Mouse Model: Pros and Cons
Ankita Das
Chetana Tamadaddi
Prashant Waiker
Indian Institute of Science Education & Research
Bhopal
MOUSE : Mammalian model organism
GenomeMammalian20 chromosomes2.6 Gb~25000 genes99% have human counterpart
StrainsInbredOutbredRecombinant inbredConsomicFluorescent
Life Cycle4-day oestrus20-day gestation4-8 pups per litter2-8 litters per female7 weeks to sexual maturity2-3 year lifespan
Reverse geneticsKnockoutsTransfenicsConditional expressionInducible expressionRetroviral vectorssiRNA
The Mouse as an Experimental System
Assisted reproductionCryopreservationEmbryo rederivationIn vitro fertilizationIntracytoplasmic sperm injectionCloning
ToolsGenome sequenceEmbryonic stem cellsExpression arraysGene-trap libraries Insertional vector librariesBAC libraries
Basic questions to be asked
1. The mouse model is the one most commonly used for studies of human physiology
and disease, but is it the best one?
2. How useful and valid are these models for mimicking human disease?
3. What characterises mouse models that have proven useful for basic science,
clinical research and drug discovery?
4. What measures are needed to improve new and existing mouse models?
Out of the model organisms which may be
genetically modified, the mouse is: •Best model for mammalian development
•Closely related to humans (mammals)
•10-15 offspring per litter and approximately one litter every month.
•Genome sequenced
•Many inbred strains characterized (450 available)
•Genetic manipulations well developed
•Mice are small, have a short generation time and an accelerated
lifespan (one mouse year equals about 30 human years)
Phylogenetic analysis
Not so far Indeed they are
Genomics
99% of mouse genes
have an equivalent in
humans making mice
ideal for the studying
the functions human
genes in health as
well as in diseases.
For significant genetic
changes, mouse
orthologs were close
to random in
matching to their
human counterparts
i.E the E-Value is
higher for the
alignment
Human
Mouse
Life cycleFast Slow
EmbryologyHUMAN MOUSE
• Gestation: Mouse: 18 days; Human:
270 Days
• Different hormonal regulation in
development of embryos
• Human: hCG; mouse: mPRL
• Human : Pituitary gland secretion not
required
Hum. Reprod. Update (2003) 9 (6):531-
539.
Development
Manipulations at the embryo level
• Allows genetic manipulation of embryo possible
• Early embryo can be split to yield two “twins”
• Two morulas can be combined to form a chimera
• Cells from an embryo can be injected into another blastocyst to form a chimera
• Embryonic manipulation difficult inside the mother
• Extra-uterine embryo culture is difficult.
• Need to cut open the uterus - ethical issue
• Similarity
Genes responsible for building and
operating both organs are 90% identical--
which means that the mouse brain can be
a powerful tool for unravelling the mystery
of human mental disorders, memory and
intelligence related phenomenon.
• Difference
Human Vs Mouse Brain
Smooth surface-less memory
More convulsions –higher order
memory
Glia appear to play a more significant role in various brain functions
70% neurons +30% glia 30% neuron+70% glia
Proportion of Neuron and Glial cells varies between Mouse and Humans
Transgenic Mouse
• Advantages :
• Contain extra genetic material integrated into the genome in every cell.
• Generated to carry cloned oncogenes provide good model for human cancer
• Good models for muscle growth study by overexpressing the transgene insulin-like Growth factor in differentiated muscle fibers.
• Disadvantages:
• Transgene integration is apparently random ;
• Many experiments reveal that the genetic surrounding of the inserted transgenic construct is modulating the expression pattern of the transgene itself both qualitatively and quantitatively.
• Transgenic rescue of knockout mice is time-consuming, expensive and labour intensive.
Knock-out mouse
Disadvantages:
• About 15% of Knock-outs are developmentally lethal. This limits studies to only embryonic development.
• It is difficult to determine a gene’s function in relation to human diseases.
• Custom knock-out mice is very expensive ($3000 -$30,000)
Advantages :
• Very specific endogenous gene has been altered in such a way that interferes with normal expression.
