFN-α for chronic HCV infection (Table 1: paper 5), Nevirapine in HIV patients (Table 1: paper 16), and Cyclophosphamide for the treatment of SLE (Table 1: paper 26). Discussion Utility of chimpanzee studies in advancing biomedical knowledge On the face of it, studies of captive chimpanzees or chimpanzee tissues appear to have contributed towards a large array of biomedical disciplines. However, not all knowledge has significant value, nor is worth the ethical and financial costs incurred in gaining that knowledge. A fundamental and widely-accepted principle of sound experimental science involving human or animal subjects is that the welfare-related, bioethical, financial and other costs of a proposed experiment must be exceeded by the benefit reasonably expected to result. This is particularly important when potentially harmful research on non-consenting subjects is being contemplated, as is the case with much research on captive chimpanzees. In most research centres worldwide institutional ethics committees are required by legislation to make such assessments, and are expected to veto proposed experiments in which the benefits are not likely to exceed the costs. Given that almost all of these 749 chimpanzee studies conducted worldwide during a recent decade would have been approved by ethics committees charged with engaging in precisely such deliberation, it is reasonable to expect that these experiments would have proven significantly useful. However, this examination of 95 randomly selected chimpanzee studies revealed that around half were not cited by any papers subsequently published and included in the comprehensive bibliographic databases examined. The year of publication did not appear to substantially affect this outcome, as citation frequencies were broadly 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 of published research. Citation rates may be affected by whether or not the study outcomes support the hypothesis under consideration, and by article length, number of authors, their country and university of affiliation (Leimu 2005). Citation frequencies do, however, provide a reasonable 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 unlikely to be cited. The degree to which a journal is circulated and read within the scientific community may also affect the likelihood that papers published within it will be cited. Journal impact factors (JIFs) attempt to quantify such probabilities based largely on annual assessments of journal citation frequencies. Hence it is possible that the poor citation rate of this sample of chimpanzee studies was due to their publication in lower impact factor journals, when compared to publication norms. However, the randomness of the selection of this reasonably-sized sample makes it likely that the impact factors of these journals were broadly similar to those of the larger population of journals in which the entire population of chimpanzee studies were published. It may, in fact, be true that chimpanzee studies are generally published in journals with lower JIFs; however, this would also be a reflection of the lack of importance accorded to these studies, as well as a potential cause of their lowered citation rates. Furthermore, Seglen (1989) found that citation frequencies of articles published by individual authors or research groups correlated extremely poorly with their corresponding JIFs. Seglen consequently concluded that JIFs are unsuitable as an indicator of scientific quality. Hence, it appears likely that the low citation rates of chimpanzee experiments are indeed a reflection of their lack of scientific value, rather than the result of a very large number of consistently unfortunate journal choices. The lack of any future citations for half of these randomly selected chimpanzee studies is therefore cause for considerable concern. Given that research of lesser significance is not



