Mice used as a model organism by geneticists investigating theories on inheritance and gene function.

Model organisms in genetics research: the mouse

Ben Stockton finds out how the mouse came to be a model organism

We have an extensive knowledge of a select group of animals, plants and microorganisms that are used in labs around the globe. The results of studies in these so-called ‘model organisms’ are used to better understand biological phenomena in humans and animals.

Man and mouse have an ancient love–hate relationship, and our fascination with this creature stretches far beyond cartoons such as Tom and Jerry and Mickey Mouse. Once considered an agricultural pest, the mouse, or Mus musculus in Latin, is now being used to make huge advances in human health.

Where did the lab mouse come from?

Records of research using mice date back to the 17th century when William Harvey (an English doctor), gave a detailed description of blood circulation, but the lab mice we know today originated in 18th-century Asia. The Japanese took to collecting ‘fancy’ mice and, much like the trading of any item, the rare and unusual ones became highly sought after. Such was the popularity of the hobby that it soon spread to Europe, and it held particular appeal for the Victorians in Britain.

Modern lab mice are believed to have descended directly from these original stocks. The high level of inbreeding during the fancy mouse trade has resulted in a remarkable level of genetic similarity between these modern mice, making them ideal for genetics research.

The Augustinian monk Gregor Mendel was also taken by the ‘mouse craze’. Mendel is known for his experiments on pea plants in the mid-19th century, but if it weren’t for the objections of Mendel’s bishop, mice may well have been the subjects of his studies of inheritance. Mendel was forbidden from breeding mice within the monastery, so he took to gardening as a less racy alternative.

Who were the pioneers in mouse genetics?

It wasn’t until 40 years later that Mendelian inheritance was observed in mammals. Mendel had shown that mating of two heterozygous parents – who carry one dominant and one recessive allele of a particular gene – produced offspring with a 3:1 ratio of dominant phenotype to recessive phenotype. A phenotype, put simply, is the way an organism looks, or their ‘observable traits’. Mendel found that the green gene in peas was recessive and the yellow gene was dominant: when the offspring had one green gene and one yellow gene, its phenotype would be yellow.

In 1902, French biologist Lucien Cuénot used coat colours to demonstrate the same ratios of inheritance in mice. Cuénot’s work is arguably the first example of a mouse-based genetic study.

Meanwhile, several top geneticists were working in the USA. This young generation of scientists were classically trained zoologists and botanists, but they had jumped into the exciting field of genetics by 1900. One such individual was William Ernst Castle. From 1900 to the publication of his final paper in 1961, Castle devoted his academic career to studying genetics in mammals.

Castle’s dedication and scrupulous method left a lasting impression on many of his students, including Clarence Little. Together with Little, Castle produced a series of seminal papers on coat-colour genetics in mice. Little went on to develop strains of inbred mice, descendants of which are still used in modern laboratories today. He recognised the need for genetic uniformity to be able to compare new variations and, in 1909, developed the first inbred ‘lab mouse’, DBA (dilute brown non-agouti). One of Little’s strains became the first mouse genome to be sequenced in 2002.

Little established the Jackson Laboratory in Maine, USA, in 1929. To this day, the centre remains a haven for mouse genetics and has distributed 3 million mice of 7,000 varieties to laboratories in 56 countries.

Why are mice suited to genetics research?

We have more in common with mice than we may like to think. Beyond our mutual enjoyment of cheese, almost every gene in the human genome has a counterpart in the mouse.

The uncanny similarity between humans and mice was first noted in an article in ‘Life' magazine in 1937, where Little described the mouse’s life cycle as a miniature take on the human. This has since held true; from their metabolism to the structure of their internal organs, mice are very similar to humans.

In addition, our strong affiliation with mice in the past has allowed us to develop an extensive knowledge of how they work. We are now able to manipulate, insert and delete genes with relative ease. This, paired with the physiological resemblance, has been crucial in developing how we understand disease.

Have mice been used in any landmark studies?

Since the beginning of the 20th century, studies using mice have accounted for dozens of Nobel Prizes; the last six awards in Physiology or Medicine alone have all been for work involving mouse models. Mice have been involved in all kinds of research, from the discovery of penicillin to understanding the brain.

Of particular note is the work that won George D Snell the 1980 Nobel Prize in Physiology or Medicine. Snell, who was also a student of Castle, used mice to uncover the genes that make up the major histocompatibility complex, a group of genes central to the immune system. Snell also created the first congenic mouse strain, animals that differ from other strains by a single gene.

More recently, Mario Capecchi, Martin Evans and Oliver Smithies shared the 2007 Nobel Prize in Physiology or Medicine for developing ways of introducing specific gene modifications into mice using embryonic stem cells. They were able to generate offspring that expressed specific gene mutations that were carried (but not expressed) by the parent.

What research in mice is being done today, and where is it going?

Given our long history, mice will no doubt play a major part in research that tackles future challenges to human health. Arguably the greatest challenges today include understanding brain disorders, and mice are already being used in some very promising research in this area.

Optogenetics is a revolutionary technique that enables scientists to target individual neurons in the brain with remarkable precision. First, researchers insert genes that encode light-activated ion channels into specific mouse neurons. Then, they fire a laser onto the brain, which induces an action potential and mimics a particular disease. This work should allow us to understand more about how these neurons are involved in diseases such as Parkinson’s and Alzheimer’s.

Mice were used in more than 3 million procedures in the UK alone in 2012, a 14 per cent rise from the previous year, but many scientists are now searching for alternatives to using animals in research. In the future, advances in technology may allow computers to more accurately simulate disease states. Lab-grown tissues could also help reduce the need for animals. Currently, no methods provide a completely suitable alternative, but scientists continue to aim to reduce, refine and – hopefully, one day – replace the use of animals in research.

Lead image:

Mice used as a model organism by geneticists investigating theories on inheritance and gene function.

Wellcome Library, London CC BY NC ND

References

Questions for discussion

  • Thinking about independent and dependent variables and the scientific method, why is it important to have genetically similar mice for experiments?
  • The discoveries made by Capecchi, Evans and Smithies allowed scientists to introduce specific mutations into a mouse’s DNA. Considering what we know about the effect of some DNA mutations, how can these techniques be used to study disease? There might be some useful information on the Nobel site (see the References).
  • Populations across the world are ageing. Why is a better understanding of diseases such as Parkinson’s and Alzheimer’s becoming more important?

About this resource

This resource was first published in ‘Genes, Genomes and Health’ in December 2014.

Topics:
Genetics and genomics, History
Issue:
Genes, Genomes and Health
Education levels:
16–19, Continuing professional development