John Coote and Olga Hudlicka
University of Birmingham, UK

https://doi.org/10.36866/pn.88.23

In view of the Government announcement that it is updating UK law regulating research using animals to bring the UK in line with the recent EU directive (2010/63/EU), this is a good time to consider how bureaucracy can influence and affect science and scientists. To understand these issues it is important to rehearse the history of the topic.

An important feature of a civilized society is that it pursues the highest standard of care for the health of its human and animal population. Understanding the structure and working of living organisms has been pivotal to achieving this. Physiological knowledge and best practice of medicine and proper care of the ill are tightly linked. There have been many obstacles to achieving the present-day high standards of treatment, not the least by groups opposed to vivisection and by unsympathetic bureaucracy of governments and research institutions including universities. Other areas of science and scholarship have been less affected by such obstacles.

Biological research is essential for understanding the action of cells, organs and systems of the body. It is a demanding activity requiring great skill, dedication and a total commitment of time and effort. The advances are also dependent on non-medical sciences like chemistry, physics and engineering; for instance, chemists characterised and eventually synthesised nature’s compounds such as digitalis, atropine, ephedrine or anaesthetics, which first were observed in the curing action of plants. More recently, high-power imaging devices, such as positron emission tomography and magnetic resonance imaging developed by engineers and physicists, have been part of the arsenal available for fundamental research and treatment of disease.

It is also worth remembering that the rapid advances of knowledge seen in the last century have depended on the landmark discoveries over the previous 200 years. During the 18th century the biologist or medical practitioner could look for practically no help from the natural sciences. For example, John Hunter (1728–1793), one of the most celebrated of all surgeons and a pioneer of scientific method during the 18th century, realized that he really needed to know the physiology to ensure the best outcome of his surgical intervention. He therefore carried out experiments on living animals and this had to be done without anaesthesia because the actions of ether or chloroform were not discovered for another 50 years (1846). These studies, techniques that seem very crude and cruel to us today, such as cutting nerves, tying off blood vessels or removing organs and observing what happens, were very important in providing knowledge that was very valuable to a surgeon, who daily was doing similar things on human patients (also without anaesthesia).

The 19th century witnessed an explosion of biological knowledge about the working of the animal body that was dependent on experiments on living animals. This was largely driven by the desire to know how things worked. The spin-off was that this led to major advances in health and management of disease. However, biomedical scientists and the public became rightly concerned about the pain and suffering inflicted on animals in unregulated experiments. In 1876 Parliament passed an act to regulate experiments likely to cause pain by introducing a Licence which also stipulated they could only be conducted under anaesthesia and with a view to increasing physiological knowledge, or saving or prolonging life and alleviating suffering. The prime purpose of the act was to prevent animals suffering. Throughout the 20th century experiments on animals increased and there were many outstanding discoveries such as receptors controlling blood pressure and respiration, hormones, mechanisms of nerve conduction and transmission, cell membrane receptors and their pharmacology etc., providing huge medical benefits. However, the voice of moral philosophers, animal welfare and antivivisectionist groups became more strident because they considered the scope of the 1876 Act was not sufficiently well specified, leaving some important procedures open to interpretation. Too many animals were used, alternatives were not being seriously considered and reasons for experiments were not sufficiently well defined. On the other side, under the 1876 Act, researchers felt insufficiently protected from accusation of causing suffering or harm to animals. Those involved with biomedical research also strongly felt that the 1876 Act was insufficient to regulate animal welfare in light of new developments and discoveries in genetic and molecular biology that did not necessarily involve vivisection. For example, animals could be bred with genetic defects that altered organ function that had marked effects on their physiology. In 1986 Parliament approved ‘The Animals (Scientific Procedures) Act (ASPA)’ and this essentially governs experiments on living animals at present. Again the prime purpose of the act was/is animal welfare. The Act provides authority for specific work, rather than simply a list of what may be done irrespective of why and in what context. The enforcement of the Act meant that biomedical researchers in the UK were tightly regulated and the Act became a model for regulating all work in many other countries. Recently the European Parliament has adopted this strict approach and issued a directive on the ethical and legal requirements concerning the use of animals in scientific research in Europe that have now been transposed into UK legislation.

