Background: The Nobel Prize of Physiology or Medicine (NPPM) has recognized the work of 222 scientists from different nationalities, from 1901 until 2020. From the total, 186 award researchers used animal models in their projects, and 21 were attributed to scientists and projects directly related to Pharmacology. In the most recent years, genetics is a dominant scientific area, while at the beginning of the 20th century, most of the studies were more related to anatomy, cytology, and physiology. Summary: Mammalian models were used in 144 NPPM projects, being rodents the most used group of species. Moreover, 92 researchers included domestic species in their work. The criteria used to choose the species, the number of animals used and the experimental protocol is always debatable and dependent on the scientific area of the study; however, the 3R’s principle can be applied to most scientific fields. Independently of the species, the animal model can be classified in different types and criteria, depending on their ecology, genetics, and mode of action. Key-Messages: The use of animal models in NPPM awarded projects, namely in Pharmacology, illustrates their importance, need and benefit to improve scientific knowledge and create solutions. In the future, with the contribute of technology, it might be possible to refine the use of animal models in pharmacology studies.

Alfred Nobel was a chemist, inventor, entrepreneur, and industrialist of the 19th century, being one of the most notable men of his time. He was born in Stockholm in 1833 and one of his most recognized achievements was the use of nitroglycerin as an explosive and the way to control it. Before his death, he left virtually all his fortune to establish prizes for people from different nationalities who made the most compelling achievement for the global benefit, in the fields of chemistry, physics, physiology or medicine, literature, and peace among nations [1, 2].

According to his words, the Nobel Prize of Physiology or Medicine (NPPM) should be attributed to “the person who shall have made the most important discovery within the domain of physiology or medicine.” Until today, 222 scientists awarded the NPPM from 1901 to 2020 [3]. According to the Foundation for Biomedical Research, 186 award researchers (from the 222 total) used animal models in their projects [4]. From the total of NPPM awards, 23 were attributed to scientists and projects directly related to Pharmacology and the use and test of different drugs and chemicals in order to treat diseases, infectious agents, and physical conditions [4].

Animal models are based on the principle of comparative medicine that animals share physiological, pathological, behavioral, or many more other characteristics with humans. Historically, it is possible to say that the use of animals for health purposes started in ancient Greece, >2,000 years ago, when anatomy and physiology were born as scientific fields [5].

The use of animal models in the projects recognized by the NPPM is more than illustrative of the importance and need of them to improve scientific knowledge. In this way, this review aims to analyze the use of animal models as essential tools for scientific development, especially in pharmacology, using the NPPM projects as examples of worldwide recognized scientific improvements considerably depends on those models.

As mentioned above, 186 award researchers used animal models in their projects (Table 1). For instance, Emil Adolf von Behring, the 1st NPPM winner, in 1901, used horses, rabbits, and guinea pigs in order to discover a diphtheria treatment. In the same way, the 2020 winners, Harvey J. Alter, Michael Houghton, and Charles M. Rice choose the chimpanzee as a model to study the hepatitis C. Furthermore, most of the awarded discoveries required >1 species as an animal model, in different parts of their studies. In fact, 87 of the prized researchers needed >1 animal species in their award projects [4].

Table 1.

NPPMs attributed to researchers that used animal models from 1901 to 2020 [6-114]

NPPMs attributed to researchers that used animal models from 1901 to 2020 [6-114]
NPPMs attributed to researchers that used animal models from 1901 to 2020 [6-114]

Almost all the medical and biological fields require the use of animal models. Over time, the 186 NPPM winners that used animal models in their research came from distinct areas of Physiology and Medicine. In the most recent years, genetics is a dominant scientific area, with a lot of prizes attributed in this area, as the discovery of a mechanism that allows mature cells to become pluripotent, by John B. Gurdon and Shinya Yamanaka, awarded in 2012 [102]. In contrast, at the beginning of the 20th century, the majority of the studies were more related to understand the structure and function of different cells, tissues, organs, and systems. For example, Henry H. Dale and Otto Loewi won the NPPM prize in 1936 for describing the chemical transmission of nerve impulses, using animal models from 4 different taxonomic classes (cats, frogs, birds, and reptiles) [28]. Microbiology, immunology, radiology, biochemistry, and pharmacology represent other scientific areas where animal models are frequently used, also in studies developed by NPPM winners.

