“The last year has been the most exciting period in genomics since the days of the Human Genome Project,” says Eric Lander, first author on the project’s first published draft of the human genome and now head of the Broad Institute for genomic medicine in Cambridge, MA. “Sequencing is becoming cheap enough and powerful enough that it can be applied to about any problem. It’s standing the field on its head.” Francis Collins, who led the Human Genome Project for the National Institutes of Health, predicts that the new sequencing technologies “will have profound consequences for the future of biomedical research and, ultimately, for the practice of medicine.”

A Unique Solution
Jonathan Rothberg’s office has a diner theme, with a red-and-black checkerboard tile floor, red Naugahyde-covered chrome chairs, and a sofa with arms that imitate the rear of a 1959 Cadillac, complete with monster tail fins and ­bullet-shaped taillights. Instead of a desk, he has a diner bar with bar stools. Wine bottles from a Connecticut vineyard he owns line some of the shelves. Beyond the windows lies the Long Island Sound. The place screams I am unique. And so Rothberg is. In 1991, while completing his PhD in biology at Yale University, he started ­CuraGen, one of the first companies to develop drugs based on genomics. In addition to CuraGen and 454 Life Sciences, he has founded an institute for the study of childhood diseases and yet another biotech company, RainDance Technologies, which has developed what it calls “liquid circuit boards” that are designed to make experiments more efficient by manipulating tiny quantities of fluid. And all that by the age of 43.

Indeed, it was an interest in the uniqueness of each person that ultimately led him to try to design a sequencer that he hopes will one day make genome checks as routine as blood tests are now. Rothberg holds up the guts of the 454 machine, a glass slide with 1.6 million miniature wells, each approximately 50 micrometers wide (about half the width of a human hair) and 55 micrometers deep. It is this chip that allows the machine to sequence DNA so quickly, because a separate chemical reaction can be carried out in each well.

Gene sequencing takes advantage of the fact that the two strands of a DNA helix are complementary: of the four chemical “bases” adenine, guanine, thymine, and cytosine, which are strung together in various orders on each strand, adenine pairs only with thymine, and guanine only with cytosine. In the most commonly used sequencing technique, which builds on a scheme developed 30 years ago by the University of Cambridge’s Frederick Sanger, fragments of DNA are separated into single strands and exposed to free nucleotides, which bind to the original As, Cs, Ts, and Gs to generate new complementary strands. These strands vary in length because some of the free nucleotides have been modified to prevent the reaction from continuing; when one of these bases binds to its target, the chain stops growing. And each of these four types of chain terminators has a different fluorophore attached that fluoresces when struck by a laser beam. An electric current separates the strands by size, and the laser reads the colors to determine which was the last base added to each chain, spelling out the sequence. The vast majority of labs that do sequencing today use a machine made by Applied Biosystems that spits out about two million bases a day.