Voyage of discovery

Risks and rewards ... Craig Venter on a research trip in Sydney.
The maverick scientist's adventurous spirit and risk-taking
tendencies might be visible in the soon-to-be-published structure
of his DNA.
 Photo: Dallas Kilponen

Risks and rewards ... Craig Venter on a research trip in Sydney. The maverick scientist's adventurous spirit and risk-taking tendencies might be visible in the soon-to-be-published structure of his DNA.
Photo: Dallas Kilponen

Roger Highfield
July 13, 2006

Craig Venter plans to publish the entire code of his own DNA. Roger Highfield meets the maverick scientist.

'Nobody knows what the fundamentals of life are or how it works. But I'm closer to answering these questions than science has ever been." When Dr J. Craig Venter gets carried away, as he is right now, he fixes me with his intense blue eyes, and all modesty goes out of the window.

Venter, who for the most part comes across as a cautious man, has been described as the most controversial scientist on the planet. His enemies have nicknamed him "Darth Venter" and accused him of putting the future of biology in jeopardy because he was so closely identified with exploiting human genes for commercial gains.

Journalists have cast him in the role of Faust, a scientist-philosopher who has sold his soul to the devil for knowledge. Now, he is about to make headlines with a feat of genetic sorcery that will leave his admirers awestruck at his sheer chutzpah, while his detractors gasp at what might be interpreted as a monumental display of egotism.

He will become the first person in history to gaze at his own complete genetic code, the entire DNA recipe book that he inherited from his parents. And in doing so, he will prove critics of his methods wrong by once again pushing back the frontiers of genetics.

A couple of months from now, the information will be unveiled in an as-yet-unnamed journal. All 6 billion letters of Venter's own DNA will then be poured into a public computer database called GenBank, where they can be studied by any scientist anywhere.

Venter calls it the Human Reference Genome. The feat heralds a new age of medicine, the era of personal genomics. Medicine has linked fragments of DNA to disease, personality, even intelligence, but analysis of entire genomes will provide insights into the relationship between nature and nurture.

Venter's hope is that one day we will all be able to examine our own DNA code for warnings of weaknesses and propensities. The current understanding may be primitive, but Venter's DNA eventually will reveal the genes that act with education and upbringing to shape his health, outlook and even personality.

Perhaps there are clues to explain why he left home at 17 to surf. There may be glimpses of why he tried to drown himself after witnessing the Vietnam War, only to return home determined to restart his life. Perhaps his DNA will reveal how an obscure scientist who has rebelled against authority all his life became a major figure in biology.

The hub of his scientific enterprise is the J. Craig Venter Institute, near Washington, DC. We are sitting in his vast, sunny office, which is crammed with Venterabilia: scientific medals and major awards, photos of encounters with heads of state and sailing paraphernalia.

Venter, 59, has a greying beard and a bald, sunburnt head that attests to his passion for sailing. He has a disdain for niceties and diplomacy, and is a paradoxical blend of the self-deprecating and the brusque.

He first created a stir at the US government-backed National Institutes of Health, where his bosses tried to patent human genes on the basis of a fast way Venter had used to hunt for them among the rusting old genes, DNA-parasites and "junk" that makes up 98 per cent of the human genome.

Central to Venter's method was a technique for reading fragments of genes. He realised the technology could be pushed to sequence the entire genome. Rebuffed by the government, he turned to private funding. He became the first biotech billionaire, on paper at least, until March 2000 when a joint statement by Tony Blair and Bill Clinton on how human DNA "should be made freely available to scientists everywhere" pricked a bloated stock market, and shrank him to a mere multi-millionaire. All along, however, Venter has been driven by curiosity, not money.

By now he had become a figure of hate among the scientists who were trying (and often failing) to compete with him. His methods threatened to take funding, glory, even Nobel prizes away from his rivals, who objected to how he controlled his DNA data, holding it back until his commercial backers had a chance to patent what they could.

Privately funded research is controlled by the companies that pay for it; Venter's critics, however, claimed that the research was too important to hold back.

Demonised in the media and battling his bosses over when he could publish his achievements, Venter was ground down. A scar on his stomach, left from surgery to remove a perforated colon, is a testament to how the stress affected him.

Current methods to link nature to disease often work along the same lines as a drunk looking for his keys in the dark: he searches only under the lamp-post, where there is light to see. Conventional gene hunts focus on families where an affliction has been passed down.

Link a piece of DNA to this hereditary disease and, bingo, it must play a role. But whether that role is central, tangential or coincidental is another matter.

You can also knock out a gene in a mouse and see what happens. But that is as primitive as taking a part out of a car and, if it stops moving, concluding you have found its secret of propulsion.

Research team member Jiaqi Huang struggles to explain how hard it is to make sense of the literature regarding a complicated trait such as alcoholism, even when their human lab rat - Venter - should have plenty of clues in his DNA.

Venter comes from a middle-class family in Millbrae, near San Francisco, where his father was an accountant. There is a family history of drinking. "My grandfather died from the effects of alcoholism and his father died racing a horse and buggy at high speed," he says.

