If you had led a team that sequenced the human genome, then became the world's first biotechnology billionaire (on paper, at least), and had just finished sailing around the world on your own 95-foot yacht, what would you do next? How about creating life from scratch, saving the Earth from global warming and, as a by-product, ending western dependence on imported energy?
That's what Craig Venter, the scientist whose private company raced the rest of the world to sequence the human genome, is apparently up to—and I've come to meet him in his London hotel to hear more. If the stories were about anyone other than Venter, I would assume they were just dreams. But he has a record of going where no one else would dare, which is why he is described as a maverick, pirate, opportunist, egoist and the "bad boy" of science. And now he has raised a lot of money for a new company looking at novel sources of energy, and has just recruited a top US department of energy official, Aristides Patrinos, to join him. Patrinos is well connected to those who set US energy policy and is said to have had a hand in President Bush's recent state of the union commitments to finding new energy sources.
Venter is pacing his hotel room, blue-eyed and barefoot, as though still on the deck of his yacht. He was up until 3am trying to out-drink the editor-in-chief of Nature and coffee is in plentiful supply.
But first some background on how Venter got that bad boy reputation. Back in 1998, the vast publicly funded consortium to sequence the human genome had been rumbling along for years, first under the leadership of James Watson, the co-discoverer of the structure of DNA, and then under Francis Collins, who discovered the gene for cystic fibrosis. The planned completion date was 2005. Then, in May 1998, all hell broke loose. Venter announced he was going to set up a privately funded company—later named Celera—to sequence the entire human genome, using radical new methods at a fraction of the cost of the public programme and in only a couple of years.
The reaction from the public consortium was a mixture of rage that anyone would dare to compete with biology's equivalent of the Apollo programme and fear that Venter's company might not only beat it to the sequence but also obtain commercial rights over the use of the data. There was also much anxiety that governments might think twice about continuing their funding at all. Venter had not helped matters by suggesting that the global consortium of distinguished scientists should leave the human genome to him and "do the mouse genome" instead.
What followed was the scientific drama of the century. Sequencing the human genome was a great scientific goal that was expected to give a huge boost to biology and medicine. Many of the scientists involved were brilliant overachievers who had their eyes set on a possible Nobel prize. But although everyone wanted to win, no one wanted to admit he had entered into anything as unseemly as a race.
A former head of Georgetown University, an institution founded by Jesuits, once told me, "scientists are the only people more hypocritical than us Jesuits." Just as a candidate for Pope would not go around saying "vote for me," but would quietly murmur about his sole wish being to serve God, the scientist publicly claims his "god" to be the progress of truth. This progress can be achieved only by the sharing of results: everyone stands on everyone else's shoulders. But, of course, personal advancement only comes from beating everyone else. In the world of science, competition always has to wear the mask of co-operation.
Scientists on the public consortium wanted to win, but under the banner of co-operation and "the principle of free access to genetic information," as John Sulston, who ran the British part of the programme, put it. Every bit of the data should be freely available to all scientists and none of it used to give anyone a commercial edge or, even worse, patented so that others would have to pay a fee to use it.
Sulston worked at the Sanger Centre (now the Wellcome Trust Sanger Institute) in Cambridge. Thanks to hundreds of millions of pounds of funding from the Wellcome Trust, he had the biggest genome centre in the world, and he was the only player with no need to fear the US government cutting his funds if a private alternative seemed viable. He stuck firmly to his total opposition to the commercial programme.
Venter insisted both to his colleagues and to congress that the privately funded genome sequence would be made publicly available. But no one quite believed him. When Venter phoned Sulston to suggest collaboration "to get the sequence out for everyone," Sulston was tempted, as he records in his book The Common Thread, but refused, telling himself that, wherever Venter had been, "the decisions came down to profit." For Sulston, a clergyman's son, that was not acceptable.
