TechConnect - The Nano Issue

If quantum tunneling can be
perfected, the prospect of rapid,
low-cost DNA sequencing could
become a reality.

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AGOLDPROBEOUTFITTEDWITHADANGLINGNUCLEOTIDEAPPROACHESITS COMPLEMENTARYBASEPROTRUDINGUPWARDFROMAMONOLAYER.

Finely Tailored Fit

writinG by :: richard harth

mine the wealth of information DNA can provide concerning hereditary traits, hormonal and cell irregularities, longevity and predisposition to disease.

Various techniques for sequencing DNA have been used to determine the identities of the four nucleotide bases that make up the ladder rungs of the DNA’s double helical structure. Most of these require snipping DNA into hundreds of thousands of short fragments, unzipping the helix and reading a few hundred to a few thousand bases at a time. Finally, all of the information from the DNA pieces is reassembled into a picture of the complete genome, with the help of massive computing power.

Mysteries of the quantum world may
help sequence DNA

cientific efforts
to comb secrets
from the tangled
braids of the
DNA molecule
have been richly rewarded. Now
techniques for deciphering the
genetic code are routinely ap-
plied in such diverse domains
as genetic testing, bioarchaeol-
ogy and crop hybridization.

On the horizon is the prospect of personalized DNA sequencing, which would allow physicians to fine-tune disease diagnoses and therapies to each individual. We now know that the progression of common diseases like cancer is often patient-specific. Access to the full genome of every individual will offer a major advance in the ability to detect illness at a presymptomatic stage and custom-tailor specific treatments.

Despite its enormous usefulness to science, however, genetic sequencing remains a time-consuming, costly and often cumbersome undertaking. Now, a new method of DNA

sequencing has been proposed by Stewart Lindsay, director of the Biodesign Institute’s Center for Single Molecule Biophysics at Arizona State University. Lindsay’s approach relies on an esoteric property of subatomic matter called quantum tunneling. If the technique can be perfected, the prospect of rapid, low-cost DNA sequencing could become a reality.

The first unraveling of DNA in the human genome a decade ago was a remarkable achievement. Today, the task of sequencing some 3 billion chemical base pairs of the genome genome—enough information to fill a 20-volume encyclopedia—remains a daunting challenge. The work typically is slow and expensive, though costs have dropped considerably from the initial sequencing of the human genome, which took 11 years and cost $1 billion. Bringing the power of DNA sequencing to every individual requires new, affordable technologies to help

The Rules of Attraction

Lindsay’s technique for observing DNA sequences relies on devices known as scanning tunneling (STM) and atomic force microscopes (ATM). He exploits the sensitive instruments to identify complementary DNA base pairs, evaluating the hydrogen bonds formed between them. Base pairing rules for DNA dictate that nucleotide pairs join together like jigsaw pieces—adenine (A) with thymine (T) and cytosine (C) with guanine (G).

The scanning tunneling microscope used in Lindsay’s recent experiments features a delicate electrode tip held close to the DNA sample. When this tip is fitted with a particular nucleotide and brought in contact with its complementary mate, hydrogen bonds stick the bases together and they attach, like tiny magnets. As Lindsay describes the method, “you have sensing chemicals attached to one electrode and the target you want to sense attached to another one. When the junction spontaneously self-assembles, you get a signal. It’s a new way of doing recognition at the atomic scale.”

Crucial to the new technique is

the fact that the strength of the glue fastening complementary bases differs for A-T and C-G pairs. While two hydrogen bonds hold A-T bases together, C-G pairs use three hydrogen bonds. So, it’s physically harder to break C-G bonds— a difference detectable through measurement of electrical current. The new method, as Lindsay explains, combines chemical recognition with the flow of electron current as the tunnel junction—the tiny gap between nucleotide bases— is pulled apart.

Although quantum tunneling seems exotic, Lindsay points out that the routine leaking of electrons from one atom to another to form a chemical bond is a similar process. If significant challenges to reading single molecules through such a technique can be overcome, the method holds the potential for inexpensive DNA sequencing, operating at the breakneck pace of thousands of base pairs per second.