Achieving Ultra-Sensitivity and High Reproducibility in Development of Next Generation DNA Microarray Base

Sep. 17, 2004

Achieving Ultra-Sensitivity and High Reproducibility
in Development of Next Generation DNA Microarray Base
Aiming for Innovations in Drug and Healthcare Field By Integrating
Nano- and Bio-Technologies --

Toray Industries, Inc. today announced that it has succeeded in developing the world's first next generation DNA microarray base that combines superior reproducibility features (high S/N ratio¹⁾) with a detected sensitivity that is up to 100 times higher than existing DNA microarray²⁾ bases. The technological concept for this DNA microarray base was built in collaboration with Prof. Gozoh Tsujimoto of Kyoto University Graduate School of Pharmaceutical Sciences, who is a leading authority for DNA microarrays and genomic drug discovery, and the effectiveness of this concept has been proven. This DNA microarray base is one of the successful outcome of the researches conducted at the New Frontiers Research Laboratory³⁾ which was established last year. Toray plans to investigate the conditions and infrastructure required for manufacturing this DNA array base within this fiscal year.

Toray is promoting the establishment of a business model having alliances with various research organizations, with a view to making this next generation DNA microarray base the de facto international standard. At the same time, the company is also aiming to commercialize DNA microarrays incorporating Toray's unique contents⁴⁾ within two years.

The most important characteristics of this microarray base are 1) ultra-sensitivity and 2) high reproducibility and these characteristics are expected to usher in numerous innovations (as a result of ripple effects) in the drugs and healthcare fields in the future as described below and also to contribute enormously to the development of these fields in the 21st century.

Ultra-sensitivity
The amount of DNA that can be extracted from specimens of human tissue or blood is generally about 0.1% or less of the total weight and currently it is necessary to perform procedures such as operation to extract sufficient amount (from tens of mgs to few grams) of samples, which is an enormous physical and mental strain on the patients. On the other hand, the next generation DNA microarray base will enable investigations and diagnosis even with the infinitesimal amount (few mgs) of samples extracted through biopsy⁵⁾, greatly reducing the physical and mental strain on the patients.
Furthermore, in the research on disease-related genes⁶⁾ linked to the causes or symptoms of diseases, analysis of genes “that are expressed only in infinitesimal quantities,” which has been gaining lots of attention recently as promising candidates for disease-related genes, currently requires numerous analytical steps such as time-consuming PCR⁷⁾ for amplification of the small amount of DNA. However, Toray's new DNA microarray base will significantly accelerate drug discovery research as many of these steps such as PCR can be eliminated or shortened.
High reproducibility
By succeeding in exponentially increasing the S/N ratio, the “correlation between the gene representation and extraction quantities,” or in other words the quantification, improves significantly and the responding genes can be extracted extremely accurately. This will lead to highly accurate assessments of items such as the degree of malignancy, prognosis (predicting the progress or the outcome of a disease) of critical diseases including cancer that until now was relying on experience, effectiveness of medications, side effects and ease of metastasis occurrence.

The effectiveness of the aforementioned technological concept has been proven by Prof. Tsujimoto of Kyoto University Graduate School of Pharmaceutical Sciences. The development of the DNA microarray base was achieved based on the three seminal cutting-edge materials and technology of (1) a base with special minute columnar structure array and superior material characteristics, (2) nano-level surface modification technology that significantly increases the quantity of the DNA fragments to be spotted and (3) the technology that actively promotes the reaction of the fixed DNA fragments to the specimen.

Also, the contents that are incorporated into the base will be the most important key for the realization of next generation DNA microarrays. Toray has been going forward with the acquisition of highly differentiated contents (cancer etc) and collaborated with about 10 doctors from the Kyoto University's Faculty of Medicine and Prof. Tsujimoto of the Graduate School of Pharmaceutical Sciences to search for contents. By combining these contents with the next generation DNA microarray base and the simultaneously progressing proteome analysis, Toray aims to develop DNA microarrays not only for testing and diagnosis but also for creation of innovative medications and tailor-made medicines⁸⁾.

Also, some parts of the aforementioned development have been done with the assistance of NEDO (New Energy and Industrial Technology Development Organization) through its “equipment development project based on integration of biotechnology and IT.”

