Cracking the Code of Life

[Sharmarkee]

Cracking the code to life

The Guardian

06/10/2007

 

When Craig Venter announced that he was going to unravel the human genome, it sparked one of the most bitterly contested races in the history of science. Here, in an extract from his new memoir, he describes the acrimonious sprint to the finish

Craig Venter The Guardian Monday October 8 2007

The first tangible evidence that I had offended the genome scientific establishment came soon after I announced that I was going to sequence the human genome, our entire genetic sequence, with unprecedented speed. Once the publicly funded scientists had decided that they wanted nothing more to do with me or my teams, my research institute's application for government funding was turned down. In hindsight, it was inevitable that my attempt to simultaneously jump-start the human genome project and join hands with the establishment was doomed to fail.

 

What was different in my case was that I was able to find alternative sources of backing. I would head a new independent company funded by PerkinElmer, the parent company of Applied Biosystems (ABI), which dominated the market for DNA sequencers (machines that read DNA) and now proposed to build a new, automated machine to sequence the human genome. PerkinElmer would invest $300m (£147m) and the human genome sequence we produced would be published and placed in the public domain on completion. My critics had dwelled on how I was only in research for the money. They got it backward: I was interested in the money only to have the freedom to do my research. After some discussion we came up with a logo for the new company, a little dancing figure whose limbs formed a double helix. And we had a name: Celera, chosen because it was derived from the Latin for swiftness.

 

My working assumption was that my data would be essentially the only real data from the human genome for several years to come: the government-led competition was advancing at a crawl. But by September 1999, the pressure was on us. The public programme had announced that it had already sequenced about a quarter of the genome. In another change of direction, my rivals announced they would produce just a crude version of the genome and finish this "first draft" by the following spring, no doubt accompanied by a media event. The key differences in what we were doing at Celera and the altered publicly funded approach came down to standards and strategies: the whole-genome shotgun technique versus the clone-by-clone traditional approach [see Venter versus the establishment below]. I knew that we had the winning strategy with the shotgun technique, and that even with the same or even greater sequencing capacity, the government-funded labs could not compete unless they abandoned their standards and changed their plan to match ours.

 

In place of their original plan of publishing high-quality data over the course of a decade, my self-proclaimed rivals - the five surviving genome centres, which had nicknamed themselves the G5 - were now making an effort to dump as much raw sequence into the public databases as quickly as possible. They had convinced themselves that, by doing so, they were blocking me from both patenting the genome and getting credit for finishing first. I was baffled by the silliness and immaturity of their thinking. While my many critics were obsessed with the release of the Celera data, the public-funded labs were heedlessly dumping sequences into the public databases that the pharmaceutical companies were gleefully downloading nightly so they could file patents on them. This naive policy by all those opposed to patenting of the human genome therefore had precisely the opposite effect: gene patents were filed sooner and faster, and almost all were based on the government data, not Celera's.

 

The downgrading of the government objectives was met with little comment or analysis, thanks to a masterful job in public relations. No one seemed to appreciate that by changing its objectives the public effort had also, in effect, exchanged the aim of a highly accurate and complete chromosome-by-chromosome effort to sequence the human genome to a quick and dirty "rough draft" that made what we were undertaking at Celera appear thorough and comprehensive.

 

Thanks to the change in the strategy of the G5, my bosses at ABI stood to make much more money. ABI loved feeding the public programme, which now wanted to buy millions of dollars' worth of DNA sequencers from them (as well as the associated chemicals necessary for the job), and were like arms merchants who had started a war so that they could sell weapons to both sides. It was frustrating having to work so hard to build team spirit among the Celera sequencing group as they watched our business "partner" equip our rivals at a faster pace.

 

Using the same instruments for reading the genetic code meant that - aside from the not inconsiderable matter of the government-funded programme's having more than tenfold greater resources of money and manpower - the key difference between the Celera and public programmes lay in our respective scientific strategies. To most, the word "sequence" implies that the base pairs of the genetic code are actually assembled in their proper order; no one would think he had assembled a jigsaw puzzle simply by throwing the pieces on a table.

 

However, because the government-funded labs were doing thousands of mini-genome projects, they had thousands of mini-jigsaw puzzles to solve, order and orient, whereas we had only one big one to do. I was betting on the integrity of our science to prevail and on our programmers, our algorithms and our massive computer to outcompete the much bigger public effort.

