Healthy Competition Advances the Field of Biology

About 10 years ago, biology entered betting season. An upstart scientist named J. Craig Venter jolted the genetics establishment by launching his own gene-sequencing outfit, funded by commercial investment, and setting off toward biology's holy grail—the human genome—on his own. It was Venter versus the old guard—old because of where they got their money (governments and trusts) and the sequencing technique they wanted to hold onto. Venter won that race, and not because he got there first. By combining the freedom of academic inquiry and commercial capital, he came up with a new way of doing science so effective that it forced the old institutions to either ramp up or play second fiddle.

With Venter's momentum, biology has continued to surge into new territory, but now he's not alone in pushing the pace. In fact, with his staff of hundreds at the J. Craig Venter Institute, he is looking dangerously like the establishment he raced past almost a decade ago. Another maverick in the stable, Harvard biologist George Church, is a titan in the academic world, tackling the major challenges of genomic-age biology with an ingenuity distinct from Venter's. Both are building on the foundation of DNA sequencing, trying to drive down the cost of decoding individual genomes and—the more radical enterprise—using their digital control of cells and DNA to design new organisms. Between them, Venter and Church direct or influence a major portion of work in both sequencing and synthetic biology, including three different commercial efforts to develop bacteria that could produce the next generation of biofuels.

There's reason to believe that Church has a decent chance of unseating Venter as biology's next wunderkind. The field of genomics is only at the beginning of its growth spurt—sequencing, it turns out, was just phase one. Far from producing answers, the sequenced genome has instead led scientists into a thicket of questions: What exactly do combinations of genetic code produce in an organism over a lifetime? If we can read the script, can we also write it? Leading science out of the genomic wilderness arguably calls for a vision more deeply imaginative than the task of the Human Genome Project, which was clearly framed and, at heart, a code-reading slog. Radical invention—the kind of out-of-left-field inspiration that makes a thinker either brilliant or totally unrealistic—is the strength of Church, as opposed to Venter, who is more of an aggregator, a connector of existing ideas and methods. The script of this new biology is largely unwritten, and just because Venter turned the first page doesn't mean that in the end his vision will prevail. "Sometimes," Church says, "it's best to be second."

The quest for ideas farther afield may be one reason Venter joined the Harvard faculty this spring—his first academic post since 1982. (Venter declined to be interviewed for this article.) He and Church are even members of the same research initiative, called Origins of Life, where they're investigating life in its most basic genetic and molecular forms. Venter's participation is a sign of just how widely applicable the high-concept work of the university could be. More than ever, over the uncarved terrain of the new biology, Venter and Church are blurring the distinction between the academic and the commercial. Steven Shapin, a Harvard historian of science, says that at this point we must "stop categorizing—and just look at what these people are doing." On top of all the daring science, Venter and Church are also conducting a "sociology experiment": "They're making up their own social roles," Shapin says, "making up themselves." All the while, Church insists that he and Venter are "not right on top of each other" but are "part of the same ecosystem," fulfilling different roles. Then again, Shapin points out, "the lion and the wildebeest are in the same ecosystem." The question is, who's the lion?

If you were to speak of George Church as an underdog to any of his university peers, you would probably get a laugh: with more than a dozen graduate students and 18 postdoctoral researchers, he runs one of the biggest labs in the richest university in the world. Next to Venter's institute, though, his still feels like a scrappy outfit in the corner. But he likes it this way: "Sometimes—not always—the smaller operation is more nimble," he says. Church's group has produced prototypes for some of the second-generation DNA-sequencing machines, which he hopes will help bring down the cost of sequencing genomes to the point where your genes can be consulted as routinely as X-rays.

At the moment, both Venter and Church are working to construct rudimentary organisms. The promise of this technology is difficult to exaggerate. By altering the chemistry of organisms, manipulating genomes and even constructing parts of cells, they can engineer tools out of living things. Both Church and Venter think of cells as machinery. Announcing his latest breakthrough in March with the synthesis of ribosomes, the all-important protein generators of the cell, Church used a hot-rod analogy: "It's like the hood is off and you can tinker directly." Venter has described his own work with reengineering cells in terms of a PC: "We can boot up a chromosome … boot up a cell."

