The Code Breaker

Instead of patiently unraveling life's secrets gene by gene, we can now read them at breakneck speed—thanks in great part to an ingenious, admired, despised, once aimless and now wealthy biologist named Craig Venter.

By James Shreeve|Friday, May 01, 1998
RELATED TAGS: GENETICS, OCEAN
Craig Venter is making waves. He is standing at the helm of his 200-horsepower outboard, gaze fixed over the bow, a baseball cap thrust down tight against the wind. The outboard bounds along the shore toward Hyannis Harbor, beating the water behind into an angry blond froth. As he approaches another boat, he exerts a little more pressure on the throttle, leaving the larger vessel dazed and wobbling in his wake like a top at the end of its spin. August on Cape Cod, and Venter is in his element.

Some people think there’s a gene for an affinity to water, he says, when he slows down enough for his subdued voice to be heard over the engine. Maybe I’ve got it.

If there are genetic affinities for moving quickly and causing a lot of commotion in the process, Venter probably has those too. In less than a decade he has sprinted from respectful obscurity at the National Institutes of Health to become—based on sheer output—perhaps the most productive biologist in the world. He began his dash with an audacious end run around the largest directed enterprise in science; went on to establish his own institute and make a modest fortune; kindled the ire, resentment, and grudging respect of the scientific elite; and in the end, set the pace for how life will be studied in the twenty-first century.

The focus of that study is the genome—the complete genetic code for an organism, whether man or microbe. And traditionally it has been regarded as a mysterious black box, the contents of which have to be tweezed out gene by individual gene. But at the Institute for Genomic Research in Rockville, Maryland (where Venter, its head, spends most of his time on dry land), genomes are being thumbed open like overripe figs and turned inside out, their innermost contents laid open for all to work their will upon. Venter’s brand of biology isn’t pretty or romantic, and some of his colleagues would characterize Venter himself as more an opportunist than a visionary. But no one doubts his contribution. According to the Institute for Scientific Information, which tracks the number of times research papers are referred to in other papers, Craig Venter was the second most often cited biologist in the world last year. The most cited biologist, in case you’re wondering, works for him.

For the first time, we can look at organisms from the inside out, he says. It’s a fantastic time to be a biologist.

Being a biologist—or anything else in particular—hardly seemed to be Venter’s destiny. After barely graduating from high school, he drifted from San Francisco down the coast to Newport Beach, working nights so he could surf all day. Then Vietnam intruded into his California dreams. Though initially drafted by the Army, Venter was recruited by the Navy for its swim team and managed to switch services, apparently ensuring that his uniform would be no bigger than a Speedo suit. But while Venter was still in boot camp, President Lyndon Johnson announced that he would be escalating the war. As a result, military athletic teams were dismantled. Venter then chose to join the hospital corps, since it required a shorter commitment than other parts of the Navy. No one had told him that hospital corpsmen in Vietnam weren’t expected to live through their tour of duty, no matter how brief. After a posting in San Diego, Venter was sent to a hospital in Da Nang, where each day he sorted the salvageable from the dying, trying to stitch rended bodies back together while avoiding incoming shells.

By the time I was through with my tour, he says, surfing didn’t seem like an option anymore.

Among the hundreds of wounded soldiers Venter treated, two in particular would have a lingering influence on the direction of his life.

The first was a kid who died of a small bullet wound to the head. I was asked to help with the autopsy. The entry wound was really small, like a .22. I took out his brain and found that the bullet had left just a tiny track, with no obvious damage, though it must have hit something vital. I was totally stunned that this was enough to kill someone. The other soldier was a guy barely 18. They brought him in with multiple wounds to the belly. His intestines were blown apart. We gave him about 12 hours at the most. But not only did he regain consciousness, he lived for several more weeks, talking the whole time about how he wanted to get home and play basketball. By any biomedical standard, he shouldn’t have been alive. So one guy dies instantly with hardly any apparent cause, and the other clings on for weeks without any guts, out of sheer determination. I was only 21 myself. I started asking myself big naive questions. What is life in the first place? What makes it work? Two cells can be composed of exactly the same components, but one is dead and the other alive. What’s the difference? I still don’t have any explanations for why that first soldier died or what kept the other one living so long. And I’m still asking big naive questions.

