Of mice and men
Translatability of information from models to humans in medical science: some
considerations.
UMB, 12.12.2013 Fredrik Andersen
Elena Rocca
animal lab models:
animals obtained through selective mating
or/and genetic modification in order to mime
specific human conditions, human
pathologies or relationships in the ecosystem
closely enough to be able to extrapolate data
applicable to the “real world”.
Benefits of animal models are traditionally thought of as:
- ethically justifiable
- providing a living biological system, still with a lower level of complexity in respect to the system they are modeling
- controllable through genetic selection and modification - providing objective and reproducible information due to genetic and contextual “identity”
The major medical advances include the use of animal models
From: understandinganimalresearch.org.uk
But...
the thalidomide case
• 1957: Grünenthal GmbH launches a “wonder drug”
for treatment of insomnia, colds, morning sickness during pregnancy
• late 1950s/ early 1960s: more than 10,000 children in 46 countries were born with deformities such as phocomelia as a consequence of thalidomide use.
• scientists did not believe any drug taken by a pregnant woman could pass across the placental barrier and harm the developing fetus.
• Preclinical study (in vitro and in vivo models)
• Clinical study phase I (healthy humans)
• Clinical study phase II (patients)
• Clinical study phase III (patients)
• Introduction in the market
• Approval
Model thinking in drug development became heavily regulated after the thalidomide
disaster
Translatability of results from preclinical to
clinical phase is to date not predictable
Decrease of faith in medical research
“ medical research changed the world, now it needs to change itself”
“what a load of rabbish”
The Economist, October 2013
Inefficiency of clinical trials and loss of resources
- 90% of the drugs in preclinical and clinical trials do not make it to the market (1)
- it takes an average of 13 years and up to over one billion USD to launch a new drug (1)
- cancer research has been particularly inefficient
because of inadequate in vitro and in vivo models (2) - AMGEN study: only 6 out of 53 papers damned as
“landmark studies” reported repeatable results (2)
(1) Brodniewicz et al., Drug research, 2010 (2) Begley et al., Nature, 2012
Begley et al., Nature, 2012
Aim of the project
1) Symptom of a general problem of model application?
2) Create an interdisciplinary network connecting experts in different fields (biology, toxicology, ecology, microbiology, physics, engineering, computer science, philosophy...) dealing with problems related to model thinking
3) Identify general difficulties of model application
4) Develop new and better approaches
Aim of this talk
• Initial review of the literature available in medical research
• Identification of three key steps crucial for the translatability from the model to the clinical phases
• Analysis through standard philosophical
issues of model thinking
Structure of the talk
1) From simple to complex 2) Model building
3) Experimental design and observation
(work in progress)
“From simple to complex”
“From simple to complex”
Low (inbred strains) / controlled (outbred strains) genetic variation
“From simple to complex”
Low (inbred strains) / controlled (outbred strains) genetic variation
“From simple to complex”
Low (inbred strains) / controlled (outbred strains) genetic variation
Kacew & al 1995
Kacew 2001
“From simple to complex”
Reduction and emergence Reduction approach:
A dysfunction is due to/explained by dysfunctional substructures
Substructures are substantially similar within different levels of complexity
Dysfunctions and their cures are substantially similar in different levels of complexity
Emergentist approach: new properties/powers emerge at different levels of complexity (appearance of
consciousness)
“From simple to complex”
1) Use different models rather then the same model in repetition 2) Deal with big levels of complexity:
large number - epidemiological studies
Model building
What are we testing?
The problem of paralogistic argumentation
Model building
P1: bishops only move diagonally
P2: Rowan Williams was the bishop of Canterbury Ergo: Rowan Williams only moved diagonally
What is a paralogism?
Model building
Galileo, Copernicus and the Peripatetics
Detecting motion
P1: Only if the distance between the tower and the rock changes, then the earth moves
P2: No change of distance is observed Ergo: The earth does not move
Paralogism: shared/relative motion
The experimental set up is not fit to test the hypothesis
Model building
Alzheimer´s disease (AD) case example
Mainstream hypothesis: AD is caused by an accumulation of APP protein
Model building
More than 300 molecules inhibit accumulation of APP in mouse model for AD
It therefore seems that AD is cured in mouse models
Problem: AD is not (yet) curable in humans
Model building
Did we cure AD in the mouse models?
Is the accumulation of APP protein the general cause of AD?
All mouse models of AD are models of APP protein accumulation
Model building
Model building
Model building
Model building
* accumulation of APP is correlated with AD, but
has also been shown to have endogenous functions in neuronal protection
* 25% of old people with APP accumulation do not show AD symptoms
* on these and other evidence is based the hypothesis that APP
is NOT the cause of AD, but it has rather a protective role against degeneration.
Model building
Treating a cure for the accumulation of APP protein in mouse models as a cure for AD might be a case of Paralogistic
argumentation where APP protein accumulation is taken as equivalent to AD in general.
• Solution
Rigorous testing of whether the specific hypothesis can be generalized prior to introducing it within the model
Model building
Experimental design and observation
Work in progress....
Preliminary suggestions
• Large variety of models
• Large numbers and population data
• Hypothesis verification prior to inclusion into the model
...
Regulation for the introduction of a new DRUG in the market
Safety controls required for the introduction of new products of biotechnology in the food
Pre-clinical phase (models)
Clinical phase 1 Clinical phase 2 Clinical phase 3
Launch
Pre-clinical phase (models)
Launch
Spiroux et al., Int. Jour. Biol. Sci, 2010,6
