Animal Rights

Basic science using animals

| by Dr Ray Greek

A myth perpetuated by the basic science community that uses animals as predictive models is that most great discoveries are the result of such research. For example:

Animal research has played a vital role in virtually every major medical advance of the last century - for both human and animal health. Thanks to recent medical research breakthroughs, scientists are closer than ever to finding new preventions, therapies, and cures for myriad diseases shared by humans and animals. As yet, there is no complete alternative to biomedical research with animals. The Food and Drug Administration mandates the testing of drugs, medical devices and other promising treatments on animals before they can be safely administered to humans. (1)

From Sir John Vane, originally published in the Pfizer Forum, 1996:

All the medical advances of this century have been the product of both basic and applied research. Although this research has relied on the full range of techniques available, it would have been impossible without animal experiments. Indeed, if one reviews the history of medical science, it is clear that every major medical advance has depended on animal experiments. (2)

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Finally, from the UK-based Understanding Animal Research:

Every major breakthrough in medical science that we know today has depended in part on animals. This doesn't just mean medicines (for diabetes, asthma, leukaemia and many other serious illnesses), but medical procedures too such as blood transfusions and transplant surgery. And it isn't just humans that have benefited. Nearly all of the medicines and medical procedures that we use for animals were also developed through the use of animal research. (3)

The facts are much different. (As is to be expected when evaluating the propaganda masquerading as facts that usually comes from vested interest groups). First of all, many great discoveries were the result of plain old luck. Barnes and Hayes writing in Drug Discovery World 2002:

Iproniazid, the earliest inhibitor of monoamine oxidase, was developed first as a treatment for tuberculosis and only later was it found to elevate mood. The phenothiazines, exemplified by chlorpromazine, started their clinical life as anesthetic potentiators and only later were they shown to reduce paranoia. More recently, we have seen the approval of gabapentin, as an analgesic agent, a milestone that was initiated by clinical findings that certain anticonvulsants could reduce chronic pain. (4) (Also see (5)  (6) (7))

The use of nitrogen mustard, prednisone, and actinomycin D to treat cancer were also discovered serendipitously (8-10). Davis 1985:

Many of the psychotropic drugs were discovered by chance when they were administered for one indication and observed to be helpful for an entirely different condition. The history of the development of both the major antidepressants and the antipsychotic drugs points up the fact that major scientific discoveries can evolve as a consequence of clinical investigation, rather than deductions from basic animal research. (11)

Dunne in Textbook of Adverse Drug Reactions:

In other instances, and notably in the identification of central nervous system activity, animal models are unreliable indicators: some drugs of proven value in man have negligible or paradoxical activity in laboratory animals. Imipramine, for example, is a weak tranquilizer in rodents, and its antidepressant action was detected only as a result of fortuitous experiments in man. Such inconsistencies are an inevitable outcome of fundamental species-determined differences: and doubtless a number of compounds of potential therapeutic value are lost to medicine, having demonstrated little activity in an array of inappropriate animal models. (12)

Antabuse developers designed the drug as an antiparasitic agent. They took it themselves, then had a cocktail and became violently nauseous. Antabuse is now used to discourage alcoholics from imbibing [(13) p99]. Morton A. Meyers wrote the following in 2007 in Happy Accidents: Serendipity in Modern Medical Breakthroughs:

In 1980 a Pennsylvania physician was treating a bald man for high blood pressure with the oral drug minoxidil The doctor was surprised to note new follicles growing on the patient's scalp, and this hair-raising experience soon led to a commercial product. Approved by the FDA for men in 1988 and for women in 1991, it is now sold over the counter in the form of a lotion called Rogaine. It is believed to work by inducing dilation of scalp blood vessels. Balding American men spent $96 million on Rogaine in 2005. Two other drugs related to remedying the problems of either not enough or too much hair were also discovered unexpectedly. Propecia was originally approved to treat benign prostatic hyperplasia, an enlargement of the prostate gland, by blocking a testosterone. This hormone has long been known to be associated with baldness. A drug in pill form was approved in 1997 only for men because it may cause birth defects in women of childbearing age…. [(14) p300-320]

