December 2011

Article explores the human predictivity of animal models

An article just published in Personalized Medicine has questioned contemporary reliance on animal models for investigating human diseases and responses to pharmaceuticals. The authors note that humans and animals are complex systems, in which small changes in initial conditions - including genetic makeup - can dramatically alter outcomes. One result is that animal models are often poorly predictive for humans. The article explores at length the relevant characteristics of complex systems, and genetic differences between and within species.

Assessing the necessity of chimpanzee experimentation

On December 15th, the Institute of Medicine (IOM) released Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity. The report responded to a National Institutes of Health request for expert guidance on the scientific need to use chimpanzees within such research.

The IOM committee concluded that most current use of chimpanzees for biomedical research — including RSV vaccine, therapeutic hepatitis C (HCV) vaccine, and HCV antiviral drug development — is not warranted, with the possible exception of two very limited research uses: for the production of monoclonal antibodies (mAbs) and the development of prophylactic HCV vaccines. The committee stated, “it will be very difficult to defend the necessity of nearly all current biomedical research on chimpanzees.” Yet it stopped short of recommending an outright ban (Altevogt et al 2011).

Even this limited support of invasive chimpanzee research is questionable, however. The committee noted that, “Production of monoclonal antibodies after immunization in other species or through in vitro synthetic methods is equally powerful for the generation of such reagents.” They also noted four methods currently in use that lessen the need for safety tests of mAbs in chimpanzees. However, they still supported the use of chimpanzees for mAbs developed using older technologies, although they expected such use would cease within five years. Yet, it would seem far more ethical, and could also potentially yield safety, efficacy and financial benefits, if the most modern technologies were used without delay. As Bettauer (2011) noted with respect to chimpanzee use in mAb research and drug development, “Available alternatives, together with ethical and economic reasons, suggest that the use of the chimpanzee in this manner may not be necessary or appropriate.”

The committee noted that HCV antiviral drug and therapeutic vaccine development does not require the use of chimpanzees, but were uncertain about their necessity for the development of prophylactic vaccines. However, they also noted the existence of alternative research strategies: “studies in consenting individuals at high risk for natural HCV infection can be ethically done provided that these vaccines are first shown to be safe and immunogenic in experimental animals, such as mice and nonhuman primates”. After reviewing 109 chimpanzee HCV studies, Bettauer (2010) found considerable problems with statistical validity, repeatability, and the biological relevance of the chimpanzee model. Bailey (2010) similarly found that, “claims of the necessity of chimpanzees in historical and future hepatitis C research are exaggerated and unjustifiable, respectively.” He concluded that, “Unfounded claims of its necessity should not discourage changes in public policy regarding the use of chimpanzees in US laboratories.”

Although the committee failed to identify any current biomedical research field in which invasive chimpanzee studies are definitely necessary, it concluded that, “a new, emerging, or reemerging disease or disorder may present challenges to treatment, prevention, and/or control that defy nonchimpanzee models and technologies and thus may require their future use. Therefore, an outright ban on biomedical chimpanzee research would not be appropriate.”

In reaching this conclusion, however, the committee made very little mention of the profound animal welfare and ethical problems raised by invasive chimpanzee research. The advanced cognitive, sociological and related characteristics of chimpanzees render their use particularly ethically problematic. Such research is also particularly costly. Accordingly, the concrete benefits of such research — particularly in advancing human healthcare — must be particularly substantial, obvious and verifiable, in order for it to be ethically and fiscally justifiable. Yet the relevant systematic reviews published to date suggest that this is not the case. The contributions of invasive chimpanzee research to biomedical progress appear highly questionable, and it rarely, if ever, makes important contributions to clinical interventions efficacious in human patients (Bailey 2008, 2008 & 2010, Bettauer 2010 & 2011, Knight 2007 & 2008).

This is why almost all nations that have considered invasive chimpanzee experimentation have implemented policy or legislative bans on such research, with the exception of noninvasive observational or behavioural research, or research conducted at ensuring the survival of the individual in question, or of the species. Only the US, and possibly Gabon — whose status is unclear — are known to persist with invasive chimpanzee research.

