Thursday, Jan. 24, 2008
Scientist Creates Life — Almost
By Alice Park
Not only has Venter constructed the first man-made genome, he has also sequenced his own dna, which is now part of a public genetic database
If you were setting out to design a human being from scratch, odds are you wouldn't take J. Craig Venter as your template. You wouldn't choose to put him at risk for Alzheimer's disease, for example, but Venter has a predisposition that places him in danger of it. You might choose his startling blue eyes, both for their color and the hard clarity of their gaze. You'd surely go for his first-rate brain, though you might pass on what his detractors consider the vainglorious temperament that comes bundled with it.
It's something of an irony then that such an imperfect organism as Venter has devoted much of his career to understanding the engineering of other organisms. He was the leader of one of two teams that in 2000 sequenced the human genome—the entire 25,000-gene cookbook that makes us people in the first place and not chimps or birds or banana trees — and he has conducted the same work with many other organisms. But Venter, 61, may have just done something that is at once more thrilling and promising and unsettling than all that. According to a just-released paper in the journal Science, he has gone beyond merely sequencing a genome and has designed and built one. In other words, he may have created life.
Certainly, defining what we mean when we say life has become a moving target over the years. Are we alive? Yes. Is a virus alive? Maybe. Still, a half-century after the discovery of the double helix, nobody doubts that it is our DNA that determines what we are — in the same way that lines of code determine software or the digital etchings on a CD determine the music you hear. Etch new signals, and you write a new song. That, in genetic terms, is what Venter has done. Working with only the four basic nucleotides that make up all DNA — adenine, cytosine, guanine and thymine — he has assembled an entirely new chromosome for an entirely new one-celled creature. Insert that genome into a cell — like inserting a disc into a computer — and a new species of living thing will be booted up. Venter hasn't done that yet, which is why even he won't say that he has technically invented life. He has, however, already shown that a genome transplanted from an existing cell to another will shut down the host's genetic programming and bring its own online. If that cellular body-snatching works with an ordinary chromosome, there's little reason to think it won't with a manufactured one. "The fact that this is even possible is mind-boggling to most people," Venter says.
That's not an overstatement. The genome in Venter's lab in Rockville, Md., could revolutionize genetics, introducing a new world order in which the alchemy of life is broken down into the ultimate engineering project. Man-made genomes could lead to new species that churn out drugs to treat disease, finely tuned vaccines that target just the right lethal bug, even cells that convert sunlight into a biofuel.
Creating such small, single-purpose organisms is nowhere near as complex as creating larger, multicelled creatures — things with mobility, behavior, a purpose, a face. Those fanciful and frightful things are surely many years away and may prove too challenging and disturbing for society to allow. What Venter appears to have done, however, is crack the manufacturing code. Once you've done that, there may be little limit on what you can eventually build.
It was not always evident that Venter would become such a transformative figure — particularly when he was a boy. He was never a terribly engaged student (his 2007 autobiography, A Life Decoded, includes his eighth-grade report card, filled with Cs and Ds). He fondly recalls testing the patience of both his parents and the pilots at San Francisco International Airport when he and his friends, pedaling furiously on their bicycles, would race planes taxiing for takeoff on a remote runway. (Airport officials eventually fenced it off.) In 1967 he went to Vietnam, where he had been drafted to serve as a hospital corpsman in the Navy. As a relief from what he describes as "M*A*S*H without the jokes and pretty women," Venter, with the help of some Marines on China Beach, taught himself to sail 19-ft. (5.8 m) sailboats known as Lightnings. "When you're in the middle of a war, freedom is something you think a lot about," he says. "I always had a dream of sailing around the world."
Like many who live through a war, Venter returned a different man. He wanted to attend medical school and enrolled in community college and then at the University of California at San Diego. By graduation in 1972, he had become enamored of biochemistry and decided to pursue a graduate degree instead. He ended up taking a job with the National Institutes of Health (NIH) in Washington, walking the mazelike halls of the government building as a civil servant.
As energized as he was by the work, the ambitious and freethinking Venter chafed at what he calls the "bureaucratic hell" there and longed for the opportunity to test the innovative ideas he had for transforming the emerging field of genetics. In 1992 he secured private funding and created his own company, the Institute for Genomic Research in Rockville. Within three years he completed the first-ever genome sequencing of an entire organism—Haemophilus influenzae, the bacterium that causes meningitis. The firm soon became a go-to place for sequencing projects, and it wasn't long before Venter hungered for the biggest prize in biology: the map of the human genome. In the 1990s such a project was almost unthinkable, a feat of mind-numbing complexity that involved determining the placement and makeup of every one of the human genome's genes, some of which can contain thousands of nucleotides.
By now, however, Venter had brainstormed a way to automate the process, pulling in supercomputers to do the work of recording each letter in all the necessary snippets of DNA and then knitting the fragments together in a simple and predictable way. If a page of text from a book were torn into pieces, it could be easily reconstructed as long as the tears were made at predetermined places — always before the word only, for example, whenever it appeared on the same page as the word and. Venter's system worked in a similar way, and in 1998 he brashly predicted that using his method, which he called shotgun sequencing, he could finish the map faster and less expensively than the government's $3 billion sequencing effort led by Dr. Francis Collins.
