The Biochemical Group of the American Chemical Society (New York Section) and the Biochemical Pharmacology Discussion Group
Beasts in the Genomic Jungle: Use of Model Organisms in Drug Discovery
Posted June 13, 2007
Animal models have become a crucial discovery and testing ground for pharmaceutical research, enabling scientists to screen compounds, validate drug targets, and assess potential toxicity. A January 23, 2007, symposium of the Biochemical Pharmacology Discussion Group showed how a variety of model organisms—particularly mice, the fruit fly Drosophila melanogaster, the roundworm C. elegans, and the zebrafish Danio rerio—are playing important roles in drug discovery and evaluation. Speakers described strategies they have used to leverage the power of animal models, and some promising findings they have produced related to neurodegenerative diseases, diabetes, various cancers, cardiovascular disease, and cystic fibrosis, as well as important toxicological information. The event also featured a special presentation from Princeton University's Lee Silver, who addressed prospects of targeted gene enhancement and the development of multiple human species.
Carroll PM, Fitzgerald K, eds. 2003. Model Organisms in Drug Discovery. Wiley, Hoboken, NJ.
Silver LM. 2006. Challenging Nature: The Clash of Science and Spirituality at the New Frontiers of Life. Ecco Press, New York.
Silver LM. 1998. Remaking Eden. Harper Perennial, New York.
Silver LM. 1995. Mouse Genetics: Concepts and Applications. Oxford University Press, New York.
Phenotype Pfinder: The Case for Comprehensive Phenotyping of Knockout Mice
Zambrowicz BP, Sands AT. 2003. Knockouts model the 100 best-selling drugs: will they model the next 100? Nat. Rev. Drug Discov. 2: 38-51.
Drosophila in Drug Discovery: Genes, Pathways and Compounds
Hao L, Garza D. 2003. Drosophila as a Tool for Drug Discovery. In: Model Organisms in Drug Discovery. Carroll PM, Fitzgerald K, eds. Wiley, Hoboken, NJ.
Iijima K, Liu HP, Chiang AS, et al. 2004. Dissecting the pathological effects of human Aβ40 and Aβ42 in Drosophila: a potential model for Alzheimer's disease. Proc. Natl. Acad. Sci. USA 101: 6623-6628. FULL TEXT
Kornbger TB, Krasnow MA. 2000. The Drosophila genome sequence: implications for biology and medicine. Science 287: 2218-2220.
C. elegans in Drug Discovery: High-throughput Chemical GeneticsBenzer S. 2002. Nature's gift to science. Nobelprize.org. (Sydney Benzer's Nobel Prize lecture – PDF, 47 KB)
Link EM, Hardiman G, Sluder AE, et al. 2000. Therapeutic target discovery using Caenorhabditis elegans. Pharmacogenomics 1: 203-217.
Westlund B, Stilwell G, Sluder A. 2004. Invertebrate disease models in neurotherapeutic discovery. Curr. Opin. Drug Discov. Devel. 7: 169-178.
The Zebrafish as Disruptive Technology for Drug Discovery and Development
Dahm R. 2006. The zebrafish exposed. American Scientist (September/October). FULL TEXT
Peterson RT, Shaw SY, Peterson TA, et al. 2004. Chemical suppression of a genetic mutation in a zebrafish model of aortic coarctation. Nat. Biotechnol. 22: 595-599.
Peterson RT, Fishman MC. 2004. Discovery and use of small molecules for probing biological processes in zebrafish. Methods Cell Biol. 76: 569-591.
Zon LI, Peterson RT. 2005. In vivo drug discovery in the zebrafish. Nat. Rev. Drug Discov. 4: 35-44.
Model Systems to Study Small Molecule Suppression of Premature Stop Mutations
Bedwell DM, Kaenjak A, Benos DJ, et al. 1997. Suppression of a CFTR premature stop mutation in a bronchial epithelial cell line. Nat. Med. 3: 1280-1284.
Howard M, Frizzell RA, Bedwell DM. 1996. Aminoglycoside antibiotics restore CFTR function by overcoming premature stop mutations. Nat. Med. 2: 467-469.
Lee M. Silver, PhD
Lee Silver is professor of molecular biology and public affairs at the Woodrow Wilson School of Public and International Affairs at Princeton University. He is the author of several books, including Remaking Eden and Challenging Nature, and has written for The New York Times, the Washington Post, Time, and Newsweek International. Silver has been elected a lifetime fellow of the American Association for the Advancement of Science, and he received a prestigious MERIT Award for outstanding research in genetics from the National Institutes of Health. Silver holds a PhD in biophysics from Harvard University and lives with his family in New Jersey and New York.
Sandra Engle, PhD
Sandra Engle is a principal scientist in the Genetically Modified Models Center of Emphasis at Pfizer Inc. She received a BA in biology from Ball State University and a PhD in medical and molecular genetics from Indiana University School of Medicine. She has contributed to the generation and characterization of numerous genetically modified mouse models in academic and pharmaceutical settings.
Dan Garza, PhD
Dan Garza is an expert in Drosophila genetics and a member of the Developmental and Molecular Pathways Division at the Novartis Institutes for Biomedical Research in Cambridge, MA.
Ann Sluder, PhD
Ann Sluder has over 20 years of academic and industrial experience in basic and applied genetics and comparative genomics. She obtained a PhD in Drosophila biochemistry at Duke University, completed a postdoctoral fellowship in C. elegans genetics at Harvard Medical School and Massachusetts General Hospital, and was a professor of cellular biology and genetics at the University of Georgia before joining Cambria Biosciences. At Cambria, Sluder has directed the expansion of the company's compound screening, mechanism of action, and target validation programs, in addition to managing external partnerships in parasiticide and neurotherapeutic discovery.
Randall Peterson, PhD
Randall Peterson is an assistant professor of medicine at Harvard Medical School, an assistant professor of biology at Massachusetts General Hospital, and an associate member at the Broad Institute. His research focuses on chemical and genetic approaches to studying diseases of the blood and the circulatory system. His group uses high-throughput chemical screens in intact zebrafish to identify small molecules that perturb normal development or that suppress disease phenotypes in zebrafish disease models. With these small molecules, his laboratory can investigate different biological processes, including arterial-venous fate specification, cardiac chamber patterning and hematopoietic differentiation. In addition, some of the disease-suppressing compounds with therapeutic potential can be further studied using zebrafish and mammalian models of disease.
David Bedwell, PhD
David Bedwell is a professor in the Department of Microbiology at the University of Alabama at Birmingham. He and members of his laboratory are working to understand the mechanistic details of translation termination in eukaryotes. Using a combination of genetics, biochemistry, and cell biology in a yeast experimental system they hope to better explain the molecular details of how these processes are carried out. Also part of this effort is work to discover whether pharmacological agents can be used to suppress premature stop mutations that cause human diseases such as cystic fibrosis (CF) and Hurler syndrome.
John Galbraith Simmons
John Galbraith Simmons is a nonfiction author, novelist, and journalist who writes about science and medicine for popular and professional audiences. He is the author of The Scientific 100, which profiles one hundred of the most influential scientists in history, and Doctors and Discoveries: Lives that Created Today's Medicine.