Advancing Disease Modeling in Animal-Based Research in Support of Precision Medicine Proceedings of a Workshop (2018) / Chapter Skim
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3 The Promise and Perils of Animal Models
3 The Promise and Perils of Animal Models
Pages 26-50
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(Burgess) • New approaches to animal modeling, such as co-clinical trials, can improve the usefulness of animal models and their transla tion to human health.
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Subsequent presentations focused on new approaches to disease modeling, including devel oping "non-model" model systems and new modeling platforms. MOUSE MODELS Introduction to Model Organisms David Valle introduced workshop participants to the five most commonly used model organisms for research: Escherichia coli (bacterium)
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Using mouse models allowed researchers to have complete control over the diet and to observe retinal degeneration at a much faster pace. Despite differences in eye structure between mice and humans, researchers were able
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All of the data, as well as the mouse models themselves, are open source and available for researchers to use. For example, programs collecting data from vast numbers of patients -- such as the 100,000 Genomes project -- can use the IMPC data to provide information on gene function, to validate potential gene–phenotype relationships, and to perform synergistic analyses with the multidimensional genetic and phenotypic data that are collected.
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• Revelations about pervasive sexual dimorphism • Opportunities for the identification of new gene and phenotype to elicit novel biological mechanisms • Insights into human disease from the analysis of mouse lethal (es sential) genes The IMPC project is a substantive step toward a comprehensive catalog of mammalian gene function, Brown said.
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The phenotype information often helps to identify the reasons the mice die, said Dickinson, but in some cases the reasons remain completely unknown. Fully understanding the defects of these embryos is valuable for identifying mechanistic relationships between genes and development, and understanding potential implications for human disease, said Dickinson.
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Precision Mouse Models Robert Burgess, principal investigator of the Jackson Center for Precision Genetics, started his presentation by asking, "What are we modeling precisely? " There are three different ways in which an animal can model a human phenotype or disease: face validity, construct validity, and predictive validity.
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The patient mutation was introduced into the mouse genome using CRISPR/Cas-9, and a control model with the wildtype sequence was also created. Researchers found that the patient mutation did cause a dominant axonal neuropathy in the models, while the control mice were normal.
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SOURCE: Burgess, slide 13. FIGURE 3-1: Genetic Background of Mouse Models SOURCE: Burgess slide 13
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FIGURE 3-2: Idealized Mouse Models inbred murine strain has idiosyncrasies, and that testing on multiple back Source- burgess slide 14 grounds can help expose the potential degree of variability in response to treatment, can reveal how robust the treatment is, and can improve predictive validity. He said that testing 1,000 C57 black 6 mice is similar to testing 1 C57 black 6 mouse 1,000 times, making it difficult to extrapolate findings.
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There are a number of resources available for monodelphis research, including a well-annotated genome, husbandry guides, transcriptome libraries, a well-established embryology guide, and the OpossumBase website, which contains genetic and genomic data for the species. The research that Maier presented focused on the development and evolution of the limbs.
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In conclusion, Maier said that opossums are an excellent model for biomedical and evolutionary questions, and that advances in genetic modification of the species will make the opossum an even more useful species for research. Precision Pathology Keith Mansfield, director of Discovery and Investigative Pathology at Novartis Institutes for Biomedical Research, spoke to workshop participants about using molecular pathology to evaluate animal models for precision disease modeling.
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Molecular pathology is frequently used in the clinical diagnosis and management of cancer patients and is one of the foundations of precision medicine. Mansfield's presentation focused on describing a few of the main molecular pathology techniques and tools and how they may relate to precision medicine.
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Mansfield noted that, in this case, genetically engineered organoids were better at reproducing the morphology than mouse models. Mansfield stressed that these differences between human and animal models do not mean that animal models are not useful, but that we need to understand how differences in morphology may impact the relevance of the disease in modeling human cancer.
