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Mice have revealed many of biology’s secrets. Stuart Read/APN

Animals in research: mice

Our series, Animals in Research, profiles the top organisms used for science experimentation. Here, we look at a species familiar to most: Mus musculus, or the mouse.

Mice have been close companions of humans for millennia but often in competition for food. Indeed, the word “mouse” is thought to be derived from the Sanskrit verb “mūṣ” meaning “to steal”.

In recent decades those thieving house mice have paid us back a thousand-fold by revealing many of biology’s secrets.

The Stuart Read/APN

From the humble object of mouse fanciers of the 18th and 19th centuries, the mouse has risen to become a pivotal experimental organism and continues to play a leading role in advancing medical goals of the 21st century, which include:

  • to understand the functional parts of the genome
  • to have models for the study of human disease
  • to develop genomic-based therapies for human disease

Achieving those goals by studying human subjects is confounded by the fact our health status is a product of a combination of our genes and our environment.

This can be understood by considering that that even identical twins will generally accrue different medical histories over their lifetimes.

Much more than a pest

The scientific method is the best approach to achieve these goals and is founded on the ability to change one variable at a time and to observe the effect of this change.

To understand disease we therefore need to generate populations in which genes and the environment can be kept constant or manipulated in precise and defined ways.

The impediment to generating human populations with an identical genetic make-up in which each individual is exposed to the same environmental conditions should be immediately obvious.

A genetic mouse model of obsessive compulsive disorder.

Providently, we have on hand the hundreds of inbred strains of mice initially established by those mouse fanciers of centuries past, plus those added by biologists more recently.

Each strain represents a population of mice with identical genetic makeup, and each inbred strain is distinct from every other strain.

Many disease-causing genetic variations produce different effects dependent upon the genetic background of the inbred strain.

In an extreme example the same defect in a gene that produces keratin causes embryos to die early at mid-gestation on one genetic background but causes inflammatory bowel disease in adult animals on another genetic background.

Another advantage is that mice can be kept in controlled environments enabling one variable, such as genetic composition, to be varied in each experiment.

Together, the multitude of mouse inbred strains and tightly controlled environmental conditions provide a well-defined set of genetic and environmental features that can be selected and combined to answer specific research questions.

Master (gene) manipulators

The mouse also comes with a comprehensive toolbox to introduce precise and defined genetic alterations.

A phenomenal international effort is currently underway to disrupt each gene one by one in the mouse and to put each modified mouse through a series of physical tests and measurements to determine the effect of each gene disruption (the phenotypic consequences).

A genetic mouse model of mitochondrial deafness.

Moreover, the human disease forms of genes can be inserted into the mouse genome to replicate specific aspects of human disease such as Alzheimer’s disease – towards an “avatar” mouse, if you like.

While this is certainly not a complete list, mouse phenotypes include:

  • obesity
  • diabetes
  • growth retardation
  • haematology defects
  • immune defects including autoimmunity
  • kidney disease
  • blood cancers – leukaemia/lymphoma
  • solid tumours
  • bone defects
  • development (embryonic) disorders
  • neurological disorders
  • gastrointestinal defects

Because of this ability to manipulate and control both genetic and environmental parameters in a precise manner, the mouse was the first non-human mammal to have its genome sequenced.

We now know that the human and mouse genomes have almost exactly the same number of genes and that about 80% of human genes have a direct counterpart (orthologue) in the mouse genome.

Along with its similarity at the genome level the mouse shares anatomical, physiological, and metabolic similarities with humans – many of which are not shared by other experimental organisms.

A narcoleptic mouse.

But the differences between humans and mice can also be informative.

Some diseases were only properly defined in humans after being first described in mice carrying the same genetic faults, where the mice displayed features that had been missed in human cohorts.

This is exemplified by the recent recognition that a group of previously disparate diseases all have in common a problem with the formation of cilia and flagella (whip-like structures that moves liquid past the surface of a cell and help locomotion, such as the tail of a sperm cell).

Together, these diseases have become recognised as ciliopathies. This new knowledge potentially has both predictive and therapeutic value.

Hence, the mouse data improves the human clinical knowledge and gives clues to the underlying disease mechanisms, pointing to therapeutic targets.

Fitting the right genes

Recognising the might of the mouse, the Commonwealth, states and several Australian universities and medical research institutes have together co-funded the Australian Phenomics Network (APN).

The APN harnesses Australian expertise to contribute to international mouse genetic activities and enable local researchers to benefit from this expertise.

An obese mouse weighing 52 grams (right) and a normal mouse weighing 20 grams in a laboratory of the tissue bank of the Integrated Research and Treatment Center for Adipositas (IFL) at Leipzig University in Leipzig, Germany. AAP

The APN’s suite of services crafts characterises and curates mouse strains and facilitates ready access to the multitude of international resources including the International Knockout Mouse Consortium repositories and the International Mouse Phenotyping Consortium capabilities.

The APN has most recently begun building a vast, unique collection of mice that represent the most common form of disease-causing genetic variations in the human population (the Missense Mutation Library) and has established a world-class DNA sequencing service.

The Stuart Read/APN

The Australian Phenome Bank (APB) is responsible for freezing sperm from mouse strains used in medical research in Australia, thereby safeguarding and distributing this valuable resource.

This post-genomic era has heralded a new-found reverence for the mouse as our shared biological secrets are gradually revealed.

Over the coming decades the wealth of data and insights that the mouse offers will fuel biomedical discoveries and clinical advances.

Our relationship with mice is more intimate and healthy than ever.

To read more in the Animals in Research series, follow the links below:

Drosophila melanogaster (the fruit fly)
Danio rerio (zebrafish)
C. elegans (roundworm)

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