A Personal Foreword

As animal well being is a prerequisite for reliable experimental results, it is of utmost importance to seek for methods and procedures that can reduce suffering of the animals and improve their welfare.

This sentence, closing Vera Baumans' conclusion in a 2004 paper on ethical dilemmas in animal research [1], unfolds the dilemma of what suffering means for animals. What is the perspective to be taken, where to position the borderline between objectivity and subjectivity? Are anthropocentric views the good or the flipside of the coin?

While it is uncontested that animals feel pain, the question remains of which kind it is. The McGill pain questionnaire will not apply to rodents. This question has been around in the literature for almost 4000 years. Animals as "tools" for research are ascribed to the times of Hippocrates, which is still under dispute. The famous Roman physician Galenus, however, became known as the Father of Vivisection. The debate probably flared up for the first time in the seventeenth century. One of the founding fathers of the enlightenment, the Dutch philosopher Baruch de Spinoza, "admitted that animals suffer, but we are within our moral rights to use them, as we please, treating them in the way which best suits us; for their nature is not like ours, and their emotions are naturally different from human emotions" [2]. This view seems to be enforced by what is widely known as the "Cartesian Gap," assuming that Descartes categorized animals as "meaty machines" or as automata. However, when it comes to emotions I get the impression that Descartes - at least for the human being - is somewhat conciliating: Ainsi que souuent vne mesme action, qui nous est agreable lors que nous sommes en bonne humeur, nous peut déplaire lors que nous sommes tristes & chagrins.1 It has been more than 100 years later that Jeremy Bentham fiercely and provokingly opposed the Cartesian perspective:

The French have already discovered that the blackness of the skin is no reason why a human being should be abandoned without redress to the caprice of a tormentor. It may one day come to be recognized that the number of the legs, the villosity of the skin, or the termination of the os sacrum [tailbone),are reasons equally insufficient for abandoning a sensitive being to the same fate. What else is it that should trace the insuperable line? Is it the faculty of reason, or perhaps the faculty of discourse? But a full grown horse or dog is beyond comparison a more rational as well as more conversable animal, than an infant of a day, or even, a month old. But suppose they were otherwise, what would it avail? The question is not, Can they reason? nor Can they talk? but Can they suffer? [3]

Bentham is regarded among the first to foster animal rights, the ability to suffer being the benchmark, the insuperable line, instead of the ability to reason. Again approximately after a century Darwin established the biological similarities between man and animal. Not surprisingly, however, his seminal scientific findings led to an increase in animal experimentation [1], since they paved the ground for a rationale to use animals as a model for human physiology and biological function.

It was Darwin's contemporary, the great physiologist Claude Bernard, who established this similarity between man and animal as a scientific method and became the founding father of modern experimental medicine [4]. His key message precisely describes the contemporary paradigm of biomedical research:

Le médecin qui est jaloux de mériter ce nom dans le sens scientifique doit, en sortant de l'hôpital, aller dans son laboratoire, et c'est là qu'il cherchera par des expériences sur les animaux à se rendre compte de ce qu'il a observé chez ses malades, soit relativement au mécanisme des maladies, soit relativement à l'action des médicaments, soit relativement à l'origine des lésions morbides des organes ou des tissus. C'est là, en un mot, qu'il fera la vraie science médicale.2

Claude Bernard incorporated the principles of "hard science," in particular physics and chemistry, into the realm of medical research and made them the cornerstones of his scientific method [4]. Since (physical or chemical) experiments in humans are clearly beyond any moral or legal acceptance, animal "deputies" became the scientific object to serve as the mere substance in modeling a human disease.

With the advent of genetic modification techniques in the 1980s, transgenic animals and in particular rodents-mice being the working horses of modern biomedical animal experimentation-opened a new era in disease modeling. Single gene function, genetic components, and regulatory networks could be correlated with diseased conditions in humans. Still, we are facing the problem of "bridging the gap" in between mouse genomics and the disease phenomenon in the individual human being. Hence, the front edge research in biomedical is focusing on non-human primates (NHPs).

Due to physiologic differences between rodents and higher primates, such as life span, brain size and complexity and motor repertoire, as well as the availability of cognitive behavioral testing, NHPs are considered one of the best animal models; especially for complex disorders that correlate with aging, cognitive behavioral function, mental development, and psychiatric dysfunctions. In addition to neural psychiatric related disorders, metabolic function, reproductive physiology, and immunology are other areas of research where the NHP model has been widely used. [5]

Given the complexity of a disease or illness, the causality of which is, as we increasingly understand, far from a simple "one gene, one disease" situation that can be reduced to a single biochemical step in the cell only in a few cases. Many more parameters in animal experimentation have to be considered than just measurement of the chemistry and physics, often termed "surrogate parameters." Referring back to the opening quotation, environmental conditions play a crucial role in obtaining reliable scientific results from the models. Overcoming structuralistic views and granting animals a body-mind relation too, probably very similar to humans, does not facilitate animal experimentation and its interpretation. The human-animal boundary is closer.

But besides ethical and moral concerns in general, there are good scientific and economical reasons to scrutinize and carefully optimize laboratory experimentation with animals. Those experiments are costly, need special infrastructure, lots of paperwork and hence quite a number of laboratory staff; each outcome of the experiments should contribute to our knowledge. The battle between hypothesis-driven or explorative research can already be found in the musings of Claude Bernard.2 The demand for both is to extract the maximum of information. Scanning current scientific papers seems, provocatively, to be rather the exception than the rule as the editors and their distinguished invited authors of the present volume show in their contributions. Good laboratory practice as randomization, clear endpoints, sound statistics, selective reporting, and publication bias are at stake and are often ruthlessly abandoned. There seems to be much room for improvement.

Emerging from a fellowship at the Collegium Helveticum, Marianne Martic-Kehl and P. August Schubiger, with their background of active researchers in life sciences, focused for several years on getting hard data about the practice of animal experiments, mostly in rodents, with importance placed on cancer research. Over the years they have continuously confronted their colleagues with their findings and elicited fierce debates in the interdisciplinary environment of the Collegium. The project culminated in a final symposium, the results of which yielded the contents of this book. The author is extremely grateful to both of the editors to have picked up a kind of taboo topic in biomedical research and sometimes stubbornly to follow its traces in the vast universe of biomedical publications.

The book deserves a wide readership the scientific community and beyond.

Gerd Folkers

January 2016

References

1. 1. Baumans, V. (2004) Use of animals in experimental research: an ethical dilemma? Gene Ther., 11, 64-66.
2. 2. Soccio, D.J. (2009) Archetypes of Wisdom. 9th edn, Boston, MA: Cengage Learning, p. 55f.
3. 3. Bentham, J. (1828) Of the limits of the penal branch of jurisprudence. In: An Introduction to the Principles of Morals and Legislation. A new edition, corrected by the author. Footnote 122: Interest of the inferior animals improperly neglected in legislation, London: Dover Classics, pp. 235, 236.
4. 4. LaFollette H. and Shanks, N. 1994) Animal experimentation: the legacy of Claude Bernard. Int. Stud. Philos. Sci., 8, 195-210.
5. 5. Chan, A.W.S. (2013) Progress and prospects for genetic modification of nonhuman primate models in biomedical research. ILAR J., 54, 211-223.