To pursue those big questions, Venter studied biochemistry when he returned from Vietnam, getting both his B.A. and Ph.D. from the University of California at San Diego in only six years. From there he began working at the State University of New York at Buffalo, where he worked with his wife and colleague, Claire Fraser, on a protein that serves as a receptor for adrenaline in human brain cells. In 1984 they moved to the National Institutes of Health, where they continued their work on the receptor and eventually succeeded in finding the gene that contains its blueprint too. Venter was well funded, well published, and ensconced. But he was losing sight of the big questions.

Claire and I and a whole team of investigators had spent ten years trying to understand one molecule, he says. I didn’t feel I was enriching anybody’s understanding of life.

Then Venter began reading about an enterprise scaled more to his liking—the Human Genome Project, a proposal to spell out the entire genetic code of Homo sapiens. Biologists were violently split over the idea. Proponents touted the incalculable value of knowing the complete genetic script to human life, along with the hope of cures for genetic disorders. Critics both in academia and in Congress lambasted the project as a colossal boondoggle that would suck nih’s resources from worthier, more directed research. Venter sided firmly with the project’s supporters.

I couldn’t understand the controversy, he says. We had tens of thousands of questions and no answers. And for the first time, here was the means of getting to those answers.

The answers were hidden in the precise order of the rungs on the helical ladder of our dna—rungs that are composed of paired combinations of four bases called adenine and thymine, guanine and cytosine (or A,T, G, and C). At the time the Human Genome Project was proposed, sequencing genes—spelling out the concatenation of base pairs, letter by letter—was a tedious process. The four bases in a given sample of dna first had to be isolated from one another and ordered in separate columns on a laboratory plate called a gel. The researcher then had to look both across and down the gel at the same time to get clues to the sequence—a task that was both error prone and squintingly slow. Biologists expected that sorting out the arrangement of all 3 billion base pairs in the human genome would take several decades. Many critics thought it could not be accomplished at all.

The prospect of success brightened with the invention of an automated sequencing method at the laboratory of Leroy Hood, then at Caltech and now at the University of Washington in Seattle. Hood’s idea was to tag each of the four bases with a colored fluorescent dye, allowing a laser beam attached to a computer to read their order down a single column. If the device really worked, the Human Genome Project’s hope of sequencing the human genome might not be so unrealistic after all.

Venter sensed there might be great potential in Hood’s ideas, and he got his own lab chosen as nih’s test site for a prototype of the new machine. Venter and his colleagues needed a full year using conventional methods to sequence the adrenaline receptor gene; with the automated device, they sequenced two related genes in only six months. While this was a promising acceleration, it wasn’t fast enough in Venter’s opinion to reach the answers to the big questions. But on a long flight back from a meeting in Japan, at which he had expressed his frustration at the slow pace of genomic research, he got an idea.

I realized, Venter says, that we had the technology in my lab to do the entire human genome project.

Only the unassuming tone of Venter’s voice keeps this remark from sounding like pure hubris. (Though to some of his colleagues it may sound like hubris no matter how it’s said.) In fact, no single laboratory in the world—Venter’s included—has the kind of technology that could allow it to sequence the entire genome in a reasonable amount of time. But Venter’s claim is not mere hyperbole either: he figured out a way to home in on the part of the genome that mattered most.

Lacking sufficient computational horsepower to sequence the genome completely, Venter relied instead on conceptual dexterity. In 1990 the project, provisionally funded by the nih, was beginning its first phase, in which biologists would pin down the location of markers—stretches of dna whose sequence of base pairs was already known. Once those markers were mapped, the biologists could then slowly fill in the vast missing stretches between them. The ultimate goal of the project—a massive international undertaking with a projected cost of $3 billion—was to fill in the entire sequence between the markers by 2005.

Venter decided to try a different approach. It occurred to me that every cell in our body can do a much better job of sequencing dna than our fastest computers, he explains. A cell manufactures a protein by first transcribing its genes, letter by letter, onto single-stranded molecules called messenger rnas. But in the process, most of the genome’s sequence actually gets edited out. (This ignored dna—often misleadingly called junk dna—may play some role in the cell, but what it is remains unknown.) Once formed, messenger rna leaves the nucleus and seeks out molecular factories floating about the interior of the cell; there its code is read and used for building a protein. Thus messenger rnas represent a tightly abridged version of an organism’s genomic book, consisting of only the dna sequences of genes that are actively making proteins within a particular cell. Messenger rna itself is chemically fragile. But with the help of certain enzymes, biologists can readily turn the single-stranded rna into a durable double-stranded synthetic molecule called complementary dna.