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published at all, these published chimpanzee experiments can be safely assumed to be those with the greatest potential for advancing biomedical knowledge. Consequently, these results indicate that the majority of chimpanzee research generates data of little use, and contributes very little to the advancement of biomedical knowledge. Of considerable further concern is that virtually all of these experiments would have been approved by an ethics committee required by legislation—and expected by society—to allow only those chimpanzee experiments clearly likely to result in significant benefits. Consequently, this demonstrates a widespread failure of the ethics committee system. Utility of chimpanzee studies in combating human diseases Most would agree that the most justifiable use of captive chimpanzees in biomedical research lies in the advancement of human health. Advocates of research on captive chimpanzees claim such research has been of critical importance during our struggles against major human diseases (Vandeberg et al. 2005). Perhaps the best means of assessing the true value of the large amount of chimpanzee research conducted is to assess its contribution towards papers published in peer-reviewed journals describing methods efficacious in combating human diseases. Of 95 randomly-selected chimpanzee experiments, just over one third were cited by 116 papers that did not describe well developed prophylactic, diagnostic or therapeutic methods for combating human diseases (Figure 7). Instead, these focused primarily on a sizeable array of non-human species, including a large variety of primates, or on human subjects in relation to a variety of biological disciplines other than pathology, or on examinations of the aetiological or other aspects of human diseases. Just under 15% of these chimpanzee studies were cited by a total of 27 papers that abstracts indicated might describe well developed methods for combating human diseases (Figure 7). However, detailed examination of each of these 27 medical papers individually revealed that in vitro studies, human clinical and epidemiological studies, molecular assays and methods, and genomic studies contributed most to the development of the methods described. Studies in a variety of animal species other than chimpanzees were cited in at least five papers, but their applicability to human outcomes was questioned by some authors. The chimpanzee studies cited by the 27 medical papers did not appear to contribute substantially to the development of the medical methods under consideration. Almost two-thirds of these medical papers were found to be wide-ranging reviews of 26-300 (median 104) studies, to which the cited chimpanzee study made only a small contribution. In nine cases the cited chimpanzee studies appeared to be redundant, as humans or human sera were studied concurrently, or because they only served to confirm observations previously made in humans. In six cases the methods explored in the chimpanzee study were not developed further, sometimes because later clinical trials in humans failed to demonstrate safety or efficacy, contrary to positive chimpanzee results. In four cases the chimpanzee study examined a disease or method peripheral to the medical method described, while in most of the remaining cases the chimpanzee study yielded results inconsistent with other human or NHP data, or merely illustrated historical findings, or was only cited in order to discuss human outcomes described concurrently within the cited chimpanzee study. Finally, on detailed examination, the great majority of these 27 medical papers were not found to describe methods for combating human diseases that were efficacious in a sizeable proportion of patients and sufficiently developed for routine human use. 17 additional studies out of a total of 160 (10.6%) papers that cited chimpanzee experiments lacked abstracts and were not examined due to resource constraints. Hence it is possible that the true number of chimpanzee studies that were cited by medical papers appearing to describe well-developed methods for combating human diseases may have been slightly higher than indicated by these results. However, any such error is likely to be small. 14.7% of the



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143 studies for which abstracts were available were cited by such medical papers. Were 14.7% of the 17 studies lacking abstracts to have proven similarly useful, only 2-3 additional medical papers would have resulted. These results indicate a marked lack of utility of chimpanzees as an experimental model for combating human diseases. On the face of it, this appears contrary to expectations, given the genetic similarities of chimpanzees to humans. Our two species shared a common ancestor just 5-7 million years ago—a very short time span in phylogenetic terms. A 2005 draft of the chimpanzee genome confirmed it to be 98.77% identical to the human genome in terms of base pairs (The Chimpanzee Sequencing and Analysis Consortium 2005), however insertions, deletions and consequent misalignments raise the total estimated difference to around 4-5% (Britten 2002, Varki and Altheide 2005). While a minority of these genetic differences between humans and chimpanzees lie within structural genes, most are now known to lie within the regulatory regions of our DNA. In regulating 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 (Bailey 2005). Striking differences have been found in the levels of gene expression between chimpanzees and humans in the brain and liver, for example (Ruvolo, 2004). Although chimpanzees and humans differ in only 4-5% of their DNA, that difference is sufficiently important to result in a difference of around 20% in protein expression (Glazko et al., 2005), resulting in marked phenotypic differences between the species, including: differences in the susceptibility to, aetiology and progression of various diseases; differing absorption, tissue distribution, metabolism, and excretion of chemotherapeutic agents; and differences in the toxicity and efficacy of pharmaceuticals (Bailey 2005). Furthermore, the tissue responses to disease agents and test chemotherapeutics in laboratory chimpanzees is likely to be distorted by the neurological, endocrinological and immunological abnormalities that result from the variety of stresses these chimpanzees commonly endure. These stresses include standardised small, barren laboratory housing, immobilisation, isolation, or less frequently, overcrowding, aggression from fearful or frustrated cagemates, trauma, chronic boredom, and a variety of stressful laboratory procedures (Fouts 1995). The substantial differences in protein expression between chimpanzees and humans, and the further distortions of normal physiology that result from the stressful laboratory environment and procedures endemic to chimpanzee experimentation, are the most likely causes of the observed lack of utility of chimpanzee research in the development of prophylactic, diagnostic and therapeutic methods efficacious in combating human diseases. While initial examination of abstracts indicated that just under 15% of published chimpanzee experiments were cited by medical papers describing methods with sound potential for combating human diseases, detailed examination of these papers individually revealed that the fraction offering real hope to a reasonable proportion of patients was, in fact, far smaller. It is a damning indictment of chimpanzee experimentation that even in this area of potentially greatest human utility, such research was found to be minimally beneficial, if at all, in comparison to a range of in vitro, human-based, molecular and genomic studies that yielded far greater benefits. Additionally, chimpanzee experimentation is far from cheap. The maintenance of a breeding facility, combined with the specialised housing and husbandry requirements of chimpanzees, for the duration of their relatively lengthy life spans, when compared with most other laboratory species, all contribute to the relatively high costs of chimpanzee research. Similarly, research funding is far from unlimited. Considerably more progress in combating human diseases may well have been achieved had the funds spent on chimpanzee experimentation been spent, instead, on the demonstrably more beneficial and, often, substantially cheaper non-animal research tools that featured prominently in these medical papers.