Many drugs have gone from discovery to humans without animal testing and it is a good thing, as most would have been canceled as a result of side effects that do not occur in humans. Ipecac, cinchona bark, digitalis, and the early inhalation anesthetics to name but a few (15). Furosemide, commonly called Lasix, is another example of such a medication. It is a diuretic, used to treat high blood pressure and heart disease. Mice, rats and hamsters suffer liver damage from this widely used drug, but people do not. The drug is metabolized differs from species to species (16, 17). Nabilone produced toxic reaction in dogs but not rhesus monkeys or rats [(25) p7]. Lazzarini et al. 2006:

Drugs which were unsuccessful in animal models were not used in clinical osteomyelitis, with few exceptions. Teicoplanin and linezolid were successful in the treatment of osteomyelitis in clinical trials, despite being completely inactive in two animal model studies of staphylococcal osteomyelitis. Therefore, the value of animal models as predictors of failure should also be carefully assessed. (18)

Navarro and Senior writing the New England Journal of Medicine in 2006:

Statins have been shown to cause elevations of aminotransferase levels and severe liver injury in animals; in humans such elevations are common but rarely, if ever, lead to clinically significant hepatotoxicity. [They reference (19)] (20)

FK 506 (Tacrolimus) was almost shelved before proceeding to clinical trials (21). Researchers stated: “Animal toxicity was too severe to proceed to clinical trial” (22). That was based on experiments with dogs. The researchers went on to experiment with baboons. Different results were obtained with the baboons once again proving that we cannot extrapolate results from one species to another. Test enough species and you are bound to find one that gives you the results you want. Scientists also suggested that the combination of FK 506 with cyclosporin might prove more useful (23). In fact, just the opposite was to be true in humans (24).

Clayson:

Presently, we recognize the ability of the effective antituberculosis drug, isoniazid, to induce lung adenocarcinomas cancer in a wide variety of mice that are susceptible to this tumor. Despite the fact that this drug has been effectively and extensively used since 1953, a period of 24 years, I know of no convincing evidence of its carcinogenic effect in man. Unfortunately, we know of no sure way to differentiate accurately between those drugs and other chemicals which induce cancer in both animals and man and those which although effective in animals, are ineffective in man. (26)

An editorial in Nature Reviews Drug Discovery 2003:

In Tamoxifen’s case, a drug first developed as a potential contraceptive languished for many years before its present application was found. Furthermore, its propensity to cause liver tumours in rats, a toxicity problem that thankfully does not carry over into humans, was not detected until after the drug had been on the market for many years. If it had been found in preclinical testing, the drug would almost certainly have been withdrawn from the pipeline. With the COX2 inhibitors, Rod Flower notes that the transgenic animal models used to test the hypothesis that COX2 would make an anti-inflammatory target gave results that, if relied upon, might have killed the project. Both stories emphasize the role of the dogged researchers who kept their eyes focused on the prize while navigating around obstacles and exploiting any opportunity that came along. It might sound a bit trite, but at the very least we can say that one of the best strategies for drug discovery is to start with a group of people who really want to discover drugs. (27)

As I have said many times, animals can be used in basic science research. Such research however, makes no prediction claims, present or future. In order to obtain funding however, basic researchers who want to use animals feel they must link such research to cures and thus promises are made and checks are written. Perform any research or activity long enough (and in many cases to the exclusion of other worthier modalities) and eventually luck will prevail and something useful will be discovered. But using animals in basic research in order to predict human response is like playing the lottery, in terms of risk, in order to save for retirement. Yes, some people win but the odds are against you wining. Human-based research, whether basic or applied, is like the risk you take with your savings account or certificates of deposit.

