Rapid Responses to:

EDUCATION AND DEBATE: Pandora Pound, Shah Ebrahim, Peter Sandercock, Michael B Bracken, and Ian Roberts Where is the evidence that animal research benefits humans? BMJ 2004; 328: 514-517 [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

A Plea for Mercy

Irene Mazis   (27 February 2004)

Systematic Review of Animal Research

Aviel Roy-Shapira   (28 February 2004)

The power of one

Richard G Fiddian-Green   (29 February 2004)

the culture of secrecy in animal experiments

Michael C Morris, Wellington 5 New Zealand   (1 March 2004)

Perverse Logic

Danny Penman   (1 March 2004)

Where is the evidence it doesn't?

Paul R Matthews   (2 March 2004)

"From the Bench to the Bedside to the Pharmacy": Contributions of Animal Research to Survival and Quality of Life for Preterm Infants

David M. Coulter   (2 March 2004)

Journalists shouldn't think in black or white

mark sillender   (2 March 2004)

Medicine needs rational knowledge from all sources.

Andre E McLean   (3 March 2004)

The title is misleading and damaging.

Patrick Vallance   (4 March 2004)

two pieces to add to the debate

Nathan M Nobis   (5 March 2004)

The evidence is all around us

Y. S. Bakhle   (5 March 2004)

Animal Research and Human Benefit

Colin Blakemore, Tony Peatfield, Head of Policy, Medical Research Council   (8 March 2004)

Re: Animal Research and Human Benefit

Paul A Dawkins, Robert A. Stockley   (9 March 2004)

Human holocaust - Animal holocaust

Sheila Edwards   (9 March 2004)

An unavoidable bias, and an important role for systematic review and meta-analysis in neuroprotection

Malcolm R Macleod   (11 March 2004)

Animals matter, too

Jonathan Balcombe   (12 March 2004)

There is no evidence-base for animal research

Susan Green   (15 March 2004)

Re: There is no evidence-base for animal research

Paul R Matthews   (16 March 2004)

Re: A Plea for Mercy

Roelof A. Bijkerk   (17 March 2004)

Re: Re: A Plea for Mercy

Irene Mazis   (17 March 2004)

The invalidity of animal experiments

Michael C Morris   (18 March 2004)

Confusion of two issues

J Martin B Dace   (18 March 2004)

The need for a thorough review of the efficacy of animal experiments

Richard W Tweedy   (18 March 2004)

There remains an urgent need for systematically reviewing the results of animal experimentation

Pandora Pound, Shah Ebrahim, Peter Sandercock, Michael B Bracken, Ian Roberts   (23 March 2004)

Re: Animal Research and Human Benefit

Marlene A. Thompson   (25 March 2004)

Point of (duplicate) information

ROBERT BEDDOWS   (25 March 2004)

Lack of accuracy on the first meta-analysis of experimental animal studies

Alejandro A. Nava-Ocampo, Angélica M. Bello-Ramírez, Research Fellow, Faculty of Pharmacy, University of Toronto, Toronto, Canada   (23 April 2004)

Animal studies can endanger humans

Alfred N Jackson   (6 May 2004)

Paper by Pound et al. validates the use of animals in research

Jürgen V Seier   (20 May 2004)

False Dichotomies

John A Mercer   (11 August 2004)

Re: False Dichotomies

Michael C Morris   (15 August 2004)

Not in the good name of medical research?

Edward J H Moore   (17 March 2005)

Cancers increases caused by ignoring animal research

Ellen C G Grant   (18 March 2005)

The evidence is right in front of you

Leigh Jackson   (8 July 2006)