A number of scientists in the 1980s realized that sequencing complementary dna would be a worthwhile endeavor. But it was Venter who figured out how to get the method to work. Knowing that dna has the natural property of glomming onto other dna with a corresponding sequence of bases, he realized that just a tiny fragment of the complementary dna of a gene—which Venter called an expressed sequence tag, or est—could act as molecular bait to fish out the entire sequence of the gene from a pool of complementary dna. And best of all, the est method could do all this lickety-split.

To understand how the est method works, think of the letters in the paragraph above as the dna sequence of a gene (keeping in mind that the genetic alphabet contains only 4 letters rather than 26). The first step in the est method is to clone many copies of the complementary dna gene and chop them into random fragments, so imagine that someone has made thousands of photocopies of the paragraph, sliced them into short stretches of the text, and then handed them to you, challenging you to figure out how the paragraph actually reads.

To do so, you could take one short sequence—let’s say the word glomming. Make many copies of the letter sequence G-L-O-M-M-I-N-G and toss them back into the pool of unknown random word fragments. Those copies will bond to whatever random fragments contain any part of the sequence—for instance, the partial sentence property of glom. Combining the two fragments now gives you the correct sequence of letters for the larger fragment property of glomming. With the help of a decent computer program that could quickly search out more matches, you could easily put together the entire paragraph from beginning to end.

Venter had great expectations for this method, but other scientists were skeptical. It was generally thought that only a handful of genes would be turned on at any one time. You could trawl in the complementary dna pool as long as you liked, but you would almost always catch the same kind of fish.

Venter and his colleagues (including Mark Adams, that most-often-cited biologist of the year) ignored the skeptics and went ahead anyway. They put together a library of commercially available complementary dnas that had been created from various brain cells. When they sequenced their neuron library, they hit a mother lode of genes far richer than anyone had ever imagined. In 1991 there were less than 2,000 human genes known, says Venter. We doubled that number in a few months. Virtually everywhere we looked, we found a new gene.

Venter was convinced he could reveal much of the genome within four or five years, at a cost of only $10 million—in sharp contrast to the Human Genome Project’s $3 billion price tag for laying open the entire genome, junk and all. Yet when Venter tried to secure funding for using est on a large scale, he was refused. According to Norton Zinder, who was then head of the nih advisory committee overseeing the project, the decision had more to do with politics than science. Craig was asking for a substantial amount of our budget at the time, says Zinder. Throwing so much of the budget to an nih scientist would have roused the ire of other geneticists working on the project in their own labs.

Rebuffed, Venter continued working on his est method on his own, and a few months later he found himself in the thick of a much deeper political morass: the controversy over patenting genes. The quest for scientific knowledge in this century has been driven by the two intertwined forces of intellectual curiosity and money. A biologist like Venter might spend a decade reconstructing a protein for the love of it, but a biotech firm puts hundreds of millions of dollars of research into creating a new medicine because it has a hunch that it may make billions of dollars in sales. Central to that hunch is the patenting system, which allows companies proprietary rights to new discoveries—a system that goes against the spirit of openness championed by scientists outside industry. And as biological research has moved down to the level of individual genes, the patenting system has followed—along with a huge amount of controversy. Do corporations have the right to have dominion over the very code of life?

The government has tried over the years to act as a broker between these two camps. It sponsors a huge amount of research into biology, but it also wants to encourage biotech companies to carry their work further, creating new drugs and therapies to fight disease. To do so, the government sometimes takes out patents on its own work, which it then licenses exclusively to private companies. In 1991, Reid Adler, who was then director of nih’s Office of Technology Transfer, advised Venter that the nih should file patent applications on the expressed sequence tags to the genes he had discovered so far. Adler reasoned that publishing the tags without patents would be tantamount to putting the entire gene sequence in the public domain. After all, once you had an est and a complementary dna library, you could get the gene sequence with no trouble at all. That would discourage pharmaceutical companies from taking the time to use the sequences to create commercial drugs, since they wouldn’t be able to obtain exclusive rights to them.

