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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…

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

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 “Dorian” mouse turns grey at 30–40 days of age. Severe mutations in the affected Bcl2 gene cause cancers in mice and man. 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 “Dwarf” mouse is 60% small than its unaffected siblings and is used as a model for childhood development. 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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21 Comments sorted by

  1. Monika Merkes

    Honorary Associate, Australian Institute for Primary Care & Ageing at La Trobe University

    It horrifies me to read about the usefulness of animal research. Animals are NOT useful predictors of important disease responses in humans.
    In Victoria, NSW and Tasmania (no data available for other states) 928,217 mice were used for research and teaching purposes in 2011. http://www.humaneresearch.org.au/statistics/ What do we have to show for this? What diseases can now be cured due to research on mice?
    Having some common genetic make-up does not translate into similar disease responses, as…

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    1. Michael Pollard

      Associate Professor

      In reply to Monika Merkes

      A significant problem with the Seok, J. et al paper in PNAS, at least from my reading, is that while a large number of human patients were studied the actual number of mice studied was N=1! This is because a single strain, the C57BL/6, was used in the various inflammatory models. In murine studies, which I have been doing for several decades, a fatal flaw is to use just one mouse strain when trying to draw comparisons with human disease. For example one would not use the C57BL/6 to study idiopathic…

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    2. Monika Merkes

      Honorary Associate, Australian Institute for Primary Care & Ageing at La Trobe University

      In reply to Michael Pollard

      Hi Michael,
      “It is important for the lay readership of The Conversation to understand that animal studies are not performed at the whim of researchers.” I’d like to believe you, but how can I, if vital details about animal research are not in the public domain? As Rob Buttrose and I wrote in another article on The Conversation http://theconversation.com/the-elusive-ethics-of-animal-ethics-committees-10056, a veil of secrecy hangs over animal ethics committees (AECs). We wrote to the AECs of major…

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    3. Michael Pollard

      Associate Professor

      In reply to Monika Merkes

      Hi Monika,
      It would seem to me that if you could not find the information on AECs then it becomes hard to judge whether or not institutional review boards are doing their job. I would find it difficult to provide an opinion under those circumstances.

      Speaking from my own experience it is very clear that the animal ethics applied today are far superior to those when I was an Honours student in Australia in 1974. In those early days my work used tissue from abattoirs which was not a positive experience…

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    4. Monika Merkes

      Honorary Associate, Australian Institute for Primary Care & Ageing at La Trobe University

      In reply to Michael Pollard

      Hi Michael
      I don’t doubt that there have been improvements over the years. Exsanguination may no longer be used in the laboratory, but it’s still used in some abattoirs – better known under the name halal slaughter.
      It is indeed difficult to form an opinion without having sufficient information. If everything were above board, why the secrecy?
      We did find one report: “Research and Graduate Studies Committee, Animal Ethics Committee, Annual Report to the Research and Graduate Studies Committee…

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    5. Sandra Mornington

      Nurse

      In reply to Monika Merkes

      Monika, just to keep saying over and over again that research on animals is of no benefit to humans will not ever make it true.

      We have debated this already in your previous articles, and some people in the subsequnet discussion raised their voice to support animal research as something that has already made a difference to their lives, and is likely to create further benefots. Your factual errors there have been pointed out by many readers, but at no point whatsoever did you stop to acknowledge…

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  2. Rob Buttrose

    University of Melbourne

    There is not a single word in this article about the ethics of the research described, apart from the flippant remark that mice are "paying us back" for all the food they have stolen from humans over the millenia. And how the animal experimentation industry in Australia is making mice pay! Researchers and the NHMRC are generally very secretive about numbers of animals used by biomedicine , but in Victoria alone in 2011, approximately 420,000 mice were killed in the lab.

    There was also a…

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    1. Michael Dobbie

      Chief Executive Officer, Australian Phenomics Network at Australian National University

      In reply to Rob Buttrose

      Our article, as part of the series about different species used in research, set out to explain in a few words why we use mice and how they are used. A proper consideration of the ethical and welfare aspects of using any species in this way could be the basis for a separate article or, indeed, a series or articles.

      The welfare of animals is paramount and all such activity must be in line with the Australian Code of Practice for the Care and Use of Animals for Scientific Research (http://www.nhmrc.gov.au/guidelines/publications/ea16

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    2. Rob Buttrose

      University of Melbourne

      In reply to Michael Dobbie

      Thanks for your reply Michael. It would come to you as no surprise that I am very familiar with the Code of Practice, the Animal Ethics Committee (AEC) system and the 3Rs. I am also very aware of all the shortcomings of this framework for the proper ethical assessment of animal experimentation proposals - see my https://theconversation.com/the-elusive-ethics-of-animal-ethics-committees-10056 and https://theconversation.com/scientific-research-on-primates-what-do-we-owe-animals-like-us-11673 (written…

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    3. Sandra Mornington

      Nurse

      In reply to Rob Buttrose

      Hello Rob

      Nice to hear from you again. At least, you try to keep your arguments clear, and there is an underlying logic, even though I don't agree with your conclusions.