The species of animals used as models in projects recognized by the NPPM are very diverse. Considering the taxonomic classes, the mammalian class is the most used, since 144 recognized projects and winners used mammalian species in some part of their work, followed by the birds, used in 35 discoveries (Fig. 1, 2). However, among the years, due to public opinion and animal welfare concerns, more primitive tend to use, as insects and nematodes, comparing to mammalian species. Nevertheless, in some studies and scientific fields, mammals, including primates, are needed to reach the proper conclusions (Fig. 1) [115].

Fig. 1.

Timeline illustrating some animal species used as models in NPPMs. NPPM, Nobel Prize of Physiology or Medicine.

Fig. 1.

Timeline illustrating some animal species used as models in NPPMs. NPPM, Nobel Prize of Physiology or Medicine.

Close modal
Fig. 2.

Groups of animals used as models in different NPPMs. NPPM, Nobel Prize of Physiology or Medicine.

Fig. 2.

Groups of animals used as models in different NPPMs. NPPM, Nobel Prize of Physiology or Medicine.

Close modal

Regarding the use of mammalian species in NPPM recognized works, the order Rodentia, which includes rats, mice, and guinea pigs, is the most used as an animal model. In detail, 86 projects used rodents, 29 used dogs, and 27 required rabbits, being those the most common mammals used (Fig. 3). Considering the use of domestic species (namely dogs, cats, ruminants, horses, chickens, and turkeys), 92 of the researchers used at least one domestic animal model in their works (Table 1).

Fig. 3.

Proportion of mammalian species used as animal models in NPPMs. NPPM, Nobel Prize of Physiology or Medicine.

Fig. 3.

Proportion of mammalian species used as animal models in NPPMs. NPPM, Nobel Prize of Physiology or Medicine.

Close modal

The use of animal models in different scientific areas has always been a topic of debate in multiple conferences, interviews, and discussions. In the same way, the criteria used to choose the species, the number of animals, used and the experimental protocol is always debatable [116]. Therefore, it can be challenging to understand what criteria are used by recognized scientists for choosing a species instead of others as animal model. August Krogh, who was also a NPPM winner, was one of the 1st scientists to argue that despite the number of animals used and the research conditions, there is always the “most convenient species” to study a particular biology issue. Currently, concrete criteria are suggested in the literature mostly based on empirical data and ethical arguments. Very recently, in 2020, Dietrich et al. [117] established a total of 20 criteria, divided into 5 clusters. Some of them include, for instance, the ease of supply, the financial considerations, and the cultural attributes, that can contribute to the use of rodents. On the other hand, the researcher risks can be an explanation for the use of domestic species, and the comparative potential has a considerable impact on the choice of primates as animal models.

Moreover, some authors argue that the model choice depends on the biological area of the study and on the phase of the biological process. For example, in teratogenic studies, it is crucial to understand that embryonic development can be very distinctive among taxonomic groups and different phases of the development have distinct ideal animal models. In fact, invertebrates (as Caenorhabditis elegans and Drosophila melanogaster) are adequate for screening simple mechanisms in the early periods of the reproductive cycle, while mammalians, as rodents and rabbits, are phylogenetically closer to humans, allowing the possibility of taking better extrapolations and conclusions [118].

However, when choosing an animal model, it is not only essential to select the appropriate species but also the method to simulate a specific scenario. Thus, different types of animal models are usually defined in the literature and classified according to distinct criteria. Regarding their ecology or microecology, the models can be gnotobiotics, where the microbiota is totally known, germ free, where there is no microorganisms present, specific germ free, which means that the organism is free from specific bacteria or pathogens, or conventional, which is an animal with a normal microbiota [119]. On the other hand, according to genetics, they can be classified as outbred, defined as a closed population that are bred to maintain maximal heterozygosity, inbred, individuals of a particular species which are nearly identical to each other in genotype due to long inbreeding in order to preserve a characteristic, and transgenic, created by manipulating and adding a specific genetic material [120]. Finally, they can be categorized according to their mode of action. One of them is the induced model, where the studied condition is experimentally created in the animal and can be either through the exposition to chemical, biological or physical agents or surgically induced. For instance, the use of alloxan to kill the beta cells to study diabetes mellitus or the intestine reduction surgery to create a short-bowel syndrome model represent, respectively, examples of the 2 types of induced model [121, 122]. Furthermore, there is the negative model, which is referred to a species, strain or breed that does not develop a certain disease following an experimental treatment. This model is frequently used to study infectious diseases, which are often restricted to a limited number of susceptible species, being innocuous to the negative model [123]. Moreover, the orphan model is used to study a condition that occurs naturally in a nonhuman species but has not yet been described in humans. Finally, the spontaneous model is a mutant, a natural organism with a genetic variant, being the athymic nude mouse an example of this model, used to study heterotransplanted tumors and allowing the 1st description of natural killer cells [124].

