Jonathan Rothberg has done more than most to catalyze the revolution in what he calls “Genomics 2.0.” His personal vision eight years ago led to the creation of 454 Life Sciences as a subsidiary of CuraGen (which Rothberg also founded), and the debut of the first next-generation sequencing instrument in 2005.
But while Rothberg happily discussed the characteristics and applications of 454’s successful platform during his keynote address at the 2007 Bio-IT World Conference & Expo held earlier this month, he also excited the audience with his latest high-tech vision -- RainDance Technologies.
Rothberg credited IT and robotics for enabling “Genomics 1.0,” noting CuraGen’s efforts in producing comprehensive interactome maps of gene products. That was analog information, he said. Today, IT and miniaturization is enabling personalized genomics and an explosion of digital information. Moore’s Law comes to genomics, said Rothberg, pointing out that the original 454 instrument was 100 times faster than conventional Sanger instrumentation.
Birth of a Revolution
The development of 454 was motivated by personal reasons. “In 1999, my son Noah was rushed to newborn intensive care,” said Rothberg. “I panicked -- what’s going on, what’s wrong with my son? … I just wished at that moment, I could read off my son’s [DNA] sequence.”
During his vigil that night, Rothberg glanced at the latest issue of InfoWorld. “I noticed a new Pentium chip was on the cover. Boy, if we could move sequencing to a chip and miniaturize it, we’d be able to sequence quickly.” Fortunately, Rothberg’s son recovered quickly.
One of the early successes for 454 has come in the field of ancient DNA, a field set back by the paucity and degradation of recovered DNA. Neanderthal DNA extracted from skeletal remains is only 90-120 basepairs long, but a perfect match for 454, which sequences fragments of about 250 bases. “454 technology is a match made in heaven for ancient DNA,” said Rothberg. “If you can sequence Neanderthal, you can sequence anybody.”
Rothberg said that 454’s breakthrough role in sequencing of more than 1 million bases of the Neanderthal genome paves the way for major breakthroughs in the biology of human cognition – a longstanding interest of his. The Neanderthal paper was one of more than 30 major publications last year in a wide range of fields featuring 454 technology. Rothberg predicted that sales would exceed $70 million this year, with more than 100 machines sold this year.
Rothberg also noted the preliminary sequencing of the genome of James D. Watson, who was happy to donate his DNA. The sequencing -- about 40 million reads – cost under $200,000, said Rothberg. Interestingly, about 1.3 million reads did not match the reference sequence – it turns out the consensus genome is missing about 1-2 percent (because those DNA fragments underwent bacterial cloning and Sanger sequencing.)
Rothberg noted that Watson’s genome contains more than 68,000 insertions and deletions compared to the reference sequence. “We’ve now crossed an inflection point – the new technology is not only cheaper and faster, but has advantages [over old technology]… You cannot just map to a scaffold. There’s no genome you can’t assemble with 250-base paired end reads.”
Dancing in the Rain
With the sale of 454 to Roche announced earlier this year, Rothberg is now pushing his latest venture – RainDance Technologies. “Genomics 2.0” requires much more than sequencing. His latest goal is to miniaturize not just sequencing, but almost every facet of general laboratory practice.
The key, said Rothberg, was “to get the smartest people you can first to sign up!” He then dismissed conventional lab-on-a-chip designs, which he termed “a disaster.” Charting the evolution of laboratory research from test tubes and handwritten labels to microtiter plates and barcodes, Rothberg presented the next phase – nanoreactors with quantum dot labeling that are like a personal laboratory system.
The system, which shrouds chemicals in tiny droplets (not unlike the 454 system), enables thousands of assay reactions per second. Just as in semiconductors, electronic gates control the flow of electrons, RainDance’s nanoreactors use modules to gate the flow of reagents as well as the mixing, heating, and storing of tiny droplets.
A wide range of modules enables virtually any application, said Rothberg. Examples include enzymatic reactions, PCR, protein-protein interactions, cell counting, RNAi screening, as well as chemistry applications. New chips can be designed and manufactured in weeks, said Rothberg, who foresees a plethora of applications in drug development, genomics, cancer diagnostics, and biofuels. RainDance is already collaborating with Bayer Pharmaceuticals on high-throughput screening assays, noting the vastly superior statistics and reagent costs. “One of the beautiful things about these drops,” said Rothberg, “is once you make these drops, they’re stable [at room temperature].”
“Moore’s Law has been good to me,” Rothberg concluded, predicting the evolution of macro- to micro- for lab science in the very near future.
Photo by Mark Gabrenya
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