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Translational Medicine Animal Models Using DO mice, his team mapped a clus- ter of genes conferring sensitivity to doxy- rubicine, a common chemotherapy agent. Within the cluster, protective, susceptible and neutral alleles were identified. The Jack- son lab is collaborating with the National In- stitute for Environmental Health and Safety to identify susceptibility genes for other envi- ronmental pollutants. "We hope that in the future these results will support toxicology analysis of human therapeutics," says Dr. Churchill. Linking Genotype with Phenotype "Genetics of the outbred mouse popula- tion seem to provide theoretical consistency with human population," agrees Michael D. Hayward, Ph.D., group leader, Taconic (www.taconic.com). "However, it would be difficult to use such a population as a model to study func- tion of individual genes. Taconic fully recog- nizes the profound influence of the genetic background of inbred strains on the pheno- Continued from page 52 type. But we use this fact to our advantage to design our phenotyping methodology." The genetic background of lab mice may vary even between populations of the same strain maintained at different locations. Such sub-populations accumulate minor poly- morphisms, leading to "genetic drifts." To control for the background diversity in their phenotyping experiments, Taconic produces a litter of heterozygous progeny of a geneti- cally engineered mouse (knockout or trans- genic) that are congenic to a characterized background strain. The second cross of heterozygous lit- termates produces mice that are genetically identical except for the gene of interest. This approach is especially important to correlate for subtle phenotypical manifestations such as behavioral or psychiatric changes. To tease out these differences, Taconic developed what essentially represents a high- throughput screening of animal phenotypes in vivo. Marketed as "PhenoTac," the analy- sis platform is a panel of fully validated as- says representing several therapeutic areas of interest (i.e., obesity, diabetes, inflammation, neurology). "In contrast with traditional approaches that use a large number of mice to achieve statistical significance, we conduct PhenoTac assays in the same animals, which decreases the number of mice and associated breeding costs," continues Dr. Hayward. "To perform phenotypic assessment of each genetic modification on most of the major aspects of mouse physiology we need only 40 experimental animals and the same number of controls. This is 10 times less than what would be required otherwise. "Validation of our sequential strategy confirmed that the outcomes of the assays conducted later in the sequence are not af- fected by assays conducted in the beginning." Using its breeding approach and Pheno- Tac analysis, Taconic uncovered numerous clinically relevant phenotypes in laboratory strains with targeted and spontaneously oc- curring mutations. "Our next step is to harness the power of the platform to study novel therapeutic compounds," says Dr. Hayward. "In col- laboration with industry partners, we plan to characterize phenotypes of animals carrying selected human genes. Using this carefully de- signed strategy, genetically modified mice can provide information for drug development that is not practical using any other method." Hallmarks of Cancer Development "In the near future oncology therapy will be undergoing a paradigm shift," comments Murray Robinson, Ph.D., senior vp of re- search, Aveo Oncology (www.aveooncol ogy. com). "Physicians will have an ability to tailor therapy according to the tumor genotype and the gene-expression profile of each individu- al patient. Aveo is working on new animal models to support this emerging paradigm. Our approach is conceptually similar to the JAX Diversity Outbred mouse population. Only we create population-diverse tumors." ! Alike But Not the Same Innovative procedures set us apart: Premium quality with a competitive price. ! ! For 25 years the pharmaceutical industry has relied on DSM for innovative contract manufacturing solutions to deliver products of high quality. We offer you tailored technologies for manufacturing Biosimilars which enable: • 500 kg annual output on the footprint of ~ 2000 m2 # ! $ ■ ■ ! #" # $ $$$$ # $ ! ■ $$$$ $ "!!# $ "! $ # $ # $ "!!# $ # ! $" $#" $" $ "! " $ ! #$ "!!# $ # ! $"! $#" #$ $ #$ #$ $"$ $ "! #$ $ # ! $ $#" $ ! # "! #" #$ # ! $ #" $ #$ "! #$ $ $ $ $ # $ ! 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