A Plea for Mercy 27 February 2004
Irene Mazis, librarian Private H3Z 1J5 Send response to journal: Re: A Plea for Mercy	How can I make a convincing plea to the medical community that a day will come when man will be ashamed of these experiments on cognizant creatures unable to defend themselves. Surely, our superiour position on the planet doesn't justify such tyranny. I beg the physicians to find another way to experiment, indirectly or mechanically or through computer animation. Irene Mazis CANADA Competing interests: Consumer of drugs (all at least 50 yrs old)
Systematic Review of Animal Research 28 February 2004
Aviel Roy-Shapira, Consultant Surgeon Depts of Surgery and Critical Care Medicine Soroka University Medical Center Send response to journal: Re: Systematic Review of Animal Research	The authors claim that because animal research is often poorly done, animal research, in general, should be critically and systematically reviewed. This is a non-sequitor. Clinical research is often poorly done too. Do the authors propose to critically review clinical research? Competing interests: I have been engaged in animal research
The power of one 29 February 2004
Richard G Fiddian-Green, None None Send response to journal: Re: The power of one	During a lecture given to medical students on peptic uleration some 23 or 24 years ago I told them that the focus of ulcerogenic influences occurred where acid chyme mixed with pancreatic bicarbonate secretions, that the back-diffusion of acid caused the intramural pH to fall, and that the fall in intramural pH appeared to be the final common pathway for acute mucosal injury in animals. The thinking at the time was that the back-diffuson of hydrogen ions might be the cause of stress ulceration. A student made the most profound of observations. "But", he said, acid crosses red cell membranes as carbon dioxide not as hydrogen ions". Some days later I had my technician ligate oesophagus and pylorus on two dogs and introduce into the one stomach a fixed abount of HCl and into the other an equimolar amount of HCl and simultanously an equimolar amount of NaHCO3 (1). All of the acid disappeared from the stomach of the second dog but almost none disappeared from the stomach of the first dog. I developed the indirect tonometric method for calculating intramucosal pH in order to determine the effect the back-diffuson of CO2 might have had upon intramucosal pH. To validate the method I had my technician measure the pCO2 in saline instilled in a Gortex balloon, to facilitate aspiration without contaminating enteric contents, introduced into the lumen of the small bowel and measure the pH in the submucosal space with a pH microprobe. It was only when we divided all sources of collateral blood supply, which we found had to include transecting the bowel above and below the balloon to eliminate the remarkably efficient collateral flow from adjacent well perfused bowel, that we were able to make the intraluminal pCO2 rise impressively. It was apparent from the first successful experiment that the intramucosal pH, derived from the intraluminal pCO2 and arterial bicarbonate, was better able to detect the gut ischaemia than the pCO2 alone. In retrospect this may have been because my technician was not very good at controlling the ventilator and the arterial pCO2 fluctuated. The clinial significance of the observation was immediately apparent for intestinal ischaemia was notoriously difficult to detect before transmural infarction had occured following abdominal aortic surgery. After repeating the experiment to be sure of the findings I found a patent lawyer and filed the first of my 14 patents on tonometry (2). The first journal article showing the value of gasric tonometry in acutely ill patients was published in 1983 (3). The first showing its value in abdominal aortic surgery was published in 1986 (4). The patent was not issued until 1987, the initial applications having been rejected by the examiner. In the 23 years that have elapsed since filing the patent Pubmed lists 1415 papers that have been published on gastric tonometry and 123 on sigmoid tonometry. I wonder just how much longer it will be before what was obvious to me as a clinican from the very first successful animal experiment I performed will become incorporated into routine clinical care. Many of the Pubmed references concern animal experiments. As a clinician what I find of interest is that some if not many of these experiments appear to have been performed to determine whether the observations made in clinical studies and the conclusions drawn are valid. Some studies are quite obviously been me-too studies and have not added anything the published literature. I am sure, however, they have added to local knowledge and experience. One fact is certain. Tonometry could not have evolved without animal experiements. 1. Fiddian-Green RG, Pittenger G, Whitehouse WM Jr. Back-diffusion of CO2 and its influence on the intramural pH in gastric mucosa. J Surg Res. 1982 Jul;33(1):39-48. 2. Fiddian-Green RG. US patent: 4,643,192 Hollow viscus tonometry. February 17, 1987. 3. Predictive value of intramural pH and other risk factors for massive bleeding from stress ulceration. Gastroenterology. 1983 Sep;85(3):613-20. 4. Fiddian-Green RG, Amelin PM, Herrmann JB, Arous E, Cutler BS, Schiedler M, Wheeler HB, Baker S. Prediction of the development of sigmoid ischemia on the day of aortic operations. Indirect measurements of intramural pH in the colon. Arch Surg. 1986 Jun;121(6):654-60. Competing interests: Patents filed in my name
the culture of secrecy in animal experiments 1 March 2004
Michael C Morris, ex senior lecturer 57 Cornford St Karori, Wellington 5 New Zealand Send response to journal: Re: the culture of secrecy in animal experiments	The paper by Pandora Pound et al in the recent issue of the British Medical Journal (1) provides a valuable addition to the scientific debate over animal testing. The assertion that animal experimentation has no medical benefit due to the inherent difficulty of extrapolating from animals to humans is not new (2-4). Previous authors have based this assertion on the general scientific principle that small differences in the structure of complex systems such as human and animal bodies can manifest themselves in a vastly different cellular biochemistry and physiology, and it is this difference which makes extrapolation from animals to humans unreliable (3-4). What is new in the Pound study (1) is the description of a methodology for testing this assertion, together with experimental confirmation on the invalidity of animal experimentation through meta-analyses of animal and clinical studies. The authors' conclusion is that there is an urgent need for formal evaluation of animal experiments. Such a formal evaluation will require more openness among animal experimenters, and a greater willingness to be held accountable for the decisions they make to continue with animal experiments. Sadly, this will not be easy to achieve. In New Zealand for example, the Animal Welfare Act stipulates that experimenters must "promote efforts to reduce the numbers of animals used in research, testing and teaching to the minimum possible". The Act also states that the benefits derived from the use of animals must not be outweighed by the likely harm to the animal. Each institution conducting experiments has to set up an animal ethics committee whose job it is to assess animal experimentation on these criteria. I have conducted two reviews of recent published agricultural animal experimentation (5,6), and one of experiments on control of a vertebrate pest (7) in New Zealand. During the course of these studies I came across a number of cases where animal ethics committees failed in their statutory obligations. In some experiments the only application was economic gain, yet the suffering was "severe" or "very severe" according to the government scale. Other experiments duplicated work already done, and yet others used far more animals than required due to an incomplete understanding of statistics. The failings of the animal ethics committees are exacerbated, or perhaps partly caused, by the secrecy involved in animal experimentation. In contrast with the ethics committees overseeing experimental work on humans, animal ethics committees are stacked with active researchers from the same institute as the one conducting the experiment, meet behind closed doors, and strongly resist any attempts by the public to find out what is going on in the laboratories (8-10). As a first step in achieving an evaluation of animal experimentation, it is vitally important that the "veil of secrecy" (9-10) in the animal experimentation industry is lifted, and that greater public debate is encouraged. 1. Pound P; Ebrahim S; Sandercock P; Bracken MB; Roberts I et al. Where is the evidence that animal research benefits humans. British Medical Journal 2004; 328: 514-517. 2. Barnard, ND.; Kaufman, S. R. 1997: Animal research is wasteful and misleading. Scientific American, February 1997: 64–66. 3. LaFollette H; Shanks N. Animal experimentation: the legacy of Claude Bernard. International Studies in the Philosophy of Science 1994; 8: 195–210. 4. Greek CR; Greek JS. Specious science: How genetics and evolution reveal why medical research on animals harms humans. New York: Continuum. 5. Morris M. C. Issues associated with research on sheep parasite control in New Zealand—a descriptive ethic. Journal of Agricultural and Environmental Ethics 2003; 16: 187–207. 6. Morris MC; Weaver SA. Minimising harm in agricultural animal experiments in New Zealand. Journal of Agricultural and Environmental Ethics 2003; 16: 421–437. 7. Morris MC.; Weaver SA. Ethical issues associated with possum research and control in New Zealand. Journal of Agricultural and Environmental Ethics 2003; 16: 367–385. 8. Cowperthwaite A. Animal ethics committees and the accountability of animal research, testing and teaching in New Zealand. LLB (Hons.) dissertation 2003; The University of Auckland. 9. Bourke D.; Eden, M. Lifting the veil of secrecy on live animal experiments. Christchurch: The Coalition against Vivisection, 2003. 10. Kedgley S. Lifting the veil of secrecy surrounding animal experimentation. in: Lifting the veil: finding common ground. ANZCCART Proceedings, ANZCCART, Wellington, New Zealand, 2004. Competing interests: I used to support animal experiments, and applied (unsuccessfully) to a funding agency in 1990 to work on a lamb "model" for sudden infant death syndrome. Since 1998 I have actively supported a ban on animal experimentation for ethical and scientific reasons.
Perverse Logic 1 March 2004
Danny Penman, Journalist London Send response to journal: Re: Perverse Logic	Unless I'm very much mistaken, stomach ulcers are generally caused after infection by H. pylori rather than stomach acid per se. It seems that Fiddian- Green has reinforced the notion that animal experiments are a poor guide to human disease rather than the opposite. I don't think that was his aim. The gulf of mutual incomprehension between the medical establishment and the animal welfare movement is as wide as ever. Yours sincerely. Danny Penman Competing interests: None declared
Where is the evidence it doesn't? 2 March 2004
Paul R Matthews, Graduate Student Dept Psychiatry, University of Oxford OX3 7JX Send response to journal: Re: Where is the evidence it doesn't?	Rather than "[shedding] the most light on the contribution that animal research makes to clinical medicine" most of the systematic reviews of animal models in this article were prompted by unsuccesful clinical trials in humans. The remainder appear to have been prompted directly by inconsistency between animal models and clinical data. This suggests a publication bias in systematic reviews of animal models (under this search stategy) which renders the conclusions reached in the paper invalid. It seems intuitively plausible that animal models in those fields which lead to unsuccesful clinical trials or inconsistency are of poor quality but the findings cannot generalise to all animal models. Reviews following unsuccesful clinical trials: Horn et al 2001; Lucas et al 2002; Roberts et al 2002, Mapstone et al 2003; Lee et al (2003). The unpublished Ciccone & Candelise review followed "the finding that clinical trials of thrombolysis for acute stroke had found a substantial excess risk of intracranial haemorrhage that had not been predicted by individual animal studies". The Petticrew & Davel Smith paper is also a review highlighting the inconsistency of primate models of stress and coronary heart disease with human epidemiology. Competing interests: None declared
"From the Bench to the Bedside to the Pharmacy": Contributions of Animal Research to Survival and Quality of Life for Preterm Infants 2 March 2004
