Perspective
Modeling Human Disease Phenotype in Model Organisms
“It’s Only a Model!”
Ali J. Marian
A
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There in the laboratory, the postdoctoral fellows, the principal
investigator, and the research assistant cast the characters of
Knights, King Arthur, and Patsy, the naive and loyal assistant
of King Arthur, respectively. Like the preconceived exuberance of the “Knights of the Round Table” on sighting of a
model of the “Castle of Camelot,” the overenthusiastic
interpretation of the laboratory data combined with unconscious biases have the risk of contriving a model that might
only partially resemble the human phenotype but is far from
fully recapitulating it. The primed excitement often mollifies
the unpleasant reality that “it is only a model,” as Patsy would
say, and that no modeling is perfect.
The main reason for scientific research is to understand
“how,” whether the “how” relates to human disease or the
operation of the universe. Likewise, the primary reason to
develop an animal model of a human disease is to gain
insights into the pathogenesis of the phenotype with the
ultimate goal of identifying therapeutic targets and diagnostic
markers. The model organisms are instrumental in understanding of the “how” in biological processes, which ultimately relates to human health and diseases. Our current
ideas about basic cardiac physiology, muscle contraction,
glucose metabolism, hormones, neurotransmitters, oxidative
metabolism, lipid metabolism, and many other processes are
all based on model organisms, not only animals but also
microbes and plants. Studies in Caenorhabditis elegans, one
of the simplest multicellular eukaryotic model organisms,
have led to numerous fundamental discoveries that have clear
relevance to human diseases. Perhaps the discovery of RNA
interference by Andrew Fire and Craig Mello in C elegans is
a palpable utility of the model organisms, in terms of their
relevance to human health and disease.4 The discovery, which
was honored by the 2006 Nobel Prize in Physiology or
Medicine, laid the foundation for findings of more than 1000
microRNAs in humans, which regulate various biological
processes. No reasonable person would argue against the
value of the model organisms in providing fundamental
insights into biological processes that are generalizable to
human biology (Table 1). However, to consider the phenotype in the C elegans as a true model of a human disease is
simply overlooking more than 700 million years of evolution
that separates humans from this most valuable multicellular
eukaryote.5 Nobel Laureate Sydney Brenner, who in 1965
proposed the C elegans as a model metazoan for studying
higher organisms and won the Nobel Prize for his pioneering
work on developmental genetics of this nematode, shared an
enlightening conversation that took place between him and a
visiting scientist.
The scene: Dr Brenner’s office
Visiting scientist: By the way, where is your vivarium?
perspective by definition is a viewpoint. A viewpoint,
like any other opinion, could be utterly erroneous. This
perspective is meant to be provocative but not to lessen the
accomplishments of the scientific community as a whole or
belittle any particular field of science or investigators. Scientific discoveries are typically incremental, with various levels
of increments. Often the significance of the discoveries
remains unrecognized for many years if not decades, as was
the case for the discovery of DNA by Friedrich Miescher in
1868.1 The significance of this discovery remained unappreciated for about 75 years, until simple and elegant experiments by Avery and subsequently by Hershey and Chase
showed that DNA and not protein, as was commonly thought,
was the genetic material.2,3 Our shortcomings in recognizing
the significance of specific scientific discoveries should not
deter us from Cartesian skepticism, which was pioneered by
the Persian philosopher Ghazali and popularized by Rene
Descartes’ “I doubt, therefore I think, therefore I am.”
An essential component of our academic society is the
freedom to express viewpoints. Yet, personal opinions must
not guide judgment on merits of the scientific discoveries and
other peer-review matters. Science must be judged by the
scientific standards of the time. It must not be judged by
personal views. Scientific referees, like all judges, must be
impartial and devoid of personal biases on rendering judgments. Accordingly, this viewpoint is simply that, a viewpoint. It is not indicative of the author’s personal biases on
any specific scientific discipline. The perspective is aimed to
raise doubts, as doubt is an incentive to truth.
Scene From “Monty Python and the Holy Grail”
Sir Lancelot: Look, my liege!
King Arthur: Camelot!
Sir Galahad: Camelot!
Sir Lancelot: Camelot!
Patsy: It’s only a model!
King Arthur: Shh!
The scene might be germane to research laboratories that aim
to construct a human disease phenotype in model organisms.
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Center for Cardiovascular Genetics, Brown Foundation
Institute of Molecular Medicine, The University of Texas Health Science
Center and Texas Heart Institute, Houston, TX.
Correspondence to Ali J. Marian, MD, The University of Texas Health
Sciences Center, 6770 Bertner St, Suite C900A, Houston, TX 77030.
E-mail [email protected]
(Circ Res. 2011;109:356-359.)
© 2011 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.111.249409
356
Marian
Table 1. Selected Scientific Discoveries in Model Organisms
That Have Been Recognized by the Nobel Prize in Physiology
or Medicine
Model Organism
Discovery
Nobel Laureate
Saccharomyces
cerevisiae
“Discoveries of key
regulators of the cell
cycle”
Leland H. Hartwell, Tim
Hunt, Sir Paul M.