 

By now the race to read the genome had captured the imagination of many, and the public perception of who was winning became an important issue for both sides. The government-backed labs wanted to impress on the politicians that they still deserved funding. As for Celera, we were a public company, which relied on the support of its investors.

 

Every government-funded lab had one or more press officers. The media, however, returned again and again to one theme: Craig Venter as underdog, a sole crusader and outsider who was pitted against the collective might of the establishment. Under his leadership, Celera was taking on the official Human Genome Project, a $3bn to $5bn, government-backed international effort with major centres in Britain, France, Germany, Japan and the United States.

 

While my team liked this David and Goliath spin, Francis Collins and his colleagues at the National Institutes of Health in Bethesda, Maryland would grumble about how they were overwhelmed by my "huge public relations advantage". Collins griped about the unseemly articles depicting the race to the genome, where I was standing on the helm of my yacht as he crouched on his motorcycle. John Sulston moaned: "Trying to get reporters to print the admittedly more complex analyses that we felt were being ignored was going to be an uphill struggle."

 

The whining of the public project about my massed ranks of spin merchants was a constant source of amusement at Celera, for my "PR army" was in fact a young woman named Heather Kowalski, now my fiancee. Heather knew there was only one way to cultivate the media: by being honest. Most important of all, she did not shrink from telling me when she thought I was saying or doing something ****** or misguided (a not infrequent occurrence).

 

Work did continue despite the increasing public scrutiny. We were now producing between 50m and 100m base pairs of DNA every 24 hours, and the sequence was of extremely high quality. If we wanted to, we could also draw on the data released by the government effort every day into the public database, GenBank. Like other taxpayers, we had helped to fund this effort, after all. Pharmaceutical companies downloaded the data nightly, and Incyte was very open about its use of GenBank to create a database that they used to compete with us. Francis Collins did not complain about these outright commercial uses and, indeed, used them as a further justification of the value of federal effort. Yet after I indicated that we would do a de facto collaboration with the taxpayer-funded effort by including its data in our assembly, there were anguished howls of protest. The G5 had discussed whether they could withhold their data from Celera even though their mantra had always been that they were providing the sequence free to all. There were even suggestions of scientific fraud, such as when Sulston told the BBC that the Celera effort was a "con job".

 

As the grandstanding continued, the press battles became more and more wearing. I worried that Collins would manoeuvre to use the White House to give the impression that the government and Wellcome Trust were the only parties involved in sequencing the human genome, whether they finished or not. A triumphal broadcast from the Rose Garden was going to carry more weight than anything my one-woman PR army could put together. We set ourselves a simple goal: to make a joint announcement with President Clinton when at the White House when Celera finished its first assembly of the human genome. At that time, the government effort would give a progress report on its own efforts, and we would announce that we would work together toward a joint publication in Science.

 

As the date drew closer, the tension increased, but by then the momentum was unstoppable. Once I had agreed to a draw [see Venter versus the establishment below] we wanted to announce it at the White House as quickly as possible before hostilities could flare up again. When I turned my attention to my White House speech, the pressure increased after we were informed that this would be the first time in history that a key scientific advance would be announced from the White House, and I found myself struggling over the decision of what to say and how to say it.

 

I did not sleep the night before not one but two world leaders - Tony Blair and President Clinton - were to unveil the results of the greatest concerted undertaking in biology. The coming celebration would be hailed by some as the most notable intellectual moment in history itself. Happily, on June 26 2000 all the rivalries were swept aside by everyone's feeling of being part of an historic achievement. At the White House, there was an electric atmosphere and a mood of high anticipation.

 

The press conference was unlike any I have been to before or since. Held in the ballroom, it included close to 600 people and an unbelievable collection of television cameras and photographers. Flash after flash strobed across our faces. To everyone's surprise the tone remained positive, cooperative and cordial. We were all one big happy genome family.

 

· This is an edited extract from A Life Decoded: My Genome, My Life, by J Craig Venter, to be published by Allen Lane on October 25, priced £25. To order a copy for £23, with free UK p&p, go to guardian.co.uk/bookshop or call 0870 8360875. Craig Venter will be giving public lectures in London and Oxford, October 23-25. Further information from: penguin.co.uk/events

 

Venter versus the establishment

[Sharmarkee]

Ian Sample explains the genome wars

 

The Human Genome Project came into being in an atmosphere of deep unease. Many scientists saw it as an extravaganza that would suck up vast sums of money. They feared other research would wither and die.

