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Translational Medicine Animal Models Get Closer to Mimicking Humans Kate Marusina, Ph.D. Animal models contribute significantly to our understanding of molecular mechanisms underlying disease pathologies. However, few models predictably translate preclinical find- ings into what will happen in humans. Investigational drugs are able to cure mice from many diseases, but continue to fail in clinical trials. This fact is largely at- tributed to poor model designs that do not sufficiently reflect the pathophysiology of disease in humans. In addition, tremendous diversity of human genetic background, co- medications, dosing, timing of treatment, and many other factors greatly influence the treatment outcome. The new generation of animal models, described in this article, takes into consider- ation previous shortcomings. These models aim to reflect the human condition as closely as possible and to close the gap between translational research and the bedside. Inbred lab mouse strains with fixed and highly reproducible genotypes are a power- ful tool for genetic manipulation. Mouse embryonic stem cells are easily amenable to genetic modifications, and thousands of ge- netically modified mouse strains were devel- oped in the last 20 years. "And yet, the inbred lab strains proved to be a poor system for discovery of specific genes associated with a particular trait, such as obesity or high blood pressure," com- ments Gary A. Churchill, Ph.D., professor and principal investigator, The Jackson Lab- oratory. "This is a result of their limited genetic di- versity and large 'blind spots' largely devoid of genetic variations. We cannot resolve trait association at the level of an individual gene. "In contrast, human genome association studies map individual genes to traits with a high degree of accuracy, but this is not enough to make a conclusive disease diagnosis. "Therefore, discovery of a genetic basis of a complex trait required a radically new genetic strategy." Jackson Labs is a key participant in the NEWS Molecular Diagnostics > Akonni Gets $500K Grant for Microarray Film Dx Platform Akonni Bioystems was awarded a $498,780 Phase II SBIR Grant from the Na- tional Science Foundation to further de- velop its Lab-on-a-Film, which has been designed as an ultra-low-cost microarray film manufactured using an automated reel-to-reel production process. The firm claims the Lab-on-a-Film technology has the potential to allow the production of multiplexed microarray consumables for just a few dollars. The platform hinges on Akonni's TruArray™ gel-drop multiplex microarray technol- ogy, and is being designed to allow the production of a hands-free, end-to-end genetic testing system. Akonni's TruArray technology involves attaching capture probes covalently to an ultra-high surface area polymer backbone of discrete three dimensional gel-drops rather than a two-dimensional substrate. The firm says this means the individual gel drops behave as individual nanoliter, solution-phase test tubes, which negates the potential for unpredictable and/or uncharacterized artifacts arising from probe deposition directly on a two-di- mensional surface. > FDA Sanctions Roche's HSV IgG Assays FDA approved Roche's Elecsys (HSV) types 1 and 2 IgG assays for use on the cobas™ platform. The assays are for use with sexually active individuals and pregnant women as an aid to the pre- sumptive diagnosis of HSV1 or 2 infec- tion. Roche says the HSV tests are the first automated assays available for integrat- ed analyzer platforms, "which will enable labs to integrate efficient herpes testing into their existing workflow, " comments Randy Pritchard, vp of marketing at Roche Diagnostics. "The Elecsys HSV-2 IgG and HSV-3 IgG assays provide qualitative determination of IgG antibodies in serum or plasma. The tests are used with Roche's electro- chemiluminescence technology, and are approved for use on a range of systems, including the Elecsys 2010, cobas e 411, cobas e 601, cobas e 602, and Modular Analytics E170 analyzers. > Cervical Cancer Test Based on NIH's TERC Gene Marker Launched Quest Diagnostics reported the avail- ability of a new lab test that identifies molecular changes to cervical cells that increase the likelihood a woman may de- velop cervical cancer. According to Daniel M. Jones, M.D., Ph.D., medical director, cancer diagnos- tics services at Quest, "Testing for ab- normalities of the TERC gene is based on the most advanced scientific knowl- edge available of the molecular chang- es that turn cervical dysplasia into ma- lignancy. It can potentially act like a 'second opinion' for the thousands of women whose Pap and HPV test results produce an indeterminate picture of 52 | October 1, 2012 | genengnews.com | Genetic Engineering & Biotechnology News cancer risk each year." The Quest Diagnostics Cervical Cancer TERC test is based on the human telomer- ase RNA component (TERC) gene marker under a nonexclusive patent license from the NIH. > Beta Cell Loss Measurement Technology in Diabetes Licensed for Commercialization Islet Sciences exclusively licensed technology from Winthrop University Hospital that is complimentary to an early Beta cell destruction diagnostic that Islet Sciences licensed last month. The new technique is entitled "Method for Us- ing Probe Based PCR Detection to Measure the Levels of Circulating Demethylated Beta Cell Derived DNA as a Measure of Beta Cell Loss in Diabetes. " The novel technology "provides a non- invasive approach for detecting Beta cell death in vivo that may be used to track the progression of diabetes and guide its treatment, search scientist at Winthrop. " says Eitan Akirav, Ph.D., re- Q International Collaborative Cross (CC) proj- ect, with the goal to create new types of in- bred strains based on eight parents selected from the existing laboratory and wild strains. "CC mice demonstrate high levels of genetic diversity," continues Dr. Churchill. "Jackson Labs used this opportunity to take CC ideas to the next level." The same progenitor lines served as the parent lines for the JAX Diversity Outbred (DO) Population. This unique mouse popu- lation is maintained by a carefully designed outbreeding strategy. While still not as di- verse as humans, DO mice more accurately reflect human genetic architecture and may provide better insight into genetic mecha- nisms of human diseases. "The DO animals proved to be an excel- lent tool for mapping trait-associated loci to a higher level of resolution," says Dr. Churchill. See Animal Models on page 54 Population-based breast tumor model exhibits molecular variation reflecting that seen in human tumor populations. This RNA microarray profile of 107 tumors shows significant intertumor variation among tumor populations. Aveo Oncology