Faster, Cheaper DNA Sequencing

A U.K. company hopes to dramatically reduce the cost of reading a person's genome.

The race to build a fast, inexpensive device to sequence individual human genomes has a new entrant: a British company that uses a technique called nanopore sequencing. Cheaper genome sequencing--the fabled $1,000 genome--could lead not only to medical treatments tailored to a patient's specific genetic makeup, but also to better ways to diagnose disease, identify biological threats, and discover new drugs.

Nano sequencer: An exonuclease (in green) slices the DNA into individual bases, which pass through the blue nanopore and bind to the pink cyclodextrin, giving off characteristic electrical signals. The nanopore system is built into an array on a silicon chip. Credit: Oxford Nanopore Technologies

The company, Oxford Nanopore Technologies, has raised approximately $20 million in funding and recently licensed separate nanopore technologies developed at the University of Oxford, Harvard University, and the University of California, Santa Cruz.

Like the sequencing systems from Helicos BioSciences of Cambridge, MA, and Pacific Biosciences of Menlo Park, CA, nanopore sequencing can analyze individual strands of DNA, eliminating much of the time and expense of sample preparation. In a conventional DNA-sequencing scheme, the DNA sample must be copied many times.

But nanopore sequencing has the added advantage of doing away with the fluorescent molecules typically used to label DNA bases so that their sequence can be read by cameras. "We think we're the only label-free technology out there," says company president Gordon Sanghera. "There's no labeling. There's no amplification. And that really does take out the bulk of what you're doing." He says that sample preparation for the nanopore system takes hours, rather than the days it takes for others.

Nanopore sequencing is not as mature as other technologies, says Jeffrey Schloss, program director for technology development at the U.S. National Human Genome Research Institute (NHGRI). "The challenge is that people haven't read DNA sequences yet with nanopores," he says. But he adds that "we seem to be getting very, very close with Oxford Nanopore."

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Nanopores are naturally occurring proteins about a nanometer in diameter that provide openings in cell membranes so that the cells can eject or ingest materials. (To appreciate how tiny nanopores are, consider that the average human hair is about 100,000 nanometers thick.) The Oxford system employs an alpha-hemolysin protein produced by the Staphylococcus bacterium, which uses it to extract the contents of other organisms' cells. The Oxford team places the nanopore in an artificial membrane made of lipids. Above and below the membrane are a solution of salt and a pair of electrodes. An electrical current can flow from the solution above to the solution below, but only through the nanopore, because the membrane has a high electrical resistance.

Inside the nanopore is a cyclodextrin, a sugar molecule. Single bases of DNA are small enough to pass through the nanopore, and as they passes through, each of the four nucleic acids binds briefly to the cyclodextrin, then lets go again. When an acid binds to the sugar, it disrupts the flow of the electrical current in a recognizable way, so telling the base cytosine from guanine, or adenine from thymine, is a simple matter of reading the characteristic electrical signal.