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Bioethical considerations: chimpanzee sourcing The use of chimpanzees in biomedical research incurs several serious welfare-related and bioethical costs. The first of these relates to the sourcing of chimpanzees. Although most new laboratory chimpanzees are now sourced from breeding facilities, with life spans of 40 - 50 years or more (Prince et al. 1989), many older chimpanzees were originally captured from the wild, as other primate species continue to be today. The capture of wild primates presents serious welfare issues. Trapping is a stressful procedure and results in the highest incidence of mortality and serious injury of all stages of acquisition. Trappers often have little knowledge or awareness of animal welfare. Trapping methods, which include netting and bait-traps, are indiscriminate, with no regard for the demographic status of the remaining wild population. This means that trapping can cause suffering even to those individuals that escape being trapped (Prescott & Jennings 2004). Holding facilities in the trapping area are often unsatisfactory, and there may be long delays before the animals are transferred to more permanent accommodation. Methods of transport to the base and holding facilities of the trappers are not controlled, and animals may be deprived of water and food and held under unsanitary conditions (Prescott & Jennings 2004). They may also acquire human diseases such as tuberculosis, and thus, present a human health hazard. The zoonotic hazard to laboratory animal personnel posed by NHPs exceeds those of all non-primate species (Peli et al. 2002). Staff responsible for the care and management of primates require special knowledge, practical skills and the highest standard of training, and this may not be available in source countries (Poole & Thomas 1995). In transit, primates may be exposed to extreme temperatures, pressure, humidity and lighting, excessive noise and vibration from the vehicle or aircraft, severely restricted movement inside the transport container, lack of food and water for long periods of time, motion sickness, exposure to unfamiliar and frightening stimuli, and unpredictable movement during changeovers from one form of transport to another (Maas 2000). On release, the animals may have to undergo a period of quarantine and acclimatise physiologically and behaviourally to completely unfamiliar physical and social conditions (Prescott & Jennings 2004). In short, the process of capture followed by lengthy, multistaged travel from the country of origin to the holding centre, quarantine and final transportation to the destination laboratory, frequently results in serious welfare deficits (Prescott & Jennings 2004). Although with most laboratory chimpanzees being sourced from breeding facilities such welfare violations are now rare, they have been suffered in the past by many chimpanzees presently subjected to biomedical research, and hence must be added to the ethical equation when considering whether or not to continue to conduct potentially harmful experiments on these chimpanzees. Bioethical considerations: chimpanzee characteristics Chimpanzees are highly evolved to maximise their survival chances within their own ecological niche, and accordingly possess an array of physical, sensory, and other unique abilities that humans lack. However, it is also true that, while different to humans in some important ways, chimpanzees nevertheless possess many cognitive, communication and social abilities once considered uniquely human (Goodall 1995). At least 39 behaviour patterns including courtship, grooming, tool manufacturing and use, that essentially comprise discreet ‘cultures,’ are passed from generation to generation via chimpanzees’ abilities to learn through observation, imitation and practice. As with human cultures and customs, these have been shown to vary substantially between different chimpanzee communities (Whiten et al., 1999, Smith & Boyd 2002 p. 25). As seen (Figure 2), many chimpanzee experiments have investigated their cognitive abilities, which are much more advanced than once assumed. Chimpanzees are capable of abstract reasoning, symbolic representation and self-awareness. They experience joy and sadness, fear and anxiety, rage and despair, and even possess a sense of humour. Their relationships with



