Named for Dr. Frederick Sanger, an English biochemist and two-time Nobel laureate in chemistry, the Sanger method provided science in the late 1970s an advanced tool for automating DNA sequencing, eventually leading to the deciphering of whole genes, and in 2003, an entire human genome.

While significantly faster, and with reduced handling of toxic chemicals and radioisotopes than previous laboratory experiments, Sanger’s method still required hundreds of DNA capillary sequencers and dozens of employees in huge factory-like sequencing centers.

In recent years, a new technology has eclipsed the Sanger system: next-generation or “next-gen” sequencing, systems housed in freezer-sized devices run by a single operator.

“Next–gen sequencing allows us to dig deeper into the genome than ever before by providing more information and increasing our probability of identifying something significant,” said Dr. John Carpten, Director of TGen’s Integrated Cancer Genomics Division. “The long-term hope is that doctors will leverage this information to inform decisions about patient care.’’

The holy grail of sequencing is the ability to spell out the entire 3 billion bases of an individual human genome for $1,000 or less, allowing more people to be tested for disease causing genetic lesions and matched to better treatments. But it may be a while before people walk around with their own genome on a memory stick.

Still, next generation sequencing is quicker, costs less, produces more data and holds the promise of advancing biomedical science at a faster rate than ever before. The prospect of a $1,000 genome would allow researchers to scale up their investigations, providing more data at less cost.

“I think we have a long way to go before realizing the power of these technologies from a consumer-genetics standpoint,’’ said Dr. Carpten, who has worked at the cutting edge of genomic science for more than 20 years. “I believe that one of the most immediate uses of these technologies for clinical practice, from my point of view, lies in the area of genomics-guided therapeutics for cancer.”

Sequencing can help researchers find the answers to many pressing questions: Are there mutations associated with the initiation of cancer? Are there mutations associated with drug-resistance in cancer? Are there mutations associated with progression of cancer?

According to Dr. Carpten, 15 years ago he could examine at most 5 genes at a time: 5 years ago, maybe 50 genes.

Next-gen Benefits TGen Research

“Now I can look at the entire set (more than 21,000) of annotated genes across the genome in a relatively efficient and cost effective manner. As the technology continues to improve – as throughput and resolution improve – it will allow us to search more panoramically across the genome, rather than having to focus on a specific region, based on a priori knowledge of the biological relevance of a given gene. This will allow for more global interrogation the genomic landscape of tumors. To me, nothing could more exciting.’’

So, can we sequence the full genome of a tumor and identify targets for treatments?

“We are there,” said Dr. Carpten. “We’re hoping to perform a demonstration study to fully sequence the genome (DNA) and transcriptomes (messenger RNA) for a series of patients with late-stage cancer in hopes of informing the best and most appropriate target for treatment for each patient’s specific tumor. To perform and complete a study of that type to me would be fulfilling my purpose in life. It would be a dream come true. To be honest, this is the reason I came to TGen.’’

Although Dr. Carpten is not yet ready to release details, he hopes that the study will start sometime in 2010.

TGen’s Team Effort

The increased information generated by next-gen sequencing requires a team of computational experts to sift through the billions of data points in search of relevance and order. On this front, Dr. Carpten is quick to praise the efforts of TGen colleagues – Dr. David Craig, John Pearson and Dr. Ed Suh – in working towards overcoming these bioinformatic and computational challenges.

And to remain an elite institute, TGen must continue to be associated with the world’s best technology, he said. “It is important for TGen, if we are going to remain competitive, to engage with the providers, acquire the equipment and optimize the assays.’’

TGen’s Neurogenomics Division had acquired an Illumina next-gen platform in 2007. After some consideration, Dr. Carpten decided to look into a new platform offered by Applied Biosystems, now a division of Life Technologies Corp. He based the decision on his long-standing relationship with the company. “Since my post-doc days, Applied Biosystems had always treated me like a partner rather than just another customer,” he said.

Dr. Carpten and his lab team of Christiane Robbins and Tracy Moses successfully tested TGen’s first Applied Biosystems SOLiD device in 2008. According to Carpten, “you need to have great laboratory staff to bring up these types of technologies and TGen’s Research Associates are second to none.” Through a partnership with Life Technologies, TGen this year acquired additional SOLiD devices to meet demand, as a growing number of TGen investigators take advantage of the technology.

According to Dr. Carpten, several TGen investigators are funded to incorporate next-gen sequencing technologies in their research, including Drs. Jeffrey Trent, Paul Keim, David Duggan, Matthew Huentelman and Kevin Brown. Others are quickly following suit.

“Our scientific vision, clinical motivation, strong informatics and computational infrastructure, puts us in a fairly elite category as an institute, and it shouldn’t be taken for granted,’’ said Dr. Carpten, who ticks off Boston’s Broad Institute, Seattle’s Fred Hutchinson Cancer Research Institute, and Washington University in St. Louis as a few examples.

“I just don’t know if the general public realizes how incredible this place really is,” Dr. Carpten said. “We’re playing in Yankee Stadium. This is Major League. Now its time to step up to the plate and try to knock a few of these diseases out of the park!’’

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