As the most common research mammal in the world, mice are key to many aspects of biomedical research and, in turn, scientific and medical advancements. Without mice, we would lack a crucial understanding of major diseases, including cancer and genetic disorders like muscular dystrophy, which has led to lasting benefits for humans and animals alike. It was only due to studies in mice and other animals, for example, that we were able to develop vaccines for Covid-19, and at such a rapid rate.
By using mice, researchers can study how these diseases work in a living organism, and, importantly, in one that is a good match for humans in many aspects. These principles then underpin the development and testing of new drugs, therapies and interventions. It is therefore not surprising to find that mice are the most used animal for scientific purposes in the EU, making up more than half (52.5%) of the total number of animals used in research – 5,459,433 animals in 2019.
In this article we will explore some of the research areas in which mice have played a central role, as well as the discoveries and breakthroughs that have come about as a result, and the efforts in Europe to reduce, replace and refine their use.
Why are mice so important in biomedical research?
There are several important reasons why mice are so widely used in animal studies for biomedical research:
• Mice experience many of the same diseases as humans and have the same types of organs and bodily systems, which makes them excellent models for human disease. Around 95% of the genes that code for proteins are identical in humans and mice. Researchers can compare mice with humans to look for similarities or differences (for example in symptoms or DNA changes) that may be clinically and medically significant.
• Few mammals have been as closely studied as the mouse and its genetic map (genome) has been fully sequenced, which means that its genes can be switched on and off to study their effects.
• Mice have short lifespans (2-3 years), making them ideal for looking at the progression of diseases that may otherwise take years to develop and study in humans.
• Mice are quick and easy to breed, and wean large litters, with a gestation period of around three weeks. This means that sufficient numbers of mice needed for research are available, which doesn’t slow the pace of research – something particularly important for studying the effects of ageing, and in vaccine development for a new, or rapidly developing disease.
• Fruit flies and zebrafish are increasingly used in research, but if neither is a suitable model, the mouse is often the first type of mammal considered instead.
• Some scientists consider the differences between wild and laboratory mice to be so great that they think these laboratory animals could be classified as a separate species.
Which areas of biomedical research use mice?
Mice have been central to the study of many infectious diseases, including influenza, hepatitis and Ebola – all of which have the potential to be life-threatening. Where mice can be especially useful is in assessing how prone people are to certain infections and investigating why some do not develop immunity. While researchers can investigate these questions in human cells in the lab, these studies cannot model the complex interactions that take place during an infection as accurately as in a living organism.
Researchers do conduct studies on humans, but not to the extent that is possible in mice. For instance, mice can be fed identical and tightly controlled diets, or be inbred to target the effect of different procedures on the same individuals – things that would be considered unacceptable using humans. It would also be too dangerous to test compounds and drugs on people without first knowing what the possible effects (and risks) would be, so animals such as mice are needed to fulfil this crucial role in toxicity and safety testing, in everything from experimental cancer drugs to vaccines.
Fighting Covid-19 – the vital role of mice
Covid-19 vaccines were developed at exceptional speed and studies using mice were vital in this process. Even though mice cannot catch Covid naturally, they can be infected with the SARS-CoV-2 virus, by creating genetically altered ‘humanised’ mice (see box) that can then be used to examine the disease in detail. The genomes of these mice are altered so that they have a receptor for the ACE2 protein, found in humans, that allows SARS-Cov-2 to enter and infect cells.
Years before the Covid-19 pandemic, mice had already been used to gain important insights about other related diseases, such as SARS, which caused deadly widespread outbreaks in the early 2000s, and MERS, which first emerged in 2012. It was thanks to these earlier studies that researchers could study how the SARS-CoV-2 virus infected human cells, without needing to start from scratch with a new mouse model that would have inevitably slowed the pace of Covid-19 research.
For example, in research at the University of Iowa, USA, back in 2007, scientists used humanised mice expressing ACE2 to identify a path to lethal infection by the coronavirus that causes SARS, helping to understand how the disease develops to devise new treatments.
Humanised mice for Covid-19 allow researchers to answer key questions about the virus itself, such as how it begins to infect organisms and is transmitted from one body to another, how an infected host’s immune response reacts, as well as the short- and long-term effect of various treatments and experimental vaccines. All of these aspects are needed to shed light on how the disease works in order to develop effective drugs and measures against it.
Credit: University Medicine at Johannes Gutenberg University of Mainz
Mice and humans are genetically very similar, with almost all mouse genes sharing the same functions as our genes. But there are still limits to how much we can compare ourselves to mice, especially when it comes to research. That is why large numbers of mice used in biomedical research are genetically altered (GA) to mirror more human-like traits and biology, typically at the level of cells or genes.
This ‘humanising’ process is done by inserting something like a fragment of human DNA or a tumour into them, so that the mice react in a similar way to a human. Humanised mice therefore allow researchers to explore far more human genes, proteins and processes than would otherwise be possible.
Because of the current technical limitations of gene editing, not every GA animal that is bred for this purpose can be guaranteed to display the genetic mutations or characteristics that were intended for a particular type of research. It means therefore that they are bred but not used in research. However, the actual breeding of a GA mouse is counted as a research procedure and is recorded – these mice came to a total of around 12.5 million animals in 2017 (when they were last recorded).