David M. Coulter, Associate Professor of Pediatrics University of Utah School of Medicine, 30 North 1900 East, Salt Lake City, UT, 84132-2202. USA Send response to journal: Re: "From the Bench to the Bedside to the Pharmacy": Contributions of Animal Research to Survival and Quality of Life for Preterm Infants	Pound et al ask, "Where is the evidence that animal research benefits humans?" The authors need look no further than the fields of perinatology and neonatology for an answer to this provocative question. Two therapies, prenatal treatment with glucocorticoids to improve neonatal pulmonary function and the use of surfactant to treat respiratory distress syndrome (RDS), both solidly based on animal research, have markedly improved survival and decreased morbidity of premature babies. Dr. Avery has elegantly summarized the history of antenatal therapy with glucocorticoids (1). This story began with the seminal observation by Liggins that after prenatal treatment with glucocorticoids preterm lambs exhibited precocious aeration of the lungs. It evolved through further animal experiments that delineated the effects of steroids on synthesis of pulmonary surfactant. Then large controlled human studies documented similar effects in preterm babies. The risk of RDS decreased (Odds Ratio [OR] <0.4) and mortality decreased (OR <0.7). These studies further demonstrated that prematal steroids substantially reduced the risk of severe complications of prematurity: intraventricular intracranial hemorrhage, a cause of death or severe brain injury) (OR 0.4), and necrotizing enterocolitis., a cause of death and long-term morbidity) (0R <0.4) (2). An NIH concensus conference later that year endorsed prenatal treatment with steroids. No adverse long-term effects are known when steroids are employed as a single course of treatment in women with threatened preterm delivery. This use of steroids has become "standard of care" worldwide. The prophylactic and therapeutic use of surfactant for RDS has a similar history and denouement. The seminal discovery that lungs of infants dying with RDS are deficient in surfactant (3)led to animal research that described the ontogeny of surfactant synthesis in the fetus, defined the role of pulmonary surfactant in treating experimental RDS, and led to development of exogenous surfactant preparations that could be used to treat RDS. Multiple prospective controlled trials of surfactant therapy in premature babies ensued. They demonstrated that treatment is effective in reducing mortality from RDS and is devoid of long-term complications (4). Exogenous surfactant preparations are in use worldwide to prevent or treat RDS in preterm infants. Advancing "from the bench to the bedside to the pharmacy" (5), these two therapies provide a paradigm of the applicability of animal research to the improvement of human health. They provide an unequivocal answer to the question posed by Pound et al. Many other problems of the newborn infant remain to be addressed. These questions demand investigation in appropriate animal models to provide a better understanding of mechanisms of disease, studies which are underway in centers around the world. These investigations in turn should generate therapeutic concepts that require animal testing before advancing to human trials. For example, ongoing animal studies in this institution are addressing the pathophysiology of bronchopulmonary dysplasia and the mechanisms of respirator-induced lung injury in premature animals. The goal of these studies is to identify potential therapies to prevent chronic lung disease in premature babies and to improve respirator management of these fragile patients. In no way do I intend to suggest that inadequately designed and poorly conducted research in animals is justifiable or useful. Pound et al raise important issues about the quality and utility of some animal studies. However, it is obvious that all research in animals cannot be tarred with the same brush. Important, significant improvements in human health and well being have resulted and continue to evolve from appropriately conducted research in animals. 1. Avery ME. Historical overview of antenatal steroid use. Pediatrics 1995;95:133-135. 2. Crowley PA. Antenatal corticosteroid therapy: A meta-analysis of the randomized trials, 1972-1994. Am J Obstet Gynecol 1995;173:322. 3. Avery ME, Mead J. Surface properties in relation to atelectasis and hyaline membrane disease. Am J Dis Child 1959;97:517. 4. Jobe A. Surfactant treatment in Fetal and Neonatal Physiology, 3rd ed, (Polin RA, Fox WW, Abman SH, eds), Saunders, Philadelphia, 2004, p1074. 5. Avery ME. Surfactant: Historical perspective in Fetal and Neonatal Physiology, 3rd ed, (Polin RA, Fox WW, Abman SH, eds), Saunders, Philadelphia, 2004, p1003. Competing interests: None declared
Journalists shouldn't think in black or white 2 March 2004
mark sillender, SpR O&G Oxford Send response to journal: Re: Journalists shouldn't think in black or white	Penman is not mistaken about the aetiology of stomach ulceration, but did he read (or understand) Fiddian-Green's response? It seems to me that F-G used his understanding of the aetiology of peptic ulceration to develop (with the help of animals) a test for 2 seperate conditions. They were: bleeding from an ulcer (distinct from just ulceration); or bowel damage folowing vascular surgery. He then alludes to the needless repetition of animal experiments. I think many doctors would disapprove of unnecessary animal suffering, accept the limitations of animal studies, and hope to work towards other experimental methods. It isn't black or white however. Animal experiments have led to the alleviation of much human suffering. Perhaps the gulf of mutual incomprehension between the medical establishment and the journalistic movement is as wide as ever. Competing interests: None declared
Medicine needs rational knowledge from all sources. 3 March 2004
Andre E McLean, Professor of Toxicology emeritus Dept ClinicalPharmacology . UCL Medical School . London WC1E 6JJ Send response to journal: Re: Medicine needs rational knowledge from all sources.	Pound and colleagues(Feb 28th p514) ask the question whether there is evidence that animal research benefits humans. They try to answer their question by looking for published systematic reviews of animal and clinical research on the same topic, to see if these two approaches give the same answer. They find plenty of poorly designed and executed experiments, and conclude that animal experiments are useless.That is not surprising,they were looking in the wrong place. First, most clinical research cannot even be thought of without the previous accumulated understanding of how the body works and how pathology develops, and how much of biochemistry is similar between species. All that knowledge is as basic to research as learning to read or understand numbers, but there are no systematic reviews of literacy as an essential for research. Secondly much animal work is concerned with deciding whether it is reasonably safe for a study to go ahead in humans , after an idea has developed from basic science. Much of the animal safety data is in pharmaceutical industry files, and never published,and that is a separate scandal. I doubt that even the authors would be prepared to try, say , a new anti-malarial drug in patients , without some animal data to give a reasonable expectation that the patients would not drop dead, or the new drug stay in the body for ever. Unfortunately there are no reliable in vitro methods to predict overall toxicity, and even animals tell us little about chronic toxic effects, so we are left with imperfect safety assessments based on animal studies, which are the best we have to tell us if it is reasonable to proceed to human studies. Let me cite two examples from my own field of interest . There are observations that rats fed a diet deficient in vitamin E and Selenium develop fatal liver necrosis . No such disease exists in humans, but Kesan heart disease found in selenium deficient areas of China killed thousands of children,over many years. The idea that selenium was an essential element , and deficiency could cause cell damage led to the large scale trials of selenium supplementation , and successful prevention of the disease. It shows that the link is more complex than Pound et al imagine.It is a vital link but not so direct as to be measurable by the simple methods that they use. In the treatment of paracetamol overdose the effective methods are giving SH compounds that are glutathione precursors. No one could have guessed this from epidemiology, or bedside observation. It needed a long line of animal experiments on essential amino acids, and the glutathione depleting effects of a number of poisons.Later on we needed epidemiology to show that treatment with methionine or n-acetyl cysteine worked in the first 8 – 12 hours. Now, to develop treatment for the later stages , we need to go back to experiments using cells , receptors, molecular biology, and back to mice and then people again. The conclusions that I draw from their paper is that poorly designed experiments give no useful information, bad science does not produce good medicine , and that in the long run we benefit from the ideas about how molecules may be organised to form people, and illnesses, or poetry . Competing interests: None declared
The title is misleading and damaging. 4 March 2004
Patrick Vallance, Professor of Medicine UCL, WC1E 6JJ Send response to journal: Re: The title is misleading and damaging.	The article by Pound and colleagues raises many important issues that need to be discussed. Of course animal experiments should only be undertaken if they address an important question, if there is no other reasonable way to answer the question, if the experimental design is correct, if the number of animals to be used is the minimum necessary to provide adequate statistical power, if suffering is kept to an absolute minimum and if the study isn't an unecessary repeat of earlier work. I suspect they are right that there is room for improvement in many of these areas. However where I disagree strongly with the article is in the inference drawn from their brief survey. In the introduction they attempt to distinguish between "clinical" and "scientific" contribtuions. Indeed the article is largely based on observations on the potential of effects in an animal model to predict therapeutic effect in patients. This is an interesting area that merits discussion. However the title is "Where is the evidence that animal research benefits humans?". This is a much broader question and not tackled at all in the article. Jim Black explored the effects of adrenaline and potential antagonists on the beating rates of animal hearts. Thus emerged beta blockers. John Vane explored the release of inflammatory mediators from tissues and identified the mechanism of action of aspirin and a whole class of anti-inflammatory agents, as well as identifying potential cardioprotective effects of aspirin. Presumably the authors would accept that these drugs have benefitted humans? In such a sensitive area as animal research in which articles such as this are bound to be used in support of political and campaigning aims, it is essential that scientists and journals report their findings accurately. A more appropriate title would have been "A preliminary survey of the ability of animal models to predict clinical outcomes" and the discussion should have reflected this. Competing interests: I undertake experiments using animals. The drugs I use in patients have all been tested on animals.
two pieces to add to the debate 5 March 2004
Nathan M Nobis, Philosophy Department University of Rochester, NY Send response to journal: Re: two pieces to add to the debate	Here are two related and recetn publications. I post them in hopes that they might help advance the ethical and scientific debates here: Review of Why Animal Experimentation Matters: The Use of Animals in Medical Research, American Journal of Bioethics, Vol. 3, No. 1, online Bioethics Education Network. "Carl Cohen's 'Kind' Argument FOR Animal Rights and AGAINST Human Rights," Journal of Applied Philosophy, March 2004 Competing interests: None declared
The evidence is all around us 5 March 2004
Y. S. Bakhle, Senior Research Fellow Biomedical Sciences, Faculty of Medicine, Imperial College London SW7 2AZ Send response to journal: Re: The evidence is all around us	I have many reservations about the recent article by Pound et al. Let me start with the title. Not ALL animal research can be summarised or represented, adequately, by the six studies this article has considered. However, the title certainly appears to make that claim. The subtitle “Much animal research into potential treatments for humans is wasted because it is poorly conducted and not evaluated through systematic reviews” is similarly unjustifiable. Do they consider the total of animal research summarised in their examples to be such a high proportion of all animal research, that it could be correctly labelled as “Much...”? I would have thought “Some..” was a more appropriate quantifier in this context. Without question, there is poorly conducted animal research (and many of us as editors of Pharmacology journals do our best to keep it from appearing in print) but I am not convinced that there is any more of this quality of research with animals than, say, with cell cultures or with patients. I would imagine the BMJ and most other clinical Journals have seen and rejected many poorly conducted clinical studies which have indeed been a waste of money, time, effort, and opportunity. One place to look for systematic evaluations of animal research is in the processes of testing and validating a new drug. In order to permit clinical trials of a new compound, licensing authorities require evidence of a considerable amount of animal research in more than one model and species to show both pharmacological activity and lack of toxicity. ALL this evidence IS (one hopes) critically evaluated by the licensing body before clinical studies can begin. As Andre MacLean has already pointed out, this evidence and its assessment is not published but that is, I believe, a matter of “commercial confidentiality” and not evidence for absence of evaluation. The first line of Pound et al’s Conclusion asserts - “The contribution of animal studies to clinical medicine requires urgent formal evaluation”. This assertion misses the point. The problem highlighted by their examples is not that the animal research was “valueless” but that it was either not done at the right time or it was disregarded or selectively presented. In four of the six examples quoted, the animal studies agreed with the clinical results. So there would have been a good correlation between animal and clinical research and the clinical trials should not have been started, if the results from animal studies had been known. Surely the criticism should be aimed more at the reasons for the clinical trial, not at what the animal results showed. The problem of selective referencing (example 5) is not an example of animal research giving the wrong signals, it is an example of the Nelson Syndrome –choosing which signals to see. I should add here that some of the faults ascribed to the animal models are inherent in what can or should be done with animals. Animal models cannot reproduce all the features of human disease; some models are closer than others but all are approximations. For instance, the long- term consequences of stroke (case 1) are difficult if not impossible to model in animals and the ischaemia, infection and necrotic debris in wounds (case 3) appear to me to be unethical conditions for animals. Finally, it seems to me that the real message of the article is not about the value of animal research but about the design of, and justification for, clinical trials. Surely, before a clinical trial is started, all relevant existing research IS critically examined, regardless of its origins, animal or human. If the trial is supported by non- industry funds (MRC / Wellcome Trust / charities, etc) that critical examination is what the grant reviewers perform. One possible reason for the relative lack of funding of clinical research might be that few such proposals are of the high quality the reviewers demand. Nowhere in this article is there adequate justification of the wholesale rejection of animal research in providing benefit for humans, as implied in this article. The evidence that animal research IS a benefit to humans is like Christopher Wren’s monument –it is all around us. Many of us are benefiting now from, say, ACE inhibitors for hypertension, selective beta-agonists for asthma, neuromuscular blockers and anaesthetics for surgery or statins for lowering cholesterol. All will have been introduced as a result of animal research, leading to assessment in humans. I would support the authors in asking for better designed clinical research but this is not a reflection on the value of the preceding animal research and its results but of what those who undertake clinical research do with the results from animal research. Competing interests: I held a Home Office Licence for more than 30 years.
