The Chip is the Machine

San Francisco, CA, USA. December 8, 2010. (TSR)- A device that reads the sequence of DNA using semiconductor technology could bring the power of sequencing to a much broader swath of the science world. The desktop machine, developed by a startup called Ion Torrent, is slated to go on sale this month and will cost $50,000, about one-tenth of the cost of other sequencing machines on the market. By combining semiconductor sequencing technology with natural biochemistry,  the Ion Torrent system democratizes sequencing and makes it accessible to virtually any lab or clinic.

Ion Torrent uses the simplest sequencing chemistry including natural nucleotides, no enzymatic cascade, no fluorescence, no chemiluminescence, no optics, no light: The Chip is the Machine.^TM Ion Torrent is compatible with most upfront library and target selection protocols.

Ion Semiconductor Sequencing Chips are designed, manufactured and packaged like any other semiconductor chips. Wafers are cut from a silicon boule. The transistors and circuits are then pattern-transferred and subsequently etched onto the wafers using photolithography. This process is repeated 20 times or more, creating a multi-layer system of circuits that looks something like the subway system under a large city—different layers with many interconnections.

Ion Torrent has created a direct connection between chemical and digital information, bringing these two languages together for the first time. This innovation will democratize research, enabling every lab to have a sequencer on its bench. Ultimately, Ion Torrent technology will also provide less expensive and more reliable diagnostic tests to improve human health throughout the world.

Life Technologies, a major player in the genomics industry, bought Ion Torrent for $315 million in cash and stock last August. Ion Torrent’s founder, Jonathan Rothberg, says that Life Technologies was particularly interested in his technology because of the potential diagnostic applications, though he is careful to note that the machine is only meant for research use at the moment.

The new device reads a much smaller amount of DNA than larger, more expensive machines. The current version analyzes 10 to 20 million bases per run, while the human genome is 3 billion bases. (Machines made by genomics giant Illumina, in contrast, can sequence about 250 billion bases of DNA in a weeklong run.)

However, diagnostic and other applications only require analysis of limited stretches of DNA.

At the heart of Ion Torrent’s technology is a semiconductor chip manufactured in the same foundries as computer and cell-phone microprocessors. The chip holds an array of 1.5 million sensors, each topped with a small well designed to hold a single-stranded fragment of DNA. To sequence a strand of DNA, the machine synthesizes a complementary strand, sequentially attempting to add each of the four bases that make up DNA one by one to the well. When the correct base is incorporated into the growing sequence, it triggers a chemical reaction that releases a positively charged hydrogen atom, which is detected by the sensor. A computer stitches together the sequence by integrating these signals with knowledge of when each base was flowed through the chip.

THE BIOCHEMICAL PROCESS

STEP 1: In nature, when a nucleotide is incorporated into a strand of DNA by a polymerase, a hydrogen ion is released as a byproduct.

STEP 2: Ion Torrent uses a high-density array of micro-machined wells to perform this biochemical process in a massively parallel way. Each well holds a different DNA template. Beneath the wells is an ion-sensitive layer and beneath that a proprietary Ion sensor.

STEP 3: Here’s how the technology is used to call a base: If a nucleotide, for example a C, is added to a DNA template and is then incorporated into a strand of DNA, a hydrogen ion will be released. The charge from that ion will change the pH of the solution, which can be detected by our proprietary ion sensor. Our sequencer—essentially the world’s smallest solid-state pH meter—will call the base, going directly from chemical information to digital information.

STEP 4: The Ion Personal Genome Machine (PGM™) sequencer then sequentially floods the chip with one nucleotide after another. If the next nucleotide that floods the chip is not a match, no voltage change will be recorded and no base will be called.

STEP 5: If there are two identical bases on the DNA strand, the voltage will be double, and the chip will record two identical bases called. Because this is direct detection—no scanning, no cameras, no light—each nucleotide incorporation is recorded in seconds.

The device is so much cheaper than other machines because of its simplicity; the chip itself detects the sequence, and it does so electronically. Other devices use optical systems, which require lasers, cameras, and microscopes. (These devices also read DNA sequence by synthesizing a complementary strand—but chemicals used in the reaction have to be modified to fluoresce when added to the growing piece of DNA; a camera detects the flashes of light.)

While Ion Torrent’s machines are cheap, the cost of sequencing per base pair is higher than for other instruments because each chip can only be used once, and the disposable chip currently costs about $250. But Rothberg says that, as with standard microprocessors, the price will drop with larger volumes of chips. “Every time we make 10 times as many chips in these factories, the cost drops in half,” he says. And because they are manufactured using standard semiconductor fabrication methods, he says it will be easy to scale up the chips to contain 10 to 100 times as many sensors.

Rothberg likens the evolution of sequencing technology to that of the computer industry. “The original computers were expensive; [they were] hard to build, ship, and set up; and they required a special environment to operate.” DNA sequencing was similarly once limited to the realm of large sequencing centers, but new technologies on the market over the last five years have greatly expanded its purview. These machines brought down the cost of sequencing dramatically, largely by reading millions of DNA sequencing reactions in parallel.

Within this scheme, Rothberg equates Ion Torrent’s machines to personal computers. Thousands of labs across the globe will now have access to sequencing machines that can fit on a standard lab bench, but as Harvard geneticist George Church points out, the machines are still out of reach for the average consumer. Furthermore, while many labs will have the capacity to buy a $50,000 sequencer, it’s not yet clear that they will. “Lots of labs are outsourcing these days,” says Church. “But I do think a lot of people want their own device. They don’t want to be in queue. If they have a sample, they want an answer immediately.”

It’s also difficult to predict how Ion Torrent will compete with other high-profile companies with new sequencing technologies on the market, most notably Pacific Biosciences. That company raised $200 million through an initial public offering in October of this year.