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others encompass friendship and empathy, acts of altruism, close and affectionate family bonds, and mourning behaviour following the deaths of companions (Goodall 1995). They are able to suffer emotional, as well as physical, pain (Fouts 1995), and to anticipate and understand the psychological states of others, especially in competitive situations, where deceptive and manipulatory behaviour is observed (de Waal 1982, Goodall 1986, Whiten & Byrne 1988, Byrne 1998, Hare et al 2000, Tomasello et al. 2003). de Waal (1982, 1996) asserted that the social sophistication of chimpanzees is similar to that of humans, and that reciprocity among chimpanzees is governed by the same sense of moral rightness and justice as that among humans. As with humans, chimpanzees have long memories, and they plan for the future and cooperate with one another, e.g. during coordinated activities such as foraging and hunting (Boesch & Boesch 1989, Byrne 1998). These advanced cognitive abilities evolved to enable chimpanzees to cope with their relatively complex natural environments and social structures (Goodall 1995). Similarly, the non-verbal communication patterns of chimpanzees are remarkably similar to those of humans. Chimpanzees kiss, hold hands, pat one another on the back, embrace, tickle, punch and swagger (Goodall 1995). Gestural dialects vary between communities (McGrew 1994). Additionally, the ability of chimpanzees to converse with humans using symbols such as computerised lexigrams (Goodall 1995) and American Sign Language is well established, as is their ability to teach and converse with new chimpanzees in the absence of humans (Jensvold & Gardner 2000, Garnder 2002). Calculations of the waiting times between the invocation of new words or symbols, and of the cumulative informational complexity of word use, have demonstrated expressive language structures in chimpanzees that are even described by some as “resembling those from the works of human poets like Shakespeare,” and in short, comparable to those of human beings (Langs et al., 1996). However, chimpanzees in laboratories are frequently confined in small, barren cages, on the assumption that these facilitate cage cleaning, minimise the incidence of diseases, and facilitate regular easy access to the chimpanzees, e.g., for blood sampling. They are frequently caged individually based on the assumption that this avoids the risk of cross-infection. They are frequently confined in laboratories lacking even windows. Many, in fact, are underground (Goodall 1995). Finally, they are involuntarily subjected to potentially harmful experiments including the artificial induction of diseases, and tests of the toxicity and efficacy of chemotherapeutic agents. The advanced cognitive abilities of chimpanzees enhances their capacity for suffering, rendering it impossible in practice to provide laboratory environments that meet their minimum physiological and behavioural requirements, and, in the opinion of a number of experts, unethical to confine them in laboratories for experimental purposes (Balls 1995, Smith & Boyd 2002, p. 3). Despite these highly sentient creatures being in no way responsible for any human grievance, such as the serious diseases we attempt to induce in them, we subject them to conditions that would cause widespread outrage if used to punish the most heinous of criminals—for years on end, and in some cases, for decades. Both the unique biological characteristics of chimpanzees—which are rare in their own right—and also their advanced cognitive, communication and social abilities—which have some similarities with the abilities of humans—provide 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, arguably, captivity (Cavalieri & Singer 1993, Morton 2000). Such an ethical burden applies to any researchers, legislators or others who would consider themselves ethical agents, regardless of the extent to which chimpanzees may or may not prove efficacious in assisting us to further our own scientific or medical goals. Bioethical considerations such as these consequently have profound ramifications for the use of chimpanzees in biomedical research.