Animal Research and Human Benefit 8 March 2004
Colin Blakemore, Chief Executive, Medical Research Council 20 Park Crescent, London W1B 1AL, Tony Peatfield, Head of Policy, Medical Research Council Send response to journal: Re: Animal Research and Human Benefit	Pound et al. (1) take an extremely narrow approach to the question: 'Where is the evidence that animal research benefits humans?', and they misinterpret their own data. They open their paper with the extraordinary statement: 'Clinicians and the public often consider it axiomatic that animal research has contributed to the treatment of human disease, yet little evidence is available to support this view'. This is simply untrue and is seriously misleading. There is a huge amount of evidence for the contribution made by animal research. Summaries are included, for example, in the MRC booklet 'Mice and Medicine' (2), in evidence provided to the House of Lords Select Committee on Animals in Scientific Procedures (3), on the website of the Research Defence Society (4), and in a very recent Royal Society publication (5), which starts with the statement: 'Humans have benefited immensely from scientific research involving animals, with virtually every medical achievement in the past century reliant on the use of animals in some way.' Pound et al. used a Medline search to identify 277 reviews of animal experiments but they chose to describe just six systematic reviews conducted to discover whether animal research had informed particular clinical studies. One pointed out that there is no simple animal analogue of the established relationship between social status and coronary heart disease in humans. This is hardly surprising in view of the complexities of human society, which have no clear parallel in animal hierarchies. The other five papers all described clinical trials that had apparently been started without full analysis of prior animal studies or even in parallel with animal work. In each case the putative therapy turned out to have no benefit and subsequent systematic review showed that animal research revealed exactly the same problems. Far from providing evidence that animal research doesn't work, these studies revealed excellent agreement between animal results and clinical experience. It is, of course, imperative that animal research is properly evaluated before the results are transferred to medical practice. The authors have identified some clinical trials of ineffective treatments that were based on inadequate analysis of results from animal research. One would have expected the relevant Ethics Committees and the regulatory authorities to have identified this problem. Results on animals can show when it is not appropriate to move to human trials, as much as when it is. If these animal studies had been evaluated properly, it is likely that they would not have proceeded to clinical trials. It is not the animal studies that were at fault but the interpretation of them. In the UK, animals can be used in research only where it is strictly necessary, and the minimum number of animals must be used to answer the question. This requires good experimental design; an area in which the MRC is leading through high-quality peer review and our Centre for Best Practice for Animals in Research. The vast majority of the animal research funded by the MRC is not trials of new drugs but is aimed at studying normal bodily function and disease processes. By their own admission, Pound et al. did not even consider the important research involving animals that makes a scientific contribution, as opposed to animal-based trials of putative treatments. This is a curious distinction to make: it is not meaningful and it ignores all the research on normal life processes and the natural history of disease, not to mention safety-testing. All these make essential contributions to the development of new therapies for humans (and animals), and much of this work is required by law. Some of the authors of this paper and their supporting organization (Scientists for Accountability in Biomedical Research and Education) have called publicly for a 'moratorium' on animal research (6). This is irresponsible and is totally unjustified by the results that they describe. Colin Blakemore (Chief Executive) and Tony Peatfield (Head of Policy), Medical Research Council 1. Pound P, Ebrahim S, Sandercock P, Bracken MB, Roberts I. Where is the evidence that animal research benefits humans? BMJ 2004;328:514-7.(28 February.) 2. Medical Research Council 'Mice and Medicine' (2000): www.mrc.ac.uk/pdf-mice_and_medicine.pdf 3. House of Lords Select Committee on Animals in Scientific Procedures (2002). www.publications.parliament.uk/pa/ld/ldanimal.htm 4. Research Defence Society: www.rds-online.org.uk 5. Royal Society (2004): The use of non-human animals in research: a guide for scientists. www.royalsoc.ac.uk/framer.asp?page=/policy/AnimalsResearch.htm 6. Scientists for Accountability in Biomedical Research and Education. Press Release, 27 February. www.S-A-B-R-E.org Competing interests: None declared
Re: Animal Research and Human Benefit 9 March 2004
Paul A Dawkins, Clinical Lecturer Queen Elizabeth Hospital, Birmingham. B15 2TH., Robert A. Stockley Send response to journal: Re: Re: Animal Research and Human Benefit	Dear Editor, We read with some concern the paper by Pound et al on the benefits of animal research to humans1. The authors’ analysis was entirely descriptive and their arguments were focussed on only six papers, all reviews, that covered areas of research whose findings could be directly translated to clinical trials. They found that clinical trials either went ahead despite the contrary results of animal studies, or ran concurrently with them. The authors therefore stood by their statement that there is little evidence to support the view that animal research has contributed to the treatment of human disease. Clearly this is a reasonable conclusion bearing in mind the question being asked. However, most animal research is directed at understanding the basic mechanisms of disease from which future therapies may arise. The Medical Research Council has summarised many areas where such research is leading to treatments or prevention, including cystic fibrosis, deafness, depression, tuberculosis, malaria and cancer2. In our area of interest, much of the understanding of the pathogenesis of emphysema has come from studying rodent models3,4, and this is leading to the development of new therapies such as the retinoic acid receptor agonists5 that are now in clinical trials. Only a minority of animal studies are a direct precursor to clinical trials, although obviously such studies are also important. The fact that sometimes the results are either ignored or not awaited by clinical researchers is surely a criticism of the speed with which such studies are undertaken, often ahead of true understanding, rather than of the importance of the animal research itself. That is not to say that coordination of research efforts cannot be improved, or that quality of study design does not need addressing. However, the fact is that this paper in a high profile journal will be interpreted by the media and the general public as evidence that animal research is not benefiting medical science. This is unfortunate since if, instead of this quite narrow meta-analysis, the BMJ had published a review of the high quality translational animal research that is produced in the UK and internationally, they probably would draw a quite different conclusion. 1. Pound P, Ebrahim S, Sandercock P, Bracken M.B, Roberts I. Where is the evidence that animal research benefits humans? BMJ 2004;328:514-517. 2. Mice and Medicine: animal experiments, medical advances and the MRC. Medical Research Council 1993. 3. Shapiro S.D, Goldstein N.M, Houghton A.M, Kobayashi D.K, Kelley D, Belaaouaj A. Neutrophil elastase contributes to cigarette-induced emphysema in mice. Am. J. Path. 2003;163(6):2329-35. 4. Hautamaki R.D, Kobayashi D.K, Senior R.M, Shapiro S.D. Requirement for macrophage elastase for cigarette-induced emphysema in mice. Science 1997;277(5334):2002-4. 5. Massaro G.D, Massaro D. Retinoic acid treatment abrogates elastase -induced pulmonary emphysema in rats. Nat. Med 1997;3(6):675-7. Yours sincerely, Paul A. Dawkins (Clinical Lecturer, Respiratory Medicine) Robert A. Stockley (Professor of Medicine) Competing interests: None declared
Human holocaust - Animal holocaust 9 March 2004
Sheila Edwards, retired teacher PO Box 15825 Dubai UAE Send response to journal: Re: Human holocaust - Animal holocaust	The paper by Pound, Ebrahim, Sandercock, Bracken & Roberts is a welcome and timely development apropos the controversial issue of animal experimentation and its contribution to human health. Defenders of animal experiments perpetuate the view that there has hardly ever been a cure for any disease which was not due to animal research and that medical progress would be threatened by a moratorium.Since it has been a tradition of western medical science to use animals widely for over a century and a half, it is easy for proponents to claim the use of animals has been vital to progress. But this by no means proves that the animal experiments themselves were the real key to the most important discoveries.Animals have been killed in their billions in medical research, but this neither automatically proves that the experiments were vital or irreplaceable,nor that medical progress will be severely hampered by their abandonment. Not so well publicised are the historical and long-term consequences of this legislated protocol that secures funding, tenure or promotion and protects drug companies rather than human beings. Thalidomide is but one high profile disaster.Medical history is strewn with hazardous medications and human fatalities traceable to drug development's dependency on the animal model. Diethylstilbestrol[1][2][3]and Zimeldine [4][5][6]were predicted safe by animal tests but resulted in severe adverse effects in humans. Benzene was not withdrawn from use as an industrial chemical despite clinical and epidemiological evidence that exposure caused leukemia in humans because manufacturer-supported tests failed to reproduce leukemia in mice.[7] Animal testing can also delay progress and lead to the rejection of medicines which are potentially valuable for treating human illnesses.The plant digitalis has been used for centuries to treat heart disorders but clinical trials of the digitalis-derived drug were delayed because it caused high blood pressure in animals. Fortunately, human evidence overrode and as a result,digoxin, an analogue of digitalis, has saved countless lives. Many more people could have survived had the animal testing been ignored and digitalis been released earlier.[8][9][10][11]More recently,Multiple Sclerosis sufferers must have been pleased to learn that scientists studying human brain tissue may have advanced MS research along a different path from misleading earlier animal studies on which all subsequent research has been based.[12] What explanation and words of comfort would proponents of animal experiments offer victims of the disastrous effects, delays in progress and misleading results of animal based medicine? Put enough money in the slot machine and you will occasionally triumph but this does not make it either a reliable or logical method of pursuing your goal.Who can be certain whether or not as much or more useful knowledge could have been obtained from other sources if medical science had been force to take an alternative direction? It is impossible to unravel every medical discovery in order to measure precisely the part paid by animal experiments but the doom predicted by research scientists if a ban were to be implemented is irrational. Animal experiments have exhausted resources that could have been dedicated to educating the public about health hazards and health maintenance, thereby diminishing the incidence of diseases that require treatment. Proponents of vivisection claim the welfare of lab animals in the UK is strictly regulated, but documentary evidence and the recent legal victory over Imutran/Novartis by Uncaged campaigns proves otherwise.The lack of effective regulatory oversight provided by the Animal Procedures Committee was a factor in Uncaged's successful legal argument for the public interest in disclosure of the documentation.In addition to the barbaric cruelty, the documents reveal a shameful record of broken regulations, exaggerated claims and haphazard science. The whole research project was eventually abandoned in 2000 as a total failure.[13] [1]NEJM, 333;1099-1105, 1995. [2]J. NIH Res., 1993, 5, pp33-35. [3]Nature, 1993, July 22, p275. [4]B. Blackwell in Side Effects of Drugs Annual, vol. 8, eds M. N. G. Dukesand J. Elis (Elsevier, 1984). [5]R. D. Mann, Modern Drug Use; An Inquiry on Historical Principles (MTP Press, 1984). [6]R. C. Heel, et al, Drugs, 1982, vol. 24, pp.169- 206. [7]Lancet, June 25 1977, pp1348-9. [8]W. Sneader, Drug Discovery: The Evolution of Modern Medicine, Wiley,1985. [9]T. Lewis, Clinical Science, Shaw and Sons Ltd., 1934. [10]Federation Proceedings, 1967, vol.26, pp1125-30. [11]Toxicology In Vitro, 1992, vol.6, pp.47-52. [12]New Scientist (26 February 2004) [13]Uncaged campaigns:www.xenodiaries.org Competing interests: None declared
An unavoidable bias, and an important role for systematic review and meta-analysis in neuroprotection 11 March 2004
Malcolm R Macleod, SpR, Neurology Westren General Hospital, Edinburgh EH4 2XU Send response to journal: Re: An unavoidable bias, and an important role for systematic review and meta-analysis in neuroprotection	The paper by Pound et al, and the resulting discussion, has touched on many important issues. However, there is a structural bias in the approach used by Pound et al in that is seems to me highly unlikely that anyone would perform a systematic review of animal experiments where there was already a safe and effective treatment for human disease. So where animal experiments have resulted in effective treatments, systematic reviews will not have been performed. The only reason for doing them is in conditions where there are not (yet) effective treatments. Almost by definition, these are the areas where animal experiments - or any other approach - have not (yet) led to effective treatments. For this reason, the findings of Pound et al were almost inevitable. Systematic review and meta-analysis of animal experiments does have a very important role. Firstly, it can provide an overview of the efficacy of a particular drug. Secondly, it can identify areas where evidence is lacking, and therefore direct the priorities for further animal research. Thirdly, it may provide the basis for a more rational system of drug classification based on in vivo rather than in vitro properties. Finally, it can identify those aspects of study design and study quality which lead to bias in the estimate of efficacy, thus improving leading to improvements in study quality (1). Some animal experiments are poorly designed, and some clinical trials are based on a limited interpretation of that animal evidence which exists. Most stroke trials, for instance, have used a clinical time window which is much longer than is justified on the basis of the available animal evidence. For the future, we need both to continue to improve the quality and relevance of animal research and to improve the interpretation of that research in the planning of clinical trials. Finding cures for disabling conditions like stroke is, as we have seen, very difficult. It will not be made any easier by a moratorium on animal research. (1) Macleod MR, O'Collins T, Howells D, Donnan GA. Pooling of animal experimental data reveals influence of study design and publication bias. Stroke. In Press. Competing interests: Use animals in experiments; author of systematic review and meta-analysis of nicotinamide in focal cerebral ischemia