Initially Venter was reluctant about the idea. Mark and I had decided we were definitely not going to file a patent application, he remembers. I wanted this new approach to have the maximum impact on science, and I assumed that patenting would inhibit that. But Reid made a compelling argument. No pharmaceutical company was going to invest $500 million to develop a drug if it couldn’t get the rights to it. Having the sequences in the public domain could end up slowing down medical advances rather than speeding them up. So we agreed to go along, on the condition that the nih get public comment first.

He got a lot more comment than he’d bargained for. The response from the scientific community ran from disbelief to apoplectic rage. Scientists found it unconscionable that the nih planned to patent ests with no idea of the full sequence of the genes they tagged, not to mention the functions of the genes in the human body. Even more galling, Venter’s method was based on basic knowledge that had been around for years.

Venter, Leroy Hood later remarked to Business Week, has never invented anything, and the est approach offered no insight into anything.

Venter’s harshest critic of all was also the loftiest—the director of the Human Genome Project, James Watson, the Nobel Prize–winning codiscoverer of the structure of dna. At a Senate hearing on the patent issue, he declared the patenting idea sheer lunacy, while also testifying that Venter’s method could be run by monkeys.

I was stunned, says Venter. He acted as if it was the first time he’d heard about it. Here was a guy who was one of my heroes, and because I was moving in a direction contrary to his, he was using the power of his position to attack me personally. It still burns, though he’s apologized for it. These days he’s back in my hero category. But that doesn’t make me stop feeling the sting of those attacks.

The next year, Watson resigned his post at the nih, reportedly in large part because of the lingering conflicts he had with the institute’s director at the time, Bernadine Healy, over the patent issue. At that point Venter had moved on as well, but by then the public fracas that made him an outcast in the academic science community had ironically won him plenty of admirers beyond it.

I got hundreds of calls from business people, all asking me to take their money and set up a company, he says. I kept saying no, which they took as a ploy to up the price, and they offered more. At the time, Claire and I had maybe $2,000 in the bank. It was tempting. But I didn’t want to spend my life making money. I knew the intrinsic value of the work we were doing and how it was going to change things. The only thing we would leave the nih for would be our own research institute, where we would have control over what we were doing.

In 1992 the late venture capitalist Wallace Steinberg worked out an arrangement whereby Venter could head a nonprofit institute, which was dubbed the Institute for Genomic Research. The initial funding was $70 million, an astounding level of support for basic research. In return, tigr would give proprietary commercial rights to any major discoveries it made to a profit-making enterprise to be set up and named Human Genome Sciences. Steinberg brought in William Haseltine, a prominent Harvard-based aids researcher and entrepreneur, to serve as head of hgs. Venter got 10 percent of hgs’s stock, worth millions. It seemed like a deal too good to be true. Perhaps it was.

I would have my institute, and the investors promised they would file patents only on a limited number of genes, he says quietly. For the first time, there’s an edge in his voice. Later I learned that investors lie.

TIGR’s home in Rockville consists of twin buff buildings crouching in the grass alongside a medical boulevard 20 miles from Washington, D.C., their windows tucked up high beneath shallow pagoda roofs. Off a circular courtyard, wooden portals swing open with a touch. The air in the lobby feels hushed and expensive. A receptionist waits for visitors on the far side of a pond-size Oriental carpet, hands them pretyped name tags, and arranges their escort upstairs. In the stairwell an imposing hanging tapestry expresses a human dna sequence in colored wool. At the top of the stairs, just outside Venter’s glass-fronted suite, a bronze tiger waits with a perpetual snarl, muscles aroused, claws dug deep into the thick carpet.

On one wall of the vestibule to Venter’s office hang his numerous awards, plaques, and medals of achievement. Everything Craig does seems to work, shrugs his assistant. On another wall, a cover of Business Week from 1995 blazoned with the title The Gene Kings shows Venter and Haseltine dressed in white lab jackets and posed against an iconic spiral of dna. But someone has pasted a yellow Post-it over Haseltine’s face. At tigr these days there is only one Gene King.