As Church and Venter lay the groundwork for a new way of understanding and using biology, their respective approaches reveal their essential differences. Venter's great stride toward designing life forms was in transplanting the genome of one bacterium into another—two different species of the genus Mycoplasma. The transplanted genome took over its new cells and turned them into cells of its own species. Preceding Church at the Harvard lectern in March at an Origins of Life symposium, Venter described this as creating "software that makes its own hardware"—but in truth both software and hardware were already present and living; he came up with a different combination, and got it to do something completely novel. Church, in making ribosomes, has surmounted a different kind of barrier. The ribosome is regarded as the living cell's most irreducible part, and something common to every kind of cell—those that make up bacteria as well as plants and humans. The physicist Freeman Dyson has spoken of the ribosome as the key to the origin of life; two years ago, at an intimate gathering of some of the world's most imaginative scientists on a Connecticut farm, Dyson told Church, Venter and the three other researchers present that "the invention of the ribosome is the central mystery" of how living things ever came to be. Church has now managed to take a ribosome apart and build it up again, which means he can make something even more primitive—until, with a simple collection of atoms, he jump-starts a living organism of his own making. "I'm not quite ready to say that we have connected all the dots," he says, but it's now conceivable that "you can get from chemicals to RNAs, to smallish ribosomes, to full ribosomes, and then to a cell."

Right now, for both scientists, the bacterial equivalent of a hot rod is an organism that can consume carbon dioxide and make engine fuel. Last year Venter told newsweek that Synthetic Genomics, the commercial counterpart of his nonprofit research institute, was one or two years away from producing its first fuels. Church, though, had already founded a startup, LS9, in 2005 to develop a commercial product. The idea behind both ventures is to exploit the ability of natural bacteria to turn sugar into fatty acids, which is only a few chemical steps removed from diesel fuel.

At this stage, both Church and Venter welcome a crowded playing field, with different startups testing a variety of approaches, but this race, more than that for the human genome, has a far more tangible prize for whoever is first—or maybe, if they succeed better, second. "There will be convergence on whatever works," Church says. "Until there's actually somebody making a lot of money, there's not going to be convergence." In the meantime, Church cheerfully points out that Venter is manipulating the wrong kind of bacterium. While he and others are using E. coli, Venter has stuck with Mycoplasma, which has very few genes to manipulate but grows far more slowly and has a sensitive membrane, so that it is likely to come apart on contact with the fuel it's meant to produce. "He's like Captain Ahab," says Church of Venter. "The Mycoplasma is his white whale. He decided that small is beautiful and he's going to synthesize it. Partly because he wasn't prepared to change the technology enough so he could synthesize something bigger."

Church is, foremost, an inventor in the purest sense, someone who would make something completely new to perform a function that no one even thought might be helpful. His chief preoccupation in graduate school was making an automated DNA sequencer that could process vast amounts of data as quickly as possible. In 1979, even people in his own lab didn't see why you would ever want something like that. "That was really ridiculously out of touch with where the market was," Church admits now, but his eyes smile. Years later, Leroy Hood, at Caltech, made the prototype that became the ABI 3700, the first-generation automated sequencer that inspired Venter to crash through the gates of the genome. Hood disparaged that early model as the equivalent of a Ford Model A, but Venter couldn't wait; he pushed on with it, worked out the inevitable bugs and, by running 300 imperfect machines instead of 230 perfect ones, ground out the human genome. Church, though, was already working ahead.

Venter's genius lies in using invented technologies and techniques to produce unexpected breakthroughs. The ABI 3700s, those Model A's, nevertheless became famous because of what he got them to do. The shotgun sequencing technique didn't originate from him, but he showed the range of its utility, first by sequencing whole genomes, and then by taking genetic snapshots of the ocean and the earth's soil by sequencing samples of living things. When he saw how the ABI machine worked, he realized that all the parts needed for a new genomic age were now in place: a collection of complementary DNA plasmids; a company that purified those plasmids, so they could be sequenced; an automated sequencer; and a public database where sequences of genes could be stored. The connections Venter saw between these four groups gave way to his vision.

There is a price, though, to precipitous application: though Venter sequenced the first diploid human genome (his own, completed in 2007) for far less than the $3 billion originally projected by the federal budget, it was still on the order of $70 million—for one genome. Church, using his own second-generation sequencing instruments just two years later, has now sequenced 95 percent of his genome, while running a tab of about $5,000. He simultaneously sequenced the genomes of nine other people, too, to launch the Personal Genome Project, an open database of genomes matched with each individual's phenotypic traits and medical history. The aim is to amass a statistically significant pool of data that would begin to show the complex connections between a person's genes and the traits and diseases that actually manifest in one's life. The project now has more than 13,000 volunteers for sequencing, and Church hopes to collect 100,000. None of this would have been possible with first-generation sequencing technology, and, says Church, "I didn't really want to do it until the price was right."

When asked, at the Connecticut retreat, how their work was different, Church replied, "Craig is more productive." To which Venter graciously added, "I use George's techniques." As they build the new biology, they have moved closer and closer into each other's orbit, perhaps the better to see, in the work of the other, how the future is shaping up. And though their work gets at the core of living things—in ways that may give humans control over the very process that created life—they are capable of an almost comical diffidence. This isn't "playing God": "You're certainly not creating a universe," said Church at the discussion table in Connecticut. "You're constructing things."

"You're only so big," Venter added.

"Pretty small," agreed Church. "Pretty small."

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