Updated: Feb 1
Millions of laboratory mice and rats have been sacrificed for the scientific advancement. This statue of a donnish-looking mouse knitting DNA is standing in front of the Institute of Cytology and Genetics of the Russian Academy of Sciences in the city of Novosibirsk, Siberia. It was designed by Andrey Kharkevich as an homage to the remarkable association between a scientist and a laboratory mouse which drives scientific exploration. It is interesting to note that it was an experiment performed on mice by Frederick Griffith in 1928 that paved the way for the discovery of DNA as the genetic material.
Galadriel Mirkwood and Polly Matzinger co-authored a paper in 1978 titled “In a fully H-2 incompatible chimera, T cells of donor origin can respond to minor histocompatibility antigens in association with either donor or host H-2 type” (Fig. 1) which has been cited 140 times as of January 31, 2021. If you are not an immunology enthusiast, you might not find anything unusual or particularly interesting in the previous sentence, unless someone tells you that Galadriel Mirkwood was an Afghan hound, yes! a dog! Popular for her ‘danger theory’, Polly Matzinger has been recognized as one of the 100 most important women in science yet her introduction is probably incomplete without this controversy.
Figure 1: Polly Matzinger co-authored a paper with her dog, Galadriel Mirkwood. It wasn’t that she thought that her dog has contributed to the work in any way, it was her way to avoid using passive sentences and also writing sentences in the first person. Inventing a new author helped her avoid both at the same time. The then editor of the journal barred her from submitting any papers with her as the main author while she also faced internal review at her university. Leaving aside her reason for doing it (gift authorship is questionable even for humans), why is it so unimaginable for us to give authorship to animals?
The association between scientists and animals  goes back a long way although rarely as co-authors on a research paper. Due to the taboos associated with the dissection of human bodies, ancient Greeks and Romans began using animals instead, to gain insights into human anatomy and physiology. Since then, animals have mostly served as tools in the process of scientific inquiry. Their use as test subjects (a practice that also gave us the expression “guinea pig” which was one of the most preferred animal models for vivisection  studies during the 19th and 20th centuries) gave us the confidence to set out for outer space (Fig. 2), enabled us to explore brain and behavior, understand fundamentals of genetics and heredity, develop and evaluate life-saving drugs, vaccines and therapies to combat diseases like diabetes, cancer, AIDS and recently COVID-19 (Table 1). Animals share remarkable physiological and anatomical similarities with humans, making them ideal substitutes to study the human body. The contribution of animal research to human welfare is indeed invaluable and untold. But at what cost?
Figure 2: Animals have been used in astronomic exploration to test the suitability of space flights. The first animal to be sent into space was a dog. As part of Project Mercury, NASA sent a chimpanzee, popularly known as Ham (in the picture), to test the effects of space on the ability of a living creature to perform actions. The above picture was taken after its successful return to earth.
A variety of animals, such as birds, reptiles, fish, dogs, and monkeys, is used for scientific procedures (Table 1). It is estimated that more than 50-100 million animals are used (and often killed) for scientific procedures every year globally. The reality is a lot more gut-churning than mere statistics can convey. Animal-based research routinely involves housing the test animals in cages, injecting them with potentially lethal substances like pathogenic microbes, controlling their reproduction and other social habits, and killing them either to collect tissues/organs or to dissect their bodies for analysis. Quite often, the animal models are euthanized after the completion of experiments to avoid later pain and distress. It is natural to ask if it is okay for us to exploit animals for the benefit of human society or to expand our understanding of the physical world? Can the benefits of animal research to human species outweigh the suffering of these animals? Such questions challenge the foundations of human morality and collectively constitute one of the most controversial subjects of public debate.
In the following sections, I will try to address these moral dilemmas by answering three important questions, i.e. (1) is animal research morally acceptable? (2) what are the current guidelines and regulations regarding the use of animals in research and (3) should we acknowledge (recognize) their invaluable contribution to research? If yes, why and how.
Table 1: Many significant scientific developments have been made with the help of animal models and this table does not even scratch the surface. The intent here is to highlight how the association between scientists and animal models have shaped the scientific history. (References: 1, 2, 3, 4, 5, 6, 7, 8, 9)
Is animal research morally acceptable?
This is a complex question that requires systematic evaluation of our moral principles and a harm-benefit analysis of animal research. I will attempt to answer this question by considering two hypothetical limiting scenarios:
Scenario 1: Animal research is useful to humans and does not harm animals
In this situation, it is easy to conclude that we should continue performing experiments on animals.
