Biology’s Odd Couple

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."