A brief history of the animals' scientific research, international rules and Brazilian regulations.

Several countries and non-governmental organizations have discussed the use of animals in industry and biomedical areas. This work shows the progression of animal' rights for scientific purposes in Brazil and how Brazilian Councils have advanced to follow worldwide regulations. Since the first rules about animals' usage in Ireland in 1635, the British Cruelty to Animals Act in 1876, and the Brazilian animal protection rules in 1924 and 1934, most worldwide actions culminated in the Universal Declaration of Animal Rights (1978). In 1979, the Brazilian Law 6.638 displayed directives for didactic-scientific practice of vivisection. In 2008, the Arouca Law 11.794 filled regulatory gaps and created the National Council for the Control of Animal Experimentation (CONCEA). In 2014, the CONCEA incorporated the 3R's philosophy and recognized substitute techniques, but only in 2023 it prohibited vertebrate animals in scientific research, development and control of personal hygiene products, cosmetics and perfumes. It is clear current Brazilian and international rules are unable to cover all aspects of animal wellbeing, even for regulations of commercial issues. Certainly, innovative tools, as organ-on-chip, in vitro techniques and bioinformatical advancements will provide a crucial animal welfare and new laws will minimize animal pain and distress, including for disregarded invertebrates.

The use of animals in physiological science: the past, the presence, and the future.

Physiology is a scientific discipline of how people's and animals' bodies function that requires traditionally suitable experimental models that often rely on animals. However, at the end of the 50th of the last century, researchers themselves addressed concerns about the use of animals for biomedical science and physiology in particular. At that time, the so-called 3R strategy was implicated where the three "R" stand for replacement, reduction, and refinement. When addressing these concerns, researchers nevertheless realized that a critical dispute about experimental models in the light of the 3R initiative may require further attention to other points such as robustness, registration, reporting, reproducibility, and rigor of the work. The question that has to be addressed now is first whether the use of animals in physiology changed in the post-3R period, whether it led to a replacement, reduction, or refinement of animal handling, and most importantly, how this affected the scientific progress in (patho)physiology. In order to address open questions concerning the relationship between the use of animals and physiological research, complete volumes of the Pflügers Archiv - European Journal of Physiology were analyzed every 10 years starting in 1950 and ending in 2020 and compared to volumes of the Journal of Physiology. It analyzed how scientists organize their projects published in the journal and what kind of models they used. The results show that physiological science has dramatically changed in the last 70 years. Replacement, reduction, and refinement were achieved to a certain level. However, during the last years, no further achievement could be seen. It seems that a certain level of animal testing is required for biomedical science and physiology in particular. Physiological studies in the present time are dominated by investigation of the physiological function of small rodents mainly mice and rats with only a few exceptions. The analysis also shows that in the future, researchers must have a critical look at further requirements of their research such as data robustness, improvement of reproducibility of data, and generation of rigor data as a prerequisite to improve our physiological view on life.

Mobile Monkeys and Modified Microbes: Medical Experimentation between Metropolitan and Colonial Laboratories, 1880-ca. 1925.

Following the medical breakthroughs of Pasteur and Koch after 1880, the use of simians became pivotal to laboratory research to develop vaccines and cultivate microbes through the technique of serial passage. These innovations fueled research on multiple diseases and unleashed a demand for simians, which died easily in captivity. European and American colonial expansion facilitated a burgeoning market for laboratory animals that intensified hunting for live animals. This demand created novel opportunities for disease transfers and viral recombinations as simians of different species were confined in precarious settings. As laboratories moved into the colonies for research into a variety of diseases, notably syphilis, sleeping sickness, and malaria, the simian market was intensified. While researchers expected that colonial laboratories offered more natural environments than their metropolitan affiliates, amassing apes, people, microbes, and insects at close quarters instead created unnatural conditions that may have facilitated the spread of undetectable diseases.

The trial of David Ferrier, November 1881: Context, proceedings, and aftermath.