The US should utilize the opportunity afforded by the Great Ape Protection and Cost Savings Act of 2011 to similarly ban invasive chimpanzee experimentation. This would not require the banning of all chimpanzee research, however. Clear-cut examples include non-invasive observational or behavioural studies of free-living or sanctuary chimpanzees; the education of veterinary students and veterinary medical technicians via participation in beneficial clinical or surgical procedures on genuine animal patients; and experimental treatment of chimpanzees genuinely suffering from severe, naturally occurring disease or injury, when conventional treatment is ineffective. Rigorous implementation of policies such as these would restore to chimpanzee research the balance between human and animal interests expected by society, and demanded by detailed ethical review.

Instead however, the committee concluded that invasive chimpanzee research would be acceptable if it met certain criteria: the knowledge gained must be necessary to advance public health; the research cannot ethically be done on a human being, and is impossible using other species or inanimate research tools; and the chimpanzees used in the research must be given appropriate living conditions. Additionally, forgoing the use of chimpanzees for the research in question must significantly slow or prevent important advancements to prevent, control, and/or treat life-threatening or debilitating conditions. For studies of comparative genomics and behavioural research, the criteria were that studies must provide otherwise unobtainable insight into comparative genomics, normal and abnormal behaviour, mental health, emotion, or cognition; and that all experiments must be performed on acquiescent animals (who participate voluntarily, without coercion), using techniques that are at most minimally invasive, painful or distressing.

NIH Director Francis Collins reportedly accepted the committee's recommendations. The NIH will not award any new grants for such research until an assessment process is in place, and a project-by-project review will be conducted to determine if ongoing research fits the criteria. Dr Collins estimated that about 37 research projects might be affected, of which perhaps half could be discontinued (Anon. 2011).

See the Washington Post for further information. Further information about the IOM report is available here.

References (most available here)

• Altevogt BM, Pankevich DE, Pope AM, and Kahn JP. Guiding limited use of chimpanzees in research. Science epublication ahead of print 15 Dec. 2011. DOI: 10.1126/science.1217521.
• Anon. NIH to adopt strict new limits on using chimpanzees in medical research, saying most unneeded.
The Washington Post 15 Dec, 2011., accessed 15 Dec. 2011.
• Bailey J. An assessment of the role of chimpanzees in AIDS vaccine research.
Altern Lab Anim 2008; 36: 381–428.
• Bailey J. An examination of chimpanzee use in human cancer research.
Altern Lab Anim 2009; 37: 399-416.
• Bailey J. An assessment of the use of chimpanzees in hepatitis C research past, present and future: 1. validity of the chimpanzee model.
Altern Lab Anim 2010; 38: 387-418.
• Bettauer RH. Chimpanzees in hepatitis C virus research: 1998–2007.
J Med Primatol 2010; 39: 9-23.
• Bettauer RH. Systematic review of chimpanzee use in monoclonal antibody research and drug development: 1981-2010.
ALTEX 2011; 28(2): 103-16.
• Knight A. The poor contribution of chimpanzee experiments to biomedical progress.
J Appl Anim Welf Sci 2007; 10(4): 281-308.
• Knight A. The beginning of the end for chimpanzee experiments?
Philos Ethics Humanit Med 2008; 3:16 (2 June 2008).

Scientists question value of primate experiments

Public surveys have consistently shown the general public to be uneasy about the use of non human primates in scientific research. For example, 80 per cent of respondents to the European Commission’s public consultation on the revision of Directive 86/609/EEC, which directs laboratory animal use in EU member states, responded that the use of primates in laboratories was “not acceptable”.

Now, a team of scientists, including a professor of neuroscience based at the University of California in San Diego, has published an analysis that questions not just the ethics of using these animals in research, but also the science that underpins their use as ‘models’ of human diseases. The article, published December 6th, 2011 in the online peer-reviewed journal Medicolegal and Bioethics, represents a rare challenge to the use of non human primates in science. It was published in response to the 2011 Review of Research Using Non-Human Primates by Bateson and colleagues, which concluded that 91% of 67 primate studies conducted from 1997 – 2006 were ethically justifiable.