• To study effects of gene products, biochemical pathways, alternative (compensatory) pathways, and developmental pathways
• Models to test the beneficial effects of drugs or gene therapy
Behavioural studies
Disadvantages :• Lab Environment Vs Natural environment
• Animals lack self- consciousness, self-reflection and
consideration
• Hallmarks of behavioural disorder such as
Depressed mood, Low-self esteem, suicidal
tendency are hardly accessible in mice
• Hence behaviours like Depression, Autism, suicidal
tendency can not be studied in mouse models.
(wikipedia)
Advantages :• Mouse model shares many Features with
human brain functions like Anxiety, Hunger,
circadian rhythm, memory and other emotional
responses (Peter van Meer and Jacob Raber)
• Robust phenotypes in mouse models -effective
treatments for components of Autism spectuam
disorders (Jill L. Silverman et.al 2010)
• Effects of alcoholism
Neurodegenerative disorders
1. Mice live only about two years, while people
can live for 80 years or more.
2. Neurodegenrative disorders are normally late
onset disorders.
3. Hence not a good model to study parkinson’s
and alzheimer’s disease and other diseases of
aging.
4. Incapable of expressing some cognitive
human disease symptoms.
Cancer Model
Drug Target Studies
Few more Limitations:1. Early acting mutant phenotype difficult to study
2. Poor models to study inflammation in humans, a condition present in many
humans
3. Research mice are inbred and do not capture the genetic variation existing in
human population.
4.The research works have found that the responses in mice correlated poorly not
with those in humans but also with one another.
5.Drugs that have shown promise in mice have done poorly in humans.
6.Forward genetics : To identify novel gees involved in embryogenesis is difficult as
it is prohibitively expensive.
Poor models to study inflammation in humans, a condition present in many
humans
• Mice are resistant to infections and inflammations.
• Mice have lived for millennia in environments
teaming with microbes and they short gestation
periods and large litters. This shows they have
evolved with different strategies for dealing with
infections
Research mice are inbred and do not capture the genetic variation existing in
human population
• The research works have found that the responses in mice correlated poorly not with those in humans but also with one another.
Proc Natl Acad Sci U S A. Feb 26, 2013; 110(9): 3507–3512.
Mice trials did not translated to human!!!
Cost-ineffectiveness of mouse models:
http://www.ohsu.edu/xd/research/research-cores/transgenics/services-costs.cfm
Humanised mouse
A mouse's liver reacts differently to drugs as compared to the liver of
humans.
This makes it difficult to predict whether or not the potential drug being
tested will be toxic in humans.
Various types of human cells and tissues are
engrafted and function, as they would in
humans are considered extremely useful in
basic and applied human disease research
DRUG FACTORY FOR FUTURE
Few more advantages of mouse model
Brown Norway Rat
• Similarities to human sensitization
• Serotonergic bronchoconstriction
• IgE mediated
• Early and late phase reactions
• Airway hyperreactivity
• Tissue + BAL accumulation of neutrophils, eosinophils,
lymphocytes
• Good inflammatory responses
Concluding remarks
Just as no one human is representative of an entire population of humans, no one
strain of mouse is representative of all mice or much less, humans.
Although each of these systems can provide valuable insight, as researchers, we
know that the models are just that: models.
The only perfect model of human disease would be humans themselves, but
performing many kinds of research on humans is an ethical and practical
impossibility.
But, Thanks to animal research, primarily in mice, cancer survival rates have continued
to rise.
Herceptin – a humanised mouse protein – has helped to increase the survival rate
of those with breast cancer; it could not have been attained without animal
research in mice.
While Fleming discovered penicillin without using animals, he shared the Nobel
Prize with Florey and Chain who, by testing it on mice, discovered how penicillin
could be used to fight infections inside the body.
http://www.understandinganimalresearch.org.uk/about-us/the-science-action-network/forty-reasons-why-we-need-animals-in-research/
Alternatives for Human models other than mouse/ any
model organism
Human, inducible pluripotent stem cells can also elucidate new
mechanisms for understanding cancer and cell regeneration.
Imaging studies (such as MRI or PET scans) enable non-invasive study of
human subjects.
Recent advances in genetics and genomics can identify disease-associated
genes, which can be targeted for therapies.
THANK YOU