In November 1881, the eminent physiologist and physician David Ferrier was prosecuted under the Cruelty to Animals Act 1876. The prosecution was raised by the Victoria Street Society, formerly known as the Society for the Protection of Animals Liable to Vivisection, through its activist founder, Frances Power Cobbe. This article examines the legislative context prior to Ferrier's trial, the personalities involved in the prosecution, and its course and outcome. The resultant impact, both personal, on Cobbe and Ferrier, and professional, on experimental neurophysiology, is discussed, in particular the foundation of the Association for the Advancement of Medicine by Research (AAMR) and the provision of legal support for medical practitioners subject to litigation.

Public perception of laboratory animal testing: Historical, philosophical, and ethical view.

The use of laboratory animals in biomedical research is a matter of intense public debate. Recent statistics indicates that about half of the western population, sensitive to this discussion, would be in favor of animal testing while the other half would oppose it. Here, outlining scientific, historical, ethical, and philosophical aspects, we provide an integrated view explaining the reasons why biomedical research can hardly abandon laboratory animal testing. In this paper, we retrace the historical moments that mark the relationship between humans and other animal species. Then starting from Darwin's position on animal experimentation, we outline the steps that over time allowed the introduction of laws and rules that regulate animals' use in biomedical research. In our analysis, we present the perspectives of various authors, with the aim of delineating a theoretical framework within which to insert the ethical debate on laboratory animals research. Through the analysis of fundamental philosophical concepts and some practical examples, we propose a view according to which laboratory animals experimentation become ethically acceptable as far as it is guided by the goal of improving humans and other animal species (i.e., pets) life. Among the elements analyzed, there is the concept of responsibility that only active moral subjects (humans) have towards themselves and towards passive moral subjects (other animal species). We delineate the principle of cruelty that is useful to understand why research in laboratory animals should not be assimilated to a cruel act. Moreover, we touch upon the concepts of necessity and "good cause" to underline that, if biomedical research would have the possibility to avoid using animals, it would surely do that. To provide an example of the negative consequences occurring from not allowing laboratory animal research, we analyze the recent experience of Covid-19 epidemic. Finally, recalling the principle of "heuristics and biases" by Kahneman, we discuss why scientists should reconsider the way they are conveying information about their research to the general public.

A Note on Semmelweis's Animal Experiments and Their Historical Significance.

This article seeks to establish what animal experiments Semmelweis conducted, and when and why he conducted them, because the Semmelweis literature contains conflicting claims about these topics or has ignored them altogether. Semmelweis first conducted animal experiments between 22 March and 20 August 1849 with Rokitansky's assistant, Georg Maria Lautner, because his chief, Johann Klein, did not accept that by merely reducing the mortality rate from childbed fever with chlorine hand-disinfection, Semmelweis had proved his theory of the cause of childbed fever. However, Skoda concluded that the Lautner experiments did not resolve the doubts about Semmelweis's theory they were intended to resolve, and, therefore, asked the Academy of Sciences to award Semmelweis a grant to conduct further and more varied experiments with the physiologist, Ernst Ritter von Brücke. These additional experiments were conducted in the spring and summer of 1850, but yielded only ambiguous results, and led Brücke to conclude that questions about Semmelweis's theory could only be resolved by clinical observations, not animal experiments. This article discusses the reasoning behind these animal experiments, and Skoda's and Brücke's responses to them, and argues that their responses to the experiments caused Semmelweis to delay publishing his research until he had collected sufficient clinical evidence to prove his theory.

A Belmont Report for Animals?

Human and animal research both operate within established standards. In the United States, criticism of the human research environment and recorded abuses of human research subjects served as the impetus for the establishment of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, and the resulting Belmont Report. The Belmont Report established key ethical principles to which human research should adhere: respect for autonomy, obligations to beneficence and justice, and special protections for vulnerable individuals and populations. While current guidelines appropriately aim to protect the individual interests of human participants in research, no similar, comprehensive, and principled effort has addressed the use of (nonhuman) animals in research. Although published policies regarding animal research provide relevant regulatory guidance, the lack of a fundamental effort to explore the ethical issues and principles that should guide decisions about the potential use of animals in research has led to unclear and disparate policies. Here, we explore how the ethical principles outlined in the Belmont Report could be applied consistently to animals. We describe how concepts such as respect for autonomy and obligations to beneficence and justice could be applied to animals, as well as how animals are entitled to special protections as a result of their vulnerability.

