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High-Content Cell-Based Imaging


By Robert M. Frederickson

April 14, 2006 | Drug development is an expensive business. Millions of dollars can be spent on the design of a drug to hit a target of interest, only to find that the drug fails when tested in living systems. Failure of compounds occurs most often because of toxicity and a poor understanding of its systemic effects. Because of this, a challenge for drug makers is to design assays during the discovery and development process that are more predictive of a compound or disease target’s “druggability.”

The response has been to move assays into living cells earlier in the process, so as to complement in vitro and biochemical assays that have been the mainstay of early development. Assays performed in cells or tissues offer the possibility of monitoring a more complete set of biological parameters to a particular compound, and are thus considered “high-content” analyses.

High-content analysis can be applied to all stages of the drug discovery process and is well suited to tracking the intracellular processing, localization, and movement of fluorescently labeled molecules such as proteins. Another key attribute is the ability to follow many targets simultaneously, such as multiple components of a signaling pathway of interest. In addition, monitoring the activity of membrane proteins and a cell’s electrophysiological response can provide information that standard high-throughput biochemical analysis simply cannot tackle. Importantly, single cells can be monitored, providing greater subtlety in the evaluation of the variability of the response to a particular drug or treatment.

Increasingly, equipment providers are incorporating modules for high-content and single-cell analyses into their drug discovery platforms. In addition, new strategies and equipment designs are bringing new types of analysis into the drug discovery marketplace. Major players include Cellomics (a unit of Fischer Biosciences), Molecular Devices (including former Axon Instruments), GE Healthcare, BD Biosciences (including former Atto Bioscience), Evotec Technologies, and Caliper, who recently partnered with Xenogen (see last month’s column).

Evotec Technologies and Cellomics recently announced that they have entered into a worldwide, nonexclusive patent license agreement. The agreement provides Evotec access to Cellomics’ core High Content Screening (HCS) patent portfolio, which includes specific classes of HCS assays such as cytoplasm-nuclear translocation, characterization of cellular toxicity, and receptor internalization.

Complementary Platforms

Evotec and Cellomics are also collaborating to develop and market HCS platforms incorporating Cellomics’ and Evotec products as integrated solutions. The companies also aim to facilitate two-way data flow between their complementary platforms and access to enterprisewide data storage, management, and analysis.

Cellomics’ HCS assays will become compatible with Evotec’s Opera system, which is complementary to Cellomics ArrayScan instrument. The Opera system is a confocal microplate imaging reader for automated high-speed and high-resolution screening in high-throughput biology. Its major areas of use are in cell screening at subcellular resolution and bead-based screening applications from conventional plate formats to the nanoplate scale. The Cellomics platform includes automated imaging instruments such as ArrayScan and KineticScan HCS Readers and the cellWoRx High Content Cell Analysis System, which are currently in use at multiple sites within the top 15 pharma companies.

Evotec has also recently announced the next generation of its Cytocon platform for analysis of individual living cells. The lab-on-a-chip device employs electric fields combined with flow to move, trap, separate, and guide cells through the chip. The compatibility with any inverted microscope allows for a wide range of single cell analyses. The Cytocon 400 system is now equipped with an automated radio frequency chip driver addressing 32 individual channels using up to 12 individual phases. This allows for semi-automated single cell trapping and orientation in any direction, cell sorting, cell filtration, electroporation, and electrofusion. Fewer than 100 cells can be easily processed using the low-volume sample injector. Applications include single cell sorting and imaging, kinetics studies, stop-flow analysis on the single-cell level, and continuous filtering of cell samples.

 

E-mail Robert M. Frederickson at mrfreder@yahoo.com.

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