Animals matter, too 12 March 2004
Jonathan Balcombe, Research Consultant York, UK Y023 1BG Send response to journal: Re: Animals matter, too	In questioning the scientific merits of animal experimentation, Pound et al. issue an important challenge to the widely-held assumption that animal research benefits humans.1 Their findings are strongly supported by other recent scientific critiques that have been sharply critical of animal models of disease.2 3 4 Unfortunately, the number of animals used in laboratory research remains in the many tens of millions and is projected to rise as we enter the new age of transgenics.5 However, what is often neglected in this debate is the plight of the animals themselves. Studies assessing animals’ physiological responses to seemingly simple and routine laboratory procedures (e.g., handling, blood collection, and gavage) have shown rapid, pronounced, persistent and statistically significant elevations in blood pressure, pulse, and stress- related hormones that do not return to normal for 60 to 90 minutes following the event. These findings indicate that animals are highly stressed by the common laboratory procedures they undergo on a daily basis, and that they do not readily habituate to them. Related studies have demonstrated neurological and behavioral deficits in rodents confined to small, unstimulating laboratory cages. The implications are both scientific and ethical. Added to the dismal track record of animal studies, notably in such disciplines as carcinogenicity and teratogenicity, these data suggest it is time for a complete and timely shift to non-animal research methods. Sincerely, Jonathan Balcombe, PhD Research Consultant, Physicians Committee for Responsible Medicine, 20 Nunthorpe Road York Y023 1BG pumilla@onetel.com Physicians Committee for Responsible Medicine, 5100 Wisconsin Avenue, NW, Suite 400, Washington, DC 20016 www.pcrm.org 1 Pound P, Ebrahim S, Sandercock P, Bracken MB, Roberts I. Where is the evidence that animal research benefits humans? BMJ 2004;328:514-7. 2 Shapiro KJ. Animal Models of Human Psychology: Critique of Science, Ethics and Policy. Seattle: Hogrefe & Huber, 1998. 3 LaFollette H, Shanks N. Brute Science. New York: Routledge, 1997. 4 Greek CR, Greek JS. Sacred Cows and Golden Geese. New York: Continuum, 2000. 5 Fishbein EA. 2001. What price mice?. JAMA 235: 939-941. Competing interests: None declared
There is no evidence-base for animal research 15 March 2004
Susan Green, Director S-A-B-R-E PO BOX 18653, Hampstead, LONDON NW3 4DG Send response to journal: Re: There is no evidence-base for animal research	Pound et. al are careful to explain the rigorous systematic research strategy they used, to arrive at what were the only [six] papers that were systematic reviews of animal studies that set out to answer the question of how the animal research had informed the clinical research. The fact that there is a dearth of such systematic research of animal studies in the medical literature illustrates one of the important points the authors make, which is that animal research does not presently adhere to the same rigorous standards that are applied to or at least expected to apply to human research. The purpose of animal research is to inform human research, so it is a major concern if standards in animal research are low. Attention is correctly drawn in the paper to the correlation in the data between the animal research and the clinical research. Most of the animal data did not warrant proceeding to clinical trial. This raises many important questions. Why were the clinical trials ever conducted if the animal data showed negative outcomes? Did the trialists or translational researchers choose to ignore the animal data? If so, why and why did they proceed with the human trials regardless? Why was the animal research methodology and design so poor? If the animal research had not been flawed, would the outcomes have been the same? Would the animal data from well-designed studies still have correlated with the human outcome and if not would the data have been acted upon in the same way? Why is it acceptable to ignore animal data? Why is it acceptable to conduct animal research at all if the data is to be ignored? Why were human trials allowed to proceed if only animal data from flawed research was available at the time? The paper summarises numerous methodological problems that exist for researchers when they try to extrapolate data from animal experiments to human research, notably metabolic differences within the species and strains of laboratory models. The selection of animal models is fraught with difficulties and attempts have been made to overcome these by transgenically altering laboratory models. However, the same methodological problems remain because the whole model cannot be altered. It is argued that ‘mechanisms of disease’ must be studied in the whole living organism and we agree that much knowledge is collected by studying disease processes in animals but this approach is limited to biological knowledge about the animals being studied. We need to know ‘What evidence is there to demonstrate the generalizability of the animal data to the human condition.’ We want to know ‘Does animal data possess sufficient predictive value of the efficacy or toxicity of therapeutic interventions in order for it to usefully inform clinical research?’ Animal research is a lengthy and expensive procedure, so we need to know the answer to the question, ‘Does animal research warrant the resources it absorbs and funding it attracts?’ It is the public’s right to expect medical research that only leads to the alleviation of disease and suffering of patients, not quantities of unusable information about animal biology stored on Medline that may only ever have applicability to veterinary research. It is time that the debate about animal research raised serious questions about its value to human medicine. More systematic research of animal research is clearly needed to answer these questions and everyone interested in medical progress must surely welcome the programme of research, suggested in the paper. There is no evidence-base for animal research but there is an unnecessary veiling of its costs and conduct. The public cannot be expected to accept anecdotal evidence as evidence of its value to human medicine. It is outside S-A-B-R-E’s remit to support individual researchers or groups of researchers but we welcome the general concept of a large-scale research programme of systematic reviews of animal studies. A moratorium would be a proper safeguard against further unevaluated animal research being used to inform human research. It is imperative that patients and research volunteers are protected from poor quality or doubtful research, whether it is animal-based or clinical. This paper illustrates that flawed research is evident in both these areas of medical research but that animal research is far less rigorously scrutinised for its quality and applicability. We encourage all forms of systematic research that will determine whether animal research can be generalized to human medicine. These include retrospective investigations into the development of treatments, critiques of animal models, historical analysis, citation analyses, systematic reviews and meta-analyses. Competing interests: Director (voluntary) - Society for Accountability of Animal Studies in Biomedical Research & Education (www.SABRE.org.uk) – whose mission is to raise awareness of the need to critically evaluate animal research to determine its contribution to human medicine.
Re: There is no evidence-base for animal research 16 March 2004
Paul R Matthews, Graduate Student Dept. Psychiatry, University of Oxford OX3 7JX Send response to journal: Re: Re: There is no evidence-base for animal research	Publishing this paper by Pound et al was spectacularly ill judged. It is not only scientifically invalid but it exhibits many of the failures of reason, endemic in the anti-vivisection literature, that undermine the case against animal research. As many rapid responses have pointed out, animal models of human disease are a relatively small part of basic animal research. Pound et al appear to refer to basic animal research in its totality and yet focus their attention entirely on translational animal models of human disease. It is as if they are unaware that the majority of basic research is carried out to examine physiological or disease processes rather than representing a direct precursor to clinical trials. The anti-vivisection movement is afraid to confront the former and so elides the distinction by using the latter to encompass all animal research. However it is this background knowledge about basic processes that is invaluable for researchers developing treatments for human disease, without this knowledge where would they start? Whilst arguments that basic animal research informs clinical developments may be anecdotal or unsupported, at least they have prima facie validity. To truly systematically assess the contribution of animal research to treating human disease you would need to study all the animal studies of a normal functioning system and then examine how that knowledge acquired in animals contributed to the development of a treatment for a human disease in that system – a truly mammoth task. This paper does not even succeed in the much more limited task of examining how animal models of disease have informed clinical trials. As I intimated in my previous response, a systematic review of systematic reviews of how animal models relate to clinical trial data is a most unsatisfactory way of evaluating the contribution of animal research to medicine. It gives a veneer of respectability by being systematic whilst lacking any real scientific credibility. A systematic review of reviews does not have the same validity as systematic reviews of the primary literature. A systematic review of the literature tells you what research has been done in a specific field, a systematic review of reviews can tell you about the nature of systematic reviews but it cannot be extrapolated to the primary literature itself, because systematic reviews do not cover the totality of primary animal research. This is partly because systematic reviews of the animal literature tend to be carried out before clinical trials to evaluate whether proceeding to clinical trials is justified. After successful clinical trials there is little need to waste time confirming the agreement between trials and the animal data. Looking at the papers considered by Pound et al it is obvious that systematic reviews of animal research and their relationship with clinical trails are prompted by unsuccessful clinical trials after the fact. This produces the ridiculous bias in studies considered by Pound et al. Therefore no conclusions can be drawn about animal models of disease, let alone basic animal research – at best the conclusions about the poor quality of basic research can be applied to the situations where animal models lead to unsuccessful and unjustified clinical trials. Questions about the wisdom of proceeding to clinical trials on insufficient or unsupportive animal research, legitimately raised by these reviews, are surely the responsibility of those carrying out the clinical trials - which are supposedly of a higher standard than animal research! The call for a moratorium on animal research based on this irrelevant and invalid review seems a little premature to say the least. There are arguments to be made against using animals in research. The most compelling is the simple moral argument that, no matter how great the benefit in treating human disease, the level of animal suffering required to achieve this is too high. This is a perfectly respectable and consistent ethical position to take, even if most people would not agree with it. A second valid criticism of animal research, particularly into animal models of disease, such as rodent models of schizophrenia, is that the models used are often very poor analogues of the human disease, particularly for diseases like schizophrenia where the aetiology is very poorly understood. This is a specific objection to specific models not a blanket objection to any and all animal research. Unfortunately anti-vivisectionists seem to focus on the claim that animal research is of no benefit in treating human disease, rather that it is positively counter productive. Given our extensive knowledge of the homologies between animals and humans it would seem that the burden of proof is on the anti-vivisectionists to support this claim. This paper represents one more attempt to espouse that view – only this time it has been given undue prominence through publication in the BMJ. There is a debate to be had about the extent and usefullness of animal models, the chronic lack of post-mortem research and the skewing of research funding, however this paper does not contribute to it. Competing interests: None declared
Re: A Plea for Mercy 17 March 2004