Biologia futura: animal testing in drug development-the past, the present and the future.

Animal experiments have served to improve our knowledge on diseases and treatment approaches since ancient times. Today, animal experiments are widely used in medical, biomedical and veterinary research, and are essential means of drug development and preclinical testing, including toxicology and safety studies. Recently, great efforts have been made to replace animal experiments with in vitro organoid culture methods and in silico predictions, in agreement with the 3R strategy to "reduce, refine and replace" animals in experimental testing, as outlined by the European Commission. Here we present a mini-review on the development of animal testing, as well as on alternative in vitro and in silico methods, that may at least partly replace animal experiments in the near future.

Charcot's paradox.

Jean-Martin Charcot (1825-1893), considered the father of modern neurology, had a particular interest in pathology and learned to value anatomical findings. Among his main contributions is the use of the anatomo-clinical method in neurology. Although described as cold and impatient in his interpersonal relations, Charcot had a great affection for animals. He had two dogs in his home, which he called Carlo and Sigurd, and a little monkey, Rosalie. Despite his fascination with neuropathology and anatomo-clinical correlations, Charcot disapproved of studies using animal species other than humans, a seemingly paradoxical attitude. As a result, Charcot's human studies resulted in important advances in neurology as, prior to his research, anatomical observations of animals were extrapolated to humans, leading to conceptual errors.

Charcot's paradox / O paradoxo de Charcot

ABSTRACT Jean-Martin Charcot (1825-1893), considered the father of modern neurology, had a particular interest in pathology and learned to value anatomical findings. Among his main contributions is the use of the anatomo-clinical method in neurology. Although described as cold and impatient in his interpersonal relations, Charcot had a great affection for animals. He had two dogs in his home, which he called Carlo and Sigurd, and a little monkey, Rosalie. Despite his fascination with neuropathology and anatomo-clinical correlations, Charcot disapproved of studies using animal species other than humans, a seemingly paradoxical attitude. As a result, Charcot's human studies resulted in important advances in neurology as, prior to his research, anatomical observations of animals were extrapolated to humans, leading to conceptual errors.

RESUMO Jean-Martin Charcot (1825-1893), considerado o pai da neurologia moderna, teve sua formação direcionada para a patologia, aprendendo a valorizar achados anatômicos. Entre as principais contribuições de Charcot está o uso do método anatomoclínico aplicado à neurologia. Descrito como frio e impaciente em suas relações interpessoais, Charcot mostrava, no entanto, um grande afeto pelos animais. Ele tinha dois cachorros em sua residência, a quem chamou de Carlo e Sigurd, e uma pequena macaca, Rosalie. Apesar de sua fascinação com a neuropatologia e as correlações anatomoclínicas, Charcot foi contra estudos com outras espécies de animais que não humanos, o que pode parecer um paradoxo. Entretanto, seus estudos trouxeram avanços importantes para a Neurologia, uma vez que, antes de suas descobertas, as observações anatômicas dos animais eram extrapoladas para os humanos, levando a erros conceituais.

Assignment of culpability to animals as a form of abuse: Historical and cultural perspectives.

How the law regards animals reflects cultural trends that have varied widely from antiquity to the present. This article argues that cultural views of animals have shaped laws, attitudes, and practices worldwide. Whereas ancient (biblical and Mesopotamian) practices turned on economics, medieval concepts of animal culpability aligned with Christian beliefs of the primacy of humans. In medieval Europe, pets, farm animals, vermin, and insects could be held accountable for damage to persons and property. Considered entitled to due process, they were represented, tried, and punished - sometimes in public executions. Centuries of regarding animals as property subordinated to humans gave way to animal cruelty laws. It was not until the 19th century that respect for animal welfare, apart from economics, assumed legal significance. Presently, animals are not considered capable of criminal intent but can be "executed" for dangerousness. However, they may possess legal standing as civil complainants in animal rights cases. Contemporary trends include animal rights activism and courts conferring legal personhood to animals. The discussion concludes that there will be disparate approaches worldwide, based on prevailing views of animal sentience, spiritually based concepts and values, litigation arguing property and environmental law, and economics.

