Medical Experimentation and Use

OVERVIEW

Introduction

In human medicine, animals are used for two main purposes:

• As experimental models of human diseases

• For the safety and efficacy (effectiveness) testing of medicinal products (drugs, vaccines, and so on) and devices (heart valves and other prostheses).

Efficacy tests often use animals for both purposes, as researchers use animal models of a human disease to test new drugs and procedures. (Toxicity or safety studies are always done on healthy animals.)

The use of animal models of human diseases goes back to the 19th century, when medical science focused on infectious conditions. However, it soon became clear that it is often difficult or impossible to infect animals with the same bacterium or virus that causes a serious condition in humans. In spite of this serious limitation, animal models were then used in the research of chronic diseases, where the use of animal models is even more problematic than in infectious disease studies.

The causes of chronic conditions like stroke, Parkinson's disease, and heart disease are not completely understood, and these conditions are not the same in animals as in humans. Therefore, to create an animal model of each disease, scientists artificially induce a similar, but not identical, condition in animals. Doing this violates the first and most important principle established by animal researchers, themselves — that human disease can be reproduced in other species, so that the animal model is almost identical to the condition in the human patient.

In safety and efficacy testing, animal studies are also undermined by species differences and by "artifacts of the experimental process" (distortions resulting from unnatural conditions). The fact that the word "medical" is attached to such studies does not mean they are scientifically or ethically valid. The term "medical" is often used by the biomedical establishment in an attempt to fight back criticism and to convince the public that animal experiments are necessary, humane, and important — despite overwhelming evidence to the contrary.

Animal Models of Human Diseases

One of the oldest paradigms in medical sciences stipulates that hypotheses about human diseases must be "proven" in appropriate animal models. The concept of animal models, which was first defined within the context of infectious disease research in the 19th century, implies that human diseases can be replicated in other species, so that the experimental model and the human condition are almost identical. However, this is rarely, if ever, the case.

The father of the animal model paradigm is the 19th century bacteriologist, Robert Koch. According to Koch's famous postulates, in order to scientifically prove that a certain microorganism causes a certain disease in humans, animals must be infected with the same microorganism. Furthermore, the pathogen should cause a similar disease in the animal model, with similar natural history, similar pathological findings and similar clinical presentation.

It is not a coincidence that the birth of the animal model concept was in the realm of infectious diseases. By their very nature, infectious diseases appeared to be easy to model in animals: finding a susceptible species was the sole requirement, so it seemed. But soon, Koch himself discovered that his animal model paradigm didn't withstand practical tests. After isolating the causative agent of human cholera, using non-animal techniques, Koch failed to infect any other species with the microorganism. After trying, in vain, to infect mice, rats, dogs, and monkeys, Koch concluded that his postulates don't have universal application. Furthermore, Koch reached the conclusion that in cases where a microorganism is consistently found in sick human patients, and the same microorganism is absent or almost absent in healthy individuals, the use of an animal model to "prove" the cause-and-effect relationship between the microorganism and the disease is unnecessary.

Yet despite Koch's conclusion, the use of animal models expanded dramatically in the 20th century, and today, animals are used not only to model infectious diseases, but also to replicate chronic conditions, whose causes are vaguely defined. Use of animal models in non-infectious diseases is even more problematic, as the case of stroke could demonstrate. In humans, stroke is the final stage of a lengthy disease process, building throughout the years, in which blood vessels in the brain become increasingly blocked through mechanisms that are only partially understood. In contrast, animal models of stroke involve artificially suturing or closing off arteries that carry blood supply to the brain. Consequently, a temporary halt of blood supply is created, leading to damage to brain cells.

Clearly, this artificial modeling process differs considerably from the origin and manifestation of stroke in humans. First, the animals used are otherwise healthy – their blood vessels are not blocked with fatty deposits, they don't suffer from underlying hypertension, as many stroke victims do, and they don't produce clots spontaneously. Second, the artificial suturing procedure is hardly an appropriate analogy of the complex pathological processes that lead to stroke in humans. Rather, the animal models reflect a sudden interference with blood supply to the brain. Finally, it is not surprising that animal models of stroke have a poor record in predicting clinical efficiency in humans. Of over 14 potential drugs that proved recently to provide protection against neural damage in animal models of stroke, not a single one showed success in clinical trials in actual human patients.

It is, therefore, not surprising that animal models of chronic conditions don't meet the basic requirements of Koch's postulates. But even in the field of infectious diseases, animal models continue to suffer from many shortcomings.

Israel's only primate breeding facility, BFC, exports macaque monkeys, mainly to the UK. (See Our Complicity: Israel's Importing, Breeding, and Exporting of Primates.) From statements submitted to Israeli Courts by the farm owners, it appears that BFC monkeys are shipped primarily to the British National Institute for Biological Standards and Control (NIBSC), where they are used for two purposes: 1. as an animal model of human AIDS; 2. for safety tests of the oral polio vaccine. Thus, BFC monkeys are reportedly used in both types of medical experimentation – animal modeling of human diseases and testing of medicinal products.

