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454 opens the door to low-cost, large-scale genomics
September 2005
by Randall C. Willis  |  Email the author


BRANFORD, Conn.óCuraGen subsidiary 454 Life Sciences recently announced the publication of a new method it developed for high-throughput, high-accuracy DNA sequencing that should open the door to widespread, cost-effective genomics efforts. The new method, which can sequence genomes 100 times faster than the more traditional Sanger method, was described in a paper published in Nature. The company will commercialize the new system through their relationship with Roche Applied Science.
According to Dr. Christopher McLeod, 454 president and CEO, the new process removes two bottlenecks of sequencing: sample prep and sequencing itself. Says McLeod, 454 has dramatically simplified the sample prep by removing many of the steps required in the Sanger method, including subcloning of DNA into bacteria and subsequent culture growth. Furthermore, the sequencing process is performed with a modified sequence-by-synthesis method that allows researchers to generate more than 20 million bases of sequence information in approximately four hours, at approximately 10 to 20 cents per kilobase, 10 percent of the current cost. It is this cost savings that he believes will most dramatically influence the marketplace.
"Many important pathogens that infect humans, animals, and plants are unsequenced," he says. "As the cost and time associated with sequencing decreases, the demand to sequence additional organisms should increase. And many of the pathogens that have been sequenced are quickly evolving. The genome sequences of clinical isolates will be valuable to understand the details of pathogenicity and drug resistance."
"Just because of the advances of the Human Genome Project, there's no reason to assume such research will not continue and large-scale sequencing will disappear from the scene," adds Dr. Kenneth Krul, an analyst with Kalorama Infor-mation."This is especially true in the age of bioterrorism, where it may be necessary to rapidly assess the genetic structure of a bioweapon in order to combat it's presence in our population."
McLeod also sees applications for new sequencing technologies in other areas of drug discovery and furthering understanding of disease pathology. The new process, he argues, is suitable for identifying the mechanism of action of antimicrobial drugs. As proof, he offers the recent use of the sequencing methodology by scientists from J&J Pharma-ceutical R&D in the development of a novel anti-tuberculosis drug.
Furthermore, by sequencing a number of clinical isolates of a given pathogen, researchers may be better able, through comparative genomics, to determine improved targets for drug discovery or improved drug design. And it may lead to improved drug target identification by identifying the variability present in the population and identifying those genes that are responsible for disease.
Personalized genome se-quen-cing is where the experts disagree.
According to McLeod: "Ulti-mately, as the technology continues to become smaller, less expensive and easier to use, we believe sequencing of individual human genomes will become routine because of the value it will provide in preventing disease and in prescribing safe and effective medication tailored to that patient's genes."
Kalorama's Krul argues that "personal genome sequencing is a fantasy. There is no need for, capacity for, or non-pernicious reason to keep this information. First,there are very few cures that can be applied to genetic diseases, and diagnostics follow therapeutics. If you have no way to address the issue, why be specific about analysis? Furthermore, SNP profiles are faster and more valuable because they don't provide a lot of extraneous data, and they can be used in specific disease applications, particularly pharmacogenetics.How---ever, even their clinical potential is limited at this time and for the foreseeable future."
Regardless, no one argues the intrinsic value of more sequence information.
"The 'post-genomic' era is a misnomer," McLeod says. "As sequencing becomes more cost effective, less time intensive, and easier to implement, researchers will want to do more comparative genomics studies to answer fundamental scientific questions. These include how organisms compare to one another, how individuals within a given species are different from one another, and the underlying meaning of those differences."
Code: E090501



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