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History of Digital PCR Trisha Dhawan and Rémi Dangla 8/8/19

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History of Digital PCR Trisha Dhawan and Rémi Dangla 8/8/19 History of Digital PCR Trisha Dhawan and Rémi Dangla 8/8/19 Outline 1.1. PCR, the start of a revolution .......................................................................................... 1 1.2. Limit dilution PCR .......................................................................................................... 1 1.3. Digital PCR, a term coined by Vogestein and Kinzler ................................................... 2 2.1. PCR meets microfluidics ................................................................................................ 2 2.2. PCR in micro-droplets .................................................................................................... 3 3.1. Digital PCR in Microarrays ............................................................................................ 4 3.2. Digital PCR in Micro-droplets ........................................................................................ 4 Combining microarrays and microdropelts with Crystal™ digital PCR ............................ 5 Discussion ........................................................................................................................... 6 The origins of Digital PCR of template nucleic acid molecules, oligonucleotide primers, dNTPs, and a 1.1. PCR, the start of a revolution thermostable DNA polymerase. Over the years, The polymerase chain reaction (PCR) was ongoing development and application of the PCR invented by Kary Mulis while he was developing reaction enabled molecular cloning, engineered methods for detection of point mutations using transgenic organisms, DNA forensics, clinical oligonucleotides at Cetus Corporation, diagnostic DNA sequencing, among many California. The idea of PCR occurred to him additional innovative technologies. while driving through the Californian mountains In a traditional PCR reaction, the template on a Friday night in 1983. Contemplating the idea DNA is usually several nanograms’ worth that occurred to him, he reasoned that using two corresponding to millions of DNA molecules. oligonucleotides of different lengths instead of The template DNA is most often a heterogeneous one to bind to the upper and lower strands of the mixture of mutated alleles, plasmids, or genomes target DNA sequence and copying it several times depending on the application. Cancer is one of the using a polymerase enzyme would amplify the clinically relevant examples of this heterogeneity, target sequence manifold, and could then be where a relatively small quantity of template separated on a gel. He developed the method over DNA originating from cancer cells may harbor a the next few months using different temperatures, cancer-causing somatic mutation relative to the polymerases, and most importantly cycling the wild-type (WT) DNA. reaction multiple times, 30 cycles, to strengthen the signal without a background1. He later 1.2. Limit dilution PCR patented the technology and in 1987, Thermal In the early 1990s, several research groups began Cyclers were made commercially available by a exploring the possibility of diluting the template joint venture between Cetus and Perkin-Elmer. DNA to an extent such that, on average, any PCR forever revolutionized the field of molecular single PCR reaction contained only a single biology and clinical genetics. template molecule, a method named “limit A PCR reaction involves the exponential dilution PCR”. A key advantage of limit dilution amplification of a target polynucleotide sequence PCR is that each DNA molecule is amplified by repeatedly thermocycling a salt-buffered mix separately, killing interferences between template 1 molecules during PCR and greatly reducing PCR allowed the detection and quantification of background noise in complex samples. the targeted mutant DNA sequences in the Additionally, when many reactions are performed partitioned sample at this level of dilution, the frequency of positive Vogelstein and Kinzler named their and negative reactions follows the Poisson method “digital PCR”, in reference to the distribution and therefore allows for calculating classification of reactions as “zeros/negatives” or the abundance of the target molecule based on the “ones/positives” in a similar fashion to bits dilution factor. classification in computer science. 