Roelof A. Bijkerk, advocate for expression GR MI 49505 Send response to journal: Re: Re: A Plea for Mercy	I don't know where to begin with such things. When it is supposedly a miracle that humans being live as long as they do (Because of drugs they say that come from animal research) but in the meantime then also in their zeal for life have destroyed many species from the mother earth, contaminated all the land on the planet, created enough weapons to destroy the earth to a wasteland, continue to live in societies which prey on alienating anyone who is different and have such bizarre rules that when two people of the same sex love each other it's a sin or even against the law – the most rich of these humans are so addicted to little mechanized devices that they turn and look the other way when corrupt businesses supply them with such consumptions and make it impossible for people exploited in other countries to have the same standard of living, that is if you believe a mechanized life is a standard of living – it still remains that way more than 90 percent of the human population live amidst the pollution of water and trash that the other minority allows them to live in to supply it's consumer oriented pretentious "paradise". At the same time most of the knowledge that is here which comes from a completely different source than the type of mechanization and control oriented phobias which "decent society" is based on are overlooked. Based on all of this the society which created the drugs from animal research would actually be more a promoter of disease........... I don't really believe that animal experiments have done anything but fueled a mania which has blinded people. There are other ways of healing but that's not something you can put on a supply and demand vicious circle. You have to have a deeper relationshiop with yourself to do that I believe. Honestly. Competing interests: None declared
Re: Re: A Plea for Mercy 17 March 2004
Irene Mazis, research H3Z 1J5 Send response to journal: Re: Re: Re: A Plea for Mercy	Roelof, When I say "plea for mercy", I mean that there is no pragmatic argument I can make against the torture of animals for our benefit; especially when it is on a mass production scale. There is no argument that can be made in the case of inflicting pain, there is only Kant's categorical imperative. We are predators, but we are extremely merciless and ambitious predators. Medical progress ironically, has allowed so many people to live longer that in itself is presenting a danger to all species, including man. Squiggles Competing interests: taking 50 yr. old drugs
The invalidity of animal experiments 18 March 2004
Michael C Morris, policy adviser New Zealand Send response to journal: Re: The invalidity of animal experiments	In response to Paul Matthews, I should point out that advocates of the anti-vivisection position are well aware of the distinction between animals as "models" for human systems, and the use of animals to foster general understanding of scientific processes. Both types of experiment are flawed, though for different reasons. For the first type of application to have any usefulness depends on the predictive value of the animal "model". It is assumed that a disease, disorder or traumatic effect in an animal is equivalent to the corresponding effect in a human, and furthermore that the animal and human will react in the same way to the same drugs, toxins or trauma. However, the inherent falsity of this assumption can be shown on general scientific principles. LaFollette & Shanks (1) point out that our assumptions about the validity of the animal model are based on the 19th Century scientific paradigm of Claude Bernard. These include a belief that equal causes produce equal effects, and a distrust of the statistical and largely anecdotal nature of clinical medicine. These beliefs, the authors propose, are now outdated. First, advances in statistical techniques have put clinical medicine on a more scientific footing, so that there is less necessity for animal experimentation. More importantly, complexity theory predicts that in complex systems such as living beings, a small difference in structure can result in vastly different effects. Similarities in the genome between humans and chimpanzees, for example, may thus result in a similar structure in terms of gross morphology, but at the more complex cellular and biochemical level even the 1% difference between the genomes of the two species will manifest itself in vastly different biochemistry (2). In fact in a complex system like the human body even extrapolations between individuals have to be treated with caution. This can be demonstrated by evidence that the opioid receptors in men and women react differently to pain killers (3), and a recent press release from Glaxo pointing out the individual differnces in responses to drugs (4). In addition, through studies of convergent evolution and natural selection we already know that organisms may evolve processes with the same function, but the causal mechanism by which this function is achieved may be vastly different. It is this causal/functional disanalogy that makes direct extrapolation of results between the species so unreliable (5). Animal experimentation advocates are keen to cite studies that have shown similarities in the response of animal and humans. However, the point about using animals as models is that it is not possible to know in advance which models will show similarities or what those similarities may be. Animal models have no predictive value and thus are misleading when used for medical purposes. Scientists are not keen to publish negative results, nor are journals keen to accept them. In addition, animal experimentation advocates are bound to concentrate on the few successes of the animal model, and ignore the many expensive and painful failures. The presence of counter-examples therefore does not refute the basic premise that direct extrapolation from animals to humans has no scientific validity, any more than the occasional accurate forecast in the newspaper horoscope column refutes the questionable nature of astrology as a scientific discipline. Pro-vivisectionists are on surer ground when it comes to pure research, and it is because we can never know in advance when a research project will yield something of value that some philosophers (6) advocate unlimited animal experimentation. However, such thinking assumes first that animals are of no moral consequence whatsoever, an opinion which is at odds both with public sensibilities (7) and with legislation Moreover, intrusive animal experimentation is not the only means of improving our understanding of living systems. Non-intrusive observations of animals, mathematical modeling and other analogues have also played a major part in scientific advancement. If we do not know in advance the fruits of a research programme involving expensive and intrusive animal experimentation, then equally we do not know whether an alternative research programme involving non-intrusive work will prove equally or more valuable. All other things being equal, the ethical alternative should therefore be preferable. When considering allocating funds to research programmes to understand more about a human disorder, it would also be appropriate to seriously consider the cheaper option of investigating preventative strategies. In conclusion therefore, it is the inherent uselessness of animal experimentation that has prima facie validity, both in terms of pure and applied research. The onus of proof should therefore rest with the pro- vivisection community, especially given the suffering caused through animal experimentation. 1. LaFollette, H.; Shanks, N. 1994: Animal experimentation: the legacy of Claude Bernard. International Studies in the Philosophy of Science 8: 195–210. 2. Greek, C. R.; Greek, J. S. 2002: Specious science: How genetics and evolution reveal why medical research on animals harms humans. New York: Continuum. 3. Gear, R. W.; Miaskowski, C.; Gordan, N. C.; Paul, S. M.; Heller, P. H.; Levine, J. D. 1996: Kappa-opioids produce significantly greater analgesia in women than in men. Nature Medicine 2: 1248–1250. 4. Glaxo chief: our drugs do not work on most patients. The independent, 8 December 2003. 5. LaFollette, H. and Shanks, N. (1996) Brute science. London: Routledge. 6. Leahy, M. P. T. 1991: Against liberation: putting animals in perspective. Routledge: London and New York. 7. Aldhouse, P. Coghlan, A. and Copley, J. (1999) Let the people speak. New Scientist, 22 May 1999, 26-31. Competing interests: Ex vivisection supporter and potential vivisector, now anti vivisection advocate.
Confusion of two issues 18 March 2004
J Martin B Dace, freelance GP Hetherington Road Group Practice SW4 7NU Send response to journal: Re: Confusion of two issues	I suspect the objectors to animal experimentation would still hold the same objections even if it were to be shown that animal experimentation is genuinely useful. So would I. I think animal experimentation reduces me as a human being (I did a number of animal experiments as part of my first degree, and felt that their cruelty and unpleasantness far outweighed any educational benefit). Nevertheless, it is an inescapable fact that my whole practice depends on, for example, a knowledge of the circulation of the blood. Have any of the contributors to this debate read Harvey lately? Could he have drawn the conclusions he did without vivisection? If our interest is human health, then it is surely a truism that education, sanitation, adequate food supplies, and lack of war have each of them hugely greater impacts on health than any amount of medicine. I should be happy to ply my trade in a society with sensible priorities, even if the science of medicine itself were a little less advanced. Competing interests: General medical practitioner whose training is based partly on the science of physiology
The need for a thorough review of the efficacy of animal experiments 18 March 2004
Richard W Tweedy, Campaign manager Naturewatch, GL53 7JX Send response to journal: Re: The need for a thorough review of the efficacy of animal experiments	I congratulate the BMJ on publishing the paper by Pound et al., and the subsequent energetic debate in the rapid responses shows the benefit, rather than otherwise, of having done so. The point that Matthews and others make about the limited scope of the reviews selected by Pound et al. is an important one - but I think it points to a rather different conclusion than that which they wish to draw. Instead, it highlights the necessity of a thorough review of the efficacy of animal experiments, in a more wide-ranging and systematic manner than the preliminary work of Pound et al. Exactly how a more thorough review could not inform and enlighten the debate, in a way that would be beneficial to almost everyone of sane disposition, seems unclear. The necessity for such a review is also becoming increasingly apparent from comments emerging elsewhere as well. May I quote from a couple of significant sources? Allen Roses, the worldwide vice-president of genetics at GlaxoSmithKline stated in December 2003 that “the vast majority of drugs – more than 90 per cent – only work in 30 or 50 per cent of the people.” Thus, in the worldwide medical experiment known as the commercial market place, in which the subjects are humans rather than animals, fewer than 10% of the drugs which pass the clinical trial phase are effective for more than half the rest of the human population. If drug test results cannot be reliably transferred within the human species, it is hardly surprising that there is some doubt over the efficacy of animal experiments which require cross-species transference. Professor Ian Wilmut, famed for Dolly the sheep among other things, wrote in an article in the New Scientist in February 2004 that, “It is a surprising fact that bad reactions to prescription drugs, even when those drugs are used correctly, kill thousands of people every year.” This alarming statement casts further doubt on the ability of the current testing regime to safely screen drugs for use on humans. Given that these statements are coming from authoritative sources within the medical research community, it would seem that there is real cause for concern about the efficacy both of animal experiments and of the current drug-testing regime. Facing these questions and conducting a thorough review, as Pound et al. have begun to do, is imperative. Competing interests: I work for an animal welfare group, Naturewatch.
There remains an urgent need for systematically reviewing the results of animal experimentation 23 March 2004
Pandora Pound, Research Fellow Department of Social Medicine, Bristol University, BS8 2PR, Shah Ebrahim, Peter Sandercock, Michael B Bracken, Ian Roberts Send response to journal: Re: There remains an urgent need for systematically reviewing the results of animal experimentation	Before conducting any kind of new research the results from existing research should be taken into account. Modern research synthesis demands that appropriate steps are taken to avoid bias and random error and that the validity of the extant research base is critically examined; systematic reviews offer a means of doing this [1]. Few argue with the need to conduct systematic reviews of clinical research, and we suggest the imperative for systematically reviewing the results of animal experimentation is exactly the same [2]. That the UK Medical Research Council asks for evidence of systematic reviews in clinical trials, but not for animal experiments, suggests a double standard operates. Drs Blakemore and Peatfield suggest that ethical committees are responsible for establishing whether or not there is enough evidence to proceed from animal research to clinical trials, while Dr Bakhle suggests that grant reviewers undertake this task. There is no evidence that either group currently does this, nor is it a feasible expectation. For example, a recent systematic review of randomised controlled trials of fluid resuscitation in animal models of uncontrolled bleeding identified 44 trials from as far afield as Israel, USA, Norway and Greece [3]. It is very unlikely that ethics committees or reviewers could be expected to be aware of this amount of information and it can take several months to conduct a systematic review. This amount of time is simply unavailable to grant reviewers and ethical committee members. Investigators applying to do research should assess the preceding relevant research but too often such assessments are haphazard, biased and incomplete. Ethics committees and the like should be able to refer to systematic reviews of animal studies but at present there are almost none to draw upon. Some letters drew attention to selected areas where the animal and human studies appeared to agree. Evidence that some animal work accurately predicts the human studies does not detract from the need for systematic reviews. In addition to casting light on the issue of generaliseability, systematic reviews provide a means of finding out if the animal work was concluded in a timely way or whether unnecessarily duplicative experiments were conducted, whether the animal work correctly preceded the human trials and so on. Systematic reviews may demonstrate heterogeneous effects: these may be attributable to study design, between species differences, or more subtle sources of variability. Investigation of the causes of heterogeneity is an important aspect of the learning opportunities provided by systematic review. The six systematic reviews that we considered were not specially selected; they were the only cases, identified through an objective search strategy, in which systematic reviews of both the animal and human studies were available for the same condition. Dr Macleod suggests that our study is biased because the systematic reviews of the animal studies were only conducted because the corresponding clinical trials failed. However, such a bias could only occur if systematic reviews are done after the human trials. No bias is possible if systematic reviews of animal studies precede human trials, as we recommend. Dr Coulter uses the example of use of antenatal steroids for preterm labour as evidence that animal research benefits humans. We believe it provides evidence of the need to conduct systematic reviews. A cumulative meta analysis of the 14 human trials [4] indicates that from the first successful trial by Liggins in 1972 there were over twenty years of trials, all adding evidence for a successful therapy. Had the cumulative meta-analysis been done prospectively, perhaps half of the human antenatal steroid trials would have been avoided, as the evidence for benefit was already over-whelming. We do not know whether the accumulating animal experience for antenatal steroids would show the same pattern of growing evidence, whether unnecessary and repetitive experiments were done or whether animal experiments continued after the human evidence was already established and, if they did, what those studies added to knowledge. The call we make is for ongoing systematic reviews of a complete body of animal research, with updated meta-analysis as appropriate, to ensure that animal research is always up to date, not unnecessarily duplicative, and always relevant. References 1. Egger M, Davey Smith G, Altman DG. (Eds) Systematic reviews in health care: meta-analysis in context. 2001, BMJ Books, London. 2. Pound P, Ebrahim S, Sandercock P, Bracken M, Roberts I. Where is the evidence that animal research benefits humans? British Medical Journal 2004; 328: 514-7. 3. Mapstone J, Roberts I. Fluid resuscitation in haemorrhagic hypovolaemia: evidence from animal models. J Trauma (in press). 4. Sinclair JC. Meta-analysis of randomized controlled trials of antenatal corticosteroid for the prevention of respiratory distress syndrome: discussion. Am J Obstet Gynecol. 1995; 173(1):335-44. Competing interests: As outlined on original paper
