Biochip Platforms for DNA Diagnostics

1. Biochip Platforms for DNA Diagnostics 許文馨 游崇善 許家維 陳彥如

2. Introduction • The DNA microarray is a form of biochip. • Level of gene expression, polymorphism, and functional genomics. • Biological recognition, microlithography(微影技術). • Biosensor. • High>10,000 ,100<medium<10,000 , low<100 Microarrary=biochips, but biochips!=microarrary

3. Biorecognition • Substance: DNA, RNA, protein, along with subcellular organelles, cells and tissues. • Biomimetic surfactant (界面活性劑)bilayers, physical entrapment, chemical coupling, localization within self-assembled polyelectrolyte(聚合電解質)layers. • Unique and highly specific recognition

4. Biodetection Methods • Microelectromechanical system(MEMS) • Optical devices • Mass sensitive oscillating crystal devices • Thermal detection • Radio labelling • Mass spectrometry

5. Biodetection Methods • Sensitivity • Detection limit • Response rate • Throughput

6. Microarrays Microarray technology “promises not only to dramatically speed up the experimental work of molecular biologists but also to make possible a whole new experimental approach in molecular biology”. 不只加快了實驗的速度，也提供了新的實驗方法，是分子生化實驗的一大進展

7. Microarray Microarrays, principally DNA and proteins (although organelle, cellular and tissue microarrays are emerging), exploit an ordered, two-dimensional presentation of biorecognition entities, fluorescence or radio tagging of targets and scanning confocal or radio imaging of the recognition–target complex or product. Microarray，原則上是DNA和蛋白microarray ，發展成一個排序的，2維的生化辨識的entity，以螢光或無線電標記目標，並且掃描共焦或無線電影相來確認目標化合物或產物

8. Microarray To date, microarray technology, a largely semi-quantitative analytical technique, has been most valued in the basic research arena as a hypothesis-generating(假設發展 )technique. Studies using microarrays have served to advance understanding of the disease process and, as the technology evolves, it will become a tool for clinical medicine, providing a rich source of information on disease susceptibility, diagnosis and prognosis.

9. As a research tool, DNA microarrays have already been used in the study of breast cancer, leucaemia(白血病), heart, blood vessel and lung disease, cystic fibrosis(囊胞性纖維症 ), human immunodeficiency virus, cancer, astrocytomas(神經膠質瘤 ), toxicity(毒物) and single nucleotide polymorphisms(單一多型核甘酸). They have been used more broadly as well to study Arabidopsis thaliana(阿拉伯芥), rat, yeast(酵母 ) and Escherichia coli(下痢性大腸桿菌) genomes(基因組), mouse models and others. The evolution of microarrays is to use the information gleaned(蒐集) from genomic microarrays in the development of pathway-specific, disease-state-specific or diagnostic/prognostic microarrays that employ smaller suites of genes in highly focused assessments. • 已被廣泛用來研究 預防 診斷 預測 各種疾病 走向 反應路徑 以及各種生物病菌的研究

10. Microarray • Because of the semi-quantitative nature of today’s microarrays, the likely diagnostic arrays (biochips) of the future must be brought into a more quantitative format.

11. O p p o r t u n i t i e s f o r B i o c h i p D i a g n o s t i c s Opportunities for application of biochips are most attractive in the area of human health. The research and development (R&D) investments, marketing, sales and distribution costs, given today’s models for development of technology-based companies, do not support similar opportunities in the environment , industrial or bioprocess sectors. 生物晶片在人類健康領域上的機會與應用是目前最吸引人的，反而在工業與生物加工區塊因為投資、成本與市場環境的關係比較沒有發展。

12. The human health sector presents opportunities for drug development in the following areas: near-patient (bedside); doctor’s office; clinical laboratory; and molecular diagnostics laboratory (hospital). 而生物晶片在以下地區有機會開發： 病人身邊 醫生辦公室 臨床實驗室 醫院分子診斷實驗室

13. in the short term, diagnostic biochips are likely to have more impact in the area of drug development than in clinical molecular diagnostics. • 短期內診斷型biochip 會被用在藥物預測開發 而不是臨床分子治療

14. Diagnostic biochips will feature prominently as the means for providing the critical molecular data for drug discovery. • SNPs application • 尋找致病基因 • 診斷及預測致病風險 • 藥物基因體學及新藥的發現 • 利用SNP與現有的基因診斷體系接軌，能加速檢驗醫學從表型診斷轉向基因型診斷，並預防藥物副作用，提高療效

15. Impact and Challenges for Biochip Diagnostics • Biochips Diagnostics major challenges • Acceptable clinical detection limits • Sensitivity and specificity • Dynamic range • Repeatability and reproducibility • Response time • Immunity from false positives and false negatives

16. Biochip diagnostics of competitive advantage • Higher throughput • This may reduce the overall cost per test performed • Smaller sample volume • Such as in some tumour biopsies • Integration of sample preparation • On the same biochip platform • Cost per test

17. The impact of diagnostic biochips in molecular diagnostics must await the results of further research and targeted development. • Millennium Predictive Medicine, Abbott Diagnostics, Bayer, Motorola Clinical Microsensor Systems, Nanogen, Inc. and ABTECH Scientific, are pursuing such diagnostic products actively.

18. Abbott Diagnostics

19. Bayer

20. ABTECH Scientific

21. Issues Related to Diagnostic Biochips 1.Software system 2.Appropriate complement of genes 3.Privacy rights 4.Powerful Databank

22. 1.Software system The absence of a standard format for compating and transferring microaarrar data has produced proposals to create a standard ‘language’ to facilitate the sharing of sata among scientists.

23. 2.Appropriate complement of genes An equitable and streamlined mechanism for licensing genes and allels would help to promote continued research,development and commercalization.

24. 3.Privacy rights • Are there adequate interventions or therapies for all conditions revealed by the screen? • Are the privacy rights of patients protected adequately? • Can adequate informed consent be obtained given the broad range of possible outcomes of the screen?

25. 4.Powerful Databank • Detailed health information(likely anomised or key-coded) in databank arepowerful and valuable tools to help understand and counteract disease process but raise questions of equitty of acess and parity of use in structuring enquiry for societal benefits.

26. Epilogue A key driver for a biochip diagnostic must be a business case that is linked to technology acquisition or development . Even though biochip platforms have a long way to go before being revolutionise all aspects of preventing,diagnosing and treating disease that traditional drug-based medicine cannot hope to accomplish.