Nurse (2001)
Caenorhabditis
elegans
“Genetic regulation of
organ development and
programmed cell death”
Sydney Brenner, H. Robert
Horvitz, and John
Sulston (2002)
C elegans
“RNA interference—gene
silencing by
double-stranded RNA”
Andrew Fire and Craig
Mello (2006)
Drosophila
melanogaster
“Genetic control of early
embryonic development”
Edward B. Lewis, Christiane
Nüsslein-Volhard, Eric F.
Wieschaus (1995)
“Introducing specific
gene modifications in
mice by the use of
embryonic stem cells”
Mario R. Capecchi, Sir
Martin J. Evans, Oliver
Smithies (2007)
Mouse
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Dr Brenner (walking to a window and pointing out to a
building): There.
Visiting scientist: But, that is the hospital.
Dr Brenner: That is right. That is where my vivarium is, the
hospital, where the patients are.
Then, he continued: “We have generated so much data
from mouse models that if we stop doing research today, we
have enough material to analyze in the next decade!” Dr
Brenner’s witty points should not be interpreted as refuting
the indispensible value of model organisms in understanding
vital biological processes but rather as an indication of
inadequacies of the model organisms in truly representing the
human phenotype. The shortcomings are equally relevant in
our attempts to capture the human phenotype in cell models,
whether isolated cardiac myocytes or induced pluripotent
stem cells. It seems that we scientists have a contagious trait
for “irrational overexuberance,” whether it relates to the gene
therapy aura of 1990s, the dot.com era of the 2000s, or the
current fascination with trying to model human diseases in
induced pluripotent stem cells. The induced pluripotent stem
cell models are likely to advance our understanding of
transcriptional regulation of cell fate, differentiation, and
various other important biological processes. However, it is
surreal to consider induced pluripotent stem cells, generated
through unnatural expression of selected transcription factors
in culture environment, as a model of a complex phenotype,
such as a human disease. The cells, as many other culture
models, would display various genetic or genomics as well as
endophenotypic changes that not only diminish but perhaps
even abolish their utility as a model of human phenotype that
they are hoped to recapitulate.6,7
Evolutionary divergence of humans and model organisms
simply emphasizes the fact that no model organism, whether
C elegans, mouse, or a higher primate, can truly reiterate the
human phenotype. The modeling is particularly challenging
for chronic human diseases, wherein multiple stimuli— often
modest in intensity— operate in conjunction with a very large
number of other causal fields, which are typically not shared
Modeling Human Disease in Model Organisms
357
by the model organisms to induce the phenotype. The most
commonly used model organism, the mouse, is separated
from humans by about 75 to 100 million years of evolution,
and a newer fashionable model organism, the zebrafish, by
about 450 million years.8,9 Even the model organisms closest
to humans, namely African apes, which are separated from
humans by about 5 million years, are not expected to fully
recapitulate the human phenotype.10 The proponents have
emphasized high levels of genomic synteny (evolutionary
conservation) between humans and model organisms to
emphasize the robustness of these models for studying human
diseases. However, synteny does not indicate genetic identity
at the syntenic chromosomal regions. Chromosomal synteny
may simply point to potential utility of the models in
understanding basic biological principles but may not be
much relevant to modeling the human disease. The genomes
of the human and chimpanzee, our closest relative species,
differ by about 35 million single nucleotide polymorphisms,
5 million insertion/deletions(indels), and various chromosomal rearrangements.10 The phenotypic consequences of
such differences in DNA sequence variants—although not
adequately known— cannot be ignored. It merits reminding
ourselves that intraindividual differences in the frequencies of
DNA sequence variants is the essence of genetic studies of
complex diseases in humans, whether the study is a genomewide association study or a whole-genome/exome sequencing
project.11 The complexity is beyond the mere presence of
differences in DNA sequence variants, because the DNA
sequence variants in the same genes could lead to different
phenotypic consequences in different individuals. Phenotypic
plasticity of DNA sequence variants is best illustrated for
LMNA, which codes for the nuclear envelope protein Lamin
A/C. LMNA mutations lead to at least a dozen of distinct
phenotypes in humans, ranging from progeria to cardiomyopathy.12 Furthermore, compounding the limitations of the
model organisms in properly representing the human disease
is the enormous genetic diversity of mankind, the magnitude
of which has only recently been recognized.13–15 Throughout
evolution, new mutations have occurred and continue to
occur at an estimated rate of about 10⫺8 per bp, which equals
about 30 new mutations per each generation.14 During the last
10 000 years, the rapid growth of our population has led to
considerable expansion of new alleles, which are, as would be
expected, restricted to humans and not found in model
organisms. The majority of these new DNA sequence variants
might not have significant phenotypic consequences, but a
considerable number of them would be expected to influence
phenotypic expression of diseases. Moreover, considering
that the evolutionary selective filtering takes time to apply,
the new alleles are typically spared from such filtering and
hence are more likely to be pathogenic than the ancient
alleles. Accordingly, the human-specific alleles would be
expected to exert substantial effect sizes on the disease
phenotype. This is in contrast to ancient alleles, shared
between humans and model organisms, which have been
subjected to evolutionary selective pressure in eliminating
those with severe phenotypic effects. Consequently, genetic
dissimilarities between humans and model organisms are
phenotypically more consequential than genetic similarities.
