Ethics of Research involving animals
Diseases for which treatments and cures have been difficult to develop
HIV/AIDS
6.33 Mounting epidemiological evidence led to the recognition of the infectious nature of the HIV/AIDS disease in the early 1980s. Shortly after, it was demonstrated through studies with chimpanzees that the primary disease-causing virus, HIV-1, was transmitted in blood and blood products and body fluids. These findings revealed that national blood banks were at high risk of providing contaminated transfusions and transfusion products to patients. Widespread screening of blood supplies was quickly initiated. Two major groups of HIV viruses, termed HIV-1 and HIV-2, were identified, each consisting of a complex range of variants. As the virus replicates in infected people and populations, it generates natural variants that continuously escape and evade the human immune system. In addition, the complexity of the virus within each person depends on their own genetic makeup so that within a population of infected people there develops a large variety of different types of HIV. This rapidly evolving virus population is a ’moving target’, and has become one of the major scientific obstacles facing the medical research community. The virus also has complex interactions with a number of different types of cells within the body, particularly those that have a primary role in the immune system. For these reasons it has not yet been possible to develop a vaccine or effective means of ridding the body of the virus.
6.34 An ideal animal model for HIV-1/HIV-2 infection would have the following features: practicalities such as ease of handling and housing of the animals, a well-characterised physiology and immunology, and readily available species-specific reagents. It would also need to be susceptible to the form of HIV-1 that causes HIV/AIDS in humans or a very closely related virus. The model would require similar routes of infection and target cells, and should develop similar symptoms to those of the human disease.34
6.35 However, no single ideal animal model perfectly reproduces the symptoms of HIV-1 infection and development of the disease in the diverse human population. The primate models that are currently available have inherent limitations.35 Despite the fact that chimpanzees are naturally infected with the virus SIVcpz, which is the most likely forebear of HIV-1 in humans, they are resistant to AIDS. Some macaque species are infected by an HIV-2-related lentivirus called SIVsm, which causes a form of AIDS that closely resembles the human disease. In addition, rhesus macaques are outbred like the human population, and have a similar spectrum of disease outcomes. But while similarities with humans and cross-reactive immunological reagents exist, the current human epidemic is predominantly caused by HIV- 1 and therefore the model does not provide all the features needed. More recently, GM rodents engineered to express human receptors on their cells have provided replacements for primates in certain experiments.36
6.36 Scientists have developed a hybrid virus SIV/HIV-1, termed SHIV, which infects rhesus macaques. This allowed the replacement of chimpanzees with a new model for the research into the HIV-1 disease and potential vaccines. Although some progress has been made in understanding the disease, the HIV/AIDS disease is rapidly changing. The viral variants that are engineered and used in the laboratory are often outdated before they are evaluated against new vaccine candidates.37
6.37 The first two Phase III clinical trials of vaccines in humans have recently failed.38 The strategy pursued was one that had originally seemed effective in a laboratory setting using chimpanzees in the late 1980s and early 1990s. While it is important to consider this example as a possible failure of an animal model to predict the outcome in humans, scientists also assert that it is imperative to closely examine the data and the interpretations made from these studies. It proved possible to protect chimpanzees vaccinated with HIV-1 vaccine strains from closely related viral variants. But when tested in humans, the vaccines were exposed to an extremely wide variety of HIV-1 variants circulating in the population.39 It could therefore be concluded that the failure was primarily a result of invalid extrapolation of data and/or the use of an untested hypothesis by the investigators before proceeding to Phase III clinical trials.40
Cancer
6.38 Cancer encompasses a wide range of complex and different diseases of many different cell types and organ systems, characterised by uncontrolled cell division and abnormal tissue growth. Some forms of cancer are genetically inherited, others are caused by the environment, viral infections or chronic inflammation. Some affect the young whereas others more commonly emerge late in life. Animal research has contributed to many advances in the treatment of cancers, and in contrast to the situation 25 years ago, some cancer types are now largely curable diseases. Nevertheless, cancer remains a leading cause of death in developed countries, and it has been observed that research progress has been slow despite the extensive use of animal models.
6.39 Many animal models in cancer are provided by various strains of rodents. There have been difficulties in translating cancer treatments that are effective in rodents (mostly mice) to humans. This is commonly due to genetic, physiological and immunological differences between the mouse and humans. Primate models of cancer are rare, expensive and the animals are difficult to handle and house. Thus, there is a large gap between ‘proof of concept’ studies in mice and an effective therapy in humans. With a lack of primate models, the genetic differences which remain between humans and mice mean that therapies developed in mice cannot be moved with any confidence to the clinic. The translation of observations from basic research in the laboratory to human cancer trials has often been a slow and disappointing process. Nonetheless, there have been some notable successes such as tamoxifen for the treatment of breast cancer and goserelin for prostate cancer, both developed using experiments in rats and mice
Footnotes33 Rutty CJ (1996) The Middle-Class Plague: Epidemic Polio and the Canadian State, 1936-1937 Can Bull Med Hist 13: 277–314.
34 Adapted from Lewis AD and Johnson PR (1995) Developing animal models for AIDS research – progress and problems Trends
Biotechnol 13: 142–50.
35 Lewis AD and Johnson PR (1995) Developing animal models for AIDS research – progress and problems Trends Biotechnol 13: 142–50.
36 For example, see the description of research at the Biomedical Primate Research Centre, available at:
http://www.bprc.nl/BPRCE/L4/AltRep.html. Accessed on: 27 Apr 2005; Van Maanen M and Sutton RE (2003) Rodent models
for HIV-1 infection and disease Curr HIV Res 1: 121–30.
37 In addition, evidence now indicates that the HIV-1 epidemic is having an impact on the genetics of the human population
that is most heavily affected by the epidemic, thus further increasing the complexity.
38 Cohen J (2003) AIDS Vaccine Trial Produces Disappointment and Confusion Science 299: 1290–1; Cohen J (2003) AIDS Vaccine
Still Alive as Booster After Second Failure in Thailand Science 302: 1309–10.
39 Klausner RD, Fauci AS, Corey L et al. (2003) Enhanced: The Need for a Global HIV Vaccine Enterprise Science 300: 2036–9.
40 See also Lemon R, Dunnett SB (2005) Editorial: Surveying the literature from animal experiments BMJ 330: 977-978. The
authors comment on reviews which claim that animal research frequently fails to prevent problems which arise in later trials
in humans, or once a medicine has been marketed. They refer to a case given to support this view, in which problems arose in human trials of a post-stroke treatment involving the calcium channel blocker nimodipine. They observe that the example is not suited to support a lack of scientific validity of animal research in this area, as the researchers conducting the nimodipine trials failed to take into account publications which showed that the medicine had deleterious effects in animal experiments. The authors highlight the importance of ensuring that all relevant results from animal research are reviewed before commencing a clinical trial of a new treatment, and that care needs to be taken to avoid that scientific, commercial or personal pressures lead to an inappropriately narrow selection of evidence.