It did not take long for Venter to realize that the relationship between tigr and hgs was not the perfect symbiosis he had envisioned. Although well-financed and free to guide the direction of his research, he had far less control over the fate of his results. hgs had six months to review any genes tigr sequenced before they were published, with an extension to 18 months for genes on which hgs or its partners were conducting research to determine whether they were useful for making drugs. The holdup on data was intended to give hgs a head start over other companies, but academic scientists could see the data if they agreed not to make commercial use of it. According to Venter, however, hgs frequently used the extension clause and other tactics to protect its rights to practically everything tigr produced. Haseltine disputes this, saying that he can’t recall the extension ever being invoked. In any case, he says, academic scientists could easily access the data in the meantime by signing the release.

Nevertheless, many basic researchers, accustomed to free, uninhibited access to new data, seethed over what appeared to be an attempt to market the recipe for human life. Much of this resentment was again directed toward Craig Venter. The pressure, especially from the battles with Haseltine, began taking a toll. In 1994, Venter was whisked back from a business trip in France to undergo emergency surgery for diverticulitis, a potentially lethal condition of the colon often associated with high anxiety.

It was a stressful time, he says. I lost a couple feet of intestines.

As Venter talks about these troubles, sitting in his office on a couch, he shows little of that strain. Bald, sparing of gesture, casually dressed, he seems poised and at ease. His office is spacious, accented here and there with nautical embellishments. To one side of a fireplace, a female figurehead from a ship’s bow rolls her eyes toward the heavens, praying for fair winds or perhaps clean data. Under a glass case beside his desk stands a gorgeously detailed model of his 82-foot racing yacht Sorcerer (the outboard is named Apprentice), which he captained in a transatlantic race just a couple of weeks before. It was Venter’s first attempt. Naturally, he won. One of his strategies was to look for big waves he could surf with his yacht, reaching speeds of over 20 knots.

My surfing experience has helped out in science too, he says. Good surfers learn to look as many as ten waves back. They select which one to ride long before it’s on top of them.

By 1994, the alliance between tigr and hgs had decoded the sequence of some 35,000 genes active in various human organs and tissues. The following year the data—minus those genes that hgs wanted to withhold for their possible commercial value—were published in a special supplement to the scientific journal Nature: 83 million nucleotides spelled out page after page in the order that makes human life possible. The est approach was rapidly becoming the most widely used sequencing technique in the world. But Venter was getting restless—he didn’t relish the prospect of simply churning out more human genes. Fortunately, at about the same time, he saw a new swell forming on the horizon, a monster wave with the power to send genomics speeding into the next century.

At a bioethics meeting in Spain, Venter happened to meet Hamilton Smith of Johns Hopkins. Smith had won the Nobel Prize in 1978 for his discovery of a new class of restriction enzymes, which are the protein scissors that cut dna strands into smaller pieces and are now an essential biotech tool. He had isolated the enzymes in a bacterium called Haemophilus influenzae, a human pathogen (unrelated to the flu virus) that causes ear and respiratory infections and occasionally meningitis in children.

Like almost everybody else in the academic community, I had a rather negative opinion of Craig, Smith remembers. But when he presented his work, I could see that this guy was discovering genes at an incredible rate, leaving everybody else behind.

Smith was particularly impressed with Venter’s description of a recently developed software program called tigr Assembler, which could handle hundreds of thousands of fragments of dna. Over dinner the two scientists conceived a radical idea. Why not see if the tigr Assembler could reconstruct the entire 2-million-base-pair genome of H. influenzae all at once? Conquering such territory was not a new idea. A few virus genomes had already been sequenced, including the smallpox virus at tigr. But viruses, which are dependent on their host’s dna to survive, have genomes that are minuscule, even compared with bacteria. Ongoing projects on bacteria were mind-bogglingly inefficient, as Venter puts it, with many more years to go.

Venter and Smith applied for an nih grant and, while waiting for their application to be reviewed, went to work using private money. First, Smith constructed a library of H. influenzae gene bits by making thousands of copies of its dna and chopping each one into more than a million fragments, each 1,000 to 2,000 base pairs long. Then Smith and Venter sequenced 500 base-pair stretches on about 25,000 of the fragments, which were then fed into the tigr Assembler and patched together at overlapping segments. But unlike the est method, which could look only for active genes, Smith and Venter could now assemble the entire genome, stitching together genes into the full code. Gradually, joined fragments congealed into several large spans of dna called contigs, and the gaps between the contigs were closed one by one by returning to the original library of dna and fishing out the missing segments using the known sequences straddling the gaps on either side.