Re: Animal Research and Human Benefit 25 March 2004
Marlene A. Thompson, member EFMA (Europeans for Medical Advancement) NG15 6DN Send response to journal: Re: Re: Animal Research and Human Benefit	That animals contributed to medical discoveries hundreds of years ago is debateable. Covering over thirty years research, in his thoroughly referenced book, 'Who Goes First', senior medical correspondent to The New York Times, Lawrence Altman MD, has put the history together and uncovered a solid but previously unrecognised part of the underpinning of modern medical science. It should be required reading for anyone interested in medical history and contains documented evidence of pioneers of past centuries who used themselves as guinea-pigs to advance our knowledge of medicine, and the discoveries that have been mistakenly attributed to animal experiments. A hundred years ago childbirth and infectious diseases were the main causes of death due to poor living conditions, but as living conditions improved infant mortality declined and life expectancy soared. Many of todays diseases didn't exist, were rare or unheard of, and infectious diseases had declined to almost zero, before the introduction of vaccines. However short memories and vested interests have turned medical history upside down. Today despite billions of animal experiments, millions spent on research, hi-tech equipment, screening devices, more hospitals, doctors and drugs, we have more sickness and disease than at any time in history, new diseases unheard of before, and drug related diseases have reached epidemic proportions. An appalling testimony to animal rsearch. The overuse of drugs and vaccines have created new diseases and caused viruses and germs to mutate creating more virulent strains that are drug resistant. Medicines answer? Stronger drugs and vaccines. Chemicals- developed in animals-are linked to neurological disorders, birth defects and genetic diseases, all of which are a bonanza for the pharmaceutical industry to develop more drugs. The bulk of medical research today commissioned by the pharmaceutical industry, motivated by profit. Animals are used by researchers to try out their ideas and theories in the hope of developing drugs for their funding source. However an artifically induced disease in an animal cannot accurately mimic a naturally ocurring human diseas. Scientists admit the difficulty of extrapolating results from animals to humans, and are unable to unravel the thousands of chemical and biologial reactions a drug triggers in the human body. (systems biology). Drug reactions differ between different strains of the same species. Even age, sex or race can make a difference. Only after a drug is marketed can they really be evaluted. In other words, after trial and error in human patients - the real guinea-pigs. Many important discoveries have been accidental. The fact that drugs are a major cause of death is ignored, as is the means by which they were developed! If, as Mr. Blakemore claims animal research is successful, shouldn't we be seeing a decline sickness and disease? In fact the opposite is true. In a recent interview Mr. Blakemore says that future medicine will be in treating the patient rather than the disease, embracing diet and lifestyle factors - something the alternative professions have always known and practised! This is indeed a step in the right direction. Tailoring the treatment to suit the patient cannot be studied in any other species, and will hopefully consign animal experiments to history. Competing interests: EFMA - Europeans for Medical Advancement
Point of (duplicate) information 25 March 2004
ROBERT BEDDOWS, writer London N10 3TS Send response to journal: Re: Point of (duplicate) information	Dear Editor - Please see the commentary by two of the authors of the BMJ paper, Peter Sandercock and Ian Roberts, in The Lancet of August 24, 2002. It is entitled "Systematic reviews of animal experiments". Many of the same arguments are made there as here in the BMJ. The nimodipine example is duplicated. The Lancet reference does not appear in the BMJ reference list. It should, shouldn't it? Competing interests: None declared
Lack of accuracy on the first meta-analysis of experimental animal studies 23 April 2004
Alejandro A. Nava-Ocampo, Senior Scientist Dept. Anaesthesia, Hospital Infantil de México, Dr. Márquez No. 132, México DF 06720, Mexico, Angélica M. Bello-Ramírez, Research Fellow, Faculty of Pharmacy, University of Toronto, Toronto, Canada Send response to journal: Re: Lack of accuracy on the first meta-analysis of experimental animal studies	Sir, We read with interest the manuscript written by Pound et al.(1) and agree with the authors on the need of systematic review of animal trials. We also congratulate them for initiating the Reviewing Animal Trials Systematically (RATS) Group in order to assure that experimental animal studies are designed to provide sufficient support for future human studies. However, the authors quoted the study by Horn et al. on nimodipine in experimental animal models(2), published in 2001, as the first systematic review of animal research. In 2000, we published a meta- analysis of animal studies investigating the neuroprotective effects of drugs inhibiting glutamate release (3). This study was incepted in Mexico while we were discussing the possibility of testing lamotrigine as a neuroprotective agent in cardiac surgical patients. The meta-analysis, conducted and analyzed according with the method described by D’Agostino and Weintraub,4 revealed that the administration of drugs inhibiting glutamate release produce a “meta-analytic” reduction of 0.5 mm3 (95%CI - 0.35 to -0.65 mm3) of infarct volume. We discussed that although the difference was statistically significant, the extrapolation to humans was difficult because the clinical translation of such a reduction was unknown. This information appeared summarized in the abstract of our meta- analysis. Although Pound et al. cited our manuscript, they did not recognize it as the first meta-analysis on animal studies. This omission would not be important in a typical review paper, however, in a document written by a group that is proposing to systematically review the studies performed in experimental animal models, this is a significant omission that demonstrates a lack of a thorough review of the literature by them. The scientific literature is not only abundant in poorly conducted animal studies but also in reviews performed with imprecision and bias. References: 1. Pound P, Ebrahim S, Sandercock P, Bracken MB, Roberts I. Where is the evidence that animal research benefits humans? BMJ 2004; 328: 514-7. 2. Horn J, de Haan RJ, Vermeulen M, Luiten PGM, Limburg M. Nimodipine in animal model experiments of focal cerebral ischemia:a systematic review. Stroke 2001; 32: 2433-8. 3. Nava-Ocampo AA, Reyes-Perez H, Bello-Ramirez AM, Mansilla-Olivares A, Ponce-Monter H. For ischemic brain damage, is preclinical evidence of neuroprotection by presynaptic blockade of glutamate release enough? Med. Hypotheses 2000; 54: 77-9. Competing interests: None declared
Animal studies can endanger humans 6 May 2004
Alfred N Jackson, Primary care physician Bulawayo Zimbabwe Send response to journal: Re: Animal studies can endanger humans	This contentious topic is dramatically illustrated by an event related in BMJ No7149(25April 1998 p1296 second paragraph) Although animal studies have undoubtedly benefited us in many ways,the animal studies related in BMJ No 7140p1296 had tragic consequences.The whole rationale for animal studies, if based upon the assumption that we share a common evolutionary ancestry with other animals(particularly those subjected to animal studies)is irrational.Let me explain. Animal survival depends upon reproduction.In sexually reproducing animals reproduction requires the genesis of gametes which requires meiotic cell division.Meiosis requires the synapsis of homologous chromosomes,which requires a certain degree of structural and genetic homology between each of each of the pairs of such chromosomes in the sexually reproducing animal. Each animal species has a uniquely different chromosome number(apart from those which incidentally share a similar chromosome number).Please visit www.kean.edu/~breid/chrom2.htm The requirements of synapsis(and therefore of meiosis) have consequently "fixed"the chromosome numbers of species,which means there is no way we could share a common ancestry with other animals.Unless multiple generations of our forebears had accidentally spawned almost identical new chromosomes in the gametes of each of a mating couple in the same place at the same time ,and unless such new chromosomes were compatible with life and were inherited by succeeding generations. Does this sound feasible?I think not. This is the fundamental flaw in the rationale for animal experiments,since we cannot be phylogenetically related to other animals,and therefore the only similarities in our respective reactions to experiments are the result of accident or design,and whether by accident or whether by design,we cannot know them,except by experimentation,and not by deduction. Competing interests: None declared
Paper by Pound et al. validates the use of animals in research 20 May 2004
Jürgen V Seier, Senior Specialist Scientist MRC, PO Box 19070, Tygerberg 7505, South Africa Send response to journal: Re: Paper by Pound et al. validates the use of animals in research	For an answer to the question asked in the title, the authors need to look no further than their own paper. Their own cited references confirm consistency of results obtained with animal and human studies. Horn et al. (Nimodipine) conclude that "There were no differences between the results of the animal experiments and clinical studies", Lucas C et al. (laser therapy)state "In fact, there were no differences between the results of these experiments (animals) and clinical trials". Even the fluid rescuscitation experiments were generally inconclusive. The fact that a number of responders appear to interpret this paper by Pound et al. as more proof of the invalidity of using animals in research, makes me think that some did not process the actual information contained in this paper. This may have been due to the catchy title. The fact that data obtained from animal studies were ignored in the human trials, does not invalidate the use of animals nor the results obtained. It is unfortunate that from this already very small section of research reviewed, most papers deal with drug testing. Only one deals in some way with basic research, the other major area in which animals are used. This study has found that contrary to humans, dominant nonhuman primates are reported to be more prone to heart disase. The actual results of research are not as simplistic as that. Kaplan et al. found that dominant nonhuman primate males are more prone to develop coronary artery atherosclerosis only if they are constantly exposed to an unstable social environment. The message of the paper by Pound et al. is that scientists and clinicians must not conduct animal and human trials concurrently, and that human trials must not proceed despite inconclusive or negative animal data. The title of this paper is therefore inconsistent with the content. As far as flaws in methodology is concerned, these are difficult to comment on without seeing the papers. A major criticism appears to be the use of too few animals resulting in insufficient statistical power. However, even one author cited by Pound et al. as reference (Roberts et al. 2002)alludes to the dilemma of balancing reduction (3Rs), as well as legislative requirements of using the minimum number of animals, with the need for enough statistical power. Roberts et al: Does animal experimentation inform human healthcare? Observations from a systematic review of international animal experiments on fluid resuscitation. BMJ 2002, 324: 474-476. Kaplan et al.: Social behaviour and gender in biomedical investigation using monkeys: studies in atherogenesis. Lab An Sci 1991, 41: 334 - 343 PS: Above represents my own opinion and not necessarily that of my employer Competing interests: None declared
False Dichotomies 11 August 2004