 

But while senior researchers openly attacked the idea, one threw enough weight behind it to convince the US congress. That person was James Watson, joint discoverer of the structure of DNA, and he was appointed director of the Human Genome Project at the US National Institutes of Health in 1988.

 

At the time, only short strands of DNA had been read, and then at great expense. To unravel the entire human genetic code (or genome), with its 46 chromosomes each made up millions of "base pairs" of nucleotides - denoted by the letters G, T, A and C - was close to unthinkable. Once every letter had been read, scientists would scan the chromosome for genes - self-contained segments of DNA which contain the basic instructions for making an organism.

 

Watson set out to establish an international consortium to take on the challenge. Britain was an obvious partner; scientists at the Sanger Centre in Cambridge had already begun learning the black art of sequencing. Soon, France, Germany, Japan and China were on board.

 

The attempt was officially launched in 1990, and according to Watson would take 15 years to complete. The timescale reflected the laborious approach. Each chromosome was broken into short fragments which were copied (to produce large quantities) and tagged with fluorescent dyes. These were then squirted on to a gel and sorted by length using an electrical field before each letter of each fragment was read. "A more important set of instruction books will never be found by human beings," Watson wrote.

 

But the project was to descend into what ultimately became the most acrimonious race in modern science. The consortium used DNA sequencers supplied by Applied Biosystems, a company that had started work on a new generation of machines. With those, the company's president, Michael Hunkapiller, realised, it would be possible for a single institution to beat the consortium to the finishing line.

 

Aware, too, that competition would increase demand for his sequencers, Hunkapiller oversaw the creation of a rival team. At its head, he appointed Craig Venter, a former government scientist already controversial for applying for patents on 337 human genes. Venter was also backed by Tony White, then president of the scientific instrument company, PerkinElmer.

 

The Venter team's approach was dirtier and faster. Instead of painstakingly reading each chromosome in turn, they would use a "shotgun" method that first shattered the entire human genome with ultrasound, then read the fragments. Complex software was then used to work out how to stitch the letters of the code back together again. Venter's company, Celera, declared it was joining the race to sequence the human genome in 1998, adding that it would have the job done in just three years.

 

Venter made no secret of his wish to profit from the human genome. He envisaged a huge DNA database that companies would pay to search through. Sir John Sulston, who headed the British arm of the Human Genome Project, was furious at what he saw as a bid for private ownership of our genetic inheritance.

 

Though many scientists were dismayed at Venter's plans, the rivalry gave a much needed kick to the human genome project, which for 10 years had progressed at a crawl. The consortium rapidly refocused its efforts and claimed it would complete the genome two years faster than planned. Likewise, the public effort kept Celera from monopolising the data, from which it could have generated a huge income.

 

Around the world, labs working for the public consortium churned out genetic data as fast as they could, immediately uploading it to public databases, a bid designed to prevent Venter from patenting them. Venter, who did not disclose any of his own sequence data, made no secret of using the consortium's results to boost his own. Ironically, as Venter records in his book, pharmaceutical companies began trawling the public database in search of future moneyspinners.

 

In 2000, several meetings to bring the two sides together broke down in acrimony, but eventually, the two rivals agreed to an uneasy and temporary suspension of hostilities, each realising that a coordinated draw was in both their interests. In June, both declared the genome effectively complete. From the White House, Bill Clinton said: "Today, we are learning the language in which God created life." From Downing Street, Tony Blair said: "Let us be in no doubt about what we are witnessing today." What they were witnessing, in fact, was a deeply manufactured truce, with the genome only 85% complete.

 

Two years later, Craig Venter was forced out of Celera by Tony White, who was intent on turning the company into a drugs giant. Four months after leaving, Venter admitted that Celera's human genome, supposedly a mix of DNA from five anonymous individuals, was predominantly made up of his DNA.

 

In 2003, the public consortium announced once more that it had completed the human genome. This time, the claim was closer to the truth, though chunks of the code remain unread even now. Even so, it was the most extensive and highly accurate sequence of the 3.1bn nucleotides that are responsible for turning a one cell egg into an adult of 10 trillion cells. The final price tag was approximately $3bn (£1.47bn).