Anthony Dent Ethics of Animals in Research

Introduction Using animals in research has been a fundamental step in the process to not only discover human behavior, but also to enhance our understanding of human biology and the development of treatments, cures, and preventions for human diseases. Animal use research has proponents and opponents that question the utilization, need, and validity of the resulting research as well as the ethical implications of using these animals for research. Arguments for the use of animal research include the identification of risks with new treatments, discovery of novel genetic diseases, and elimination of some risks when applied to human subjects. Critics to the use of animals in research point out the ethical concerns dealing with the welfare of the animals, applicability of the science that is produced, and a false assumption of safety when the science applied in human medicine. In light of the arguments of both sides, the use of animals in research that will be intended for human subjects has become an integral part for regulators, funders, and scientists alike. Importance of Animal Research in Vaccine Development Animal research has been central to discovering disease mechanism, developing treatments, and testing the efficacy of the treatments. This has been very evident in the development of a vaccine for the SARS-CoV-2 virus responsible for the 2020 pandemic. Animal studies allowed researchers to test how pathogens interacted with biological systems; a critical foundation for developing vaccines. For example, animal research was used to test the immune response after vaccine administration, allowing for the vaccine to be optimized for the fewest adverse effects prior to the start of human trials. Stern indicates the preclinical studies provide a platform for refining the vaccine in terms host-pathogen interaction, protective immune mechanism, and appropriate antigen and adjuvant combination prior to testing in human subjects. Prior to pre-clinical trials, Jonas Salk used monkeys to test the effectiveness of the Salk version of the polio vaccine. This vaccine became one of the first effective preventatives against poliomyelitis. The success of the polio vaccine exhibits the value of using animals in research, Salk and Sabin both using non-human primates before testing in human volunteers. This lead to better methods of improvement for vaccine development . This quickly became an indispensable method to save countless lives through the development of vaccines using animal research. One of the major justifications for the use of animal models in vaccine research is dependent on the biological similarities in humans and some of the animal models, particularly non-human primates. The focus being on similar Organ systems, cellular structures, immune responses, and decent from common ancestors (Diaz). Non-human primates are used due to their high genetic similarity, similar physiology, similar biochemical processes, and psychological activities similar to humans (Mukherjee). Diaz et al. indicates animal models have been used to make advancements in developming treatments and vaccines for numerous conditions, including diabetes, obesity, cancer, hypertension, kidney, brain, cardiovascular, and pulmonary disease; among several others (Diaz). These predictable and translatable results in vaccine and treatment development show the utility of these shared characteristics and their ultimate benefit to human subjects research. Throughout rigorous studies, animal models have consistently demonstrated their efficacy and effectiveness in advancement of human medical research. Non-human primates were also used in the development of the SARS-CoV-2 vaccine, again, indicating its safety and effectiveness prior to human trials (Diaz). Animal research was also instrumental for the rapid development of the SARS-CoV-2 vaccines. These studies did build off of data obtained from studies in other coronaviruses, SARS and MERS (Gebre). Laboratory mice have also been used due to their well-characterized immune system and have contributed significantly to the understanding of vaccine mechanisms also allowing researchers to observe immune responses and modify the formulations (Le). Ethical Considerations Animal use in vaccine development raises ethical concerns and moral dilemmas that require careful consideration. Some of the concerns deal with animal welfare. For example, does the pain and distress of an animal justify the scientific progress that has been made. The research community has developed the Institutional Animal Care and Use Committee (IACUC) to ensure the minimization for the suffering of animals used in teaching and research. Researchers have developed a set of guidelines to minimize animal suffering and use that is known by its shorthand as the three R’s (3R). The 3R’s can be distilled down to replace, reduce, and refine. Replace covers the need to replace animal models with other methods are satisfactorily available. This include mathematical modeling (in silico), research using human or animal cell lines that are harvested and grown in petri dishes (in vitro), and the use of simpler organisms such as yeast and bacteria, and newer methods such as “Organs-onchips”. Organs-on-chips are an advancement of in vitro culture. These chips are microfluidic cell culture devices that contain populated by living cells of differing lineage or origin. This allows the to interact in a multi-system fashion, emulating a more complex system (Diaz). Reduce covers the need to reduce the number of animals used to the absolute minimum number need when replacing animal models with another method (i.e. in vitro, in silico) cannot be accomplished. Refinement covers the decrease in the number or severity of procedures that will be used on an animal. This is used to minimize the pain and stress put on an animal to enhance its welfare. This also covers the responsibility for scientists to accurately design tests that experimental protocols to properly test what they intend to test. The 3R’s are used to address the ethical issues that are present when using animals to further human research. These ethical frameworks are intended to balance scientific advancement and our obligation care for and minimize animal suffering. While we do have these frameworks in place, it is still the responsibility of the scientific community to continuously improve our techniques and seek alternatives that offer a similar or better scientific understanding. This will ultimately minimize the scientific community’s reliance on animal models eventually reducing the use of animal models to an absolute minimum, not just in vaccine development, but in biological research at large. These frameworks are further cemented into research based on the laws that have been enacted to enshrine these principles. In 1966, the United States of America enacted the Animal Welfare Act (AWA). This has been amended four times, most recently in 1991. The AWA is integrated into the Public Health Service policy that requires institutions to establish and maintain appropriate measure to ensure the adequate care and use of animals in research (Petetta). Regulatory bodies