Choosing the correct animal model for pharmaceutical research is essential for obtaining accurate results. From rodents to zebrafish, there are many options available to researchers. The animal model must be as close to the human genome as possible to meet the objectives of the research. In this article, we'll discuss how to choose an animal model for research.
The Importance of Using Animal Models in Research
As the pharmaceutical industry develops it demands faster and more efficient treatments for human diseases. Prolonging life and disease prevention is paramount to humanity. One example of this is the Covid-19 virus, that we have seen virtually paralyze much of the world in terms of infection, death, and damage to economies.
Animal models are an alternative that can accurately replicate many human diseases. This allows scientists to research the effect of new drugs for diseases that do not yet have a cure or effective treatment. However, to limit suffering and protect animal welfare it is important to choose a model appropriate to the research.
Animal models are mainly used in the research for:
- Disease prevention, diagnosis, and treatment.
- Vaccine development.
- Medicinal products.
However, it can take between 10-20 years for a new drug to reach the approval stage and the cost can be approximately $4 billion for each individual drug.
Therefore, the correct choice of animal model is vital, with regard to minimizing suffering and cost, and maximizing efficiency and the success of the research.
The Selection of Animal Models
The selection of the animal model is the combination of a scientific and practical decision. Before selection it is fundamental to consider:
- The species
- Genetic properties
- Relevance to the research
- Historical research
The choice of animal model also depends on to what extent its genome (DNA and organism sequence) represents that of the human genome. The animal model should be as close as possible to the human genetic and organ configuration to promote a similar response to the human body when research is carried out. This similarity produces more precise and relevant results.
When selecting a model, it is crucial to understand the anatomy, metabolism, and characteristics of the animal to be used. This influences the choice of species and for what research purpose it will be used. Not every animal model can be used for every type of research and likewise, no animal model emulates all diseases. For this reason, research on animal models is sometimes combined to study different pharmaceutical areas.
Two Common Animal Research Models
The most commonly used species for animal research are:
Rodents (mainly mice and rats) have been used in medical research for many years due to their similarities to the human genome. The Foundation for Biomedical Research states that 95% of animal models for research are mice and rats.
Most human disease genes exist in mice and rats, making them suitable for research. They are commonly used for research on:
- Cardiovascular disease
- Alzheimer’s disease
- Parkinson’s disease
- Cystic fibrosis
- Respiratory problems
- Substance addiction (for anti-craving)
- Behavior studies (rats have a larger brain than mice and are frequently used in psychological research)
Rodents are a cost-effective choice for animal models in research as they are cheap to purchase, breed fast (mice can reproduce every three weeks), require minimal living space, and are easy to care for.
Also, the existing in-depth understanding of the genetics of rodents, coupled with the already available data, makes new research more practical.
Zebrafish (Danio rerio)
Zebrafish are used in 80% of medical research projects and are the main non-mammal in research. These tiny Asian freshwater fish hold 80% of the human genome code and are becoming increasingly popular for use in research. They have many similar organs to humans; two eyes, a heart, a brain, a pancreas, a liver, and kidneys.
A zebrafish lays several hundred eggs at one time (which can be weekly) and the embryos hatch quickly outside of the mother’s body (within 48-72 hours). Zebrafish development is fast, with anatomical structures forming at about 3 days and independent feeding and swimming occurring at around 6 days, giving scientists plenty of research stock. This makes the zebrafish particularly suitable for large research projects.
As the zebrafish and its embryos are transparent, scientists are able to study the effect testing has on their internal organs and what occurs inside them as cells grow and reproduce. This gives zebrafish an advantage over other laboratory animals when studying internal diseases, as research can take place while the fish are still alive. A mouse or rat has to be dissected to study the effects of particular tests on its internal organs.
Research using zebrafish includes:
- Cardiovascular disease (a zebrafish can regenerate its heart)
- Metabolic diseases
- Neurological disorders and Motor behavior
- Tissue regeneration after injury
The zebrafish is an extremely economical animal research model as it is so tiny it takes up little storage space. Many can be housed together as they are social animals.
