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The Need for Cheaper and Faster DNA Sequencing

Next Generation Sequencing and Beyond

By

Updated September 08, 2013

The DNA Sequencing Market

According to Life Science Market research firm Decibio, the DNA sequencing market was just over one billion dollars in 2011 and it is expected to double by 2016. What's driving this development and growth in sequencing?

Of course, basic researchers use DNA sequencing to better understand the biology of plants, animals, and microbes, and biomedical researchers analyze DNA sequences to find differences associated with various diseases. As more differences in DNA sequences are linked to different pathologies, sequencing becomes more essential for understanding disease biology. Also, though, as more DNA sequence characteristics are linked to various diseases, it becomes a useful tool in the clinic to identify patients that already have or have a tendency to develop certain diseases, and determine which treatments will work best to either prevent or cure them.

We have already reached a point where some DNA sequence features are being used to help determine which patients will respond best to specific drugs. With more sequence information and further improvements in sequencing technology, treatments will become more personalized based on an individual's specific genome sequence. It is this emerging market of personalized medicine that is driving the DNA sequencing market.

First Generation DNA Sequencing

Until about 10 years ago, there was really only one DNA sequencing technology in general use, Sanger sequencing. The Sanger approach relied on DNA replication to identify which of the four A, T, C, or G nucleotide bases that make up the genetic code were at each position in a fragment of DNA. With Sanger sequencing, researchers could read almost a thousand nucleotides of DNA sequence in a reaction. Although automated Sanger sequencing techniques enabled completion of the Human Genome Project ahead of schedule in just under 13 years, in fact, the technology still required too much DNA, reagents, effort, and time to meet the needs of genomic researchers.

To develop a thorough understanding of the genetic features controlling organism development and determining an individual's biological attributes, it would be necessary to sequence hundreds of thousands of genomes of animals and people many many times over. Since most genes are typically a couple thousand bases long and the whole genome of most mammals contains about 3 billion bases, significant improvements in DNA sequencing throughput were necessary. Even systems that automated the Sanger method, such as those offered by Li-Cor or Applied Biosystems, were too expensive and slow. As a result, new techniques that enabled cheaper sequencing of more DNA from less material came on the scene in the early 2000s. It is this next generation of sequencing technology that became the basis of a rapidly developing billion dollar business.

Next Generation Sequencing Systems

The first next generation sequencing systems were introduced in the early/mid-2000s. The 454 Corporation, founded in 2000 and later purchased by Roche in 2007, was the first alternative high-throughput sequencing platform on the market. This system relied on DNA replication similar to the previously developed Sanger approach but, instead of stopping synthesis of a portion of the strands at each nucleotide, the 454 instrument used the firefly luciferase enzyme to generate a burst of light when it detected a chemical called pyrophosphatase that was produced each time one of the A, T, C, or G nucleotides was added to a new growing DNA strand (see a short video of this reaction). This approach, used less DNA and allowed a lot of sequences to be run in parallel so that several million nucleotides could be sequenced in a day.

Solexa, a competitor of 454 that was purchased by Illumina in 2007, launched its own system using Sanger-like DNA replication that could also sequence over a billion nucleotides in a run. The Solexa system used fluorescent dyes on the nucleotides to monitor growing DNA strands on beads.

The other early next generation sequencing system was the ABI SOLiD sequencing platform. Unlike the Solexa and 454 systems, SOLiD did not rely on DNA replication but detected small fluorescently labeled DNA fragments that chemically recognized and bound to (i.e., hybridized to) each sequences of DNA, and then acted as primers for the polymerase chain reaction.

Since the full genome of a human would stretch for about 6 feet and all of the sequencing approaches actually provide sequences for short segments of DNA of several hundred nucleotides, millions of these DNA stretches need to be pieced together like a puzzle to create the full genome. While these systems have vastly improved the feasibility of direct sequencing for biomedical research, the cost of these systems has still been too high for general clinical medicine.

A New Generation of DNA Sequencing

For routine clinical diagnostic use, newer DNA sequencing systems are being introduced that are pushing the cost down and generating more data from less DNA. For instance, the Ion Torrent system does not require any specially labeled chemicals since it uses an ion sensor to detect the hydrogen atom released when one of four sequentially added nucleotides is added to a single growing complementary strand. Since this method doesn't require any special labeling of the DNA, it makes the running cost much cheaper than other sequencing platforms.

Another sequencing approach that significantly reduces the cost of sequencing is the Pacific Biosystems platform which uses the standard Sanger sequencing approach but just sequences a single DNA strand at a time.

Also, there is the Complete Genomics platform, which uses an approach that breaks up a very large DNA sequence into small individual fragments on a flat surface, then detects them by binding small fluorescently labeled DNA.

Whole New DNA Sequencing Approaches

Some newer companies are taking even more innovative approaches to DNA sequencing. For example, Oxford's Nanopore DNA sequencing technology identifies the individual bases of a DNA strand electronically when they close the gap as they pass through a single molecule sized opening possessing an electric potential. Nabsys in Rhode Island also uses electronic detection but, instead of sequentially "reading" the nucleotide bases in a DNA strand, this technology senses electrical conductivity changes when short DNA fragments bind to specific nucleotide sequences. For an even more unique approach, ZS Genetics has been developing a technique to directly label and read the nucleotide bases in a single DNA strand using electron microscopy.

Of course, the current sequencing providers also continue to develop their technology platforms. To remain competitive, they continue to improve their systems to provide more convenient, robust, and cost effective DNA sequencing. For instance, Illumina has released the "personal" MiSeq instrument earlier this year.

DNA Sequencing and Personalized Medicine

With such a rapid pace of change, it is really not clear which platforms will come to dominate the market. New approaches are bringing the cost of sequencing down to a point that is becoming accessible to run for individual patients as a diagnostic procedure. Sequencing technology is finally reaching a point where applications in personalized medicine are feasible. As these applications evolve, it is likely this emerging market segment will introduce a new dynamic to sequencing technology development.

No one really knows how the DNA sequencing market will develop or what other novel sequencing systems may have yet surface and revolutionize the industry. However, it is finally reaching a point in terms of cost, reliability, and throughput that the anticipated revolution in health and medicine that was the promise of the Human Genome Project has started to materialize.

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