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Modeling human diseases: an education in interactions and interdisciplinary approaches.

Zon L - Dis Model Mech (2016)

Bottom Line: The selection of a suitable model system is a crucial step in research design.Factors to consider include the accuracy of the model as a reflection of the human disease under investigation, the numbers of animals needed and ease of husbandry, its physiology and developmental biology, and the ability to apply genetics and harness the model for drug discovery.In my lab, we have primarily used the zebrafish but combined it with other animal models and provided a framework for others to consider the application of developmental biology for therapeutic discovery.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Stem Cell Program and Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA 02138, USA zon@enders.tch.harvard.edu.

No MeSH data available.


Models that have been used in the Zon lab. Key attributes of different animal models used for the study of human diseases are highlighted.
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DMM025882F2: Models that have been used in the Zon lab. Key attributes of different animal models used for the study of human diseases are highlighted.

Mentions: Our early zebrafish work included the discovery of five previously undescribed human blood diseases, based on the analyses of mutant fish found by ENU mutagenesis screens (North and Zon, 2003). The human orthologs of zebrafish genes mutated in our anemic mutants were found to be the causative genes in several newly described human diseases. We also uncovered many findings that defined the process of blood development and gave insight into cancer formation. Using chemical screening, we were able to pinpoint two drugs that made it from the initial assay in embryos to successful testing in adults and, ultimately through to a human clinical trial. In the first case, we found that prostaglandin E2 (PGE2) can increase the number of stem cells in the developing aorta and also expand hematopoietic cells upon transplantation in adult zebrafish (North et al., 2007). We had thus discovered the first small molecule to increase a stem cell pool, with implications for the treatment of individuals with bone marrow failure and following bone marrow transplantation. From publication of the initial findings through to Phase II clinical trial – still ongoing – the route to translation has taken almost 10 years (Fig. 1). This is slightly faster than traditional drug development by pharma but still leaves an opportunity to accelerate the process. In another study, we examined the ability to block neural crest development as a potential therapy for melanoma (White et al., 2011; Phillips and Westerfield, 2014). This led to the discovery that leflunomide, a drug commonly used to treat arthritis, could eliminate neural crest development based on transcriptional pausing. Additional studies in other animal models were required in both of these cases to be able to bring the basic findings to the clinic (Fig. 2).Fig. 1.


Modeling human diseases: an education in interactions and interdisciplinary approaches.

Zon L - Dis Model Mech (2016)

Models that have been used in the Zon lab. Key attributes of different animal models used for the study of human diseases are highlighted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4920153&req=5

DMM025882F2: Models that have been used in the Zon lab. Key attributes of different animal models used for the study of human diseases are highlighted.
Mentions: Our early zebrafish work included the discovery of five previously undescribed human blood diseases, based on the analyses of mutant fish found by ENU mutagenesis screens (North and Zon, 2003). The human orthologs of zebrafish genes mutated in our anemic mutants were found to be the causative genes in several newly described human diseases. We also uncovered many findings that defined the process of blood development and gave insight into cancer formation. Using chemical screening, we were able to pinpoint two drugs that made it from the initial assay in embryos to successful testing in adults and, ultimately through to a human clinical trial. In the first case, we found that prostaglandin E2 (PGE2) can increase the number of stem cells in the developing aorta and also expand hematopoietic cells upon transplantation in adult zebrafish (North et al., 2007). We had thus discovered the first small molecule to increase a stem cell pool, with implications for the treatment of individuals with bone marrow failure and following bone marrow transplantation. From publication of the initial findings through to Phase II clinical trial – still ongoing – the route to translation has taken almost 10 years (Fig. 1). This is slightly faster than traditional drug development by pharma but still leaves an opportunity to accelerate the process. In another study, we examined the ability to block neural crest development as a potential therapy for melanoma (White et al., 2011; Phillips and Westerfield, 2014). This led to the discovery that leflunomide, a drug commonly used to treat arthritis, could eliminate neural crest development based on transcriptional pausing. Additional studies in other animal models were required in both of these cases to be able to bring the basic findings to the clinic (Fig. 2).Fig. 1.

Bottom Line: The selection of a suitable model system is a crucial step in research design.Factors to consider include the accuracy of the model as a reflection of the human disease under investigation, the numbers of animals needed and ease of husbandry, its physiology and developmental biology, and the ability to apply genetics and harness the model for drug discovery.In my lab, we have primarily used the zebrafish but combined it with other animal models and provided a framework for others to consider the application of developmental biology for therapeutic discovery.

View Article: PubMed Central - PubMed

Affiliation: Howard Hughes Medical Institute, Stem Cell Program and Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA 02138, USA zon@enders.tch.harvard.edu.

No MeSH data available.