358
Circulation Research
August 5, 2011
Table 2. Partial Resemblance and Dissociation of the Phenotype From the Human Disease Phenotype in Selected Animal
Models of Cardiomyopathies
Animal Model
Expected Disease Model
Phenotypic Similarity to
Human Disease
Unclear Phenotypic
Similarity to Humans
Phenotypic Dissimilarity to
Human Disease
␤-Myosin heavy chain:
Q403 transgenic rabbit17–20
Hypertrophic cardiomyopathy
Hypertrophy, myocyte disarray,
fibrosis, preserved global
systolic function but regional
dysfunction
Reduced Ca⫹2 sensitivity of
myofibrillar ATPase activity
(human phenotype unknown)
Higher incidence of systolic
dysfunction in old animals,
statins prevented and
reversed cardiac phenotype
in transgenic rabbits but
had no or minimal effects
in humans
Cardiac troponin T:
Q92 transgenic mice21
Hypertrophic cardiomyopathy
Enhanced systolic function,
fibrosis
Enhanced Ca⫹2 sensitivity
myofibrillar ATPase activity
(human phenotype unknown)
Smaller hearts, smaller
cardiac myocytes (no
cardiac hypertrophy in
transgenic mice)
Dilated cardiomyopathy
Cardiac dilatation and
dysfunction, fibrosis
Reduced Ca⫹2 sensitivity
myofibrillar ATPase activity
(human phenotype unknown)
Arrhythmogenic right
ventricular cardiomyopathy
Fibrosis, excess adipocytes,
cardiac dysfunction
Cardiac troponin T:
W141 transgenic mice21
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Cardiac-restricted deletion
of desmoplakin22
Adiposis is relatively mild,
polymorphic as opposed to
monomorphic ventricular
tachycardia
Note: The author apologizes for not including a large number of animal models of cardiomyopathies that others have generated and characterized. The purpose
is to avoid potential misinterpretation of others’ data or criticizing them without detailed knowledge.
Moreover, there is considerable genetic variability across
strains of every model organism, as best documented by
sequencing genomes of 15 mouse strains (http://www.niehs.
nih.gov/research/resources/collab/crg/index.cfm). Thus, differences among the strains of the same species further
compound the efforts to model the human disease phenotype.
The emphasis on genetic differences between humans and
model organisms is only one facet of the differences that
restrict the utility of the model organisms in modeling the
human phenotype. The disease phenotype is the consequence
of stochastic and typically nonlinear interactions among
various constituents, which are composed of complex intracellular and extracellular causal fields. The causal fields
interact through complex networks that link the etiologic
constituents, such as DNA sequence variants, epigenetics,
microRNAs, long noncoding RNAs, splice variants, posttranslational modifications of proteins, and metabolites, as
well as the environmental factors including microbiome.
Considering the presence of 23 500 protein-coding genes and
more than 4 million DNA sequence variants in each human
genome, more than 1000 microRNAs, several hundred metabolites, and a large number of yet-to-be characterized
determinants, the complexity of the interactomes that ultimately determine the disease phenotype, is limited only by
one’s imagination.16 Simply based on the genetic differences
between model organisms and humans, let alone other causal
fields, it is clear that the etiologic interactomes in any model
organism would not be identical to interactomes that determine the phenotype in humans. Hence, no model organism is
expected to faithfully replicate the human disease phenotype.
At best, it might exhibit some resemblance to the components
of the disease phenotype in humans (Table 2). Considering
this inherent limitation, it will not be surprising but rather
somewhat anticipated that the “translational” findings in the
model organisms would not always effectively translate to the
human phenotype.
The judicious words of Sir William Osler, the father of
modern clinical medicine, that no two humans have the same
disease, are best reflected by our inability to exploit the group
data, whether clinical or genetic, to predict the phenotype in
a single individual. Interindividual differences in expression
of a disease state are well appreciated and very much form the
essence of population genetic studies. Perhaps the scientific
society might have opted to remain heedless of the limitations
of the model organisms in correctly replicating the human
disease phenotype. As stated earlier, contributions of model
organisms to our understanding of generalizable fundamental
processes are irrefutable. To decipher complex biological
enigma, gathering data from multiple sources and origins is
essential, as advocated by Edward O. Wilson in “Consilience:
The Unity of knowledge.” As for specificity, however, no
organism would accurately model the human disease. Patsy,
the honest assistant to King Arthur, is perfectly on the mark
by whispering: “It is only a model.”
Sources of Funding
This work was supported by NHLBI (R01-088498), NIA (R21
AG038597-01), a Burroughs Wellcome Award in Translational
Research (No. 1005907), and the TexGen Fund from Greater
Houston Community Foundation.
Disclosures
None.
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KEY WORDS: cardiomyopathy
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genetics
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humans
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mouse
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mutation
Modeling Human Disease Phenotype in Model Organisms: ''It's Only a Model!''
Ali J. Marian
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Circ Res. 2011;109:356-359
doi: 10.1161/CIRCRESAHA.111.249409
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