Lindsay helps address DNA sequencing challenges
Next generation sequencing goal: $1000 genome in 24 hours
In the not too distant future, scientists envision an age when going to the doctor for a routine checkup also includes getting the vital signs of one’s genetic health. For every individual, obtaining his or her complete set of genetic information, called a genome, will become a key component to fulfilling the promise of personalized medicine.
Following the computer industry’s mantra of ‘faster, cheaper, smaller,’ ASU scientists are now in the midst of a research and development race to make an era of inexpensive, rapid DNA sequencing reality. Biodesign Institute biophysicist Stuart Lindsay is among a group of scientists pursuing a nanotechnology-based sequencing called nanopore sequencing. Lindsay, an ASU Regents Professor and the Carson Chair in Physics and Chemistry, was among 25 authors contributing to a review article in the October issue of Nature Biotechnology outlining the current progress and potential of the technology.
The trends in innovation for DNA sequencing have paralleled those often seen in the adoption of new technology in computing and electronics, where improved automation and miniaturization caused dramatic price drops. The price to sequence an individual genome has fallen from tens of millions to an estimated $100,000. Now, several startups companies and research teams are in hot pursuit of a breakthrough technology to make DNA sequencing a routine aspect of health care.
Threading the eye of the needle
DNA sequencing has progressed from Nobel laureate Fred Sanger’s original method in the early 1970s to more recent, massively parallel approaches that made possible the Human Genome Project and applications in diagnostic and forensic research. The techniques are time consuming, and work with molecular scissors to chop the 3 billion chemical units of DNA that make up the genome into readable bits a few hundred units in length at a time, using a computer to finally reassemble the full genome sequence.
In concept, nanopore-based DNA sequencing is a bit like sewing, with DNA as the thread, passing through a nanopore like the eye of the needle. Scientists use an electric current to thread the DNA through the nanopore hole.
“One of the most compelling advantages of nanopore sequencing is the prospect of inexpensive sample preparation requiring minimal chemistries or enzyme-dependent amplification,” the authors state. “Thus, the costs of nanopore sequencing… are projected to be far lower than ensemble sequencing by the Sanger method, or any of the recently commercialized massively parallel approaches.”
Nanopore sequencing has the potential to provide a breakthrough in DNA sequencing by reading lengths of DNA up to 50,000 thousand bases in length, and without the need for dyes, sample processing, and other materials that contribute to the current costs.
Lindsay and his team, including research professors Jin He and Peiming Zhang, are undertaking a collective approach incorporating many complementary elements that integrate biochemistry, chemistry and physics with nanotechnology to develop a radical strategy to breakthrough the DNA sequencing cost bottleneck.
Lindsay’s variation of the theme, called “sequencing by recognition,” involves using nanostructures to read the electrical current through DNA bases, thereby identifying the sequence (see figure). In concept, the Lindsay’s solution would work somewhat like a supermarket scanner —only shrunk down to the nanoscale— to read genomic DNA at a speed of hundreds to thousands of bases per second. It involves using nanostructures to read the electrical current through DNA bases, thereby identifying the sequence.
Speed reading DNA
In their approach, DNA is passed through a tiny hole, a nanopore, and past a ‘reader,’ which recognizes one of the four DNA bases. Combining the readouts from four different DNA readers would assemble the full DNA sequence. If successful, during the second stage of the project, Lindsay’s team plans to develop a preliminary prototype of a high-speed DNA reader.
The ultimate goal of nanopore DNA sequencing is to reduce the cost and speed of sequencing the human genome to $1000 in 24 hours. Nanopore DNA sequencing has much potential, but still faces formidable challenges before progressing from the research lab into industry.
The authors of the Nature Biotechnology review state: “There is little doubt that the accelerating rate of discovery in the field of nano-scale electronics and the proven ability of the electronics community to develop mass-production strategies for high-value components will be able to master the nano-scale science required to fabricate massive nanopore arrays. But until such time as nanopore sequencing in any form is shown to be feasible and valuable, nanopore sequencing researchers face the challenge of using only research-scale facilities rather than those that are to be found, or could be developed, in a specialized, mass-production plant.”
To help hedge their bets, Lindsay’s DNA sequencing effort is among several approaches being pursued at ASU. Lindsay also collaborates with two other ASU research teams, led by Biodesign’s Peiming Zhang and colleague Jian Gu, and Peter Williams from the School of Life Sciences. Together, they have nearly $3.5 million in next generation DNA sequencing projects funded by the National Human Genome Research Institute, a branch of the National Institutes of Health.
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Stuart Lindsay directs the Center for Single Molecule Biophysics at ASU's Biodesign Institute, and is an ASU Regents Professor and the Carson Chair in Physics and Chemistry in the College of Liberal Arts and Sciences. To read the Nature Biotechnology review, go to: http://www.nature.com/nbt/journal/v26/n10/pdf/nbt.1495.pdf