[Notes]
1) S/N ratio
Signal-to-noise ratio. Strength of signal divided by strength of noise. When the ratio is 1, signal cannot be differentiated from noise and becomes non-detectable. When the S/N ratio is increased, there will be clear difference between signal and noise. Especially, if the noise level is lowered, even weak signals can be detected, and this has a large effect on (advantageous effect on high sensitivity) sensitivity. Currently, commonly available DNA microarrays have fluorescent material attached as a marker to expressed genes of the sample and unnecessary sample is washed off after combining the expressed genes with gene fragments attached to the base. The expressed genes are then detected by illuminating it with light having the same wavelength as the fluorescent material. Only the spots where the fluorescent-marked genes of the sample have combined will glow depending on the combined quantity thus enabling detection of signals.

2) DNA microarrays
DNA microarray is formed by spotting various types of gene fragments onto a base and is a tool that can be used to simultaneously measure the existence and quantity of various types of genes in a sample. The most common products use glass slides onto which genes are fixed and optical techniques and electrochemical methods are employed for detection. Currently the market is mainly limited to the genetic research field. The domestic market is considered to be worth 5 billion yen to 10 billion yen and the global market at several tens of billions of yen. The domestic market is expected to exceed 100 billion yen in the future when its usage expands into the fields of examination and diagnosis of diseases.

3) New Frontiers Research Laboratory, Toray Industries, Inc.
A research center established by Toray Industries, Inc. on May 16, 2003 with emphasis on biotechnology and nanotechnology. The development of the DNA microarray base is the successful outcome of research that integrated biotechnology and nanotechnology. Toray is continuing with its efforts to develop new technologies in the integrated field of biotechnology and nanotechnology and aims to develop and market innovative biotechnology tools for gene analysis as well as proteome analysis. Going forward, along with the utilization of such biotechnology tools, the company plans to put significant efforts into the research on development of the diagnostic method mentioned in this release, search for drug development targets and innovative therapies that addresses an even larger market.

4) Contents (Valid gene fragments)
Gene fragments that are identified to be intrinsically valid as diagnosis makers and disease-related factors. They are fixed onto the microarray as spots and work as the sensor for detecting specific genes in the sample. They indicate genes that are expressed in certain diseases or characteristic sequences that are part of such genes.

5) Biopsy
A procedure that removes a tissue sample by using needles, etc. Tissue is removed from the affected area and is evaluated under a microscope for the purpose of diagnosing the patient. For example, if a person with a stomach discomfort visits a doctor and the doctor, using an endoscope, finds lesions in the mucous membrane of the stomach, the doctor will insert forceps through the endoscope and remove part of the mucous membrane. This sample is taken to a pathologist who examines it under a microscope and performs the diagnosis.

6) Disease-related genes
Specific genes that are related to diseases and a collective term that denotes genes that are produced/increased/decreased due to genes related to the cause of disease or disease itself. Such genes are identified by analyzing the differences between the expressed genes of healthy persons and patients.

7) PCR (abbreviation of Polymerase Chain Reaction)
Existing DNA microarrays have drawbacks such as low reactivity to genes in a sample, insufficient sensitivity for detecting genes and large noise (irregular signals stemming from false reaction.) Therefore, a special amplification procedure called Polymerase Chain Reaction, or PCR is required to detect the targeted infinitesimal gene. Due to this, the use of currently available DNA microarrays is limited to research purposes. PCR is the most common method for amplification of DNA and it artificially synthesize short DNA fragments to combine with existing DNA fragments and amplify the DNA molecules by several hundreds to one million times. Though the reaction is conducted over several hours by combining reagents and through precision control of temperature, there are cases where the amplification differs depending on the type of DNA or cases where it may amplify an unwanted portion of the DNA.

8) Tailor-made medicines
Providing medication that is best suited to each patient by studying the genes that work inside of each patient and the individual differences in proteins such as enzyme and hormones and to administer prevention for certain illnesses or predict the receptivity of drugs.

Fig. 1 Features and Ripple Effects of Toray’s Next-Generation DNA Microarray Base

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