Electrochemical DNA chip that is able to detect DNA at very low concentrations

Dec 6 2004

Toshiba Corporation has announced the development of a highly sensitive electrochemical DNA chip that is able to detect DNA at very low concentrations, a capability that will support advances in gene detection and analysis for individual treatment regimes, and the monitoring of healthy individuals for any predisposition to certain diseases.

The new chip integrates complementary metal oxide semiconductor (CMOS) circuits, one of the most widely used semiconductor-circuit technologies, with its sensors. The new chip is the latest addition to Toshiba's advanced line-up of DNA chips and related technologies, and immediate applications will include analysis of susceptibility to anticancer drugs and health monitoring for preventative identification of disease genesis.

DNA chips are increasingly used as a research tool to analyze single nucleotide polymorphisms (SNPs) and the expression of messenger ribonucleic acid (mRNA). Recent research indicates that analysis of the copy number of mRNA is more efficient in predicting susceptibility to anticancer drugs and indicating prognostic implications. This expression analysis requires more accurate, sensitive and reproducible DNA chips that support quantitative determination. Simplified genetic expression analyses using DNA chip system will open up new genetic testing market, targeting not only patients but healthy individuals.

As a leader in the development of DNA chips and related equipment, Toshiba promotes advances in all aspects of this important area of diagnostics. The company's achievements to date include a series of DNA chips, including chips developed in connection with hepatitis C treatment regimes, pharmacogenomics and diagnosis of rheumatism. The company has also developed a completely integrated DNA detection and analysis system that greatly facilitates the diagnostic progress. In developing its latest DNA chip, Toshiba concentrated on a solution that improved sensitivity.

Current DNA chips incorporate electrodes as sensors to detect DNA as an electrochemical current signal that is transmitted to an automated gene analyzer. When the concentration of sample DNA is low, the detected current signal is correspondingly low, and is also subject to interference from ambient noise when transmitted into the analyzer, resulting in incomplete gene analysis. As a consequence, current DNA chip systems require DNA amplification to a level sufficient for detection.

Toshiba's new DNA chip integrates a dedicated CMOS signal-detection circuit with each sensor. This structure minimizes signal loss due to external noise, even when the detected signal is low. The new chip also carries out on-chip amplification of the signal derived from the DNA prior to transmission, the process where most noise interference occurs. The robust performance achieved by the new chip facilitates quantitative analysis of DNA at much lower concentrations and allows a simplified DNA-amplification process. The ultimate target is advanced quantitative analysis that achieves high levels of sensitivity and precision, without any DNA amplification.

Toshiba's new chip also has other design advantages. Signal detecting circuits, which were implemented into the analyzer in Toshiba's earlier DNA-chip systems, are now fabricated on the chip substrate, an approach that reduces the overall size of the equipment. Similarly, integration of selector circuitry on the chip, not the analyzer, achieves reductions in the number of output terminals on the chip. This approach allows a single DNA chip to be used for multiple analyses, reducing the cost of the overall process.

Toshiba announced its first electrochemical DNA chip in October 2001, a device that used an original current detection method to support development of individual treatment regimes for patients infected with hepatitis C. The company continues to promote R&D in this important area of optimized personal medication regimes, and in July this year announced the development of a DNA chip that supports pharmacogenomics. Jointly developed with a team from the Graduate School of Pharmaceutical Sciences of Osaka University, led by Professor Junichi Azuma, the chip supports investigation of treatment efficacy and side effects for individual patients. This research covered six areas of illness: tuberculosis, digestive disorders, ademonia, hyperlipemia, cardiac arrest and cancer.

Also this year, Toshiba announced a DNA chip for patients with rheumatism, developed in collaboration with Professor Naoyuki Kamatani of Tokyo Women's Medical University. Based on genetic statistics, the new DNA chip can determine drug efficacy and the probabilities of side effects and complications for patients.

Alongside advances in DNA chips, Toshiba has also promoted advances in DNA analysis equipment. The five processes necessary for DNA detection and analysis—extraction, amplification, hybridization reaction, detection and identification—used to require dedicated, expensive equipment and complex manual handling, all of which confined testing to special facilities, such as clinical laboratories. In 2003, Toshiba combined the hybridization reaction, detection and identification processes into one device, and in September 2004 the company succeeded in integrating all five processes into a single device. This advance has promoted further equipment miniaturization, cost reductions, shorter time for analysis and can be used by technicians with less expertise in genetic testing. Toshiba will market this fully automated analyzer to medical facilities.