In oncology, besides using induced models, by promoting carcinogenesis physically, chemically, biological, or hormonally, it’s common to use models for cellular implantation. In this case, 4 different models using mice are frequently used (syngeneic, ectopic, orthotopic, and Hollow Fiber Assay [HFA]), all of them with advantages and disadvantages, following described. The syngeneic model is necessary to study anticancer drugs that interfere with the immune system, but it can often reduce the number of cell lines available. Even though the ectopic model promotes fast growth of the tumor, it does not allow the study of the interaction between the tumor and the primary tissue and metastasis. On the other hand, the orthotopic model permits a fast growth of the tumor, allows its study in natural microenvironment and possible metastasis. However, it usually is expensive and technically complex. Finally, although the HFA does not promote the microenvironmental interactions and is also complicated and costly, it has minimal effects on animal welfare, reduces the number of animals used and promotes fast results [125].

From the total of NPPM awards, 30 are related to different areas of therapy. Concretely, as mentioned above, 21 were attributed to scientist and projects directly related to pharmacology, as the use and test of various drugs and chemicals in order to treat diseases, infectious agents, and physical conditions [4]. From those 21 pharmacology projects, 17 used animal models and are properly marked in Table 1. In the following paragraphs, we detail some of them, all very relevant on our 21st century global society.

In 1905, Robert Koch won the NPPM for his tuberculosis studies, also presenting tuberculin as the 1st possible cure for tuberculosis. Before his studies on people with lupus vulgaris, a form of skin tuberculosis, performing skin injections of tuberculin and destroying the infected tissue, he also used cow, sheep, mouse, rabbit, and other species in different parts of his study to test his hypothesis [9, 126].

Frederick G. Banting and John J. R. Macleod were awarded in 1923 for their discovery of insulin, as a substance and the possibility of its use in diabetic patients. At 1st, dogs were used as an animal model. They created an extract from different dogs’ pancreas and injected in a dog whose pancreas was surgically removed. Consequently, they observed a change in the dog’s movements and behavior due to the dramatic decrease in their sugar levels [20, 127]. Nowadays, diabetes mellitus still requires animal models to be studied, especially rodents. To create an animal model of diabetes type I, the deficiency in insulin production is achieved by distinct mechanisms, from chemical ablation of the beta cells by streptozotocin to breeding rodents that spontaneously develop autoimmune diabetes, depending on the type of model, as mentioned above. Regarding animal models of type II diabetes, they tend to include models of beta cell failure or for insulin resistance. Additionally, many of them are obese, reflecting the human condition where obesity is closely linked to type II diabetes [127].

In 1939, Gerhard Domagk was recognized for his discovery of protosil. Domagk found, in 1932, that protosil was efficient in treating mice that were injected with a lethal dose of streptococci, and, 2 years later, was able to attribute that efficiency to sulfanilamide, as an active principle. Also concerning antibiotic therapy, Selman A. Waksman, in 1952, improved the Koch discoveries, mentioned above, to another level, by discovering that Streptomyces griseus suppressed the growth of tubercle bacteria. Its active principle, streptomycin, was also isolated after using guinea pigs as a model. Furthermore, Alexander Fleming, Ernst Boris Chain, and Howard Walter Florey were also recognized in this area of therapy, in 1945, for discovering penicillin and its potential as a treatment for multiple infectious diseases. After extracting the active principle from Penicillium rubrum and testing it in several concentrations in vitro Staphylococci, they needed to prove its efficacy in vivo, using mice [34, 128].

In 1988, Sir James W. Black, Gertrude B. Elion, and George H. Hitchings were awarded for their research on antimetabolites of nucleic acid purines, leading to the development of a variety of drugs for the treatment of different diseases. Thus, allopurinol is now used to treat gout and hyperuricemia, acyclovir is an antiviral drug that treats herpes virus infections, and azathioprine can be used to many immunological conditions and, for instance, to prevent organ transplant rejection. All of them, were frequently used in human and veterinary medicine nowadays and were previously tested in mice, rats, dogs, and small primates [74].

