The Gene: An Intimate History - Siddhartha Mukherjee Page 0,146

generations, that specified a single visible property or phenotype, such as flower color or seed texture in peas. Morgan and Muller deepened this understanding by demonstrating that genes were physical—material—structures carried on chromosomes. Avery advanced this understanding of genes by identifying the chemical form of that material: genetic information was carried in DNA. Watson, Crick, Wilkins, and Franklin solved its molecular structure as a double helix, with two paired, complementary strands.

In the 1930s, Beadle and Tatum solved the mechanism of gene action by discovering that a gene “worked” by specifying the structure of a protein. Brenner and Jacob identified a messenger intermediate—an RNA copy—that is required for the translation of genetic information into a protein. Monod and Jacob added to the dynamic conception of genes by demonstrating that genes can be turned on and off by increasing or decreasing this RNA message, using regulatory switches appended to each gene.

The comprehensive sequencing of the worm genome extended and modified these insights on the concept of a gene. A gene specifies a function in an organism, yes—but a single gene can specify more than a single function. A gene need not provide instructions to build a protein: it can be used to encode RNA alone, and no proteins. It need not be a contiguous piece of DNA: it can be split into parts. It has regulatory sequences appended to it, but these sequences need not be immediately adjacent to a gene.

Already, comprehensive genome sequencing had opened the door to an unexplored universe in organismal biology. Like an infinitely recursive encyclopedia—whose entry under encyclopedia has to be updated constantly—the sequencing of a genome had shifted our conception of genes, and therefore, of the genome itself.

The C. elegans genome—published to universal scientific acclaim in a special issue of Science magazine, with a picture of the subcentimeter nematode emblazoned on its cover in December 1998—was a powerful vindication for the Human Genome Project. Days after the worm genome announcement, Lander had exciting news of his own: the Human Genome Project had completed one-quarter of the sequence of the human genome. In a dark, dry, vaultlike warehouse on an industrial lot near Kendall Square in Cambridge, Massachusetts, 125 semiautomated sequencing machines, shaped like enormous gray boxes, were reading about two hundred DNA letters every second (Sanger’s virus, which had taken him three years to sequence, would have been completed in twenty-five seconds). The sequence of an entire human chromosome—chromosome twenty-two—had been fully assembled and was awaiting final confirmation. In about a month, the project would cross a memorable sequencing landmark: its one-billionth human base pair (a G-C, as it turned out), of the total 3 billion.

Celera, meanwhile, had no intention of lagging behind in this arms race. Flush with funds from private investors, it had doubled its output of gene sequences. On September 17, 1999, barely nine months after the publication of the worm genome, Celera opened a vast genome conference at the Fontainebleau Hotel in Miami with its own strategic counterpunch: it had sequenced the genome of the fruit fly, Drosophila melanogaster. Working with the fruit fly geneticist Gerry Rubin and a team of geneticists from Berkeley and Europe, Venter’s team had assembled the fly genome in a record spurt of eleven months—faster than any prior gene-sequencing project. As Venter, Rubin, and Mark Adams rose to the podium to give talks, the leap of the advance became clear: in the nine decades since Thomas Morgan had begun his work on fruit flies, geneticists had identified about 2,500 genes. Celera’s draft sequence contained all 2,500 known genes—and, in a single swoop, had added 10,500 new ones. In the hushed, reverential minute that followed the end of the presentations, Venter did not hesitate to drive a switchblade through his competitors’ spines: “Oh, and by the way, we [have] just started sequencing human DNA, and it looks as if [the technical hurdles are] going to be less of a problem than they had been with the fly.”

In March 2000, Science published the sequence of the fruit fly genome in yet another special issue of the journal, this time with a 1934 engraving of a male and a female fruit fly on its cover. Even the most strident critics of shotgun sequencing were sobered by the quality and depth of the data. Celera’s shotgun strategy had left some important gaps in the sequence—but significant sections of the fly genome were complete. Comparisons between human, worm, and fly genes revealed several provocative patterns. Of the 289 human genes known to