I.B.M. JOINS PURSUIT OF $1,000 PERSONAL GENOME

[ Mon. Oct. 5. 2009 ]

One of the oldest names in computing is joining the race to sequence the genome for $1,000. On Tuesday, I.B.M. plans to give technical details of its effort to reach and surpass that goal, ultimately bringing the cost to as low as $100, making a personal genome cheaper than a ticket to a Broadway play.

The project places I.B.M. squarely in the middle of an international race to drive down the cost of gene sequencing to help move toward an era of personalized medicine. The hope is that tailored genomic medicine would offer significant improvements in diagnosis and treatment.

I.B.M. already has a wide range of scientific and commercial efforts in fields like manufacturing supercomputers designed specifically for modeling biological processes. The company’s researchers and executives hope to use its expertise in semiconductor manufacturing, computing and material science to design an integrated sequencing machine that will offer advances both in accuracy and speed, and will lower the cost.

“More and more of biology is becoming an information science, which is very much a business for I.B.M.,” said Ajay Royyuru, senior manager for I.B.M.’s computational biology center at its Thomas J. Watson Laboratory in Yorktown Heights, N.Y.

DNA sequencing began at academic research centers in the 1970s, and the original Human Genome Project successfully sequenced the first genome in 2001 and cost roughly $1 billion.

Since then, the field has accelerated. In the last four to five years, the cost of sequencing has been falling at a rate of tenfold annually, according to George M. Church, a Harvard geneticist. In a recent presentation in Los Angeles, Dr. Church said he expected the industry to stay on that curve, or some fraction of that improvement rate, for the foreseeable future.

At least 17 startup and existing companies are in the sequencing race, pursuing a range of third-generation technologies. Sequencing the human genome now costs $5,000 to $50,000, although Dr. Church emphasized that none of the efforts so far had been completely successful and no research group had yet sequenced the entire genome of a single individual.

The I.B.M. approach is based on what the company describes as a “DNA transistor,” which it hopes will be capable of reading individual nucleotides in a single strand of DNA as it is pulled through an atomic-size hole known as a nanopore. A complete system would consist of two fluid reservoirs separated by a silicon membrane containing an array of up to a million nanopores, making it possible to sequence vast quantities of DNA at once.

The company said the goal of the research was to build a machine that would have the capacity to sequence an individual genome of up to three billion bases, or nucleotides, “in several hours.” A system with this power and speed is essential if progress is to be made toward personalized medicine, I.B.M. researchers said.

At the heart of the I.B.M. system is a novel mechanism, something like nanoscale electric tweezers. This mechanism repeatedly pauses a strand of DNA, which is naturally negatively charged, as an electric field pulls the strand through a nanopore, an opening just three nanometers in diameter. A nanometer, one one-billionth of a meter, is approximately one eighty-thousandth the width of a human hair.

The I.B.M. researchers said they had successfully used a transmission electron microscope to drill a hole through a semiconductor device that was intended to “ratchet” the DNA strand through the opening and then stop for perhaps a millisecond to determine the order of four nucleotide bases — adenine, guanine, cytosine or thymine — that make up the DNA molecule. The I.B.M. team said that the project, which began in 2007, could now reliably pull DNA strands through nanopore holes but that sensing technology to control the rate of movement and to read the specific bases had yet to be demonstrated.

Despite the optimism of the I.B.M. researchers, an independent scientist noted that various approaches to nanopore-based sequencing had been tried for years, with only limited success.

“DNA strands seem to have a mind of their own,” said Elaine R. Mardis, co-director of the genome center at Washington University in St. Louis, noting that DNA often takes a number of formations other than a straight rod as it passes through a nanopore.

Dr. Mardis also said previous efforts to create uniform silicon-based nanopore sensors had been disappointing.

One of the crucial advances needed to improve the quality of DNA analysis is to be able to read longer sequences. Current technology is generally in the range of 30 to 800 nucleotides, while the goal is to be able to read sequences of as long as one million bases, according to Dr. Church, who spoke in July at a forum sponsored by Edge.org, a nonprofit online science forum.

Other approaches to faster, cheaper sequencing include a biological nanopore approach being pursued by Oxford Nanopore Technologies, a start-up based in England, and an electron microscopy-based system being designed by Halcyon Molecular, a low-profile Silicon Valley start-up that has developed a technique for stretching single strands of DNA laid out on a thin carbon film. The company may be able to image strands as long as one million base pairs, said Dr. Church, who is an adviser to the company, and to several others.

“To bring about an era of personalized medicine, it isn’t enough to know the DNA of an average person,” said Gustavo Stolovitzky, an I.B.M. biophysicist, who is one of the researchers who conceived of the I.B.M. project. “As a community, it became clear we need to make efforts to sequence in a way that is fast and cheap.”

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