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Big Blue goes after holy grail
November 2009
by Jeffrey Bouley  |  Email the author


YORKTOWN HEIGHTS, N.Y.—Although it hasn't claimed victory yet in the race toward a $1,000 genome, computer technology giant IBM has boldly entered the fray in the hunt to create technology that will reach that goal—and it's already thinking down the line to something as low as a $100 genome if its DNA Transistor works as well as hoped.  
"What is the next big thing in biotechnology?" asks Dr. Gustavo Stolovitzky, manager of functional genomics and systems biology of the Computational Biology Center at IBM's T.J. Watson Research Center. "The answer is kind of simple if you are in the field, and what we need to know is how to sequence DNA, fast and cheap."  
The basic premise of the work that Stolovitzky and his colleagues are doing at IBM Research is to use something very much like a typical silicon microprocessor-style chip, with a 3-nanometer-diameter hole through which a DNA molecule would be passed. Using electrical charges turned on and off at intervals, the DNA would progress through the DNA Transistor and a sensor would read the DNA step-by-step.
"This device [has a] few tiny electrodes that allow us to make the DNA go through this little pore and be trapped by the electric field created by these electrodes," Stolovitzky explains. "We can [also] get rid of this electric field and the DNA will traverse through the pore a little bit, and then we trap it again, and each time we trap the DNA, we can do something with it. For example, interrogate each base and ask, 'Are you a C, a G, an A or a T, and that will allow us to sequence the DNA."
"What we are doing is using an electric field to control the flow of DNA strands in the nanopore," adds Dr. Stas Polonsky, another IBM researcher on the project. "By applying voltages to the metal layers lining the nanopore, we create potential wells, which interact with the charges along the backbone of the DNA strand, moving it along one base at a time."  
Using this technology, Stolovitzky says, it is very possible that IBM could make the $1,000 genome milestone achievable. That is the "holy grail—the gold medal—of the DNA sequencers," he says, and the point at which personalized medicine will truly become a feasible reality.  
In the past several years, the cost of genetic sequencing has been falling at a rate of tenfold annually, George M. Church, a Harvard geneticist, told The New York Times recently, and he anticipates the industry will continue with impressive gains along those lines for the foreseeable future.
Reporting on the IBM research, The New York Times noted that at least 17 startup and existing companies are in the sequencing race, pursuing a range of "third-generation" technologies, including United Kingdom-based startup Oxford Nanopore (see sidebar below). The newspaper also notes that human genome sequencing costs currently run between $5,000 and $50,000, although none of those efforts have yet been "completely successful" and no one has yet produced an entire genomic sequencing of a single individual.  
Writing at, Daniel MacArthur, who writes about the genetic testing and genomics industries, was intrigued by IBM's work, but he expressed much greater confidence that Oxford Nanopore would produce a mature sequencing platform before IBM would.  
"I am trying to keep my eyes in the sky but my feet on the ground," Stolovitzky says of the work he and his colleagues are doing at IBM Research. "We have a number of steps before we can overcome all the limitations. Having said all that, we expect that with the DNA Transistor, in principle, in a few hours you should be able to sequence a human genome."  
One of the great advantages of the DNA Transistor, if it works as intended, would also be that it might eliminate the "complicated and time-consuming and cost-consuming manipulations of the DNA at the input of this device," Stolovitzky notes, and make the entire process of retrieving DNA information an almost fully electronic one.
One of the key goals right now, IBM notes, is to optimize a process for controlling the rate at which a DNA strand moves through the nanoscale aperture—not surprising, since completely controlling DNA's movements has been a challenge for every company pursuing nanopore sequencing technologies.
"Slowing the speed is critical to being able to read the DNA strand," notes an IBM news release announcing the DNA Transistor research. "IBM scientists believe they have a unique approach that could tackle this challenge."  
The work that IBM is doing brings together a team of scientists from four fields in the Yorktown Height, N.Y.-based Watson Research Center—nanofabrication, microelectronics, physics and biology. Also, the IBM Research division is one of several companies to have been awarded grants totaling almost $6 million by the National Human Genome Research Institute to investigate technologies able to provide personalized genome sequencing for less than $1,000—about a half million dollars in IBM's case.
"The beauty of [what we are doing] is that [the DNA Transistor] uses technology that IBM is very good at doing," Stolovitzky notes, "which is a mixture of things like nanotechnology, very sophisticated atomic layer deposition and chemical vapor deposition—all kinds of technology that has been very much at the forefront of the thinking and innovation at IBM."  

Oxford Nanopore pursues protein-based nanopore sequencing

OXFORD, U.K.—Existing genomic sequencing methods tend to rely on expensive optical technologies, fluorescent labels and in some cases complex sample preparation, and that is why a label-free, electrical, single-molecule method is needed to make sequencing truly affordable to the masses, notes Oxford Nanopore. To that end, the United Kingdom-based company has partnered with the likes of Illumina, Harvard University and the University of California, Santa Cruz, between late last year and early this year on nanopore sequencing technologies.
In late February, Oxford Nanopore also published a paper in Nature Nanotechnology demonstrating that it can detect unlabelled DNA bases and methylated cytosine using a protein nanopore covalently attached to an adapter molecule.  
According to the company, this "validated the feasibility and accuracy of the nanopore sensing component of Oxford Nanopore's sequencing system … As such, the work represents a step toward the company's goal of developing the first label-free, single-molecule DNA sequencing technology."  
Each of the DNA bases reportedly causes a characteristic current disruption as it moves through the nanopore that Oxford Nanopore has developed, thus allowing continuous sequencing without fluorescent labeling.  
In contrast to Oxford Nanopore's technique—using a ring-shaped protein at the top of the pore through which individual base can be cut and passed through—the recently announced DNA Transistor research from IBM is said to used a "naked" nanopore. Oxford Nanopore does expect to move to a naked nanopore system ultimately, but probably not until after it has released a commercial platform that can actually handle continuous strands of DNA using the protein-based system.
Code: E110901



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