January 10, 2012 | MONTREAL—Speaking for the first time in his life as a commercial consultant rather than a public servant, Sir John Burn, a highly respected clinical geneticist in the United Kingdom, provided the first glimpse at a nanowire technology for rapid DNA genotyping that could eventually mature into the world’s first handheld DNA sequencer. Burn previewed a potentially disruptive genome diagnostic technology in a presentation on the closing day of the International Congress of Human Genetics in Montreal*.
One day a week, Burn, professor of clinical genetics at Newcastle University, serves as medical director for QuantuMDx (QMDx), a British start-up co-founded by molecular biologist Jonathan O’Halloran and health care executive Elaine Warburton.
The potential of nanowires was demonstrated in a 2001 Science paper authored by Harvard University’s Charles Lieber and colleagues. That proof of principle, according to Burn, showed that changes of impedance in silicon nanowires could record the arrival of a biomolecule. Recently, QMDx announced the exclusive license of intellectual property from Lieber’s company, Nanosys, of the diagnostic and sequencing applications of nanowires and nanotubes. (The arrangement succeeds a non-exclusive IP deal previously announced in 2009.)
QMDx operations and manufacturing are currently headquartered in Newcastle, U.K.. The company has built a prototype DNA sequencer, which Burn admitted didn’t exactly conform to handheld dimensions just yet. (The company is working on a sequencing device called Q-Seq, but Burn did not dwell on that.)
Pass the Q-Poc
The first goal is a handheld point-of-care instrument that is dubbed Q-Poc, which Burn likened to “a big fat iPhone.” Possible applications range from companion diagnostics and genetic testing to DNA forensics. The QMDx technology uses peptide nucleic acids (PNAs) to tether DNA sequencing templates to a nanowire. As the nucleotides arrive at the template, their negative charge influences the nanowire and changes its impedance. The process would use a reversible-terminating technology that is able to read through repetitive stretches of DNA.
Burn acknowledged that the electrical differences could only be detected for a range of about 100 Angstroms (10 nanometers), equivalent to about 50 bases of DNA in any one stretch. But down the road, an idea was to lay a longer DNA template, say 10 kilobases, and interrogate at multiple points along the molecule.
The manufacturing process relies on an etching technique featuring a silicon nanowire about 120 nm in diameter, and about one million features on the chip, roughly the size of a microscope slide. “It’s a highly reproducible system for mass manufacture,” says Burn.
To place the DNA templates onto the wire, QMDx has invented several methods to rapidly prepare and PCR DNA. A DNA extractor uses a nanoparticle filter to capture and elute the starting DNA. A microfluidic cartridge performs PCR (polymerase chain reaction) not by heating and cooling the liquid, but by passing it through heat zones created in the microfluidic device.
“There are up to 32 silos of passage across the heat plates,” Burn explained. “We can do PCR in 6 minutes through this device—10 minutes from sample arrival to PCR product coming onto the nanowire.”
Eventually the sample prep segments will be combined to produce a disposable chip with on-board chemistry that is inserted into the machine. The results can be read locally or transmitted to a remote reader.
Burn listed several early applications that QMDx is targeting. The first is the pharmacogenomic polymorphism that controls sensitivity to the blood thinner warfarin. Today, Burn said, “We give all [patients] the same dose; the ones that nearly bleed to death, we bring them back to hospital and transfuse them and put them on the right dose. It would be nice if we could do the genetic analysis and predict the right dose instead.” Using an algorithm developed by his Newcastle colleague Ann Daley, Burn wants to use warfarin testing as “a proof of principle for the use of this as a point-of-care test in clinics and GP surgeries.”
Another application is in the field of bowel cancer, a long-time research interest of Burn’s. The detection of key microsatellite (MSI) risk markers should be identified at the point-of-care, said Burn. “We’ll be moving into the pathology lab and doing genetic testing of MSIs, even as samples come out of the clinic or even surgery.” Burn even suggested the possibility of using the technology during live surgeries, as the process should only take some 15-20 minutes.
In short the goal is to carry genomics into the world, Burn said. The 20-minute test should prove valuable for pharmacies and hospitals. The device would be priced in the $300-400 range, with the disposable cartridges about $20. The company plans to begin clinical trials for HIV testing in South Africa in the next 1-2 years.
“I’m convinced—and obviously hope—the nanowire idea is coming to a clinic near you,” said Burn. “We’re limited more by our imagination than anything else.” Burn’s QMDx colleague, chief science officer Jonathan O’Halloran, goes even further. “I predict that we’ll be able to sequence a genome on a hand-held device within 5-7 years,” he writes on his LinkedIn page. •
* 12th International Congress of Human Genetics, October 11-15, 2011, Montreal