Scenario 2: Animal research is useless for humans and also harm the animals
In this scenario, it would be irrational to continue the practice of animal experimentation.
However, as mentioned above, animal research is undoubtedly useful and has played a crucial role in improving the average life expectancy of the human species. Animals have been used for advancing basic scientific knowledge, as models to study human diseases, as well as for surgical skill development and in pharmaceutical research for validating and testing new drugs. Human beings, like other mammals, are highly complex organisms with an intricate hierarchy of the structural organization. Trillions of cells present in our body interact in various ways to form different types of tissues with specialized functions, which in turn make up organs, which further form organ systems. Scientists investigate all these levels of organizations and their interactions with each other in healthy as well as diseased animals to develop a basic understanding of human physiology, which can be used for finding cures for diseases. Although some of these studies can be conducted alternatively with in vitro systems like cell or tissue cultures or in silico systems like computer simulations (discussed further in next section), with our current knowledge, it is very difficult to predict systemic interactions between organs and certain physiological functions from studies of separate cells, tissues or organs. For example, the study of the pathogenicity of a viral disease require a living host with its innate and adaptive immune response. Similarly, the development of brain functions cannot be properly understood without analyzing it in a living organism, at least with our current knowledge. Hence, in reality, we encounter a third scenario i.e.
Scenario 3: Animal research is useful for humans but is harmful to animals.
This conflict between human and animal interests creates a moral quandary. How should we decide now? To answer this, we first need to understand what constitutes moral behavior. According to one definition, moral behavior can be defined “as the actions of a person who takes into account in a sympathetic way the impact those actions have on others.” Conventionally, we have been following moral principles to guide us in how to behave towards ‘other’ human beings with the goal of minimizing overall human suffering in the world. Animals are generally not extended this moral concern which is reflected in our history of giving preference to human interests over animal suffering. This has its roots in the belief that human beings are categorically superior to animals because they are unique in having consciousness. However, a growing body of scientific evidence suggests that animals can also suffer and feel pain and that many animals exhibit signs of consciousness.
Considering that, should we then extend our moral concern to animals, and to what extent? Should we treat them as equals to humans? Should we treat all animals (not just vertebrates) as equals or just the ones with proven consciousness? Do animals have the same kind of consciousness as we do or is it different? Although these questions are almost impossible to answer conclusively and have inspired diverse philosophical views over the centuries, it is at least clear that we have reasonable evidence to think that animal research is morally questionable. However, considering the benefits, we have to find a middle ground, seeking scientific progress while minimizing (and potentially eliminating) animal suffering. Indeed, this is also reflected in our current legal guidelines and regulations, as discussed in the next section.
Current Guidelines and Regulations
The current animal protection and welfare legislation has its roots in the anti-vivisection movement of the eighteenth and nineteenth century, which witnessed the great philosophers like Arthur Schopenhauer and Jean-Jacques Rousseau criticize treating animals as ‘means to an end’ and advocate for their natural rights. But perhaps today’s status quo (at least in the western world) regarding animal rights is best traced back to the utilitarian views of Jeremy Bentham who opined that animal research was acceptable only if it had a determinate object, was beneficial to humans and was realizable. These principles are echoed in today’s legislative and ethical guidelines on animal use in scientific research which are based on the seminal work of William Russell and Rex Burch during the 1950s. Physiologist David Henry Smyth has beautifully summarized these tenets (popularly known as “Three Rs”) as “all procedures which can completely Replace the need for animal experiments, Reduce the numbers of animals required, or diminish (Refine) the amount of pain or distress suffered by animals in meeting the essential needs of man and other animals”. These guiding principles became the basis of legislation in several countries like the Animals (Scientific Procedures) Act 1986 in UK, the directive 2010/63 in the European Union, the Animal Welfare Act which is enforced by the Animal Care division of the Animal and Plant Health Inspection Service (APHIS) of the United States Department of Agriculture (USDA), the Guide for the care and Use of Laboratory Animals in the USA.