To ensure he'd have the resources to make good on that boast, Venter joined hands with global technology giant Perkin-Elmer, forming a new company called Celera, which took its name from the middle of the word accelerate. The Celera-backed Venter and the NIH-backed Collins briefly explored collaborating, but those efforts fell through, and over the next two years the two camps worked feverishly, occasionally volleying in the press over whose method was better or whose intentions were purer. Collins sniffed at Venter's plans to create a genome database whose basic map he would make available for free — as the NIH planned — but to charge anyone who wanted the data processed or analyzed.
In 2000, Venter delivered on his promise, finishing just ahead of Collins, but a government official who knew both men, hoping to quiet the feuding, brokered a truce between the groups, which included the sweetener of a joint announcement at the White House in 2000. President Bill Clinton lauded the completed genome as "the most important, most wondrous map ever produced."
The high times did not last long. Back at Celera, the competing interests of a free public database and a corporation's stockholders proved hard to reconcile, and just two years after the White House ceremony, Venter was fired by the board. For solace, he decided to get away. Still a sailing enthusiast, he hit on a grand plan to mimic the journey of the H.M.S. Challenger, the vessel that in the 1870s conducted the first global mission to sample life from the oceans of the world. Venter would circumnavigate the globe with a crew of scientists and sailors and every 200 miles (320 km) would dip canisters into the ocean at various depths, filter whatever life-forms floated in — mostly microscopic — and send them back to his newly created lab, the J. Craig Venter Institute in Rockville. Over 2½ years, the journey yielded 6 million new genes and 400 new microbial species. "Most people thought the ocean was a homogenous soup," Venter says. "But 85% of the species we found were unique."
As he shuttled between his ship and his lab, Venter was overseeing another, equally grand and potentially revolutionary science project: creating life in the lab. Among the organisms he and his team sequenced in the years leading up to the human-genome work was Mycoplasma genitalium, an unlovely bacterium whose preferred target on the animals it infects is evident by its name. That organism, which the team sequenced in 1995, has one of the smallest known chromosomes of any self-replicating life-form — just 485 genes. What, Venter wondered back then, was the minimum genome an organism needed to survive and reproduce? If you could figure that out, you could determine the basic DNA chassis of all living things and then use it to design your own souped-up or dressed-down versions of life.
A decade ago, the only way to establish whether the microbe needed a gene was to knock each of the 485 out, one by one and then in combinations, and see if the bug survived. By 2002, however, advances in both genetic understanding and gene-handling technology had leaped forward. Instead of having to deconstruct Mycoplasma genitalium, Venter's team could build it from scratch. This meant that whereas once they had to reverse-engineer the organism and see when it quit working, they could take the more elegant approach of assembling it from off-the-shelf nucleotides and seeing when it switched on — essentially building life.
But elegant does not mean easy. DNA's nucleotides are strung together like beads on a string, but because it adopts a crystalline structure, that string behaves more like glass. "Even doing normal things like pipetting the pieces would shatter it," says Venter. And although tiny in the microbe world, the mycoplasma's genome still required more than 580,000 nucleotides to assemble.
So Venter decided to start small, with one or two genes, and work his way up by splicing together longer and longer pieces of DNA. That very act of sticking them together proved to be a challenge, since the strands often fall apart. The answer was to design a section of Velcro-like DNA at the ends of each fragment. Since adenine sticks only to thymine and cytosine only to guanine, all the team had to do was end each strand with a nucleotide that would adhere to the one that began the next.
Such painstaking cut, study and paste eventually did the job. Not only did Venter's team members succeed in building their own mycoplasma at their own lab benches, they also took the opportunity to rewrite its genetic score. First, they introduced a mutation that would prevent it from causing disease. Then they branded it with a series of watermarks that would distinguish it as a product of their lab. Using a code built around selected genes, they spelled out five words that Venter coyly refuses to reveal, saying only that any molecular-biology study can suss them out and promising that there are no obscenities. The next step, which could happen in a matter of months, will be to insert the gene into a cell and see if it indeed stirs to life. "This team is betting its reputation that that will happen in 2008," Venter says.
Not everyone believes he will succeed — or if he does, that it will matter much. Corporate giants like DuPont already put synthetic biology to industrial use. In the company's Loudon, Tenn., plant, for example, billions of E. coli bacteria stew inside massive tanks. The bacteria's genomes contain 23 alterations that instruct it to digest sugar from corn and produce propane diol, a polyester used in carpets, clothing and plastics. The hard-working bugs churn out 100 million lbs. (45 million kg) of the stuff each day, and all it took was a little tinkering with their genomes, not the construction of a new one. "In terms of whether I can think of anything I can only do with a whole synthetic chromosome that I can't do now, the short answer is no," says John Pierce, vice president of technology at DuPont Applied BioSciences.
Collins, Venter's once and perhaps future rival, whose group at the NIH is also working on creating synthetic genes, echoes that doubt. "Suppose I have a pile of dirt in my backyard and I want to move it," he says. "I could spend months building the components, but I already have a lawn tractor, so what I need to do is add a front loader. Why not take the shortest path?"
Venter agrees that this all makes sense — but only if you accept a limited view of the science. He is not alone. "We are starting to turn the corner," says Jay Keasling, a bioengineer at the University of California, Berkeley. "The technologies are starting to be put in place, and it's crazy to keep doing biology the way we are doing it."
Still, after spending his career trying to digitize, quantify and standardize biology, even Venter recognizes that there may be some aspects of life that simply can't be understood without a nod to what he calls the "mystery and majesty" of the cell. Well before he became involved constructing artificial life, he christened his sailboat with a name that may reveal as much about that awareness as about what he is trying to accomplish: he called it Sorcerer.