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Future advances in the field of molecular pathology will build on the use of bioinformatics, particularly highly multiplex localization assays and computational interrogation of digital slide databases. Mouse Hospital Co-Clinical Trials John Clohessy, director of the Mouse Hospital/Preclinical Murine Pharmacogenetics Facility at Beth Israel Deaconess Medical Center and Harvard Medical School, presented a unique and promising approach in animalbased research for precision medicine.
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The mouse hospital's mission is to provide expertise in the design and implementation of preclinical trials to test new drugs in mouse models of human disease. By performing pre- and co-clinical trials with GEMMs and PDX models, researchers can determine which patients are more likely to respond to novel therapeutic agents, on the basis of their genetic makeup.
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The findings from the initial mouse trial are used to to screen
treatment strategy for the human patient, and at the same time, the initial outcomes of the human patient are used to inform the direction of research in the mouse models. Final outcomes from the mouse trial, along with in formation about how the human patient has responded to treatments, are used to optimize the treatment of the human patient.
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may present an opportunity to further the field of precision medicine. Through the Comparative Oncology Trials Consortium, COP facilitates clinical trials for pets with cancer at 22 veterinary teaching schools in North America.
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While dogs and humans are not always a perfect match, there are many types of cancer in dogs that are appropriate models for humans, said LeBlanc. Comparative oncology trials provide an iterative process where studies on dogs can inform studies on humans, and vice versa, with the overall gain in knowledge advancing the understanding of cancer and potential treatments, said LeBlanc (see Figure 3-4)
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In order to move precision medicine forward, comparative oncology researchers will need analytic tools and expertise to collect genetic information; LeBlanc noted that because they are not bound by privacy rules regarding human data collection, there is an opportunity to build a robust set of data in this area. LeBlanc discussed new funding initiatives from the National Cancer Institute (NCI)
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CHALLENGES OF USING ANIMAL MODELS FOR PRECISION MEDICINE Big Data Clinical care and research on humans and animals generate a huge amount of data, said Melissa Haendel, associate professor of medical informatics and clinical epidemiology at Oregon Health & Science University. There are data from individual patients regarding clinical phenotypes, -omics, socioeconomic factors, environmental exposure, and other factors; there are population-level data on population frequencies, disease correlations, risk statistics, and exposure data; and there are data stemming from model organism research.
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Using these data for diagnosis depends on the use of a fuzzy matching algorithm that compares patient genotypic and phenotypic data against similar data from human and model organism sources. Through this process, the algorithm may, for example, find that an ortholog of "Gene M" from a mouse with a similar phenotype might be a candidate for the disease of "Patient A." In addition to the new insight into a potential gene–phenotype association, this process also may result in collaboration between a clinician and a researcher, each of whom have expertise to share, said Haendel.
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She added that, in some cases, nontraditional organisms may be the best choice for a model -- for example, aged cats are good models for Alzheimer's disease, armadillos are a natural host of the myobacterium that causes leprosy, and pig eyes most closely resemble human eyes. Haendel said that she and her colleagues are currently working on new strategies to assess the suitability of different organisms for modeling specific phenotypes, so that organisms are not chosen simply because they are the ones "we happen to have in our basement." The Animal Rule and Appropriate Modeling Jens Kuhn, virology lead at the NIH/National Institute of Allergy and Infectious Diseases Integrated Research Facility (IRF)
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That is, the pathway of the disease may be the same in an animal model and in humans, but the animal model may not express the phenotype due to some other factor, for example, a stop codon. Kuhn concluded with a quote from Thomas Hartung: "If there was an animal model good enough to substitute for people we would not have a 92% failure rate in clinical trials" (Dolgin, 2013, p.
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. 1 million human genomes available and they are also fully characterized and span the entire spectrum of ethnicities." Kuhn said that in order to reach this future, researchers must start not with the practical and regulatory concerns about what is possible or acceptable, but instead by choosing the best animal model and the best approach for answering the scientific question at hand.
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