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Jan 1, 2009 (Vol. 29, No. 1)

High-Content Screening Rapidly Evolving

Researchers Are Currently Focused on Assay Development and Data Analysis

  • Data Analysis

    Stephan Heyse, GM of screening informatics at Genedata, will focus on the current point of pain for screeners—the systemic processing, analysis, and management of HCS data. According to Heyse, the focus of data analysis has broadened beyond image analysis to the extraction of full sets of numeric data from multiple parameters. Genedata has made strides to enable this kind of analysis by helping researchers set the framework by which data is captured and processed via standard workflows, Heyse explains.

    “This is an iterative process where outcomes often can’t be predetermined, nor should they be,” Heyse notes. “We see unexpected compound effects all the time, which provide us with new inroads for how to ask the right questions in the next set of experiments or in a re-analysis of this data.

    “For example, when neurons are treated with a set of compounds, neurite outgrowth may occur. What’s the key outcome from this stimulus? Is this stimulus better quantified by determining neurite length or branching? When, in the process does the branching occur? Do the neurons branch and then die, pointing to a side-effect of treatment? Such new insights come from pursuing the iterative experiment—analysis process to completion.”

    The Screener platform from Genedata integrates with software packages from the HCS instruments on the market, providing an information-rich bidirectional bridge between imaging platforms enabling data integration and a backward review of original data and images associated with a well or compound, he adds. The Genedata framework for analysis is applicable for both HCS and HTS, ultimately bringing together high-quality results obtained from multiple screening technologies.

    At the conference, Dr. Heyse will be providing case studies that highlight best-practice workflows embodied in the Genedata Screener platform to capture data from instruments, process it in efficient ways, and interactively analyze the wealth of information from high-content screens.

  • End-User Perspective

    Click Image To Enlarge +
    Rat cerebellar granule that Novartis uses in assays for neurite outgrowth and for cellular neurotoxicity.

    Marjo Simonen, Ph.D., lab head of the Novartis HCS facility in Basel, Switzerland, will provide insight on the end-user’s perspective. Her lab provides HCS screens for all the therapeutic research groups in the Basel site, including the oncology, neurobiology, and respiratory groups, wherever imaging data is an essential output for the screen.

    “We have been using HCS for compound screening since 2005 and are currently processing up to 250,000 compounds per screen,” says Dr. Simonen. “We use the InCell Analyzer 3000 for all our screens, and we’ll soon be adding a robotics system to allow for unattended screening work overnight and over the weekend to increase our throughput. We are hopeful that we’ll be able to do full library screens (>1 M compounds) in 2009.”

    This is not to say that Novartis has moved away from HTS—the company still performs biochemical and cell-based assay screens for many primary screens, but when imaging is the essential output needed by the therapeutic group, HCS is applied.

    “We perform the primary screen usually with singletons, then we validate the hits with a concentration response using quadruplicate samples. Usually we also perform counterscreens and secondary screens; sometimes only secondary screens for biochemical or other cellular screens,” Dr. Simonen adds. “We provide our customers analyzed data, IC50, max activity, not raw data. The analysis of HCS data is more laborious than that of other screening data due to the several readouts. We have in-house software to analyze and visualize the numerical data. In addition, we just bought an Opera reader, which accepts 1,536-well plates. We hope to be able to run full screenswith this.”

    At Novartis, HCS is also used both in the upstream and downstream steps of the drug discovery process for target finding, compound profiling, SAR, and further understanding of the mode of action of a drug candidate.

    At the meeting, Dr. Simonen will present a case study on the development of an imaging assay to screen for inhibitors of copy-number variation (CMV) entry to normal human fibroblasts and human retinal pigmented epithelial cells. The assay exploits a genetically modified virus expressing a green fluorescent fusion protein (GFP) as part of its virion tegument. Upon successful entry, the GFP-tagged tegument protein translocates to the nucleus, permitting monitoring of virus infection. The assay monitors localization of the GFP tag to the nucleus and granularity of the cells as a measure of compound toxicity. The goal is to identify compounds that block translocation of the tag without inducing toxicity in the cells.


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