2 In 1992, Sykes et al. first described the concept The two scientists recognized the variety of digital PCR using the principles of limiting of potential applications of digital PCR, including dilution, PCR, and Poisson statistics to quantitate detecting somatic single nucleotide variants in the total number of rare leukemic cells in a cancer, chromosomal translocations, changes in population of normal cells. Other researchers gene expression, allelic discrimination, and allelic reported using versions of limit dilution PCR imbalance. In 1999, they also noted that the limit strategy to study, for example, variation among 3 4 of detection was defined by the number of single- HIV proviruses , human genomic haplotyping , template reactions that could be analyzed, paving and to quantify the fraction of leukemic cells in 5 the way for increased sensitivity of the patient samples . These publications are the first technology by using high-throughput platforms reports of digital PCR, from pioneers who such as 1,536-well plates, microarrays, and developed the method before it was even called beyond. digital PCR. The scientific community quickly recognized key 1.3. Digital PCR, a term coined by advantages of digital PCR over traditional end- Vogestein and Kinzler point or real-time PCR: does not rely on a In 1999, Bert Vogelstein and Kenneth standard curve; has improved accuracy; provides Kinzler6 recognized the urgent importance of absolute quantification; and offers improved detecting cancer-causing somatic mutations at an detection of low copy-number variants. Other key initial stage in clinical samples to enable early advantages of digital PCR became evident later, cancer diagnosis. Indeed, reliably detecting these as the method was used more broadly7: rare somatic mutations could help diagnose repeatability of assays, over time and across primary tumors in patients who are asymptomatic different labs; robustness and tolerance to PCR and whose disease is still curable. They also inhibitors. observed that detecting these mutations depended on isolating them from a large excess of WT DNA. PCR in Microfluidic Systems Vogelstein and Kinzler developed a strategy 2.1. PCR meets microfluidics based on limit dilution PCR to selectively amplify these rare mutations, distinguish them from WT, In the mid-1990s, advances in microfabrication and quantify the fraction of mutant alleles relative techniques had allowed the production of devices to WT. The dilution PCR strategy allowed one to with feature sizes as small a few microns. partition individual template molecules such that Micromachining, photolithography, and etching the resulting amplification was either completely silicon and glass substrates produced networks of mutant or completely WT. In practice, they flow channels that could sort reagents and diluted and partitioned the starting DNA template molecules, partition chemical reactions, and act into a 384-well plate, so that any given well as droplet generators for mixtures of aqueous and contained one-half genome equivalent on oil-based fluids. These microfluidic devices were average, i.e. half the wells contained one template well-suited for performing biochemical assays, molecule and half the wells contained zero such as single-cell assays, studies of template molecules. Subsequent amplification by 2 Figure 1. Reverse micelles in square channels. Photomicrographs show the transition from the 30 mm wide channel to the 60 mm wide channel. Respective pressures for the water and oil/surfactant (hexadecane_2% Span 80) are noted in the figure13. macromolecules e.g. proteins and nucleic acids, annealing, and primer extension temperatures and the polymerase chain reaction (PCR). appropriate for PCR11,12. The partitioning capabilities of In late 1999, the first commercial lab-on- microfluidic lab-on-chip devices were a-chip, the HP 2100 Bioanalyzer, was introduced particularly useful for PCR, where a by Hewlett-Packard’s Chemical Analysis Group, microenvironment allows for increased which shortly thereafter became Agilent. Based thermocycling speeds and increased reagent on Caliper Technologies’ LabChip, the 2100 was concentrations within the reaction mixture8. the first complete instrument that could perform Several groups developed integrated systems sample handling, separation, fragment sizing, utilizing microfabricated components of glass and quantitation, and digital data processing for PCR silicon to perform restriction enzyme digests, products, restriction enzyme digests, or RNA PCR, and electrophoresis within a single chip- samples. Following the HP 2100, other lab-on- based device9,10. These systems generally relied chip platforms were commercialized by on thermocapillary pumps to perform PCR in companies including Nanogen Inc., HandyLab nanoliter-sized droplets within micron-sized Inc., and Micronit Microfluidics among others. channels and included entry ports, heating elements, and DNA detectors. They did not 2.2. PCR in micro-droplets require any novel hardware, biochemistries or By the early 2000s, water-in-oil DNA detection methods; rather, they simply emulsions were being studied for potential miniaturized existing components such as heaters applications designed to partition biological
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