Animal Rights

Vivisection Activists Willetts, Wells, Lovell-Badge, and Lord Drayson

| by Dr Ray Greek

In the UK currently, animal rights activists are attempting to pressure transport companies to stop making their services available to laboratories that use animals. British Airways, P&O, SeaFrance, DFDS Seaways and many others have complied with the request of the animal rights community. Naturally, the vivisection activist community is crying foul and threatening that the nation’s children will suffer as a result of this action. Dominic Wells from the Royal Veterinary College was quoted as stating: “When only a few companies were affected that wasn't a game changer but it's now getting to the point where enough companies have been intimidated that we can see a potentially massive impact on the collaborative nature of research, and which will slow research progress.” The BBC quoted Science Minister David Willetts as saying: “The use of animals in research remains essential to develop new treatments and drugs, improve our understanding of disease and prove the safety and effectiveness of drugs and chemicals before they go forward for human trials.” Robin Lovell-Badge president of the Institute of Animal Technology wrote in New Scientist: “We constantly see medical benefits from such work. Either by uncovering basic physiology using animal systems or testing a new treatment before human trials, every medical advance will have involved animals at some point.” Note that these spokespeople are saying that animal models are predictive for human response, a scientifically untenable position. (See Are animal models predictive for humans?)

According to the BBC, “the life sciences sector generates some £50 billion a year and employs more than 165,000 highly skilled workers. But that won't last if researchers can't get the animal models they need to study disease and develop new drugs.”

Interestingly this news came as drug companies such as Novartis, Pfizer, GlaxoSmithKline, AstraZeneca, Merck, and Sanofi announced they are cutting back on research for brain and mental disorders. Why? In part because the animal models are so misleading the companies have no idea whether a drug will be effective or have a manageable side effect profile. Eleven drugs for Alzheimer's disease have recently failed industry-sponsored clinical trials.(Unknown 2010) A 2004 Cochrane review of the literature revealed that anti-seizure medications such as phenobarbital and phenytoin controlled seizures less than 50% of the time in the pediatric population.(Booth and Evans 2004) This 50% effective figure appears to be consistent with most drugs on average.(Roses 2000)

Millan et al. (Millan et al. 2012) discussed psychiatric disorders that lead to cognitive impairment. They state that animal models are of little value in predicting human response to drugs” “numerous pro-cognitive agents and mechanisms have been documented in rodents yet little positive feedback has been acquired in patients. . . . Several compounds tested to date (including a GABAA (γ-aminobutyric acid type A) receptor α2 subunit agonist and a dopamine D1 receptor agonist) have not proven to be clearly efficacious . . . despite having solid conceptual and preclinical support; this highlights the uncertain predictive utility of cognitive tests in animals.”

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Geerts, of In Silico Biosciences wrote in 2009: “The tremendous advances in transgene animal technology, especially in the area of Alzheimer's disease, have not resulted in a significantly better success rate for drugs entering clinical development. . . . . It becomes increasingly clear that, despite a similar number of genes for humans and rodents, the expression of specific functional gene polymorphism can be dramatically different. An obvious example is the apolipoprotein B (ApoE) gene in humans, the ApoE4 polymorphism of which is an important risk factor for Alzheimer's disease,l6 with that polymorphism having the Arg at position 112 and 158. In contrast, rodents have only one ApoE version, which is slightly different. . . . In the field of psychiatry, 61 different animal models for schizophrenia have been described, of these were based upon transgene technology; however, it is difficult to assess the predictability of these models for different patient populations. Although classical antipsychotics, such as haloperidol and clozapine, have been said to 'change the phenotype' in many of these models, there has been no systematic study of the effects of a wide variety of different antipsychotics (is. partial agonists or glutamate modulators), including drugs that have shown negative results in clinical trials. In addition, human pathology is often more subtle than is usually achieved in animal models, although gene dosage effects in heterozygous mice sometimes allow for a less exaggerated pathology. For instance, in the human striatum, the increase in free dopamine levels is, at most, 100% in schizophrenia patients compared with healthy individuals in many amfetamine models, free dopamine, as assessed by microdialysis, increases between 300% and 400% in mice. . . . The successful development of new innovative drugs for chronic CNS diseases is in jeopardy and new paradigms need to be explored. The current drug-discovery paradigm is based upon detection of activity and toxicity in animal models; however, these models show a rather limited predictability for the clinical situation. This report presented a number of less appreciated and underestimated limitations of animal models that could explain, in part, the substantial number of failures in the clinic.”(Geerts 2009)

These examples could be easily multiplied.

