Five Thousand Bucks for Your Genome

Starting next spring, a complete human-genome sequence can be ordered for just $5,000, thanks to a new sequencing service announced by Complete Genomics, a startup based in Mountain View, CA. The stunning price drop--sequencing currently costs approximately 20 times that amount--could completely change the way that human-genomics research is done and open up new possibilities in personalized medicine. Researchers say that a $5,000 genome would enable new studies to identify rare genetic variants linked to common diseases, and it could open up the sequencing market to diagnostic and pharmaceutical companies, making genome sequencing a routine part of clinical drug testing.

Complete Genomics, which has received $46 million in venture funding to date and has largely stayed under the radar, plans to launch with a bang and anticipates the capacity to sequence 1,000 genomes in 2009 and 20,000 in 2010. That would represent a massive jump: with a price tag of $100,000 to $1 million over the past two years, only a handful of human genomes have been sequenced to date.

"Suddenly, these guys are talking about sequencing hundreds to thousands of genomes in the next couple of years," says Chad Nusbaum, codirector of the Genome Sequencing and Analysis program at the Broad Institute, in Cambridge, MA. "That opens up tremendous vistas for the kind of science we want to do. It's really by generating hundreds of human-genome sequences that you can start to ask hard questions about human genetics."

Complete Genomics says that it has already sequenced a human genome, although it has not yet released the data for independent review. "'Stunning' is not too strong a word, if they can do it in the very near term," says Jeffrey Schloss, program director for technology development at the U.S. National Human Genome Research Institute, on the possibility of a $5,000 genome. "But I haven't seen any data and I don't know anyone who has, which is of course critical."

J. Craig Venter, founder of the J. Craig Venter Institute, in Rockville, MD, is working with Complete Genomics to validate its technology, comparing the sequence that it generates with a reference sequence of his own genome.

Two Key Innovations Reduced Price

Complete Genomics says that its cheap price tag comes thanks to two innovations: a way to densely pack DNA, developed by Rade Drmanac, the company's chief scientific officer, and a method to randomly read DNA letters, based on sequencing technology developed at George Church's lab at Harvard.

To start with, an 80-base-pair piece of DNA is inserted into a circular piece of synthetic DNA and replicated 1,000 times with a specialized enzyme. That large aggregate of DNA spontaneously compresses into a tightly packed ball, thanks to chemical characteristics engineered into the synthetic DNA. These DNA "nanoballs" are then packed onto specially fabricated arrays with unprecedented density--about a billion balls fit on a chip the size of a microscope slide. The high density of DNA allows large volumes to be sequenced quickly with few reagents, one of the most costly components of the process.

Next, as with other approaches, Complete Genomics determines the sequence of the target DNA using a series of fluorescently labeled DNA strands designed to bind to corresponding letters. But while advanced sequencing technologies currently in use--including those from Illumina, Applied Biosystems, and 454--read the sequence sequentially, letter by letter, Complete Genomics's labels bind to the target DNA randomly. Both the labels and the DNA circle are designed to allow scientists to deduce the position of each highlighted base--information that is then used to computationally reconstruct the sequence of the target DNA. (With both Complete Genomics's and other companies' methods, the short strands are computationally stitched together to generate the entire genome sequence.)

Because the identification of each base in the sequence does not depend on the correct identification of the previous one, individual errors have less impact on the overall result, generating a more accurate sequence with less repeat sequencing. (For a more detailed explanation and schematic of Complete Genomics's sequencing process, click here.)

New Technology Could Encourage New Areas of Study

A $5,000 genome is likely to open new arenas in genetic study of common disease. Most studies to date have analyzed carefully selected portions of individuals' genomes, linking common variations to risk of common ailments, such as diabetes and heart disease. However, even studies of thousands of patients have uncovered genetic variations that account for only a small percentage of the risk for disease. Scientists say that the ability to sequence many people's genomes will allow them to search for rare variations that likely account for remaining genetic risk. "I'd love to get my hands on [this technology] and think about how I can solve new problems with it," says Phil Sharp, MIT Institute Professor and winner of the 1993 Nobel Prize in Physiology or Medicine.

Beyond its unique technology, Complete Genomics has also chosen an unusual business model: rather than selling instruments, as most sequencing companies have done, it plans to offer sequencing services through a commercial-scale genome center. Cliff Reid, the company's president and chief executive officer, hopes that both the service model and the price tag will appeal to those who don't want to do their own sequencing, such as pharmaceutical companies. "They don't want to purchase an instrument; they want to purchase data," says Reid. In an effort to further pharmacogenomics--the ability to prescribe the right drug at the right dose to a patient based on his or her individual genetic profile--genomics is a growing component of clinical trials.

The company is now building a massive data center to manage the immense volume of information it expects to generate; it's planning to have a computer cluster containing 60,000 processors online by 2010. "No one has ever put together a data processing center this size for sequencing--because no one has ever been able to sequence this many genomes," says Reid. Complete Genomics will focus entirely on human-genome sequencing, unlike other companies, which use their technology for a variety of sequencing projects. And unlike Knome, a personal-genomics startup that offers individuals a complete genome sequence and personalized analysis for $350,000, Complete Genomics provides only the genome sequence.

The company has already made its first deal: to sequence 100 genomes in 2009 and 2,000 genomes in 2010 for Leroy Hood at the Institute for Systems Biology, in Seattle. Hood, who in the 1980s developed the first automated sequencing machine, sits on the Complete Genomics advisory board. Hood's project will comprise about ten percent of the facilities sequencing capacity in the first two years.

Even if Complete Genomics faces up to its promises, "they face a lot of competition," says J. Craig Venter. For example, Applied Biosystems, a veteran in the sequencing industry, recently announced a next-generation technology that it believes will be able to sequence genomes for $10,000.

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