The regulation can be burdensome. Under the 1986 UK Act (ASPA), to carry out research involving animals, the researcher with relevant qualifications has to undergo training and to pass an examination before being granted a personal licence allowing them to carry out clearly specified, regulated procedures. Secondly, they can only work under a research project that requires a Project Licence approved by the Home Office. The Project Licence is a detailed description of the work they are intending, why it is needed, its purpose and the methodology. Here there has to be a serious consideration of the best methods which are embraced by the term refinement and the fewest number of animals needed, embraced by reduction. They must also consider carefully the need to use a protected animal or whether an alternative method could be used to achieve the aim, a principle embraced by replacement. Thirdly, the regulated procedures can only be carried out in a licensed, certificated designated place. The procedures are also classified according to severity in terms of pain, suffering, distress and lasting harm. Applications are subject to local ethical committee approval before consideration by the Inspectorate and final approval by the Secretary of State. Overall the process from start to finish can take a year or more. The Project Licence has a limited life span of 5 years.

It is little realized that the requirement for precise definitions and a clear purpose of the procedures to be used in a research protocol are so strictly regulated it can impede curiosity driven research. Of course, it is necessary to have a clear plan of research, but this should have some built-in flexibility and should not always be directly linked to human or animal disease. The truth is that many great discoveries have not been mission oriented but have come about by curiosity to understand the physiology. A recent example is the major breakthrough in the treatment of drug-resistant hypertension (Dibona & Esler, 2010). A simple operation that destroys the nerves in the wall of renal blood vessels via a radio frequency transmitting current from a catheter inserted into a renal artery was shown to bring about a clinically significant reduction in hypertension. This procedure would not have been done but for a discovery in animal experiments fifty years ago. Then researchers were just beginning to wonder what the many nerves supplying each kidney did to its function (Astrom & Crafoord 1968). There was no intended purpose to determine if they could be contributing to a sustained morbid increase in blood pressure.

The new legislation does not allow procedures to be worded with sufficient freedom to accommodate minor variations. Changes may need further approval by local ethics committee and then by Home Office. It is well accepted that any project has to have given consideration to alternatives (replacement), numbers (reduction) and refinement. A problem is the rigidity of interpretation by Home Office Inspectors that can vary from one to another. It is an offence if the terms of the Licence (Personal or Project) are not followed exactly even if no harm has come to animals. Infringement of one or more conditions of the Licence can lead to prosecution (imprisonment of up to 2 years on conviction), or the Licence may be revoked (so terminating the studies) or a period of retraining may be required. The extent of the bureaucracy means that every researcher has to be alert to the danger of carrying out even quite minor changes in a procedure. This can happen to someone who has undergone a prolonged period of training in medicine, in dentistry, in science or even in veterinary surgery. Transgressions can result in severe disruption or complete loss of career. In fact, it is much less restrictive to do experiments on humans.

With the burden of the legislated restrictions and paper work and the constant threat of animal rights campaigners, it is surprising that the desire to conduct experiments on living animals to advance biomedical knowledge has not been totally extinguished. It is, though, essential that such work continues because modern developments in cell and gene technology have not and probably will not lead to animal experimentation being superceded. For example, the new science of optogenetics enables genetically labelled cells to be selectively targeted by directed laser beams of light. This technique, shown to work so informatively on flies and simple animals, has considerable potential to manipulate cells in brain and heart or other organs in mammals, providing opportunities to explore the physiology as well as mechanism of disease. Thus, a genetic manipulation has not removed the need for studies on whole animals.