Several months into the project, Smith and Venter received word from the nih. They were turned down on the grounds that the method couldn’t possibly work. No matter: by that time the job was already 90 percent finished. Just a few weeks later, in May 1995, Venter announced at a meeting of drop-jawed microbiologists that tigr had deciphered the first complete script of a living organism. Two months after that a glossy centerfold in the journal Science treated the world to its first peek at a living naked genome. A series of little colored bars marched in rows across four pages, each a separate gene, 1,749 in all.

There was an understated magnificence in that image that even a layperson could sense. Smith, Venter, and their colleagues had not simply ordered the genes and their base pairs into a complete sequence. They’d also checked each newly discovered H. influenzae gene against the thousands of genes that had previously been discovered in other organisms. Since the discoverers of these genes had often also figured out what the genes did, Venter’s group could now assign similar roles to more than half the genes found in H. influenzae. Some were involved in energy metabolism, others in replication, still others in the transport of materials within the cell. A surprising number of genes had no analogs in other organisms, but at least their presence in the genome was locked into place. The image was like a color-coded crib sheet to the question of what made this one little microbe tick. This was not a guess or a theory. If it were a painting, it might have been called The End of Assumption.

I think it’s a great moment in science, said James Watson, Venter’s former nemesis, in the New York Times.

Perhaps the greatest thrill was the tacit promise that more such moments were soon to come. Only three months later, a tigr team led by Claire Fraser published the genome of Mycoplasma genitalium, a parasite dwelling in the genital tracts of various animals, including humans. Mycoplasma has only 470 genes, making it the smallest known genome on the planet and hence a vital clue to understanding what separates life from nonlife. By the middle of 1996, Venter’s group had also finished Methanococcus jannaschii, a deep-sea, hot-vent microbe representing the archaea, postulated by University of Illinois evolutionary biologist Carl Woese to be a third superkingdom of life separate from both the bacteria and the eukaryotes (such as plants and animals) that make up the rest of life on Earth. Woese had argued for 20 years that the traditional lumping of bacteria and archaea into the single kingdom called prokaryotes was an egregious taxonomic error, all the more damaging to understanding evolution because the flaw was committed at the very base of the tree of life. The Methanococcus genome spelled out the truth of Woese’s idea: some of its genes were shared with eukaryotes, others with bacteria, and more than half had never been seen before. Meanwhile a consortium of more than 1,000 scientists finished their reading of the genetic tome of a species of yeast, which, in the scheme of things, is actually quite similar to our own dna.

And then early last summer, tigr issued two press releases on the same day. The first announced what the genetics community had long expected: tigr and hgs had agreed to dissolve their partnership. hgs was freed from its remaining obligation of support to tigr, totaling some $38 million. It was a steep price for freedom, but the independence Venter had bought was flaunted in the second press release, a simple statement announcing that tigr was posting onto the Internet a massive load of new gene sequences, including the nearly complete genome of Helicobacter pylori, the ulcer-causing bacterium dwelling in the stomachs of more than half the people on Earth. The meaning of the simultaneous announcements was unmistakable. tigr was free to provide data to whomever it pleased, and it pleased to provide it to everyone. The gesture went a long way toward mending Venter’s reputation among academic scientists.

Some people viewed Craig as someone who was trying to take everything that there was to be taken, says Mitch Sogin, a molecular evolutionist at the Marine Biological Laboratory in Woods Hole, Massachusetts. But at the end of the day, he did the largest release of data ever done by anybody. He has to be given credit for severing his ties and risking the well-being of his institute.

TIGR seems in little danger today. Fed on a healthy diet of government research grants, private fund-raising, and occasional arrangements with biotech companies—taking in laundry, Venter calls them—the pace of discovery at the institute has only increased. Since last summer, in addition to ongoing work on the Human Genome Project, its researchers have finished up the H. pylori genome and have completed two more microbial genomes: Borrelia burgdorferi, which causes Lyme disease, and Archaeoglobus fulgidus, a sulfur-metabolizing member of the archaea known to cause industrial havoc by souring oil wells.

The potential value of this knowledge is enormous. For starters, the tedious work of locating and identifying a gene will soon be a thing of the past. Biologists will be able to jump immediately to the larger questions of how a particular gene works and interacts with others. Knowing the totality of an organism’s genetic instructions also reveals just how much it is investing in one metabolic process or another. The advantages of knowing genomes of pathogens that cause malaria, syphilis, cholera, and tuberculosis—all genomes being sequenced by tigr—are equally huge. Infectious microbes rely on subterfuges they have evolved to evade their hosts’ natural antibodies and to resist man-made antibiotics. Sequencing their genomes is like stealin their plan of attack.