John A Mercer, Scientist McLaughlin Research Institute, Great Falls MT 59405 USA Send response to journal: Re: False Dichotomies	The paper by Pound et al. should never have been published in a peer- reviewed journal. Others have pointed out the methodological problems and that that the studies cited showed concordance between animal and human trials. I will amplify on the authors’ use of incredibly deceptive polemic rhetoric introduced by Dr Blakemore above. The very subject of the paper is boldly misrepresented in the title, because the authors never bothered to look at anything approaching the breadth of “animal research.” Second, the authors compound their misrepresentation with additional misrepresentations and false dichotomies, including “Much animal research,” “basic animal research” (never addressed), “clinical (as distinct from scientific),” and “basic animal research”/”clinical research,” when all of the studies cited were clinical applications! Dr Blakemore pointed out the most dishonest part of the paper: the fact that the authors “did not even consider the important research involving animals” before arriving at a categorical conclusion. Now, for any lay people reading this, stop and take a deep breath before proceeding to the next sentence. Careful readers will note that Blakemore cited research INVOLVING animals, not research ON animals, which is but a minority of research involving animals. Pound, in her response, could not address this important point because doing so would reveal the fundamental dishonesty of the leaders of allegedly antivivisection organizations. Before assessing their claims about the ethics of experiments ON (while they conveniently ignore the much larger set of experiments USING) animals and the alleged inability to extrapolate from nonhumans to humans, one needs to know the true breadth of animal usage in science, both basic and applied. The use of animals is far more widespread than Pound, Morris, Nobis, Greek, Shanks, and Lafollette will ever admit, because doing so would demolish both their ethical and “scientific” positions. For example, Morris makes the incredible claim that “advocates of the anti- vivisection position are well aware of the distinction between animals as "models" for human systems, and the use of animals to foster general understanding of scientific processes.” I thank him for clearing this up for me, because if I accept Morris's claim as true, I can then safely conclude that all antivivisectionists are simply lying when they promote “non-animal” and/ or “alternative” methods in research and testing. This conclusion is inescapable because virtually all of the methods they actively promote (epidemiology, in vitro methods, cell culture) still use animals as tools, not merely subjects, and many of them still require functional interchangeability of animal and human mechanisms, which is much more stringent than the analogies they claim are so weak. To illustrate this hypocrisy, I offer a highly representative case. Close examination of cell culture (neither non-animal nor an alternative) methods shows the moral and intellectual bankruptcy of claiming that animals have rights, because virtually all cell culture exploits live animals as tools in the form of calf and fetal calf serum ("serum-free" culture usually uses growth factors purified from serum). Morris, in email correspondence, insisted that he has no ethical problems with cell culture and that it is “nonanimal” because the entire animal isn’t used! In addition to this false moral dichotomy, cell culture perfectly illustrates the scientific hypocrisy of claiming that animals are not analogous to humans while promoting a method that involves growing human cells in an entirely bovine growth-factor environment--in other words, using bovine serum as a model for the human environment. Why do Morris et al. hide animal exploitation and extrapolation to present patently false dichotomies to the public? Competing interests: For 25 years, I have used both whole animals and "non-animal alternatives," but they have never been alternatives to each other. Currently, I use hundreds of mice annually in experiments that are promoted by animal- rights polemicists as "non- animal," because the experiments are performed on cells in vitro. I also use bovine serum (obtained by cardiac puncture without anesthesia) to culture human and mouse cells, and antibodies made in animals to localize proteins within those cells. None of these are opposed by the animal-rights industry; however, if animals have rights, all of these things are wrong.
Re: False Dichotomies 15 August 2004
Michael C Morris, Animal rights advocate Wellington, New Zealand Send response to journal: Re: Re: False Dichotomies	John Mercer appears unable to distinguish between ethical and scientific arguments against vivisection. The ethical argument is based on the premise that regardless of whether research on animals or using animals has benefit, that it is unethical to do so. There have been hundreds of books and scholarly articles advocating this stance, from the point of view of utilitatianism, rights theory and virtue ethics. I would go as far as to suggest that the philosophical case against vivisection, as well as the use of animals for food and entertainment has largely been won, though the political battle is far from over. The scientific argument is that animals cannot be used to model human disease or reaction to drugs or toxins because it is not possible to extrapolate from one complex system to another on the cellular and biochemical level. This argument only holds for experiments where animals are used as models; it is not valid for agricultural experiments, or for the use of animals for cell culture or monoclonal antibodies such as Mercer describes. It also does not hold true for basic research, some of which has proved useful. All these uses can however be refuted on ethical grounds. It is also possible to refute them on the basis that opportunity costs have not been considered when making cost-benefit analyses. If this were done, it is likely that spending scarce resources on non-animal alternaitve, including preventative medicine and public health education, would prove to be a better investment in the nation's health and wellbeing than expensive animal experimentation. Mercer is correct that I stated I had no ethical problems with cell culture as a non-animal alternative. This is not however because of any hypocrisy or inconsistency in my ethical stance. It is simply because I was unaware that cell cultures required the regular killing of fresh mice. Now that Mercer has made me aware of my error, I oppose the use of mouse cell cultures on ethical grounds. Mercer may also be interested in the two references below that make specific reference to experiments using animals for monoclonal antibody production. http://homepages.ihug.co.nz/~nezumi1/possums.html http://homepages.ihug.co.nz/~nezumi1/ANZCCART.html Competing interests: My opposition to animal experimentation is on primarily ethical grounds
Not in the good name of medical research? 17 March 2005
Edward J H Moore, Retired Consultant in Public Health Medicine Hillhead Croft, Inverfarigaig, Inverness, IV2 6XR Send response to journal: Re: Not in the good name of medical research?	Dear Sir Not in the good name of medical research? In their article on animal research, Pound et al referred to the public accepting such research “only on the assumption it benefits humans.”1 Last year I received a photograph from Naturewatch, which shows a distressed monkey, immobilised upright in a transparent container, with two implants in its skull, from which blood has spattered the container walls. It is one of several images, apparently obtained undercover by “N”, from a laboratory in Israel, reported in the Tel-Aviv Times2 and reproduced on the internet.3 (www.aesop-project.org) The photograph, sent to 60,000 people,3 will have caused distress, presented medical researchers as cruel and diminished the standing of medicine as a caring profession. According to the newspaper report: “The research was trying to investigate which specific brain cells are active while using the visual memory.” (translation from the Hebrew) Whatever its purpose, since no human being can be subjected to such experimental conditions, the results cannot be extrapolated to humans. Lack of direct clinical applicability is a feature of animal research: the British Medical Journal hardly ever publishes such work “not because we are against animal research, but because we favour research that may have results that are directly applicable to clinicians and those making public policy.”4 Nevertheless, much more research funding is spent on basic animal research than clinical research and this may underlie the failure of research to develop effective preventive strategies in response to the rising prevalence of chronic diseases such as asthma, dementia, cancer and, particularly, diabetes.5 Growing public anxiety concerning the realities of primate research and the deterioration of health, particularly children’s health, should be addressed before public goodwill for medical research is lost. A radical shift of resources away from animal research into preventive research is required. Yours faithfully Edward Moore OstJ, MBChB, MFCM Retired Consultant in Public Health Medicine References: 1. Pound, P., Edbrahim, S., Sandercook, P., Bracken, M.B. and Roberts, I. Where is the evidence that animal research benefits humans? BMJ 2004; 328 : 514-7 2. Lahav, S. Horrific primate experiments exposed in Israel - an eye- witness account. Tel-Aviv Times, 14 December 2001 3. Tweedy, R. Personal communication 7 March 2005. Naturewatch, Cheltenham GL 52 6AA 4. Smith, R. Animal research: the need for middle ground. BMJ 2001; 322 : 248-9 5. Dyer, O. First cases of type 2 diabetes found in white UK teenagers. BMJ 2002; 324 : 506 Competing interests: None declared
Cancers increases caused by ignoring animal research 18 March 2005
Ellen C G Grant, physician amd medical gyanecologist Kingston-upon-Thames, KT2 7JU, UK Send response to journal: Re: Cancers increases caused by ignoring animal research	Much animal research is wasted1, because the results are unwelcome. Beatson demonstrated in 1898 that ovariectomy ameliorated the clinical course of breast cancer in women.2 In 1919 Loeb confirmed this observation in a rodent model.3 In 1932 Lacassagne showed a large continuous dose of oestrogen induced mammary tumours in mice.4 Since then a multiplicity of evidence from animal research has accumulated proving that exogenous sex hormones - oestrogen, progesterone and testosterone, cause cancers of the breast, ovary, endometrium, uterine cervix, testis, pituitary, thyroid, kidney, liver and lymphoid tissue.5 This evidence has been widely disregarded as not being applicable to humans. The result has been huge increases in preventable cancers caused by those with hormone-pushing agendas.6 The original animal research predicted more accurately the outcome of hormone misuse than the results of many expensive epidemiological trials which have conspired to mislead doctors for decades. 1 Pound P, Ebrahim S, Sandercock P, Braken MB, Roberts I. Reviewing Animal Trials Systematically (RATS) Group. Where is the evidence that animal research benefits humans? BMJ 2004;328:514-517 (28 February), doi:10.1136/bmj.328.7438.514 2 Beatson GT. On the treatment of inoperable cases of carcinoma of the mamma. Lancet 1898; 2:104-107. 3 Loeb L. Further investigation on the origin of tumors in mice. J Med Res 1919; 40: 477-479. 4 Lacassagne A. Apparition de cancers de la mamelle chez la souris male soumise a des injections de folleculine. Cr Acad Sci (Paris) 1932; 195:603-32. 5 Li JJ. Perspectives in hormonal carcinogenesis: animal models to human disease. Cellular and molecular mechanisms of hormonal carcinogenesis. Eds J Huff, J Boyd, J Carl Barrett. 1996 Wiley-Liss, Inc pp 447-454. 6 Grant ECG. Increases in breast cancer incidence http://bmj.com/cgi/eletters/328/7445/921#55298, 1 Apr 2004 Competing interests: None declared
The evidence is right in front of you 8 July 2006
Leigh Jackson, Manager Balham SW12 9PZ Send response to journal: Re: The evidence is right in front of you	It is a given that every department of science, however humble or auspicious, be it medical or non-medical, animal or non-animal, clinical or pre-clinical, should be subject to critical scrutiny and comparison by means of peer reviews, systematic reviews and meta-analyses. The authors of the study “Where is the evidence that animal research benefits humans?” conclude that animal research should be subject to systematic review. Is there nothing more interesting to be gleaned from this study than a statement of the obvious? Of course all areas of science should be constantly reviewed, but that is just a means not an end in itself. The end is a better understanding of the evidence. Before drawing attention to a more useful conclusion which may be drawn from this study I will make one criticism of its method. The study succeeds in identifying a total of 25 systematic reviews from a search of Medline and promptly discards 19 of them for reasons that appear altogether arbitrary given the description of their nature. They sound highly pertinent to the topic in question. It is the judgement of the authors that the six selected reviews “shed the most light on the contribution that animal research makes to clinical medicine.” 25 reviews must shed a lot more light than just half a dozen. We begin to approach the meta-analysis in scale. And it is difficult to believe that the clinical relevance of one of the six reviews – by Petticrew and Davey Smith – is worth including if these others are not. It is a great shame that these reviews were identified and then excluded. None of the five systematic reviews included in this study which feature pharmaceutical or physical interventions demonstrate a concurrence of beneficial outcome in both the clinical and animal case; nor do any of them provide an example where the animal model shows a benefit from intervention whilst clinical results demonstrate harmful effects. All five cases of intervention fail to produce any clinical benefits and they all fail to show any definite evidence of benefit on animal models. In fact all five cases are exactly concurrent in terms of the effects of intervention on humans and animals. In three cases the interventions in question are ineffective for both humans and animal models, and in the other two cases there is evidence of harmful effects for animals and humans. This exact concurrence might just be chance – or it might not. This last result constitutes the real importance of this study. The question which the study poses is whether animal research can be a benefit for humans and the more interesting conclusion than the one which the authors give is the tentative answer – yes it can. This study provides some reasonably working evidence that animal research is able to indicate when medical interventions are going to be ineffective or harmful on humans – when that evidence is carefully assessed. The benefits of this are twofold. We can protect people from exposure to unnecessary risk and at the same time we can save time and money by avoiding unnecessary clinical trials. If careful study shows that a proposed new medical treatment either does not work for, or harms animals, then we had better not go there! Competing interests: None declared