The law is there to prevent unnecessary harm to animals. Therefore, minor transgressions that do not affect animal welfare should be judged more sympathetically. In this context, it is worth considering a few cases in animal research that illustrate the often trivial nature of offences that attract the severest of penalties. These are hypothetical examples based on real cases. Say that a procedure stated, ‘In an anaesthetized animal the stellate ganglion (which supplies nerves to the heart) will be exposed retropleurally via the space between heads of ribs 1 and 2 and injected with a toxin’. If, for control purposes, the toxin injection is omitted then an infringement is committed even though there is less damage to the health of the animal and, in the end, fewer animals are used. Of course, this should have been included in the procedure but the need may only have come to light during the study. Another example is vaginal smearing, an unlicensed procedure practised on a daily basis in high street pet shops or breeding establishments, has to have a Licence if it is part of a research project. So far so good, but if the procedure in the project does not state that it will be done on more than one occasion and the researcher does this more than once, assuming it is de facto or causa sine qua non, then this is considered an infringement.

We all understand the need for some restrictions. Apart from the three categories of licence the purpose of ASPA is to ensure animal welfare by stringently applying the three principles – replacement, reduction and refinement. Yet when considering compliance and infringement, many of the cases brought have not transgressed any of these nor have they meant that experimental animals have been mistreated.

What is perhaps not appreciated is that employers also impose a code of practice intended to comply with its legal obligations but also to protect itself from accusations of being soft on possible offenders. In practise, the staff are rarely supported by their employer and they are often more severely disciplined (dismissed or removed from certain duties). This occurs even when the infringement comes into a minor category. Thus, employers appear to ignore the main purpose of ASPA and the legal regulations. Recent exposure of poor nursing care and diagnostic mistakes in the medical profession in hospitals that have gone relatively unpunished serve to highlight the imbalance of justice and how human society loves its animals more that itself.

Subjection to the interpretation and impositions of law makers and employers is but one high price we pay for research. A further concern is an increasing demand for biomedical scientists to demonstrate how their studies help in understanding and treating disease. Researchers submitting projects for funding or papers for publication are under greater pressure than ever to come up with some exciting medical benefit of the work. However, the prime purpose of much research that may result in major clinical benefits has rarely been to cure a disease. We have already given the example of studies on the function of renal nerves. A more recent example of this is the work of Frances Ashcroft, the winner of the L’Oréal-UNESCO award 2012 for women in science. She explains that it was the urge to discover how the closure of a channel in a cell membrane resulted in secretion of a hormone that underpins her research. Her excitement at the result was because she had observed one of nature’s exquisite mechanisms. Subsequently the thrill of unravelling the DNA sequence that codes for the channel protein was the ultimate reward. This, of course, was made even better when later, in collaboration with Andrew Hattersley, it was shown how a mutation in a gene normally coding for the protein led to a rare form of neonatal diabetes. This then resulted in the discovery that sulphonylurea drugs were able to aid glucose in closing the ion channel and provide good clinical control of this early type of diabetes in children.

If you have read this far you may be wondering why it is that we have raised this topic in Physiology News. Are we just stirring the embers of an old debate? A reason is that many like us (until recently) will be poorly informed about the effects of legislation and the action of authoritarian institutions on the careers of individual researchers. Our concern is that the obstacles we have outlined will deter young scientists from whole animal research, and there will be a loss of skills. By the time the discoveries in molecular biology need to be verified in living bodies there will be no one left who would know how to do it.

In conclusion, the administration of the law should be simplified and based on the original principles, the advance of knowledge and welfare of animals.

References and further reading

Astrom A & Crafoord J (1968). Afferent and efferent activity in the renal nerves of cats. Acta Physiol Scand 74, 69–78.

Dibona G F & Esler M (2010). Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Renal Physiol 298, R245–R253.

Hodgkin AL, Huxley AF, Feldberg W, Rushton WAH, Gregory RA & McCance RA (1977). The Pursuit of Nature. Informal Essays on the History of Physiology. Centenary of The Physiological Society. CUP, London. Physiology News / Autumn 2012 / Issue 88

Burch D (2007). Digging up the Dead. Vintage Books, London.

Paton W (1993). Man and Mouse: Animals in Medical Research. Second edition. OUP, Oxford.

Rassam CC (1993). The Second Culture. Aurum Press, London.