use these principles to enforce comprehensive oversight mechanisms, ensuring researchers not only justify their use, but also minimize and mitigate the animal’s distress. These entities also provide evaluation and oversight that ensures adherence to the highest standards. These entities can also penalize researchers that are found to not adhere to the ethical guidelines. These penalties can range from loss of investigator status to no longer being able to apply for federal funding and having all research materials seized by the Marshalls. Alternative Methods to Animal Research The advancement of scientific methods has allowed researchers to focus on alternative methods that reduce the reliance on animal models in research. As stated earlier, there are in vitro, in chemioco, and in silico methods. The most basic of alternative methods is in chemioco methods are experiments performed on biological molecules outside of cells that can be used to determine how molecules interact with each other and with drugs (NIH). These methods are non-invasive but are very limited in their application as they are not tested within a biological system and have limited applicability. In vitro methods use cell or tissue cultures to test biological methods directly on animal or human cells that are derived from humans or animals that may or may not have been genetically modified to simulate different biological conditions. For example, insulin used to be obtained from dog pancreas extracts in 1920. This was found to be logistically and morally problematic and way to extract insulin from commercial porcine and bovine sources. This changed the landscape by finding a source in animals that were already part of an agricultural process. In the 1990s, with the emergence of recombinant DNA research, the DNA encoding insulin was inserted into a bacteria and no animals were needed for the production of insulin (Kinter). Human cell cultures and organ-on-chip technologies have gained prominence as potentially transformative tools in vaccine research. These advanced models offering a promising avenue for evaluating vaccine safety and efficacy. Ogan-on-chip technologies can simulate critical interactions within human organ systems, allowing researchers to study complex vaccine responses in a controlled environment (Danku). These systems can be affected the surface effect. These systems are smaller than in vivo systems and the volumes are affected by the structure of the mechanism. Another drawback is the requirement of expensive equipment that is required to obtain reliable results (Danku). In silico methods are patient specific models that form virtual cohorts for testing treatments. The term in silico is not well defined, but has taken on the direct use of mathematical and computer modeling simulation for the diagnosis, treatment, or prevention of a disease. In silico methods are becoming more refined as the availability of computer processing power increases. The first mathematical models were used in the 1950s and 1960s to study nerve excitation and cardiac cell models. These were initially performed on specialized machines that took the space of an entire room (Gavaghan). Currently you can connect your computer to a network and allow it to use the excess computing power to develop new therapeutics for a variety of diseases by the means of simulating protein dynamics(https://foldingathome.org/). Alternatively, you can help scientists determine protein structure by playing a video game called foldit (https://fold.it/). Among alternatives to animal testing, in silico models have emerged as powerful tools. These enable research to predict and evaluate immunological responses and safety profiles by simulating biological systems computationally. These systems do come with setbacks. Some of the drawbacks include the amount of computational power that needs to be used. Also, perfect modeling data needs to be established to ensure calculations are being performed in the right system. Similarly, to current animal research, if the wrong model is selected, the data can be tainted and mislead the researchers wasting valuable resources. In recent years, human cell cultures and organ-on-chip technologies have gained prominence as potentially transformative tools in vaccine research. Human cell cultures facilitate the assessment of cellular immune responses, providing insights into the direct effects of vaccines on human cells without the ethical concerns associated with animal testing. These methodologies could significantly enhance the predictability of human reactions to vaccines, although they currently supplement rather than replace animal research due to limitations in fully replicating systemic biological interactions (Gebre et al. 1589-603). Examples and Evidence Animal research has proven its necessity in vaccine development. The polio vaccine was dependent on its use of nonhuman primates to develop a safe vaccine. Recently. Animal research facilitated the rapid development of the mRNA SARS-CoV-2 vaccine. Both vaccines were initially assessed in animals prior to human trials (Le). Despite advancements in alternative research methods, there is still a necessity of using animal models to validate vaccine safety and efficacy. For instance, the development of mRNA vaccines, which initially relied on computational models and in vitro systems, ultimately required confirmatory studies in animal models due to the complexities of immune response that these alternative methods lack the ability replicate (Le). Scientific research indicates even with the ethical considerations and the evolution of alternative methods, the work done in animal modes is irreplaceable and has advanced science and public health. Conclusion Historically, vaccine research has relied significantly on research to ensure safety and efficacy. Animal models have made essential contributions to not only vaccine research, but human biological research at large, we must also minimize the burden and suffering animals endure for this progress. Mixing animal research and alternative methods allows researchers to maximize efficacy while minimizing ethical concerns for research. Animal rights activists have prompted efforts to find alternative research methods. Despite these emergent methods, the alternatives cannot truly replicate the complex physiological interactions of a living organism. This creates the need to balance the need for scientific advancement with our ethical responsibility to protect animals in research. Works Cited 1. Stern PL. Key steps in vaccine development. Annals of allergy, asthma & immunology?: official publication of the American College of Allergy, Asthma, & Immunology. 2020;125(1):17-27. doi:10.1016/J.ANAI.2020.01.025 2. Díaz L, Zambrano E, Flores ME, et al. Ethical Considerations in Animal Research: The Principle of 3R’s. Revista de investigacion clinica; organo del Hospital de Enfermedades de la Nutricion. 2020;73(4):199-209. doi:10.24875/RIC.20000380 3. Mukherjee P, Roy S, Ghosh D, Nandi SK. Role of animal models in biomedical research: a review. Laboratory Animal Research. 2022;38(1):18. doi:10.1186/S42826-022-00128-1 4. 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