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Restrictions on chimpanzee research Largely because of the highly evolved cognitive, communicative, social and other relevant capabilities of chimpanzees, and the consequent public opposition to research on captive chimpanzees, certain countries have banned it altogether. In the UK, experiments on great apes (chimpanzees, gorillas and orang-utans) ceased in the early 1970s or earlier. Special justifications for such research were required under the Animals (Scientific Procedures) Act 1986, and in 1997 a policy ban was placed on these experiments by the Home Office (Home Office 1998, Smith & Boyd 2002, pp. 14-15). Sweden (since 2003, with the exception of non-invasive behavioural studies), Austria (since 2005, unless conducted in the interests of the individual test animal), the Netherlands and New Zealand have formally banned research and testing using great apes. In other countries such as Germany (since 1991), Italy and Norway, great apes have not been used in research or testing for years although national bans have not yet been passed. In 2002, the Belgian minister responsible for animal welfare announced that Belgium would be working towards a ban on all primate experiments (Langley 2006, pp. 12-13). There is increasing recognition that chimpanzees must be retired at the end of their involvement in biomedical research into sanctuaries that provide for their social and psychological well-being, for the remainder of their natural lives (Prince et al. 1989, van Akker et al. 1993), and in 2002 the Netherlands accordingly agreed to fund the re-homing of chimpanzees by the charitable foundation Stichting Aap (Anon. 2004). Several conferences and noteworthy publications have similarly passed resolutions calling for the banning of experimentation on captive chimpanzees. Cavalieri & Singer’s Great Ape Project (1993) presented the collaborative arguments of a distinguished group of 36 leading scientists and philosophers in favour of extending the circle of moral consideration outwards from humans to encompass great apes. These species clearly meet the necessary moral criteria for the granting of certain basic rights, they argued in their ‘Declaration on Great Apes,’ including: 1. The Right to Life; 2. The Protection of Individual Liberty; and 3. The Prohibition of Torture. They consequently called for the banning of experimentation on great apes and of their capture from the wild (Scharmann, 2000). Similarly, the First Conference on the Use of Chimpanzees in Biomedical Experiments in Brussels in 1993 called for an immediate end to the breeding of chimpanzees for biomedical research, their use in such research worldwide, and for the establishment of retirement facilities for research chimpanzees (Anon. 1995). The UK’s Boyd Group comprising experts in primatology, animal welfare, biomedical research and regulatory toxicology, after examining experimentation on NHPs in detail, concluded that the use of great apes in research and testing should be prohibited worldwide (Balls 1995, Smith & Boyd 2002, p. 3). Most recently, at the Fifth World Congress on Alternatives and Animal Use in the Life Sciences in Berlin in 2005, leading primatologist Jane Goodall joined 57 organisations and individuals from 19 countries in calling for an end to the use of all primates in biomedical research and testing (Langley 2006). The vast majority of biomedical research on captive chimpanzees occurs within the US. However, although some assert that US research on captive chimpanzees is governed by international, federal, and state laws, regulations, rules, guidelines, and standards (Meyers 1983), no research ban exists similar to those of other countries, and, contrary to the legislation of other key countries, the US Animal Welfare Act does not even require the use of alternatives to chimpanzees (or other laboratory animal species), when scientifically-valid alternatives exist. Consequently, the level of biomedical research conducted on captive chimpanzees within the US far exceeds those of all other countries combined (Stephens 1995, Conlee et al. 2004). Conclusions The advanced sensory, cognitive, social and communicative abilities of chimpanzees also confer upon them a profound ability to suffer when born into unnatural captive environments or captured from the wild—as many older research chimpanzees once were—and when



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subsequently subjected to confinement, social disruption, and involuntary participation in potentially harmful biomedical research. The justifications for such research proposed by advocates relies upon the crucial contributions they claim it has made towards the advancement of biomedical knowledge, and, in particular, towards combating major human diseases. However, this systematic review of 95 randomly selected studies of captive chimpanzees conducted during a recent decade revealed that half were not cited by any papers subsequently published and included within the comprehensive bibliographic databases examined, demonstrating minimal contribution towards the advancement of biomedical knowledge generally. Given that research of lesser significance is not published at all, these results indicate that the majority of chimpanzee experiments generate data of little further value. Additionally, closer examination failed to identify any chimpanzee studies that made an essential contribution, or, in a disturbing majority of cases, a significant contribution of any kind, towards papers describing well-developed prophylactic, diagnostic or therapeutic methods for combating human diseases. Despite the demonstrably poor utility of chimpanzee experiments in advancing human health, it remains true that they are the species most closely related to human beings. Hence it is highly likely that other laboratory species are even less efficacious when used as experimental models of humans in biomedical research and toxicity testing. Given the many millions of other species used annually for these purposes, particularly in the case of rodents; the profound ethical and financial costs incurred as a result, and the adverse consequences for human health if other, potentially more efficacious research models are consequently deprived of funding, systematic reviews of the utility of other laboratory species in advancing human health are also warranted as a matter of urgency. These ought to be conducted by government agencies with oversight for animal research, and by others with similar responsibilities in the private and academic sectors. Furthermore, almost all of these chimpanzee experiments would have been approved by an institutional ethics committee required by legislation to approve only those experiments likely to result in substantial benefits, given the substantial animal welfare, ethical and financial costs inherent to chimpanzee experimentation. While the concept of ethical review is sound, these results demonstrate that its implementation is seriously flawed. This flaw has resulted from an over-reliance on the assumption that animal experiments are likely to be of substantial use in advancing biomedical progress, in the absence of supportive evidence. In fact, this systematic study and several others that have examined groups of hundreds of animal experiments or more (Bailey et al. 2005, Lindl et al. 2005, Knight et al. 2006a and 2006b) have demonstrated that animals are not, in fact, sufficiently predictive of human toxicity, or of the progression of human diseases, to justify their widespread use as experimental models of humans. No large-scale review of animal experimentation exists that has demonstrated the utility of animal experiments for these purposes that is so frequently assumed by ethics committees. By approving these many hundreds of chimpanzee experiments on the basis of such false assumptions of their utility, the ethics committees responsible failed in their duty to society, and to the animals they were charged with protecting. The introduction of further regulations governing chimpanzee experimentation might be proposed as a solution. However, the financial and administrative burdens imposed on laboratories that conduct biomedical research on chimpanzees, both because of the costly nature of the research itself, and due to the necessity of complying with numerous laws, regulations and standards—which can require a separate in-house administrative program to address (Meyers 1983)—are substantial. Solutions that would involve the imposition of ever more complex regulations designed to further administer this research, rather than terminating it outright, are neither likely to decrease such burdens nor to substantially reduce the welfare-related and ethical costs of biomedical research on captive chimpanzees. Consequently, it therefore seems eminently reasonable to join numerous experts previously (Anon. 1995, Balls



