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CHAPTER 13: MOLECULAR DIAGNOSTIC TESTING

Jason Y. Park; Jason Wang

LEARNING OBJECTIVES

LEARNING OBJECTIVES

  1. Know key technology platforms for performing DNA-based clinical tests

  2. Learn specific examples of diseases that are tested by DNA-based technologies

  3. Recognize the future potential of DNA technology in the clinical laboratory based on recent historical developments

INTRODUCTION

The discovery of the structure of deoxyribonucleic acid (DNA) by Watson and Crick in 1953 revolutionized the science of genetics.1 Knowledge of the structure of DNA enabled a basic understanding of how genetic information is encoded and inherited. In addition, this discovery was the starting point of modern molecular diagnostic technology. Examination of the 60 years since the Watson and Crick publication shows an initially slow, but steady pace of innovation, leading to the sequencing of the first human genome (Table 13-1). In the 15 years since the completion of the first human genome draft, there has been an explosion of novel technologies which have been commercialized and implemented in the clinical laboratory. Here, we review the technologies, both old and new, that are utilized in today's clinical laboratory and give examples of their clinical utility in the pediatric population.

TABLE 13-1TIMELINE OF KEY EVENTS IN DNA TECHNOLOGY
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TABLE 13-1 TIMELINE OF KEY EVENTS IN DNA TECHNOLOGY
Year Event
1953 James Watson and Francis Crick's publication of the double helix structure of DNA
1977 Frederick Sanger invents DNA sequencing based on radioactively labeled chain-terminating inhibitors
1983 Kary Mullis invents polymerase chain reaction (PCR)
1986-87 Heat stable DNA polymerase (Thermus aquaticus) used for polymerase chain reaction31,32
1985-86 Leroy Hood invents DNA sequencing based on fluorescently labeled chain terminating inhibitors; Automated DNA sequencers commercialized by Applied Biosystems
1987 First thermal cycler for automated PCR, DNA Thermal Cycler TC1, commercialized by Perkin Elmer
1989 Carl Wittwer invents automated PCR based on capillary tubes with air-based temperature cycling; basis of the Lightcycler real-time PCR instrument commercialized by Roche33
1990 Human Genome Project begins
1991 Stephen Fodor invents photolithographic synthesis of high density peptide arrays; technology commercialized by Affymetrix
1996 ABI PRISM 7700 real-time PCR instrument commercialized by Applied Biosystems
1999 Nucleic acid detection in electrified alpha-hemolysin channels; precursor to synthetic nanopore sequencing
2000 Human Genome Project produces first working draft
2001 Solexa sequences the bacteriophage phiX-174 by massively parallel sequencing (aka sequencing by synthesis, foundation of the current Illumina next-generation sequencing technology)
2005 454 Life Sciences launches GS20, the first next-generation sequencer; 454 acquired by Roche in 2007 – 454 systems planned for discontinuation in 2016
2006 Solexa launches the Genome Analyzer; Solexa acquired by Illumina in 2007
2007 Applied Biosystems launches the SOLiD next generation sequencing system
2009 Pacific Biosciences launches single-molecule real-time sequencing (SMRT) platform, PacBio RS
2010 Ion Torrent Systems launches semiconductor-based DNA sequencing platform, the Ion Personal Genome Machine; Ion Torrent acquired by Life Technologies
2014 Illumina launches the HiSeq X ...

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