Science News - April 14, 2007

Now, working with a company called Biotage, based in Uppsala, Sweden, the researchers are automating the technology and miniaturizing it to put on a tiny chip. Although the current system still takes months to read a human-size genome, Ronaghi says that he expects, within the next 3 years, to streamline the process to sequence a person’s genome in a single day. He estimates the cost for such a service would be about $10,000—still expensive, but much lower than current prices.

With further tweaks that the company is contemplating, he says, “we might even have the opportunity to get it down to $1,000.”

Schloss says that other teams, such as the group led by Stephen Turner of Protea Biosciences in Morgantown, W. Va., aim to take a slightly different approach to sequencing a person’s genome. Rather than having a single light flash indicate that DNA polymerase has added a base to a lengthening DNA strand, these scientists use chemical reactions that would generate a different color of light for each base. This method would make it possible for a color-reading device to quickly register each time that DNA polymerase added a base to the DNA strand.

POKING HOLES While their developers expect these technologies to reach the market within a few years, others in earlier experimental stages might make DNA sequencing faster and cheaper still. A team of researchers led by Reza Ghadiri of the Scripps Research Institute in La Jolla, Calif., is building its method around tiny holes called nanopores.

Other researchers noticed in the early 1990s that an enzyme called alpha hemolysin pokes nanosize holes into the cell membranes of organisms that some bacteria have infected. Because each DNA base is slightly smaller than an alpha hemolysin– created pore and has a characteristic shape, Ghadiri and his colleagues reasoned that they might distinguish the bases on a DNA strand moving through membrane pores.

The scientists placed a salt solution on each side of the membrane. Then, they threaded a single strand of DNA through a nanopore. The researchers monitored the flow of salt ions traversing the hole as each of the DNA bases squeezed through in sequence.

In the team’s initial experiments, the DNA passed through the hole too quickly to let the researchers read out differences in ion flow.

The researchers have since developed several ways to avoid that problem. For example, the team recently placed chemical groups that act as stoppers on each end of the DNA strand to be analyzed. Rather than slipping out of the pore, says Ghadiri, the DNA strand moves back and forth. “It goes in and out like you’re playing the cello,” he explains. After observing numerous passes of a sample DNA strand through a pore, the team distinguished the order of the bases.

In more-recent experiments, Ghadiri’s team tested a method to control the movement of the DNA strand. The researchers added DNA polymerase to one end of a strand that’s threaded through the pore. The polymerase is too wide to enter the pore, so as the polymerase crawls along the single strand, adding bases, it pulls through the DNA at a measured pace.

Other teams are developing similar nanopore technology using holes mechanically drilled through silicon and other materials.

Ghadiri says that “the jury is still out” on whether biological nanopores, such as the one he’s developing, or those in synthetic materials will be better for sequencing genomes. While organisms such as bacteria could eventually be engineered to develop pores with advanced capabilities—such as generation of a different electrical response for each of the bases within a string of DNA—synthetic nanopores wouldn’t need care and feeding as an organism does.

Regardless of which pore material wins out, Ghadiri says that the technique could dramatically lessen the time and cost of genome sequencing. It doesn’t require expensive chemicals and equipment. Ghadiri estimates that sequencing a person’s genome using nanopores will eventually take only hours and will cost less than $1,000.

DANGLING CARROT A new competition could speed the development of faster sequencing techniques. The X Prize Foundation, a Santa Monica, Calif.–based group, runs private competitions promoting projects ranging from low-cost space travel to the invention of ultraefficient cars. The foundation announced last October that it would award $10 million to the first group to develop a way to sequence at least 100 people’s genomes in 10 days at a cost of no more than $10,000 per genome.

Three teams with sequencing experience are already on the roster of competitors for the prize, says

Laurence Keddes, scientific direc-
tor of the X Prize for Genomics.
“The solution to this problem could
involve technologies outside current
activity and may come out of left field.
We want to have a big-enough carrot
out there” to draw more than the usual
genomic researchers, Keddes says.

He notes that several other scientists from both academia and

industry have expressed interest in the contest.

Schloss says that both the new X Prize and further government funding increase the odds that patients will eventually have a routine genetic sequence in their medical records. Even then, he says, researchers have much work to do before such information can guide a doctor’s care. Scientists still don’t understand the function of most genes in the human genome.

Sequencing a person’s genome “will be relatively easy,” Schloss says. “We will soon have the ability to collect genome sequences on individuals faster than we’ll be able to interpret them.” ■