Modeling Human Disease Phenotype in Model Organisms
2011; Lippincott Williams & Wilkins; Volume: 109; Issue: 4 Linguagem: Inglês
10.1161/circresaha.111.249409
ISSN1524-4571
Autores Tópico(s)Bioinformatics and Genomic Networks
ResumoHomeCirculation ResearchVol. 109, No. 4Modeling Human Disease Phenotype in Model Organisms Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBModeling Human Disease Phenotype in Model Organisms"It's Only a Model!" Ali J. Marian Ali J. MarianAli J. Marian 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. Originally published5 Aug 2011https://doi.org/10.1161/CIRCRESAHA.111.249409Circulation Research. 2011;109:356–359IntroductionA 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. 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.Table 1. Selected Scientific Discoveries in Model Organisms That Have Been Recognized by the Nobel Prize in Physiology or MedicineModel OrganismDiscoveryNobel LaureateSaccharomyces 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)Mouse"Introducing specific gene modifications in mice by the use of embryonic stem cells"Mario R. Capecchi, Sir Martin J. Evans, Oliver Smithies (2007)The scene: Dr Brenner's officeVisiting scientist: By the way, where is your vivarium?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.6,7Evolutionary 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 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 genome-wide 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. 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.Table 2. Partial Resemblance and Dissociation of the Phenotype From the Human Disease Phenotype in Selected Animal Models of CardiomyopathiesAnimal ModelExpected Disease ModelPhenotypic Similarity to Human DiseaseUnclear Phenotypic Similarity to HumansPhenotypic Dissimilarity to Human Diseaseβ-Myosin heavy chain: Q403 transgenic rabbit17–20Hypertrophic cardiomyopathyHypertrophy, myocyte disarray, fibrosis, preserved global systolic function but regional dysfunctionReduced 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 humansCardiac troponin T: Q92 transgenic mice21Hypertrophic cardiomyopathyEnhanced systolic function, fibrosisEnhanced Ca+2 sensitivity myofibrillar ATPase activity (human phenotype unknown)Smaller hearts, smaller cardiac myocytes (no cardiac hypertrophy in transgenic mice)Cardiac troponin T: W141 transgenic mice21Dilated cardiomyopathyCardiac dilatation and dysfunction, fibrosisReduced Ca+2 sensitivity myofibrillar ATPase activity (human phenotype unknown)Cardiac-restricted deletion of desmoplakin22Arrhythmogenic right ventricular cardiomyopathyFibrosis, excess adipocytes, cardiac dysfunctionAdiposis is relatively mild, polymorphic as opposed to monomorphic ventricular tachycardiaNote: 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.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 FundingThis 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.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Ali J. Marian, MD, The University of Texas Health Sciences Center, 6770 Bertner St, Suite C900A, Houston, TX 77030. E-mail Ali.J.Marian@uth.tmc.eduReferences1. James J. Miescher's discoveries of 1869: a centenary of nuclear chemistry. J Histochem Cytochem. 1970; 18:217–219.CrossrefMedlineGoogle Scholar2. Avery OT, MacLeod CM, McCarty M. Studies on the chemical transformation of penumococcal type. 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August 5, 2011Vol 109, Issue 4 Advertisement Article Information Metrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.111.249409PMID: 21817163 Originally publishedAugust 5, 2011 KeywordscardiomyopathygeneticshumansmousemutationPDF download Advertisement Subjects Animal Models of Human Disease Genetically Altered and Transgenic Models Genetics
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