Collaboration never happened, however beneficial it might have been. Further peace meetings ended in recrimination and, as the race sped up, barrages of press releases from both teams confused the media about who was really ahead. President Clinton stepped in as peacemaker and the two teams agreed to stop fighting in public. A few months later, on 26th June 2000 and only two years after the race began, Clinton, flanked by Venter and Francis Collins, announced that both sides had reached the finishing line together. A simultaneous announcement was made by Tony Blair, although inexplicably he failed to mention the Sanger Centre. The race had officially ended in a dead heat, although at that stage the teams had finished only drafts and much work was still needed.
But even with the race long over, the dust has never entirely settled. To put the genome together at such speed, Venter's team had employed radically new methods and untried mathematical algorithms, and the quality of its work has been repeatedly attacked and defended. Sulston claims that Venter's team was merely an "distraction" and that the public programme did everything important. Yet the public programme rapidly changed its strategy in response to Venter, ruthlessly ditching smaller, less efficient labs in the consortium, and buying many of the new fast machines to get to the finish line years earlier than planned, which suggests that Venter provided a kick to the consortium's backside.
Of course, en route Venter had annoyed lots of scientists as well as some of the business people in Celera, appearing to lean too much towards business for the scientists and too much towards free publication for the business people.
Back then, everyone was caught up in the tech bubble madness of the times. In little over a year, some six biotech companies raised a total of $4bn in various stock offerings. That was something I wanted to ask Venter about. The promise was that "genomics" would deliver a quick way to create new drugs and even "personalised medicine," with drugs tailored to individual genetic characteristics. Most of these things have proved very hard to realise, and patenting genetic information has provided no guarantee of a workable drug or a profit. The human genome sequence is a great advance for basic research, but it has been much slower to deliver for the common good. The long slog of development and clinical trials continues much as before, and the boom times for biotech stocks, including Celera, are long over.
I was interested in Venter's views on this. But first I wanted to know how he began to mix science and commerce.
AA: The human genome project turned you into a figure of controversy. But you were arguing with Jim Watson over gene patenting long before that.
CV: Back in 1992, I was a government researcher at the National Institutes of Health (NIH). I developed a method for labelling genes quickly and the NIH tried to file patents on hundreds of genes. I was attacked by Watson and others even though the so-called "Venter patents" were filed by NIH, not me, and I would never have got any money from them. The irony is that, thanks to Watson attacking me, everyone heard about my work and I started to get big offers from biotech companies. One of them offered me a $5m signing fee, and when I turned it down because I wanted to keep doing science, people saw it as a negotiating ploy. But I eventually did a deal with private investors. I said, if you allow me to start my own not-for-profit institute in parallel with a for-profit institute, and they are kept independent of each other except for funding, I will do it. So I got $70m over ten years to fund my lab called the Institute for Genomic Research (TIGR) with the intellectual property rights going to the for-profit institute (Human Genome Sciences). The scientific founders of biotech companies are mostly just looking for new ways to get their science funded, and when the company comes under pressure to make products, the founder gets the chop. I was trying to avoid that fate by coming up with a model that would allow me to do basic science and reap commercial benefits.
AA: The human genome project had started small under James Watson, but by the time you entered the fray it had grown into a global project spread among many labs around the world.
CV: Initially I had the notion that the best way to sequence the human genome was to build a single industrial-style centre. But the project took a different turn and became a giant international co-operative. It planned to take $5bn of public money and distribute it around the planet. Every scientist and government in the world was involved and it became a political project with people fighting to control the money. New ideas were shut out. At the institute I had set up, meanwhile, we were trying to develop new technology to sequence faster. It had taken scientists 13 years to sequence the genome of the bacterium E coli, but using the new "shotgun" methods I developed with Hamilton Smith [a Nobel prize-winner who works closely with Venter], we did the genome of Haemophilus influenzae in four months. Instead of people saying, "Wow, here is a faster way to go," I just heard, "Oh that could not possibly work on the scale of the human genome." Everyone wanted to keep going without trying anything new. The reaction was something like: "Very nice Mr Ford, you developed the automobile, but you know our horses and buggies are just fine, thank you."
