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BT-Biochip Platforms for DNA Diagnostics

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  BUSINESS BRIEFING: PHARMATECH 2003 The DNA microarray, as a form of biochip, hasrevolutionised biological enquiry, enabling highlyparallel assessment of the levels of gene expression, of polymorphism and of functional genomics(transcriptomic variation), all in a single experimentwhile surveying the complete genome of an organism.One evolutionary consequence of the DNAmicroarray is the diagnostic or prognostic biochip. Justas the DNA microarray has revolutionised molecular biology, so too does the biochip promise torevolutionise molecular diagnostics.Biochips, broadly defined, are measurement devicesthat incorporate a biological recognition componentinto or with devices that are prepared using thetraditional techniques of microlithography and newmicroarraying (spotting and in situ synthesis)technologies. Biochips share much in common withbiosensors but are distinguished from biosensors bythe use of microlithography fabrication techniquesin their production, hence chip. The few broadclasses of biochips essentially consist of microarrays(nucleic acids or proteins usually in high (>10,000)to medium (<1,000>100) density on glass), low(<100) density bioelectronic biochips and capillaryagarose chips. Microarrays are biochips but not allbiochips are microarrays. Biorecognition Moieties DNA, RNA and proteins (enzymes, antibodies,receptors, their functional fragments and their biomimetic equivalents), along with subcellular organelles, cells and tissues, are the substance of biorecognition used in biochips. Integrated with solidstate devices, these naturally occurring recognitionentities must be immobilised and stabilised properly.For this, ingenious schemes include the use of biomimetic surfactant bilayers, physical entrapmentand/or chemical coupling within hydrogel membranelayers, covalent coupling and cross-linking to and onsurfaces and localisation within self-assembledpolyelectrolyte layers. The goal is to harness theunique and highly specific recognition properties of biological molecules, whether discretely or as part of amore complex ensemble, so that they may be madefunctionally integral to an analytical device. Biodetection Methods The wide range of possible detection methods givesthe biochip its tremendous diversity. Among these areelectronic devices (such as field effect transistors),microelectromechanical systems (MEMS) devicessuch as cantilevers, simple metallic and semiconductor electrodes for electrochemical (amperometric,voltammetric and impedimetric) detection, opticaldevices including fibres and fibre bundles (for absorption, fluorescence, luminescence and chemi-luminescence), mass sensitive oscillating crystaldevices, thermal detection methods that measure heatsof recognition reactions, radio labelling and massspectrometry. Of course, certain detection modalitiesare better suited to near-patient or clinical diagnostics.This may be influenced by the instrument’s footprint,sensitivity, parsimony and by the relative ease withwhich the technology may be hardened, i.e. renderedrobust and independent. Also, certain detectionmodalities are better suited to small, medium or high-density array formats. This influences the number of targets that may be analysed simultaneously.Ultimately, the measurement modality must matchthe decision-making context of the diagnostic test andmust do so with regard to sensitivity, detection limit,response rate and throughput. Microarrays Microarray technology “promises not only todramatically speed up the experimental work of molecular biologists but also to make possible a wholenew experimental approach in molecular biology”.Microarrays, principally DNA and proteins (althoughorganelle, cellular and tissue microarrays areemerging), exploit an ordered, two-dimensionalpresentation of biorecognition entities, fluorescence or radio tagging of targets and scanning confocal or radioimaging of the recognition–target complex or product. To date, microarray technology, a largelysemi-quantitative analytical technique, has been mostvalued in the basic research arena as a hypothesis-generating technique. Studies using microarrays haveserved to advance understanding of the disease processand, as the technology evolves, it will become a toolfor clinical medicine, providing a rich source of  Anthony Guiseppi-Elie is Director of the Center for Bioelectronics,Biosensors and Biochips at VirginiaCommonwealth University (VCU) and also Professor of ChemicalEngineering, Professor of EmergencyMedicine and Affiliate Professor of Biomedical Engineering. He is alsoPresident and Scientific Director of ABTECH Scientific, Inc., a biomedicaldiagnostics company. ProfessorGuiseppi-Elie spent 15 years inintrapreneurial and entrepreneurialindustrial research and developmentbefore becoming a professor at VCUin 1998. His research interests arein engineered biosystems in theservice of health and medicine. Thisincludes bioelectrochemistry andbioelectronic devices, bioactivehydrogels, biosensors and biochipsfor biomedical