Summary BMS41 - Advanced Models of Human Disease including all lectures with information about different animal models (Mice, C.elegans, Drosophila and Zebrafish).
Lecture 1. Introduction: importance of the use of organismal models to cure and
understand human disease.
Animal model = living organism with an inherited, naturally acquired, or induced pathological process
that in one or more respects closely resembles the same phenomenon in man.
Why use animal models?
- Gain insights into the pathogenesis of the disease phenotype
o Genetic disease: which gene causes disease?
▪ Use filters: many candidates are found at first, filter to get a few candidates.
These few candidates will be tested in animal model to see which disease is
introduced.
• Quality filter - Common variants filter- Predicted deleteriousness
filter - Genetic filter - Biological filter:
o Mechanism of disease: Which pathway? How does it work.
- Identify therapeutic targets and diagnostic markers
o E.g. Hypertensive patients: target salt reabsorption in the kidney (to reduce salt
concentration in blood).
▪ Possible drugs: furosemide, thiazide, amiloride → but which one works best
in the patient? Determine which one to use by looking at exosomes (vesicles
present in urine). Test functionality of the three drugs on the exosomes.
- Test potential treatments
o Screen potential compounds → start with 5.000-10.000 compounds to end with 5
compounds for clinical trials and eventually 1 FDA approved drug. Important to
chose right animal model.
When do we use animal models?
- When in vitro and/or computational models cannot reproduce the level of biological
complexity required to solve our scientific question.
o Animal model cannot be used if the in vitro model is valid enough for the study.
o E.g. model ataxia in EAST syndrome → animal models are required.
▪ Epilepsy, ataxia, sensorineural deafness, tubulopathy, Dysfunctional K+
channel → expressed in multiple organs.
➔ Diseases with multiple manifestations in different organs are targets for animal models.
However, it is best to combine in vitro and in vivo models.
How to choose animal model
- Similarity in anatomy
o Is the organ(s)/tissue(s) subject of study present in your animal model?
o Is the anatomy of the organ(s)/tissue(s) subject of the study conserved in your
animal model in the context of the disease studied?
➔ Is organ/tissue studied present and is functionality similar to humans?
- Similarity in physiology/organ function
o Is the physiology of the organ(s)/tissue(s) subject of study conserved in your animal
model?
- Genetic conservation of the target gene(s) to model the disease, and of the mutation in case
of inherited diseases
o Is there an ortholog (= protein with similar function that comes from the same
ancestor) of the gene that is key for the disease that is modelled? Are there paralogs
(= duplicates of a certain gene) to consider?
o How is the genetic conservation in key functional domains of the disease-relevant
proteins?
,Renske de Veer (rdeveer)
o For inherited diseases, is the disease mutation (semi-)conserved?
o Are the expression patterns of the genes/proteins relevant for the disease conserved
in your model organisms vs. humans?
- Ease and adaptability to experimental manipulation (methodological feasibility)
o Can we apply the desired technique/method to induce the disease in our animal
model?
o Can we obtain our desired readouts from our animal model?
- Ethical and ecological implications
o Article 9 of Experiments on Animal Act
▪ Zebrafish are in first 5 days not subjected to article 9, they are considered
model organisms.
- Budget and time
o Rodent are more expensive compared to fly and zebrafish.
, Renske de Veer (rdeveer)
Lecture 2. Characteristics of the mouse model of human disease.
- Mice have successfully been used in previous studies. However, observed effects in mice
might not be observed during clinical trials in humans due to different physiological aspects.
➔ Large evolutionary gap between the two, therefore they are not that comparable.
Organ development in mice is similar to organ development in humans → primordial germ cells
specification is different.
- Only difference: in human the signalling with the germ cells happens via hypoblast and
epiblast, whereas in mice the signalling is only induced via the epiblast.
➔ Put scientific question in the proper spatio-temporal context
Anatomy/physiology
- Mice have same organs as humans, however the position of the organs differs.
- Metabolic rate: mice have higher metabolic rate (more mitochondria per cell) compared to
human → mitochondria disorders has higher impact on mice. Mice produce more ROS than
humans → ages faster.
- Mice have a fore stomach but no absorption there → storage function. Food is gradually
released into stomach, steady digestion. By origin, mice are herbivores → give them meat
(omnivores). Humans are omnivores by origin. Microbial might therefore be different in
humans compared to mice.
- Kidney: very similar in humans and mice.
o Cuboidal cells in proximal tubule.
o Transport processes in mice nephrons are similar to human transport processes in
human nephrons.
o Gender differences in cardiovascular disease, due to other nephron transport in
female compared to man. Female absorb salt by excreting potassium, males do not
do this. Potassium that is not excreted accumulates in blood → osmolarity increases
→ higher risk of cardiovascular disease.
o Mouse kidney develop different from human kidney. Six1 and Six2 are important in
kidney development. After branching, six1 expression ceases in mice while in human
it persists.
- Liver of mice has multiple lobes compared to human liver, but physiology is very similar.
- Brain: olfactory bulb (important for sense of smell) in mice is located at the front of the brain
and is huge compared to human. Human brain has deeper grooves than mice (smoother
surface) → more learning capacity & memory.
o Mouse neurons display the same (patho)physiology as humans in the context of
Alzheimer’s disease.
Methods to model disease in mouse
- Non-genetic models
o Diet (food/drink): consider time of diet and different diets for different diseases.
▪ E.g. diabetes type II.
o Injection/exposure of/to compounds/virus/bacteria
- Genetic models
o Knock out: complete loss of function.
▪ Used to study function of targeted gene by comparison to non-targeted
controls.
o Knock-in (nucleotide substitution): replaces the coding region of a known gene with
an alternative sequence of the same gene containing a specific mutation.
▪ Used to study the phenotypic impact of this variation, often pulled from
human clinical observations. Functional impact is allele specific.
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