Bad bugs aren’t the only targets of genomic science. The vast majority of microbes on Earth are either harmless or critically important, speeding the recycling of nutrients through ecosystems, helping animal digestion, and providing a host of other activities that keep the biosphere healthy. Whole genomes will expose the secrets of these good bugs too, which may then be manipulated to perform tasks such as making new fertilizers and cleaning up environmental messes. Deinococcus radiodurans, another microbe whose genome has just been sequenced by tigr scientists, has the remarkable capacity to withstand 1.5 million rads of radiation—3,000 times what would kill a man.

This thing can take more radiation than the Incredible Hulk, says tigr’s Owen White, who led the Deinococcus project. A dose of radiation blasts the genome apart, but after a few hours it stitches itself back together exactly as it was. Insert the genes responsible for this kind of genetic repair into the genome of another bacterium that naturally gobbles up heavy metals, and the microbe could clean up nuclear waste sites.

The potential rewards of whole genomes, such as bioremediation and drug development, are likely to keep tigr in good financial condition on its own. But for many scientists, including Venter himself, the most tantalizing prospect of this new kind of biology is the resurgent power it brings to the study of evolution, especially the earliest branchings of the tree of life. Conventional genealogies are constructed by comparing the anatomy and fossils of organisms, which are fraught with evolutionary ambiguities. The problem becomes even more severe for those interested in the early evolution of life, when there was nothing but bacteria and archaea—organisms with little visible anatomy to help biologists distinguish them. On the other hand, by comparing proteins or genes of organisms, researchers can build molecular trees. But these can be deceptive, since distantly related microbes sometimes swap dna. Whole genomes, in contrast, offer millions of base pairs arranged in a genetic composition that doesn’t simply reflect a species’ essential nature but embodies it.

Within a few years, we’ll have 50 to 100 genomes, says Venter. You could think of each one as the discovery of an ancient text. And as soon as we have enough of these texts, we can decipher the history of life.

It will take more than additional texts, however, to even begin to understand the wisdom they contain. The six completed genomes at tigr alone contain thousands of genes made up of more than 9 million individual base pairs. Many millions more will be available within five years. But what does this great quantity of raw data mean? What are the functions of the many unknown genes? How do genes interact with each other and the environment to make life happen? In a sense, Venter’s hope for a global understanding of life seems more elusive now than ever.

When we put the first genome together, strangely all I felt was incredible frustration and inadequacy, Venter admits. I wanted to find instant enlightenment from looking at this thing. But we can’t understand the higher level of what it is telling us. Not yet.

Still, having too much data on the molecular heart of life is better than not having enough. Owen White offers a good metaphor: think of a sequenced genome as an unoccupied mansion, grand but still unfurnished. At tigr, researchers are already moving in some furniture. In one room, physicist John Quackenbush is using so-called gene chips to take snapshots of the particular genes that turn on in a genome when it responds to changes in the environment surrounding it. Down the hall, Clyde Hutchison is dismantling the lilliputian genome of Mycoplasma genitalium, knocking out genes one by one from its natural complement of 470. His first goal is to determine the minimum set of genes needed to sustain life. Ultimately that basic structure could be replaced with artificial chromosomes, creating artificial organisms—life from scratch, Venter calls it. These microbial Frankensteins could be strapped with specific genes for cleaning up oil spills or combating infections and then set to work.

Elsewhere, other tigr researchers bend to their screens, digging out the genomes of plants, tying up loose ends in the devious plots of pathogens, or dumping the daily crop of newly discovered human gene sequences onto the Internet. In brightly lit rooms, robots in glass boxes fastidiously spit their preparations into waiting trays. Banks of sequencing machines scratch out their texts in red, blue, yellow, and green. In the logo on tigr’s Web site, a snarling tiger wraps its massive limbs around a colored hunk of double helix. The cat’s posture is ambiguous: it could be wrestling playfully with a stronger opponent or about to sink its teeth into the neck of its prey.

The secrets of life are all spelled out for us in the genome, says Venter. We just have to learn how to read it.
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