Finally, and more recently, in 2018, James P. Allison and Tasuku Honjo were recognized for their discovery of inhibition of negative immune regulation as a possibility of cancer therapy. Both of them identified proteins, with different modes of action, that release or activate our immune cells to attack tumors and both used mice as animal models in order to create a new oncologic therapy that proved to be effective [111].

Historically, the use of animal models and the way they were used suffered remarkable changes associated with the concern to base these procedures on the current legal directives. From the Antiquity to the Renaissance, due to the taboos and religious issues on the dissections of humans, recognized physicians and scientists performed “vivisections,” which is the exploratory surgery of live animals, without almost no social opposition or institutional regulations. Before the end of 17th century, there was already some opposition to vivisection. However, many scientists justified that their scientific undertakings were not cruel, basing themselves in the description of animals as “machine-like” by Renée Descartes. In 18th century, anthropocentric views on human duties to animals and philosophy question on their sensibility and suffering began questioning vivisections. Only in the 2nd half of the 19th century, due to a major medicine revolution, the use of animals in experiments began to require formal justifications and regulations. The publication of the Handbook for the Physiological Laboratory (1873) and the creation of Victoria Street Society for the Protection of Animals Liable to Vivisection (1875), later known as National Anti-Vivisection Society, illustrate those mental changes. In the 20th century, the concept of “animal ethics” emerged as a new field of bioethical studies and diverse ethical views on animals and of our duties toward them. However, public debate on animal research became polarized between animal rights activists and animal research advocates [129, 130].

The 3R’s principles, established by Russell & Burch in 1959, were created to plan scientific studies that require animal models and establish criteria for them. In a resume, the 3R’s are referring to Replacement, Reduction, and Refinement. In other words, to replace the protected and more intellectually complex species to less sentient forms of life, cells, tissues, or computer models, if it is possible. To reduce the number of individuals used as much as possible to extract the necessary conclusions. Finally, to refine the procedures, ensuring the proper and ethical use of the animals and taking their health and welfare into account is essential [131, 132].

In 1999, in the 3rd World Congress on Alternatives and Animal Use in the Life Sciences, the Declaration of Bologna was signed and reaffirmed that “humane science is a prerequisite for good science, and is best achieved in relation to laboratory animal procedures by the vigorous promotion and application of the 3R’s.” Nowadays, animal research is developed in compliance with regulatory requirements which cover the inspection and licensing of animal sites, the training and competence of all the people involved in their manipulation and husbandry, and the mandatory authorization of every project by a competent authority upon ethical evaluation by an Animal Ethics Committee. The European Directive 2010/63/EU has set the regulatory framework for all animal research [133]. Moreover, the ARRIVE (Animal Research: Reporting in vivo Experiments) guidelines, established in 2010 and revised very recently, in 2020, provides practical and detailed instructions on the design of a research project, considering the sample size, husbandry, statistical analysis, and all the necessary aspects to plan a project. These guidelines are applied to all areas of research involving living animals from Drosophila or Caenorhabditis elegans to mammalian species [134].

We believe that the NPPM-awarded projects illustrate how animal models are essential for the advances in different subjects of biology and medicine, as in pharmacology or, more concretely, in antibiotherapy, endocrinotherapy, immunotherapy, and cancer therapy. However, we also consider that criteria for the use of animal models must be taken into account and applied in a practical context, according to the study area, species used, and selected type of model. Russel & Burch 3R’s criteria represent an example of simple, concise, and easy to remember criteria applicable to a variety of studies.

In the future, we believe that animal models will become more specific and informative to the different studies, as they are continuously becoming in the past 100 years. Concretely in Pharmacology, the use of mathematical models and computer science will possibly allow the real time monitoring of the effect of an active principle tested on a live model, perhaps allowing the scientist to have complete and accurate results with a less quantity of animals used and minimizing the welfare concerns.

The authors have no conflicts of interest to declare.

This work is supported by National Funds by FCT – Portuguese Foundation for Science and Technology, under the project UIDB/04033/2020.

Catarina V. Jota Baptista wrote the paper. Ana I. Faustino-Rocha and Paula A. Oliveira supported the 1st author, correcting and revising the paper.

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