Figure 3: Animal research presents a unique moral dilemma. 3R framework help us shift this balance by minimizing harm to the animals and maximizing the value of the scientific outcomes. (Source: 10.1038/laban.1220)
The ultimate goal of all the above-mentioned animal welfare reforms is ideally a complete elimination of animal models in scientific research. However, we have a long way to go to achieve that which will require continuous concerted global efforts by the scientific community. Significant progress is being made in this direction by developing new alternatives to animal experimentation and by introducing new legislation for regulating the use of animals as experimental models while minimizing their suffering. More precisely, the following strategies are being adopted to implement these goals:
1. Replacement: Within the 3R framework, researchers are required to take permission for using animals in their research work after providing a satisfactory justification. There is a strong emphasis on replacing the use of sentient animals like vertebrates with simpler animal forms like invertebrates or more preferably by in vitro experimental systems like cell culture, tissue slices, and organs (partial replacement). However, these methods could not completely eliminate the use of animals, since at least some animals need to be sacrificed as a source of cell/tissue cultures. To address this issue, new techniques are being developed using mathematical models and computer simulations to mimic complex tissue organization and function like organ-on-a-chip (a topic wonderfully covered in another of our blog posts) to completely eliminate the need of using live animals for scientific research (full replacement). It is also encouraged to use population data of patients and healthy individuals to study mechanisms of disease, wherever possible. Scientists are developing new methods that can be used to replace animal testing. For example, the Ames test can be used instead of animal testing to check for the safety of a drug in terms of its carcinogenicity or DNA damaging properties instead of mice models. Similarly, the use of rabbits for pyrogen (fever-causing bacterial contaminants) testing has been replaced by the use of horse shoe crabs or chicken and beef meat from slaughterhouses. It is clear that the principle of replacement allows the use of animal models for research only when it is completely unavoidable.
2. Reduction: The principle of ‘reduction’ calls for a regulation of the number of animals that can be used for an experiment. The experiments should be designed such that the requirement of animals to reach a valid conclusion is adjusted to a minimum. This can be achieved by using statistical analysis along with well-planned experiments, maintaining good lab practices such as keeping pure animal lines to facilitate reliable results with fewer animals, and ensuring a clean working environment for preventing unnecessary animal deaths due to diseases. With the development of new technologies, such as novel non-invasive methods to study the progression of cancer and other similar diseases, researchers are able to minimize the use of animals by using the same animal again instead of using several animals.
3. Refinement: The third principle of the animal welfare reforms calls for humane treatment of experimental animals to avoid unnecessary pain and suffering. It is important to treat animals used in research well and only when required not just because of moral reasoning but also because of scientific and economic reasons. William Russell and Rex Burch emphasized that “humane science” is the “best science”. They argued that any experiment conducted with stressed or diseased animals will not generate good data and will therefore need to be repeated. This will increase the overall cost of the experiment. Conversely, humane practices will facilitate reliable results in a shorter time and with lower expenditure. To this end, it is important to provide the best possible care and clean housing conditions for animals. For certain species like monkeys which are social animals, maintaining appropriate size social groups and ensuring a stimulating environment is recommended to avoid stress and for keeping them healthy. The refinement principle also highlights the significance of training of scientific personals or animal caretakers in ensuring the humane treatment of animals.
Coming back to the harm-benefit analysis of animal experimentation, it can be concluded that the 3Rs can shift the balance (Fig. 3) towards benefits and can help us achieve the goal of maximum benefit and minimum harm to the animals.
More than sixty years have passed since these principles were laid down, however, the implementation of the 3Rs varies considerably across the world. It is quite apparent that there is an urgent need for a universal regulatory framework regarding the humane use of animals and for strict compliance with these regulatory provisions.
Recognition: The Missing R?
Though not a part of the animal welfare reforms by convention and rarely a topic of public/scientific deliberation, I concur with people who believe that there should be a fourth R in our consideration for fair treatment of laboratory animals and that is Recognition. I suggest that it is important for us to give animals due credit for their “sacrifices” for scientific advancement. This idea may sound ridiculous to some and one may ask how will recognizing their contribution be of any use to these animals. However, I believe it is useful in the same way as the other three R’s. Acknowledging the fact that animals were sacrificed to obtain a certain piece of knowledge or to develop a particular life-saving vaccine help us appreciate the importance of those achievements. This appreciation in turn will help us be more aware and concerned for animal welfare and will motivate us further to develop novel alternative methods towards the elimination of animal research. Though some people have gone as far as giving the model animals honorary authorship, there are probably less debatable ways of achieving the same. For instance, one of the simplest and easiest way to achieve this could be by encouraging researchers to state the number and type of animals used or sacrificed for any scientific study at the time of its publication.
5. Rowlands, M., 2015. Can animals be moral?. Oxford University Press.
6. Weil, K., 2012. Thinking animals: Why animal studies now?. Columbia University Press.
 In this article, the term animal is narrowly used to mean non-human vertebrates. Check out this article by Viraj Muthye to know more about different kinds of animals.  The practice of performing dissections of live animals for scientific experimentation.
I would like to thank Ms. Lata Kalra and Ms. Charu Mehta for their valuable feedback and time which helped me in improving this article.