Earliest Animal Cranial Surgery: from Cow to Man in the Neolithic.

The earliest cranial surgery (trepanation) has been attested since the Mesolithic period. The meaning of such a practice remains elusive but it is evident that, even in prehistoric times, humans from this period and from the Neolithic period had already achieved a high degree of mastery of surgical techniques practiced on bones. How such mastery was acquired in prehistoric societies remains an open question. The analysis of an almost complete cow cranium found in the Neolithic site of Champ-Durand (France) (3400-3000 BC) presenting a hole in the right frontal bone reveals that this cranium underwent cranial surgery using the same techniques as those used on human crania. If bone surgery on the cow cranium was performed in order to save the animal, Champ-Durant would provide the earliest evidence of veterinary surgical practice. Alternatively, the evidence of surgery on this cranium can also suggest that Neolithic people practiced on domestic animals in order to perfect the technique before applying it to humans.

The Earliest Blood Transfusions in 17th-Century in Italy (1667-1668).

Historical accounts of the earliest experiments in blood transfusion celebrate work done in France and England in 1667 to 1668. Less attention has been given to pioneering experiments conducted at the same period in Italy. We review records of the first blood transfusion experiments conducted in 17th century Italy. Using original source documents, we provide details of early experiments focusing on the identity of early researchers, their instruments, and techniques. Accounts of the period describe animal-to-animal, animal-to-human, and human-to-human transfusions. We highlight how transfusion was considered a new form of emergency surgery, carried out in order to save patients who could not be cured with traditional therapy of the time.

The European politics of animal experimentation: From Victorian Britain to 'Stop Vivisection'.

This paper identifies a common political struggle behind debates on the validity and permissibility of animal experimentation, through an analysis of two recent European case studies: the Italian implementation of the European Directive 2010/63/EC regulating the use of animals in science, and the recent European Citizens' Initiative (ECI) 'Stop Vivisection'. Drawing from a historical parallel with Victorian antivivisectionism, we highlight important threads in our case studies that mark the often neglected specificities of debates on animal experimentation. From the representation of the sadistic scientist in the XIX century, to his/her claimed capture by vested interests and evasion of public scrutiny in the contemporary cases, we show that animals are not simply the focus of the debate, but also a privileged locus at which much broader issues are being raised about science, its authority, accountability and potential misalignment with public interest. By highlighting this common socio-political conflict underlying public controversies around animal experimentation, our work prompts the exploration of modes of authority and argumentation that, in establishing the usefulness of animals in science, avoid reenacting the traditional divide between epistemic and political fora.

Treinamento de Força Moderado Atenua o Aumento da Pressão Arterial e Diminui o Número de Núcleos em Cardiomiócitos de Ratos Hipertensos / Moderate Resistance Training Attenuates the Increase in Blood Pressure and Decreases the Cardiomyocyte Nuclei Number in Hypertensive Rats

O treinamento de força (TF) é uma estratégia que diminui a pressão arterial (PA) em pacientes com hipertensão arterial (HA) estágio 1 e atenua a progressão da PA em ratos hipertensos (estágio 3). A influência do TF na remodelação cardíaca na HA não controlada ainda não está estabelecida. Objetivo: O objetivo deste estudo foi avaliar os efeitos a longo prazo do TF em intensidade moderada na remodelação cardíaca em ratos espontaneamente hipertensos (SHRs) sem tratamento. Métodos: Dez SHRs machos com HA estágio 3 (PA sistólica ≥ 180 mmHg) e cinco ratos Wistar-Kyoto (WKY) normotensos (PA sistólica < 120 mmHg) foram divididos em três grupos: sedentários normotensos (SED-WKY), sedentários hipertensos (SED-SHR) e hipertensos TF (TF-SHR). O TF foi realizado em uma escada vertical (3 dias / semana por 12 semanas, em dias não consecutivos) com 70% da carga máxima. A PA e a frequência cardíaca foram registradas. Ao final do protocolo, os animais foram sacrificados e tiveram o ventrículo esquerdo seccionado para análise histológica (hematoxilina e eosina e picrosirius red). Resultados: O TF não atenuou o ganho de peso absoluto e relativo do coração e do ventrículo esquerdo no grupo TF-SHR em comparação ao grupo SED-SHR. Não houve nenhuma diferença no volume nuclear nos cardiomiócitos e conteúdo de colágeno entre os grupos. No entanto, o TF diminuiu o número de núcleos nos cardiomiócitos e atenuou o aumento da PA sistólica no grupo TF-SHR em relação ao grupo SED-SHR. O Δ do duplo produto foi menor no grupo TF-SHR em comparação aos grupos SED-WKY e SED-SHR. Conclusões: Os dados obtidos demonstram que o TF não atenuou a hipertrofia cardíaca, mas reduziu a proliferação nuclear nos cardiomiócitos e a progressão da PA em SHR com HA severa.