The ’bred but not used’ process is currently being refined through the use of powerful and accurate gene editing tools, such as CRISPR, that can directly edit mouse embryos to reduce the number of animals that are needed. You can read more about the numerous diseases that CRISPR mice have used to study in this EARA article, How animal studies play their role in a biomedical research revolution.
In the last decade, there has been a significant improvement in the survival rates of many types of cancer, and studies in mice have been among the most valuable tools used.
A major advance is the first approved treatment for breast cancer – the monoclonal antibody, Herceptin – which was only developed due to initial research in mice and other animals such as rats and hamsters. These studies laid the foundations for the discovery and understanding of the HER2 protein, which can be targeted to reduce tumour growth. Translated into the clinic, studies of breast cancer patients has shown that adding Herceptin to chemotherapy improves survival and keeps cancer at bay for longer compared to chemotherapy alone.
Some of the cancer breakthroughs that have resulted from research in mice include the development of a type of immunotherapy cancer treatment, which uses the body’s immune system to attack and kill cancer cells (called immune checkpoint inhibitors). The researchers who pioneered this treatment, James Allison and Tasuku Honjo, won the 2018 Nobel Prize in Physiology or Medicine.
Meanwhile, ongoing cancer research is using mice to help in a broad range of areas, for instance research at EPFL in Lausanne, Switzerland, has revealed a new way to stop lung cancer tumours from becoming resistant to treatment. And the University of Bristol, UK, used mice to show that a cancer drug can be repurposed to help with heart attack recovery.
Alzheimer’s disease and dementia
Mice can provide important insights into the mechanisms of Alzheimer’s, the most common type of dementia, for example by showing hallmarks of the disease, such as the loss of neurons in the brain, or symptoms like memory loss, as investigated by institutions including the Institute of Biomedicine of Seville, Spain. Our understanding of other neurodegenerative conditions, such as Huntingdon’s disease (see box below), have also benefited from the use of mice.
Mice not only allow researchers to explore new treatment options, but also to assess the potential success of drugs and compounds before they are trialled in humans – so that they don’t cause harm or work differently to how we expect them to.
However, mice are not always the best models for the human brain, especially when it comes to biology. Monkeys are usually used instead as their brains more closely resemble ours and share many of the same features.
Other diseases and conditions
Research into a range of major conditions, such as asthma, depression, lung conditions and obesity, have involved the use of mice. Mice have also been used to understand health phenomena, including one of the biggest global threats, antibiotic resistance – for example in a 2022 study by EARA member the Luxembourg Center for Systems Biomedicine – and the effects of zero gravity in space.
One of the main areas where mice are used is in studies done to gain a fundamental understanding of the body. This includes the functions of different genes and proteins, the differences between the states of health and disease, anatomy and physiology, and how biological invaders such as viruses cause infection and impact our health. Researchers can then take this information and begin to apply it to humans to provide insights into how we grow, age or become ill. A study including the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, showed how genes work to influence the development of diabetes in mice, for example.
Are mice being replaced or used in smaller numbers?
Under EU Directive 2010/63, researchers must use non-animal alternative methods whenever they are possible, with the ultimate goal of replacing animals in research entirely. Research animals in the EU can also only be used if there are no suitable alternatives. The 3Rs principle (Replace, Reduce, Refine) is an ethical framework for minimising, or avoiding the use of animals in research and is a standard practice in research around the world.
New approach methodologies (NAMs), such as studying cells in the lab (in vitro), lab-grown mini organs (organoids) and natural or engineered tissues grown inside computer chips (organs-on-chips), which mimic human systems and physiology, are emerging as alternatives to animal studies. When these non-animal methods are not possible, the use of mice can also be reduced by replacing them with other animals, such as zebrafish or fruit flies.
There are moves towards reducing the numbers of GA mice, for example by freezing the eggs, sperm or embryos from GA mouse lines, so that they can be accessed at a later date. There is also increased sharing of these strains of mice between researchers, meaning that fewer are ultimately used in the long term.
Credit: Max Planck Institute
Ways to improve the welfare of mice in the lab are continuously being developed – for instance the European Cooperation in Science and Technology (COST TEATIME) consortium aims to improve biomedical research by using 24/7 technologies like sensors to monitor the behaviour of rodents, instead of removing them from their home-cages, which can interfere with their natural behaviour. This also improves animal welfare by minimising possible stress for the mice when they are placed in an unfamiliar environment.
This article by EARA member the Max Planck Society explains more about the welfare of research mice, and you can read more about the 3Rs principles with examples in this article by UK Research and Innovation.
Credit: University Medicine at Johannes Gutenberg University of Mainz
Is research on mice and rats the same thing?
Rats are also a very common animal used in biomedical research alongside mice, but even though the two might seem similar, there are some important differences when it comes to what they bring to research. Mice and rats have different cognitive and social behaviours, and react differently to stress, handling, and certain drugs and substances, all of which mean that one is more suitable over the other, depending on the type of research. Rats are more intelligent than mice, for example, making them better models for conditions like addiction.
Banner image courtesy of University Medicine at Johannes Gutenberg University of Mainz