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1995, Scharmann 2000, Smith & Boyd 2002, p. 3, Langley 2006) in calling for the outright banning of biomedical research on captive chimpanzees in those remaining countries—notably the US—that continue to conduct it. Acknowledgements This research was partly funded by the New England Anti-Vivisection Society, Boston, and by a monetary prize awarded to the author by the German Animal Welfare Federation, Neubiberg, for previous research on animal experimentation. The author would like to thank Jarrod Bailey and Jonathan Balcombe for their assistance during the 27 medical paper reviews. References

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Appendix: 95 randomly-selected chimpanzee studies and 27 citing medical papers

Chimpanzee studies Citing medical papers Author(s) Year Journal Cites Author(s) Year Journal

1 Anderson et al. 1997

Clin Immunol & Immunopathol 84(1):73-84 1

2 Anderson et al. 2004

Proc Royal Soc London - Series B: Biol Sci 271(Suppl 6):S468-70 0

3 Baker et al. 2000 Amer J Primatol 51(3):161-75 0

4 Bard 1998

Develop Neuropsych 14(4):471-94 1

5 Bering et al. 2000 Develop Psychobiol 36(3):218-32 4

6 Bertoni et al. 1998 J Immunol 161(8):4447-55 2

Khanna et al. 1999

Immunol Rev 170:49-64

7 Bigger et al. 2001 J Virol 75(15):7059-66 10

Feld & Hoofnagle 2005

Nature 436(7053):967-72

7 Bigger et al. 2001 J Virol 75(15):7059-66

Kim & Wang 2003

Carcinogenesis 24(3):363-9

8 Black et al. 1997

AIDS Res & Human Retroviruses 13(15):1273-82 1

9 Bloomsmith et al. 2003

Anim Welfare 12(3):359-68 0

10 Bloomsmith et al. 2003

Applied Anim Behav Sci 84(3):235-50 0



28

11 Boudet et al. 1996

AIDS Res & Human Retroviruses 12(18):1671-9 0

12 Boysen & Berntson 1995

J Exp Psych: Anim Behav Processes 21(1):82-6 19

13 Brahimi et al. 2001 Infect & Immunity 69(6):3845-52 2

14 Brams et al. 2001

Intnl Immunopharmacol 1(2):277-94 6

Gescuk & Davis 2002

Curr Opinion Rheumatol 14(5):515-21

14 Brams et al. 2001

Intnl Immunopharmacol 1(2):277-94

Tong & Stone 2003

Cancer Gene Ther 10(1):1-13

15 Bukh et al. 2002 Proc Natl Acad Sci 99(22):14416-21 3

16 Butovskaia et al. 1995

Fiziologicheskii Zhurnal Imeni I M Sechenova [Russ] 81(2):89-94 0

17 Buxhoeveden & Casanova 2000

Laterality 5(4):315-30 2

18 Cacchione & Krist 2004

J Comp Psych 118(2):140-8 0

19 Call & Tomasello 1998

J Comp Psych 112(2):192-206 8

20 Cervenakova et al. 2003

Electrophoresis 24(5):853-9 1 Brown 2005

Vox Sanguinis 89(2):63-70

21 Cianelli & Fouts 1998

Human Evol 13(3-4):147-59 0

22 Cong et al. 2000 Virology 274(2):343-55 0

23 Conley et al. 1996 J Virol 70(10):6751-8 10

Armbruster et al. 2004

J Antimicrob Chemother 54(5):915-20

23 Conley et al. 1996 J Virol 70(10):6751-8

Armbruster et al. 2002

AIDS 16(2):227-33

23 Conley et al. 1996 J Virol 70(10):6751-8 Hone et al. 2002

J Human Virol 5(1):17-23