There is also an abundance of existing data on zebrafish, supplied by the ZFIN (Zebrafish Information Network). The network houses an online database of zebrafish information such as genes, alleles, transgenic lines, gene expression, gene function, phenotypes, orthology, human disease models, nomenclature, and reagents (information taken from the ZFIN website). This collective database supplies information to researchers and scientists that can facilitate their research, save time and costs, and avoid unnecessary research procedures.
Other Animal Models Used in Research
The above two groups are the most common animal research sets, but other animal models used for medical research include rabbits, dogs, birds, guinea pigs, sheep, pigs, and primates.
When considering animal models for research it is important to consider the relevance of the animal genome to the research, the cost, and the expected outcome, to justify the selection.
Animal Model Research Processes
Due to demand, cost, and development times, many experimental medicinal products never reach the approval stage and are never launched on the market. It is estimated that the current average success rate of a drug being approved and marketed is only 4.9%.
A pharmaceutical product goes through many processes before it can be considered for approval. It may be relevant to select a certain animal model depending on the process.
The main stages of these processes are:
- Drug Discovery: The identification of a molecule that could potentially lead to the development of a new medicinal product.
- Target identification and validation: The identification of the target that the new drug is to act against.
- Hit identification and validation: The identification of molecules that will act against the target, known as ‘hits’.
- Hit to Lead (lead generation): This process involves the analysis of the drug’s properties, such as potency, solubility, selectivity, and stability. In vitro and in vivo studies (using animal models) can be carried out at this stage. If the analysis is successful the drug has the intended effect on the target.
- Lead Optimization: The characterization of the drug and the study of its properties. Again, in vitro, and in vivo testing can be adopted.
- Clinical Trials: Research using human volunteers.
Toxicity and Efficacy
Animal models can be used to predict the toxicity, safety and efficacy of various compounds in clinical research. The choice of the animal will depend on the sensitivity of the model to the drug, its main organs, and what it is being tested for.
The relevant animal model must be selected to determine the presence or not of toxicity.
Zebrafish are particularly suitable for toxicity testing due to their transparency and the fact they can absorb compounds through water.
In addition, the tests can be carried out on several fish at once as they are so small, and therefore their size means they require less testing material. This compares to rodents, which are larger and therefore require more testing material and a greater number of animals.
The larger the number of tests that can be carried out the more statistically accurate the results are likely to be, which is why zebrafish are a good testing sample.
As zebrafish are so similar to humans in terms of their genetic composition, this makes them extremely suitable for the determination of drug efficacy in relation to various diseases.
Genome Editing in Animal Models
Research into rare diseases presents some difficulty due to the unavailability of animal models that exactly replicate the disease mechanisms. This can be due to the size of their bodies and organs, compared to a human, and inconsistencies in the comparable length of time a disease takes to develop. Larger mammals are also expensive.
Another problem is that some extremely rare diseases have not been studied previously, so there is no available information.
The solution to this is genome modifying, also known as gene editing, which allows scientists to amend the genome sequences in an animal model.
Zebrafish are ideally suited to genetic modification, primarily using the CRISPR (clusters of regularly interspaced short palindromic repeats) system. This technology allows scientists to modify DNA sequences and gene function. The DNA can be altered to repair or introduce mutant cells as required for the research.
In diseases that have not been studied before this method avoids the use of expensive, large mammals that may not produce effective results.
Research on animals has been a questionable subject for many years, and as more regulations are introduced it makes sense to use a suitable alternative animal model, such as the zebrafish, which fits with the policies of the 3Rs.
Many legislative bodies and associations throughout the world recommend the use of zebrafish in animal model research as a viable alternative to mammals such as rodents. One reason is that a zebrafish embryo is not considered to be in-vivo until 5-6 days after its fertilization and yet at this stage it still responds as a complete living organism.
It is imperative to choose the most suitable model for animal research, in terms of suitability to the objective of the research and the appropriateness of the animal.
As methods and technology develop it is important to stay up to date with the evolving field of animal model research to ensure the right selection is made.