Resistance training (RT) is a strategy that decreases blood pressure (BP) in patients with stage 1 hypertension and attenuates BP progression in hypertensive rats (stage 3). The influence of RT in cardiac remodeling in uncontrolled hypertension is not yet established. Objective: The aim of this study was to evaluate the long-term effects of RT in moderate intensity in cardiac remodeling in spontaneously hypertensive rats (SHRs) without treatment. Methods: Ten male SHRs with stage 3 hypertension (systolic BP ≥ 180 mmHg) and five normotensive Wistar-Kyoto (WKY) rats (systolic BP < 120 mmHg) were divided into three groups: sedentary normotensive (SED-WKY), sedentary hypertensive (SED-SHR), and RT hypertensive (RT-SHR). The RT was conducted in a vertical ladder (3 days/week for 12 weeks, on nonconsecutive days) at 70% of the maximum load. BP and heart rate were recorded. At the end of the protocol, the animals were euthanized and had their left ventricles sectioned for histological analysis (hematoxylin and eosin and picrosirius red). Results: RT did not attenuate the absolute and relative weight gains of the heart and left ventricle in the RT-SHR group compared with the sedentary group (SED-SHR). There was no difference in nuclear cardiomyocyte volume and collagen content between groups. However, RT decreased the number of nuclei in the cardiomyocytes and attenuated the increase in systolic BP in the RT-SHR when compared with the SED-SHR group. The Δ of the rate-pressure product was lower in the RT-SHR group compared with the groups SED-WKY and SED-SHR. Conclusions: The data obtained demonstrate that RT did not attenuate the cardiac hypertrophy, but reduced the nuclear proliferation in cardiomyocytes and the BP progression in SHRs with severe hypertension.

Livestock in biomedical research: history, current status and future prospective.

Livestock models have contributed significantly to biomedical and surgical advances. Their contribution is particularly prominent in the areas of physiology and assisted reproductive technologies, including understanding developmental processes and disorders, from ancient to modern times. Over the past 25 years, biomedical research that traditionally embraced a diverse species approach shifted to a small number of model species (e.g. mice and rats). The initial reasons for focusing the main efforts on the mouse were the availability of murine embryonic stem cells (ESCs) and genome sequence data. This powerful combination allowed for precise manipulation of the mouse genome (knockouts, knockins, transcriptional switches etc.) leading to ground-breaking discoveries on gene functions and regulation, and their role in health and disease. Despite the enormous contribution to biomedical research, mouse models have some major limitations. Their substantial differences compared with humans in body and organ size, lifespan and inbreeding result in pronounced metabolic, physiological and behavioural differences. Comparative studies of strategically chosen domestic species can complement mouse research and yield more rigorous findings. Because genome sequence and gene manipulation tools are now available for farm animals (cattle, pigs, sheep and goats), a larger number of livestock genetically engineered (GE) models will be accessible for biomedical research. This paper discusses the use of cattle, goats, sheep and pigs in biomedical research, provides an overview of transgenic technology in farm animals and highlights some of the beneficial characteristics of large animal models of human disease compared with the mouse. In addition, status and origin of current regulation of GE biomedical models is also reviewed.