The promise is tantalizing: A chance to know, decades ahead, of a health risk you can guard against. Therapies that match your precise genetic makeup, so you don’t suffer from needless side effects, or take drugs that won’t work well for you: Truly personalized medicine.
And sure, medicine has a long way to go before it’s quite at that level. But the single biggest obstacle is the cost and effort involved in sequencing an individual’s genome. So the National Institutes of Health set a goal: $1,000 per person.
This month, a Brown University physics team led by Xinsheng Sean Ling unveiled a new approach they believe may do the trick, using nanopores, electrical charges and magnets in a process that builds on years of research and inventions by Ling.
The basic idea is to thread multiple segments of a DNA strand simultaneously through a cluster of tiny holes, “reading” them as they go through the opening. Scientists have previously done that, but the force was too strong, and the fragments moved too fast.
So to slow them down, Ling and his team attached tiny beads to the ends, just big enough that they couldn’t make it through the pores. Then, using magnetic “tweezers,” they pulled the beads away from the pores, moving the DNA back through and allowing it to be read.
“The DNA is essentially caught in a tug of war,” Ling explained. And the speed of the movement “will be controlled not solely by the electric field but by striking some balance between the magnetic and the electric fields. From there, we can tune it to dictate the speed.”
The team named the process “reverse DNA translocation.” So far it’s only been tested with bacterial DNA, and without an actual reading mechanism, so the next step, Ling said, will be to add the reading mechanism. Then, within “a couple of years,” to test it with human DNA, which requires special approvals from the government.
“But once we get the bacterial DNA to work, human DNA is just like the bacterial DNA in many ways,” he said – in terms of physical properties at least. So within roughly a year, he said, the Brown team should know whether the technology is commercially viable.
The new method, described in the latest issue of the journal Nanotechnology, isn’t patented, so anyone can use it, Ling said. But if it does lead to a new sequencing technique that could be brought into the market, he might start a new company to do it, or else license the technology.
Two years ago, both Ling and Dr. John Oliver, NABsys’ vice president of research and development, got grants from the National Human Genome research Institute, part of the NIH, to work toward the $1,000 genome; only eight were awarded nationwide, and Ling got $820,000 for three years, while Oliver got $500,000 for two years – the only grant to a for-profit entity.
While the starting idea may have been the same, however, NABsys and Ling’s team are now pursuing different approaches. “We’re competitors at this point,” Ling said, “scientific competitors.”
Yet that’s how science is moving around the world. Ling developed the nanopores while on sabbatical in the Netherlands in 2002, and he’s been working with them since, but other scientists have also tried nanopores, running individual fragments through pores.
But with 2 billion base pairs to read, that’s too slow to be viable – just like the biochemical approach that is now widely used for DNA sequence analysis is too slow, costly and unwieldy. That’s why with the nanopores, Ling’s team found a way to do many fragments at once, though scaling up to large numbers of nanopores would require more engineering.
Meanwhile, slowing down the movement of the DNA so it can be read properly is in itself a big move forward: The scientists reported a 2,000-fold slowdown.
“Nanopore-based sequencing is one of the most promising alternatives that could drastically lower the cost of DNA sequencing,”Ling said. “What we have done in this study is solve one of the key problems that have impeded the implementation of this method.” •