diagnostics andhigh-throughput DNA/RNA screeningand analysis. Professor Guiseppi-Elieholds a Doctor of Science degree inMaterials Science and Engineeringfrom Massachusetts Institute of Technology (MIT), a Master of Sciencedegree in Chemical Engineeringfrom the University of ManchesterInstitute of Science and Technology(UMIST) and a Bachelor of Sciencedegree with majors in AnalyticalChemistry and Applied Chemistryfrom the University of the WestIndies (UWI). a report by Anthony Guiseppi-Elie Director, Center for Bioelectronics, Biosensors and Biochips, Virginia Commonwealth University Biochip Platforms for DNA Diagnostics Drug Discovery   BIOCHIPS 97  BUSINESS BRIEFING: PHARMATECH 2003 Drug Discovery   BIOCHIPS 98 information on disease susceptibility, diagnosis andprognosis. As a research tool, DNA microarrays havealready been used in the study of breat cancer,leucaemia, heart, blood vessel and lung disease, cysticfibrosis, human immunodeficiency virus, cancer,astrocytomas, toxicity and single nucleotidepolymorphisms. They have been used more broadly aswell to study  Arabidopsis thaliana , rat, yeast and Escherichia coli  genomes, mouse models and others.The evolution of microarrays is to use the informationgleaned from genomic microarrays in thedevelopment of pathway-specific, disease-state-specific or diagnostic/prognostic microarrays thatemploy smaller suites of genes in highly focusedassessments. This evolution towards so-called ‘themearrays’ has begun. SuperArray Bioscience Corporationhas developed the Human Th1-Th2-Th3 Gene Arraythat contains 96 genes relevant to understandinghelper T cell biology. These genes include thecytokines specifically expressed by both the Th1 andTh2 subtypes. The array also contains genes encodingtranscriptional factors that regulate the expression of these cytokines as well as other markers of CD4+ Tlymphocytes. Simple side-by-side hybridisation allowsrelative expression of these genes in experimentalribonucleic acid (RNA). Related products include: ã cancer drug-resistant and metabolic products; ã common cytokines; ã inflammatory cytokines and receptors; ã chemokines and receptors; and ã interleukins and receptors. IntelliGene™ DNA microarrays are medium-densitycDNAs arrayed on standard one inch by three inchglass slides for standard dual-colour analysis usinghigh-resolution fluorescent detection. Arrays targethuman cancer, human cytokines and endocrinedisruption, as well as cyanobacterial open readingframe,  Arabidopsis thaliana , mouse and Escherichia coli  gene analysis. This movement towards confocallyimaged, targeted microarrays is poised to competewith DNA biochips that use detection technologiesother than confocal fluorescence imaging. Because of the semi-quantitative nature of today’smicroarrays, the likely diagnostic arrays (biochips) of the future must be brought into a more quantitativeformat. Also, the diagnostic community will need toaccommodate decisions and interventions based onquantitative risk assessments, much like theenvironmental community does today. Opportunities for Biochip Diagnostics Opportunities for application of biochips are mostattractive in the area of human health. The researchand development investments, marketing, sales and distribution costs, given today’s models for development of technology-based companies, do notsupport similar opportunities in the environment,industrial or bioprocess sectors. The human healthsector presents opportunities for drug developmentin the following areas: ã near-patient (bedside); ã doctor’s office; ã clinical laboratory; and ã molecular diagnostics laboratory (hospital). Implantable biochips for physiological statusmonitoring (for example during long-duration spaceflights, on the battlefield and/or trauma care) of integrated systems wherein the diagnostic biochipsenses a suitable biomarker and triggers a correctiveresponse, for example the release of a drug, are alsoemerging. The current evolutionary status of biochiptechnologies –with many unit operations stillperformed off chip, the rigorous requirements for USFood and Drug Administration (FDA) approvals andthe laboratory requirements under the ClinicalLaboratory Improvement Act 1988 –suggests that,in the short term, diagnostic biochips are likely tohave more impact in the area of drug developmentthan in clinical molecular diagnostics.  Acknowledgements The author wishes to thank his collaborators Erin D Williams, S Brahim and A Deisingh and graduate studentsG S Taylor and Derk Bemeleit for their assistance. Additional Information This article is continued, with references and detailed discussionon diagnostic biochips and links to drug development, the impact and challenges for biochip diagnostics, and other issuesrelated to diagnostic biochips, in the Reference Section on the CD-ROM accompanying this business briefing.© 2003 Guiseppi-Elie  Biochips,broadly defined,are measurement devices that incorporate a biological recognition component into or with devices that are prepared using the traditional techniques of microlithography and new microarraying technologies.
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