I frequently discuss the fact that men differ from women in response to drugs and disease and point out that since such is the case, expecting an animal model to predict human response is nonsensical on its face. Along those lines, Canto et al (Canto et al. 2012) published an article in JAMA that revealed women are more likely to die, after presenting to the hospital, from heart attacks than are men. One reason for this is the fact that the symptoms of heart attack (also called a myocardial infarction or MI) are described based on how men experience heart attacks while the symptoms experienced by women can be very different. These differences in symptoms delay the diagnosis leading to a delay in the appropriate intervention and therefore women die. Canto et al discovered that 42% of women experiencing an MI did not report the classic symptoms of heart attack such as pain in the left arm, chest pain, or chest tightness. Women were more likely to report pain in the back or jaw, lightheadedness, shortness of breath, nausea and vomiting.

Men and women are members of the same species but they are also examples of complex systems and very small differences between complex systems can result in opposite outcomes to drugs and disease. Multiply the inter-human differences by several powers of ten and one can begin to appreciate inter-species differences. Contemplate those differences in the light of complexity science and one can understand why using animal models to predict human response to drugs and disease is indeed nonsense. Giri and Bader wrote: "Often, toxicity of a drug candidate is not discovered in preclinical stages until clinical trials are conducted. As an up to date example, TGN1412 (also known as CD28-Super- MAB) is an immunomodulator for the treatment of rheumatoid arthritis. In 2006 clinical trials on six volunteers were carried out using a 500-times lower dose than the dose found safe in animals (Suntharalingam et al. 2006) Nevertheless, four volunteers suffered from multiorgan failure. Clearly, drug testing on animals is unrealistic and causes unforeseen reactions in human clinical trials."(Giri and Bader 2011) And lets not forget that using animals in basic research results in medical breakthroughs at most 0.004% of the time.(Crowley 2003) It does, however, pay the researcher’s mortgage 100% of the time.

Former UK science minister Lord Drayson said that without animal-based research “it is not possible to develop new medicines.” He went on to state that animal-based research was “necessary and that people would ‘suffer and die’ without it.” According to the scientific literature and the experts in drug development, Lord Drayson, as well as those quoted above in support of animal-based research, could not be more wrong. If transport companies ceased bringing in animals for research altogether, the UK and patients in general would benefit.

References

Booth, D., and D. J. Evans. 2004. Anticonvulsants for neonates with seizures. Cochrane database of systematic reviews (4):CD004218.

Canto, John G. et al. 2012. Association of Age and Sex With Myocardial Infarction Symptom Presentation and In-Hospital Mortality. JAMA: The Journal of the American Medical Association 307 (8):813-822.

Crowley, W. F., Jr. 2003. Translation of basic research into useful treatments: how often does it occur? Am J Med 114 (6):503-5.

Geerts, H. 2009. Of mice and men: bridging the translational disconnect in CNS drug discovery. CNS drugs 23 (11):915-26.

Giri, Shibashish, and Augustinus Bader. 2011. Foundation review: Improved preclinical safety assessment using micro-BAL devices: the potential impact on human discovery and drug attrition. Drug Discovery Today 16 (9/10):382-397.

Millan, M. J. et al. 2012. Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy. Nature reviews. Drug discovery 11 (2):141-68.

Roses, A. D. 2000. Pharmacogenetics and the practice of medicine. Nature 405 (6788):857-65.

Suntharalingam, G., M. R. Perry, S. Ward, S. J. Brett, A. Castello-Cortes, M. D. Brunner, and N. Panoskaltsis. 2006. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. The New England journal of medicine 355 (10):1018-28.

Unknown. 2010. News in brief. Nat Rev Drug Discov 9 (7):505-505.