I close with the following from evolutionary biologist Massimo Pigliucci in 2010:

There is a long tradition of arguing like this: cherry-picking the few anecdotes that best fit the bill . . . From more modern times, we know the entire field of radioastronomy was made possible by the invention of radar for military purposes, and basic research into the nature of atoms led to the construction (and use) of nuclear weapons during World War II. But for every one of these anecdotes I can marshal hundreds, nay thousands, of examples where there is little to no overlap between basic and applied science. The overwhelming majority of medical research, for instance feeds on previous medical research and only occasionally gets a boost from new discoveries in molecular or cell biology [basic research] . . . Conversely, I assure you that the overwhelming majority of grants I see funded by NSF and similar agencies—and correspondingly the greatest number of research projects that are pursued by faculty and graduate students in basic science departments all over the world—have nothing whatsoever to do with applications if one defines an “application” as a result that is directly useful to human welfare. I am not trying to make the point that basic research is uninteresting, nor am I arguing that there is no connection between basic and applied science. Rather, I am cautioning against simplistic scenarios at both extremes of what is a complex, nonlinear, and highly idiosyncratic spectrum: much basic research goes on without any application at all, and much applied science does not depend (other than in a vague and very straightforward manner) on basic research. (28)

References

1.      Marshall_BioResources. (Marshall BioResources, 2010), vol. 2010.

2.      J. Vane. (AnimalResearch.info, 1996), vol. 2010.

3.      Understanding_Animal_Research. (Understanding Animal Research, 2010), vol. 2010.

4.      J. C. Barnes, A. G. Hayes, Drug Discovery World, 54 (2002).

5.      R. J. Baldessarini, Arch Gen Psychiatry 32, 1087 (Sep, 1975).

6.      A. Caldwell, in Principles of Psychopharmacology. 2nd edition, W. Clark, J. del Guidice, Eds. (Academic Press Inc, 1978),  pp. 9-40.

7.      B. Nicholson, Acta Neurol Scand 101, 359 (Jun, 2000).

8.      O. H. Pearson, L. P. Eliel, et al., Cancer 2, 943 (Nov, 1949).

9.      E. Boesen, Cytotoxic drugs in the treatment of cancer.  (Edward Arnold, 1969).

10.      W. B. Coley, The Post-Graduate 8, 278 (1893).

11.      J. Davis, in Comprehensive Textbook of Psychiatry. Fourth Edition, H. Kaplan, B. Sadock, Eds. (Williams and Wilkins, Baltimore, 1985).

12.      J. Dunne, in Textbook of adverse drug reactions, D. Davis, Ed. (Oxford University Press, New York, 1981).

13.      L. Altman, Who Goes First? The Story of Self-Experimentation in Medicine.  (University of California Press, 1998).

14.      M. A. Meyers, Happy Accidents.  (Arcade Publishing, 2007).

15.      T. Koppanyi, M. A. Avery, Clin Pharmacol Ther 7, 250 (Mar-Apr, 1966).

16.      R. M. Walker, T. F. McElligott, J Pathol 135, 301 (Dec, 1981).

17.      M. Weatherall, Nature 296, 387 (1982).

18.      L. Lazzarini, K. A. Overgaard, E. Conti, M. E. Shirtliff, J Chemother 18, 451 (Oct, 2006).

19.      K. G. Tolman, Am J Cardiol 89, 1374 (Jun 15, 2002).

20.      V. J. Navarro, J. R. Senior, N Engl J Med 354, 731 (Feb 16, 2006).

21.      AMA, JAMA 263, 1766 (Apr 4, 1990).

22.      R. Y. Calne et al., Lancet 2, 227 (Jul 22, 1989).

23.      T. E. Starzl et al., Lancet 2, 1000 (Oct 28, 1989).

24.      J. Neuberger, Hepatology 13, 1259 (Jun, 1991).

25.      D. Morton, in Animal Toxicity Studies: Their Relevance for Ma. CMR Workshop Series, C. Lumley, S. Walker, Eds. (Quay Publishing, Lancaster, 1990),  pp. 3-14.

26.      D. Clayson, in Human Epidemiology and Animal Laboratory Correlations in Chemical Carcinogenesis F. Coulston, P. Shubick, Eds. (Ablex Pub., 1980),  pp. 185-195.

27.      Editorial, Nat Rev Drug Discov 2, 167 (Mar, 2003).

28.      M. Pigliucci, Skeptical Inquirer 34, 19 (Jan/Feb, 2010).