23 Conley et al. 1996 J Virol 70(10):6751-8

Sleasman & Goodenow 2003

J Allergy Clin Immunol 111(2 Suppl iii):S582-92

23 Conley et al. 1996 J Virol 70(10):6751-8 Yang et al. 1998

J AIDS Human Retrovirol 17(1):27-34

24 Cook et al. 1997

J Pharmacol Exp Therap 281(2):677-89 0

25 Crowe et al. 1999 Virus Res 59(1):13-22 1

Kneyber & Kimpen 2002

Pediatric Infect Dis 21(7):685-96

26 Dash et al. 2001 J Med Virol 65(2):276-81 0

27 Digilio et al. 1997 J Virol 71(5):3684-92 0

28 Egger et al. 2002 J Virol 5



29

76(12):5974-84

29 Elkington et al. 2004

Eur J Immunol 34(11):3216-26 0

30 Esumi et al. 2002 Vacc 20(25-26):3095-103 0

31 Fernandez-Carriba et al. 2002

Brain Res Bull 57(3-4):561-4 1

32 Fu et al. 2001 J Virol 75(1):73-82 0

33 Fujii et al. 1997 Neurosci Lett 227(1):21-4 0

34 Fujita 1997

Percept Psychophysics 59(2):284-92 1

35 Gearing et al. 1996

Neurobiol Aging 17(6):903-8 0

36 Goh et al. 1998 Nature Med 4(1):65-71 10 Gallo 2002

Immunol Rev 185:236–265

37 Grob et al. 1997 Nature Med 3(6):665-70 2

Bardsley-Elliot & Perry 2000

Paediatric Drugs 2(5):373-407

38 Hellekant & Danilova 1996

Food Chem 56(3):323-8 1

39 Hellekant et al. 1997

Physiol Behav 61(6):829-41 2

40 Herndon & Tigges 2001

Comp Med 51(1):60-9 0

41 Hook et al. 2002 Appl Anim Behav Sci 76(2):165-76 0

42 Hopkins & Bard 2000

Develop Psychobiol 36(4):292-300 1

43 Hopkins & Russell 2004

Neuropsychologia 42(7):990-6 0

44 Huguenel et al. 1997

Amer J Resp Crit Care Med 155(4):1206-10 6

Suzuki et al. 2001

Chest 120(3):730-3

44 Huguenel et al. 1997

Amer J Resp Crit Care Med 155(4):1206-10

Turner et al. 1999

JAMA 281(19):1797-804

45 Imura 2003 Anim Cognition 6(4):253-8 0

46 Ishikawa et al. 1997

J Toxicol Sci 22(3):207-17 0

47 Jensvold et al. 2001

J Appl Anim Welf Sci 4(1):53-69 0

48 Kojima et al. 2003 Primates 44(3):225-30 0

49 Leavens et al. 2001

Amer J Primatol 55(1):1-14 2

50 Marzke et al. 1999

Amer J Physical Anthropol 110(2):163-78 0

51 Mast et al. 1998 Hepatol 27(3):857-61 13

Obriadina et al. 2002

J Gastroenterol Hepatol 17(Suppl3):S360-4



30

51 Mast et al. 1998 Hepatol 27(3):857-61

Regev & Schiff 1999

Curr Op Gastroenterol 15(3):234-9

51 Mast et al. 1998 Hepatol 27(3):857-61

Worm & Wirnsberger 2004

Drugs 64(14):1517-31

52 Morris et al. 1996 J Parasitol 82(3):444-8 0

53 Nakano et al. 2003 J Parasitol 89(3):439-43 0

54 Negishi et al. 2004 Exp Anim 53(4):391-4 0

55 Nehete et al. 1995 AIDS 9(6):567-72 1

56 Nerrienet et al. 2004

J General Virol 85(1):25-9 0

57 Newman et al. 2001

Clin Immunol 98(2):164-74 2

Hepburn et al. 2003

Rheumatol 42(1):54-61

57 Newman et al. 2001

Clin Immunol 98(2):164-74

Matthews et al. 2003

J Viral Hepatitis 3(7):794-803

58 Obriadina et al. 2002

J Gastroenterol Hepatol 17(Suppl 3):S360-4 1

59 Ogata et al. 1999 Hepatol 30(3):779-86 5 Koff 2002

Digestive Dis Sci 47(6):1183-94

