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Biomedicine

Wiring Up DNA

Measuring the conductivity of DNA could provide a way to detect mutations.

By wiring up DNA between two carbon nanotubes, researchers have measured the molecule’s ability to conduct electricity. Introducing just a single letter change can drastically alter the DNA’s resistance, the researchers found, a phenomenon that they plan to exploit with a device that can rapidly screen DNA for disease-linked mutations.

Hot-wired: By placing a double-stranded DNA segment in a gap in a single-walled carbon nanotube, researchers have measured the electrical properties of the biological molecule. Since even a single mismatch in the DNA letters affects the conductivity of the segment, the system could eventually be the basis of chemical sensors to detect mutations in DNA.

Measuring the electrical properties of DNA has proved tricky because the molecule and its attachments to electrodes tend to be very fragile. But in the new study, Colin Nuckolls, a professor of chemistry at Columbia University, in New York, teamed up with Jacqueline Barton, a professor of chemistry at Caltech, in Pasadena, CA, who’s an expert in DNA charge transport. Nuckolls’s group had previously developed a method for securely hooking up biological molecules to single-walled carbon nanotubes, which act as the electrodes in a miniscule circuit.

The researchers used an etching process to slice a gap in a carbon nanotube; they created a carboxylic acid group on the nanotube at each end of the gap. They then reacted these groups with DNA strands whose ends had been tagged with amine groups, creating tough chemical amide links that bond together the nanotubes and DNA. The amide linkages are robust enough to withstand enormous electrical fields.

The team estimated that DNA strands of around 15 base pairs (around 6 nanometers) in length had a resistance roughly equivalent to that of a similar-sized piece of graphite. This is a finding that the researchers might have expected since the chemical base pairs that constitute DNA create a stack of aromatic rings similar to those in graphite.

“In my opinion, the results of this work will survive, in contrast to many other publications on this topic,” says chemist Bernd Giese, of the University of Basel, Switzerland. Previous estimates of DNA’s conductivity have varied dramatically, Giese says, partly because it was unclear if the delicate DNA or its connection to electrodes had become damaged by the high voltages used. “One thinks one has burned the DNA to charcoal,” Giese says. “It’s extremely complicated experimentally.”

Barton and Nuckolls performed two tricks with their wired-up DNA. For their first, they introduced a restriction enzyme that bound and cut the DNA at a specific sequence. When severed, the current running through the DNA vanished. “It’s a way of biochemically blowing a fuse,” Nuckolls says. It also demonstratesthat the DNA keeps its native structure in the circuit; if it had not, the enzyme would not recognize and cut the molecule.

For their second trick, the researchers introduced a single base-pair mismatch into the DNA so that, for example, a C was paired up with an A (rather than its normal partner, G). This tweak boosted the molecule’s resistance some 300-fold, probably because it distorts the double helical structure. They could do this easily by connecting only one of DNA’s two strands into the circuit. The second strand - which can either be a perfect match to the first or contain a mismatch - can lift on or off.

Showing the electrical effect of such sequence mismatch and enzyme cutting is the real strength of the experiments, says Danny Porath, of Hebrew University, in Jerusalem, Israel, who has also measured current through DNA. “They play with the parameters and show that conductivity of DNA clearly depends on them, and that’s beautiful,” he says.

Nuckolls is now working to exploit this discovery to detect single nucleotide polymorphisms (SNPs), the one-letter variations in DNA that are linked to, for example, susceptibility to Alzheimer’s, diabetes, and many other major diseases. Nuckolls hopes that his method can be used to identify SNPs more rapidly and with greater sensitivity than existing methods. In such a device, a reference strand of DNA is wired into the circuit and other strands allowed to pair up with it. If the second strand carries a different base at the position of the SNP, this would be enough to trigger a change in the current through a nanoscale circuit, just as the base-pair mismatch did. Nuckolls says that he is already working with electrical engineers to create a sensor that can slot into existing semiconductor chips, making it cheap and readily available. “It’s one of our big focuses, and we’re pretty close,” he says.

The team is likely to have competition. Late last year, a group led by Wonbong Choi, of Florida International University, in Miami, reported that it had strung 80 base pairs of DNA between two carbon nanotubes and sent current through the DNA. Choi says that he is working to create a sensor that can rapidly reveal the presence of specific genetic sequences–such as the avian influenza virus–by looking at changes in current through the tiny circuit.

Barton, meanwhile, is intent on finding out whether the conductivity of DNA serves any biological purpose in the cell. She has evidence that proteins bound to DNA may detect DNA damage by changes in its electrical properties, perhaps triggering repair of the damage. “We think it’s something nature takes advantage of,” she says. “It’s a radical idea, but I think as we get more and more evidence, the case will be built.”

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