The macaque monkey model of AIDS is undermined by serious species differences between humans and other primates. The causative agent of most cases of human AIDS, Human Immunodeficiency Virus-1 (HIV-1), is non-infectious for all other known species, with the exception of chimpanzees. Since the latter are under threat of extinction, and since even in chimps HIV-1 rarely causes a disease, most researchers use macaques, rather than chimps. Since macaque monkeys cannot be infected with HIV-1, researchers in NIBSC and elsewhere use a somewhat similar virus that is found in monkeys (simians), SIV (Simian Immunodeficiency Virus). However, SIV is not identical to HIV-1. In fact, genetic studies show that SIV and HIV-1 are genetically only 40 percent identical. In other words, SIV and HIV-1 are different viruses, with a different evolutionary history and different hosts. HIV-1 doesn't cause diseases in monkeys, while SIV appears not to cause disease in humans. Thus, the leading animal model of AIDS fails to meet the first requirement of Koch's postulates.

In addition, while both SIV and HIV-1 cause immune deficiency syndromes in the appropriate species, there are numerous significant differences between the human and the simian conditions.

Testing of Medicinal Products

The second category of medical experimentation involves the use of animals to test either the efficacy or the safety of medicinal products such as drugs, vaccines, or medical devices. Efficacy studies are often conducted in animal models of human diseases and, as such, they suffer from all the problems associated with such models. Safety tests are conducted on normal, healthy animals. In order to compensate for the low sensitivity of most test animals, artificially large doses of the test drug or vaccine are used. But since the metabolizing of drugs is never the same in animals and in humans, animal tests often produce misleading results, which are further compounded by the artificial dosing regime (see Artifacts of the Experimental Process).

At NIBSC, monkeys sold by BFC are used routinely for safety tests of the oral polio vaccine (OPV). In order to understand the problems associated with the use of monkeys for such purposes, some background information about the two polio vaccines is necessary.

Poliomyelitis or polio is an infectious viral disease caused by 3 sub-types of the virus (polio-1, polio-2, and polio-3), and both vaccines contain all 3 sub-types. The first vaccine, developed in the 1950s by Jonas Salk, contains viruses that have been inactivated. Since this vaccine contains dead viruses only, it is considered highly safe, and no requirement to test it in monkeys has existed since the late 1970s.

In contrast, the second vaccine, OPV, contains live, weakened viruses. In theory and in practice, some of these viruses could revert to virulence and induce, in those receiving the vaccine, the same disease it was meant to prevent. In the U.S., OPV was the only cause of human polio since 1979, and finally, in 2000, American health authorities decided to stop its routine use and to replace it with the inactivated polio vaccine (IPV).

In an attempt to reduce the risk involved in the use of the OPV, which is cheaper and easier to administer, regulatory bodies such as the World Health Organization (WHO) and the Food and Drug Administration (FDA) in the U.S. issued guidelines requiring manufacturers to routinely test any batch of OPV on live monkeys. Since non-primate species cannot be infected with the polio virus, other animals could not be used. The test involves injecting the weakened viruses directly into the spinal cord or brain of live monkeys (separate tests are done for each of the three sub-types of the virus), some of whom may develop paralysis. Following a short observation period, all monkeys are killed, and their spinal cords and brains are dissected to note the pathological changes that occurred after exposure to the virus.

Obviously, the primate test is a grossly artificial experiment. Humans don't get the vaccine injected directly into their central nervous system; rather, they take it orally. In order to compensate for the lower sensitivity of monkeys, the viruses are introduced directly into the central nervous system, which renders the results of the test difficult to interpret. Positive results of the test could be due to the artificial way in which the virus is introduced into the body, or to effects that would occur only in monkeys and not in humans, or they could represent true danger to human recipients of the vaccine. While many batches of the OPV were discarded because of positive results in the monkey test, it appears that many of these batches could have been safe in ordinary use in humans. On the other hand, batches that passed the monkey test still caused dozens of cases of paralysis in humans vaccinated with OPV.

This situation led health authorities in the U.S., France, and elsewhere to eliminate the routine use of OPV and to switch to IPV, which is safer and is not tested on monkeys. Scandinavian countries like Sweden never used OPV. Instead, they controlled polio with IPV alone. And yet, OPV is widely used in many countries, including Israel, since it is cheaper, easier to administer, and has some other advantages over IPV.

In an attempt to allow the continued use of OPV without putting human health at risk, molecular biologists tried a completely different approach. Instead of conducting unreliable tests of vaccine batches in monkeys, they looked for mutations that are associated with virulence. These researchers identified several key mutations that are strongly related to virulence and to paralysis, and later developed a simple test-tube test that can identify these mutations. In 1999, the World Health Organization officially endorsed the use of this test-tube test in the production stages of OPV, and ruled that batches discarded on the basis of this in vitro test need not be tested on live monkeys. In 2000, WHO took another step towards the elimination of monkey use for the safety testing of OPV. An expert committee within WHO decided to drop the requirement for the test in primates altogether. Since 2000, WHO has required the test-tube test followed by a final safety test in genetically engineered mice, made susceptible to poliomyelitis by manipulating their genetic code.

Conclusion

While the continued reliance on animal tests is lamentable, the case of the OPV tests reflects the reality with respect to the implementation of legislation regulating animal experimentation. Both European and Israeli legislation stipulates that animals should not be used when reliable alternatives exist, and that where animals are still used, "lower" animals on the evolutionary scale should be used whenever possible. And yet, despite the official endorsement of one replacement alternative (test-tube experiment) and one refinement alternative (using mice instead of monkeys), macaques from Israel are still being used for the routine safety tests of OPV. Contrary to the statements of vivisectors, animals are often used even when well-validated alternatives exist.