      I can see that you objected to research usign mice and zebra fish, but not the worm or the fly. Care to explain how you decide what is the point hwere you start to think that the damage to the animals is more important than the benefit to humans?

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  3. Brett Lidbury

    Associate Professor at Australian National University

    A comment on Animals in research: Mice – By M. Dobbie, R. Arkell and S. Read.

    Firstly, let me applaud the Conversation for running this series on “Animals in Research”. This is an issue charged with strong views and opinions, which up to a point is healthy, but can quickly polarise these conversations and thereafter ensure no progress on the wider issue (please note that I didn’t use the term “debate” - let’s keep it as a conversation). Therefore, let’s consider the various points of view reflectively…

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    1. Monika Merkes

      Honorary Associate, Australian Institute for Primary Care & Ageing at La Trobe University

      In reply to Brett Lidbury

      Hi Brett,
      I congratulate you and your colleagues at ANU for the important work you're doing in developing and promoting alternatives to animal research.
      I don't share your optimism about the willingness and readiness of the animal research community to embrace alternatives. The number of animals used for research and education purposes is steadily increasing, not just in Australia.
      Let's continue to work for a more positive future for lab animals.

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    2. Sandra Mornington

      Nurse

      In reply to Monika Merkes

      Monika, so essentially you think that the fact that scientists do research in animals is part of a big conspiracy involving evil researchers, the government, and perhaps some multinationals? Whos making the profit?

      Isn't it a much more sensible to think that you may be basing your view on wrong information?

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    3. Sandra Mornington

      Nurse

      In reply to Monika Merkes

      Well, you make a point of consistently criticisin any article about animal research with the same old arguments- useless, waste of resources, etc. This raises the question of why are there so many people doing biomedical research, and why does the government think it is so important to support it.

      Well, you could argue, governments waste money in many things. But surely, all those doctors would find a better thing to do - all these highly educated people would surely have picked up on the fact that they are wasting their time, and that they would have more fulfilling careers and make more money working in something else! And indusrty- surely their share holders would have picked up on the fact that they are throwing their money out on something useless?

      Yet, the vast majority of the people with qualifications in this area disagree with you. Your "facts" are therefore obviously not correct to anyone who bothers to check their facts.

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    4. Brett Lidbury

      Associate Professor at Australian National University

      In reply to Monika Merkes

      Hello Monika - thanks very much for your comment. Yes, animal numbers, particularly mice, have increased in research environments over recent years. This is largely due to the increased availability of genetically engineered strains. In education, while I can't cite figures, my sense is that there are considerable efforts to reduce or eliminate animal work in at least UG programmes. For example I am aware that animal-based practicals or labs for UG education have been at least dramatically reduced…

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    5. Monika Merkes

      Honorary Associate, Australian Institute for Primary Care & Ageing at La Trobe University

      In reply to Sandra Mornington

      Sandra, there are historical reasons for the use of animals in research. Science has moved on, and these original reasons are no longer valid. Ray Greek and colleagues explain this very well:
      “Although written with the best of intentions and based on the science of the era, the Nuremberg Code set in motion a series of events that has resulted, ironically, in current research being conducted in an unethical manner. The results from animal-based research have been shown empirically to be invalid for…

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    6. Monika Merkes

      Honorary Associate, Australian Institute for Primary Care & Ageing at La Trobe University

      In reply to Brett Lidbury

      Hi Brett, would it be fair to speculate that the physical and visible presence of your team at ANU is a constant reminder to other teams/departments that there ARE viable alternatives? And therefore they might make more of an effort to innovate, replace, reduce etc.?
      Thank you for pointing me to ALTEX. In the current issue, I found this article by Marcel Leist and Thomas Hartung of particular interest: "Inflammatory findings on species extrapolations: humans are definitely no 70-kg mice" http://www.altex.ch/Current-issue.16.html?aid=7

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    7. Michael Pollard

      Associate Professor

      In reply to Monika Merkes

      I think we need to be very careful in how we interpret the blanket statements of those both pro and con the use of animals to model human disease. Conclusions such as “The results from animal-based research have been shown empirically to be invalid for predicting human response” from Greek and colleagues are naive, the situation is nowhere near as black and white.

      Those arguing against animal models appear to be making much of the PNAS paper by Seok, J. et al (Proc Natl Acad Sci U S A. 2013…

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    8. Johannes Manning

      Retired veterinarian

      In reply to Monika Merkes

      Hello Monika'

      Sorry to have to disagree with you again. However, I have had a look at the paper you mention. It is a position paper from an author that does not have anything new to say. Like your arguments here, and in your Conversation pieces about the validity of animal-based research, the authors of that paper basically are trying to find a "scientific" reason, in the form of nitpicking sentences from papers published in scholarly journals, to defend something that is inherently illogical…

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  4. Nathalie Martinek, Ph.D.

    logged in via LinkedIn

    There is at least one thing that has been overlooked in any of these conversations about using animals, insects or any organism for that matter to study human diseases which is that none of these have human consciousness.

    How can animal models of disease derived from spontaneous or induced mutations begin to address the contribution of an individual's thoughts, beliefs, values, experiences, memories, intergenerational trauma and emotions in their health or illness?

    Where does a human's capacity…

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