59 Ogata et al. 1999 Hepatol 30(3):779-86

McMahon et al. 2005

Ann Internal Med 142(5):333-41

60 Olikowsky et al. 1997

Immunol 91(1):104-8 4

61 Ondoa et al. 2003 J Med Virol 69(3):297-305 0

62 Palagi et al. 2004 Amer J Primatol 62(1):15-30 1

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66 Pecher & Finn 1996

Proc Natl Acad Sci 93(4):1699-704 1

67 Riska et al. 1999

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68 Robert-Guroff et al. 1998

J Virol 72(12):10275-80 6

69 Rodman et al. 1999

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70 Rollier et al. 2003 Hepatol 38(4):851-8 0

71 Rollier et al. 2004 J Virol 78(1):187-96 2

72 Saito et al. 2003 Primates 44(2):171-6 0

74 Shanafelt et al. 2000

Nature Biotech 18(11):1197-202 0



31

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76 Shoukry et al. 2004

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78 Smithwick & Young 1997

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80 Steiner et al. 1999 J Urol 162(4):1454-61 2

81 Stern & Larson 2001


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84 Timenetsky & Barile 1998

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32

ALTERNATIVE FIGURES: BAR CHARTS

Figure 1: Chimpanzee experiments 1995-2004 (749 total)

363

311

26 23 14 120

50

100

150

200

250

300

350

400

Biology Diseases:virology

Therapeuticinvestigations

Diseases:parasitology

Miscellaneous Diseases: other

Figure 2: Biology experiments (363 of 749)

133

75

37 3427 25 20

9 30

20

40

60

80

100

120

140

Cognit

ion/N

euroan

atomy/N

eurol

ogy

Behav

iour/C

ommun

icatio

n

Immuno

logy

Biochem

istry

Reprod

uctio

n/Endoc

rinolo

gy

Geneti

cs

Anatom

y/Hist

ology

Physio

logy

Microb

iolog

y



33

Figure 3: Virology experiments (311 of 749)

97 97

2912 11 9 8 7 7 6 4 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1

0

20

4060

80

100

120

Figure 4: Therapeutic investigations (26 of 749)

16

43 3

02468

1012141618

Pharmacology Surgicaltechniques\Prostheses

Anesthesiology Toxicology

Figure 5: Parasitology experiments (23 of 749)

6

5

4

3

2

1 1 1

0

1

2

3

4

5

6

7

Plasmodiumfalciparum, P.ovale (malaria)

Onchocercavolvulus

(roundw orm)

Schistosomamansoni

(f latw orm)

Enterobiusvermicularis, E.

gregorii(pinw orm)

Plasmodiumvivax

Balantodiumcoli

Mycoplasmaspp.

Other



34

Figure 6: Other diseases & miscellaneous experiments (26 of 749)

11

8

3

1 1 1 1

0

2

4

6

8

10

12

Labo

rato

ry/H

usba

ndry

Tech

niqu

es

Endo

toxa

emia

Rad

iatio

n st

udie

s

Ben

ign

pros

tatic

hype

rpla

sia

Cre

utzf

eldt

-Jak

ob d

is.

Gas

troin

test

inal

bact

erio

logy

(Bac

illus

thur

ingi

ensi

s)

Myc

obac

teriu

mtu

berc

ulos

is

the poor contribution of chimpanc© experiments to -

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