Alcoholism is linked to thousands of genes and also with risk-taking. There is plenty of evidence of the latter in Venter's life, from the manic way he drives to his sailing exploits and feats of scientific daring. But Bob Strausberg, Venter's deputy, admits that they have been frustrated by the limits of what they can understand from the boss's DNA.

"Here we are, working with this renegade scientist, right? But everything we check for risk-taking behaviour shows he is actually a low-risk guy," he says.

The analysis reveals that Venter has a variant of a gene linked with long life. But as if to remind us how tenuous that thread is, Venter was last year diagnosed with skin cancer. It was caught early and removed.

To his disappointment, there was not enough tissue to sequence the cancer cells to reveal the genetic insults that made his own cells spin out of control, perhaps as a result of sunlight or even too much stress.

Venter jokes that the only stress he gets is from Huang analysing his genome. However, he has a complicated private life (two ex-wives, a 29-year-old son and a girlfriend), he lectures around the world, runs two institutes with 500 staff, a foundation and a biotech company, and goes on expeditions that combine his passions for sailing with sequencing genes from seawater, and is writing his autobiography.

So what does his code tell him, other than that he does indeed have blue eyes? For one thing, he is now taking a statin drug, after finding a variant of a gene that puts him at risk of heart disease. But the big picture is mind-bogglingly complex.

"There are more than 300 genes that contribute to blood pressure regulation alone," he says. "People say there are things like 'colon cancer genes'. There are not. We all have the same genes, but with variation in their spelling."

As he puts it, "It is perfectly clear that it is not clear." And even if we understood it all, he admits, there is still the influence of the environment to consider. "I don't worry about what people will find in my genome because it is so hard to interpret."

What we really need to do to disentangle nature and nurture is to sequence the genomes of millions of people as they go about the business of living and dying; only then will we will see which bits of DNA really count.

But even before his greatest accomplishment has been unveiled, he is already on to the next big project, the ultimate expression of his scientific swagger: his efforts have moved from reading DNA to writing it. He is leading the first attempt to create artificial life.

First, he has read the genetic code of a microbe found in human genitalia to an unprecedented degree of accuracy. Now, he and Smith are leading a team that is trying to rebuild it in the laboratory, including a few DNA markers and other genes to show that this bug is their own work, the first living species designed by man.

There are still many unknowns. Journalists have often asked if the creation of artificial life is a step too far, whether Venter and his team are "playing God".

Venter had a team of ethical and religious experts ponder the implications of a made-to-order organism. If the project succeeds, he might be able to customise bugs to do clever things, such as harness sunlight for renewable energy, or even eat greenhouse gases to curb climate change.

He is eager to push on: "We will throw the soup together, give it a lightning bolt and see if we can start forming cells that have the machinery for self-replication."

Venter will then see whether one or more microbes among the 100,000 million "boots up" with a strand of man-made DNA and starts metabolising and multiplying, according to his version of life's recipe.

One day in Rockville, sometime soon, Craig Venter may just recreate Genesis in a test tube. And heaven only knows what his critics will say to that.

- The Telegraph Magazine, London

A jigsaw puzzle with 6 billion near-identical pieces

Craig Venter's genome, like yours and mine, is written in a code where the medium is the message. Almost every cell in the body contains DNA, an interwoven chain-like molecule that measures more than two metres if stretched out.

Seen in close-up, DNA looks like a ladder twisted into a double helix, where the "rungs" consist of four chemicals (adenine, guanine, cytosine and thymine: A,G,C,T). These are the "letters" that spell out the proteins that build and operate his body. Overall, his genome consists of about 6000 million letters of DNA.

Because only fragments of DNA can be read at a time, and because human DNA is so repetitive, sequencing the genome is like assembling a jigsaw puzzle with a lot of blue sky. Venter's shotgun method smashes it into "libraries" of pieces of different sizes, and then reads both ends of each one. The result is pairs of jigsaw pieces that one knows are set distances away from each other, some two pieces apart, some six and some eight.

If this is confusing, the reality of Venter's method is more so.

The three "libraries" of Venter's DNA fragments are about 4000, 10,000 and 40,000 letters long. These were put inside a laboratory strain of E coli - the gut bacterium - so they could be grown easily.

In a room that smells of nappies, colonies of bugs graze on brown jelly inside trays. A robot picks a sample from each colony - corresponding to a bug multiplying with one particular piece of Venter's DNA.

After a combination of centrifuges, fans and incubators has gone to work, Venter's genome is reduced to droplets in thousands more trays. Every postcard-size tray contains 384 tiny wells, each containing a scrap of dissolved DNA, marked with blue dye to make it visible, and mixed with chemicals to tell the sequencing machines whether to read this particular piece forwards or backwards.

There are 100 sequencing machines, grey boxes with a computer screen. At one end of each machine is what looks like a golden lock of hair from a Barbie doll: these are glass capillary tubes which, with the help of lasers and fluorescent dyes, read Venter's DNA.

The machines are kept busy: they read the sequence in 140,000 samples each day, six days a week. Every shred of information then ends up in the "compute farm", where rack upon rack of high-performance computers monitor every stage of sequencing, before putting all the sequenced pieces of DNA back together to rebuild the genome.

The data is then sent down optical fibres to workstations for analysis by his team.
