Life Script: How the Human Genome Discoveries Will Transform Medicine and Enhance Your Health - Softcover

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Born in Aylesbury, England, Nicholas Wade studied at Eton College and King's College, Cambridge. He has worked at Nature and Science and is currently a science reporter for The New York Times. The author of four previous books, he lives in Montclair, New Jersey.

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Chapter 3: The Meaning of the Life Script

Though the two sides' claim to have sequenced the human genome sparked headlines around the world, they were celebrating victory before the battle. Each team now had to interpret its genome sequence by describing its major features and locating the genes, and from the quality of the respective reports a clear winner could emerge in the eyes of their fellow scientists.

This first analysis of the human genome was just as much a landmark in scientific history as the years spent decoding the sequence. But it was compressed into a few months' whirlwind of activity as the two sides set about interpreting the strange and enigmatic script they had wrested from the human cell. Talk of a joint annotation conference at which the two sides would compare notes in interpreting the human genome soon evaporated. Celera and the consortium worked with different groups of experts and published their reports in rival scientific journals, Celera choosing Science in Washington, D.C., and the consortium Nature in London. The sharp elbowing continued to the bitter end, with academic biologists including Eric Lander, chief author of the consortium's genome report, lobbying hard to persuade the editor of Science not to accept their rival's paper except under terms unacceptable to Celera.

The academics demanded that Celera make its genome sequence freely available through GenBank, even though GenBank could not meet Celera's condition that its commercial rivals be prevented from downloading Celera's data and reselling it. The editor of Science allowed Celera to be the custodian of its own data on condition that any part of it be made freely available to scientists for checking, a decision to which the academic biologists objected. Venter felt their real purpose was to deny him the prestige of being published in a leading academic journal.

Well before the White House announcement, both sides had started preparing to analyze their respective versions of the genome. Venter had more or less founded the art of genome interpretation when he published the first genome of a bacterium in 1995. He had learned then an important lesson: the best way of interpreting a genome is to compare it with the genome of a similar organism. He had long since decided that the mouse's genome would be a critical tool for interpreting the human genome, because comparison of the two long ago mammalian cousins would reveal by their regions of DNA sequence similarity all the features that nature had found it necessary to conserve. He had risked switching his sequencing machines from human to mouse DNA at the earliest possible moment so as to have both genomes in hand for the task of locating the human genes.

Another advantage for Celera was that its version of the human genome was much less bitty than the consortium's. Celera's vast computer, the largest in civilian use, had assembled 27 million of the 500-base pieces analyzed by the sequencing machines into long, mostly continuous scaffolds that straddled the genome. The consortium's genome was divided into thousands of the small sub-jigsaws known as BACs, chunks of DNA about 150,000 bases in length. The BACs had been completed for the two shortest human chromosomes, numbers 21 and 22, but over most of the rest of the genome were still in small pieces, many 10,000 bases or so in length. It was possible to hunt through these fragments for genes, but not at all easy. The consortium had not tried to assemble them by computer because it did not see the need to do so. Robert Waterston, director of the sequencing center at Washington University in Saint Louis, had prepared a BAC map that showed how one BAC overlapped another across the genome in a complete tiling path. With this BAC map in hand, the same method by which Waterston and John Sulston at the Sanger Centre had sequenced the roundworm's genome, there seemed no need to invest in the complex computing and assembly programs that were a necessary part of Celera's strategy.

Though Sulston and Waterston had laid the scientific groundwork for the consortium's sequencing effort, it was Eric Lander, director of the Whitehead Institute's sequencing center and a mathematician by training, who took the lead in analyzing the genome. In December 1999 he started to invite computational biologists -- a new discipline devoted to computer analysis of genomes -- to join in a genome analysis group. The group had no government funding, according to Lander, and did its work mostly by phone and e-mail.

Meanwhile Venter, who had convened an "annotation jamboree" of outside experts to help find the genes in the fruit fly genome, decided there was now enough expertise within Celera to undertake the first analysis of the human genome in-house, with the help of a few consul-tants.

The consortium might have been hopelessly outgunned in the interpretation phase of the genome race had it not been for a chance encounter, although one made possible by the consortium's open nature. One of the computational biologists approached by Lander in December 1999 was David Haussler of the University of California, Santa Cruz, whom Lander invited to help locate the genes. Haussler decided that before looking for genes, it would be best to put some order into the jumble of fragments within each BAC. He believed there was enough information, some created inadvertently by the consortium and some from other sources, for an assembly program to order and orient the intra-BAC fragments, and he at once started writing such a program.

To create the computing facility to run the program, he persuaded his university chancellor to advance him the money for a network of one hundred Pentium III computers. But the programming went slowly. In May, when a graduate student of his e-mailed to ask how the genome assembly program was going, Haussler replied that things were looking grim.

The student, James Kent, then offered to write an assembly program himself, using a simpler strategy. Haussler replied, "Godspeed." Four weeks later, Kent had completed an assembly program that in his supervisor's opinion might have taken a team of five or ten programmers six months or a year. "He had to ice his wrists at night because of the fury with which he created this extraordinarily complex piece of code," Haussler said of his student. Kent, who had previously run a computer animation company before returning to school to study computational biology, first used the program to assemble and order all the pieces in the consortium's genome on June 22, 2000. In doing so he gained a three-day lead on Celera, whose assembly program had encountered unexpected problems. Venter completed his first assembly of the human genome on June 25, just the night before the White House press conference.

When Celera and the consortium published their analyses of the genome in February 2001, it was clear that the consortium's rested heavily on Kent's improvised assembly program and the computer network put together by his supervisor. Venter was astonished that his competitors had at the last minute managed to extract so much sense from a genome sequence that in his view had been so hopelessly chaotic. "They used every piece of information available," he said. "It was really quite clever, given the quality of their data. So honestly, we are impressed. We were truly amazed, because we predicted, based on their raw data, that it would be nonassemblable. So what Haussler did was, he came in and saved them. Haussler put it all together."

In their first glimpse of the human genome, the two teams came to similar conclusions, of which the most surprising was the far smaller than expected number of human genes. Both found about 30,000 protein-coding human genes, far fewer than the 100,000 human genes that textbooks had estimated for many years. The 100,000...