The idea to turn these techniques into a privately funded project did not come from me but from the equipment-maker Applied Biosystems (ABI). It developed a new instrument that is particularly powerful when combined with the shotgun sequencing and offered to put up $300m to create a new company to sequence the genome using it. It was not an altruistic move. They saw that this would help to sell a lot of these new instruments, which it did. I looked at the prototype and worked out that we could probably sequence the human genome in two or three years. I told Ham Smith that I was going to leave and try to sequence the human genome. He replied, "I don't think it will work, but I'm going with you!"
AA: That's what led to the launch of your company, Celera, and Watson's notorious remark that you "wanted to own the human genome the way Hitler wanted to own the world." In Britain, John Sulston thought the same, writing that, "Craig was aiming to gain total control of the information contained in the genome for commercial gain."
CV: They got it all wrong. I said to ABI that if I do set up this company to sequence the human genome, I will need a guarantee that I can publish it. The response was, OK we'll give you the $300m, but if you want to publish the results you'll have to come up with a business plan. So I did. I knew that the 3bn-letter human genome was worthless without the computing infrastructure and the software tools to do something with it. So my business model was to give the sequence away for free and sell the necessary software tools and the computer infrastructure. How is that against the public interest?
AA: At least the stock market liked the idea.
CV: It was insane. At one point the market capitalisation of Celera reached $24bn, making it bigger than any British company. The model could not justify that value. But I could not say that in public as it was against SEC rules and would have caused a market crash. The irony was that Francis Collins and others in the public programme were hyping the human genome, describing it as the most important thing since the moon landing. I was trying to downplay it because you can go to jail for hyping the stock! I still became the world's first biotech billionaire, but only on paper—as head of the company, I could not sell my stock.
AA: You clearly have hurt feelings about the press you got in Britain, which often followed Sulston's line: there's one bunch of people who are doing this for the benefit of humankind, and another bunch who are trying to do it for their personal gain.
CV: A study of the global press coverage of the human genome by a German university found that the coverage in Britain was uniquely biased, and there was always this mano-a-mano battle between me and Sulston. He was one of the players who made good contributions, but there is nothing unique about him except that he was railing about how evil commercialisation was. But look at it this way: the public effort consumed about $5bn of public assets. Celera, by contrast, used its own money to sequence the genome for $100m and gave it to the public for free. When you look at the amount of medicine or education that $5bn could have purchased, I think you can come up with quite a left-wing argument for letting the private sector play its part.
There are important issues here for government and political leaders. Nations take pride in their scientific accomplishments, but if we want to make national heroes out of people then it can lead to disaster. Look at what happened in Korea where the government pressured one stem cell researcher to beat the world and he ended up faking data.
We should be asking whether the best decisions are being made about the use of public money, and how to evaluate science as a whole. At the same time as those hundreds of millions of dollars from the Wellcome Trust were going to the human genome project here, a lot of scientists lost funding for their work. Many left Britain during that period. We live in a zero-sum game where there is a finite amount of money. If one thing is funded, another is not. In the "we must race against Celera" fervour, no one in Britain really stopped to ask if this made sense. Why didn't we just combine these projects and make them better, faster and cheaper? No one would answer those questions in Britain because national pride ordained that you had to support Sulston.
You have to look at the whole system, not just individual morals. Scientists can be working for altruistic reasons, people funding the science can be doing so for altruistic reasons, or they can be doing so out of financial greed, but the greed is only satisfied if the science is good and leads to a drug that actually treats disease and makes a body better. The system overall is oblivious to individual motivation. Investors in Celera wanted to make money. But when we asked employees why they wanted to work there, they wanted to be part of history. People like to make a difference. Celera published its results in the journal Science on the same day as the public project published its results in Nature, with the sequence freely available to researchers in a database, and conditions only for those with commercial aims.
AA: Then, just 11 months after that day of joint publication, you suddenly decided to leave Celera, the company you had founded. Why?
CV: I was fired.
AA: You were fired?
CV: Yes. I hadn't got along with the head of the parent company from the beginning. I had sequenced the human genome, I had a great customer database of all the top universities and companies. I had experience in raising huge sums of money and credibility in both the scientific and business communities. I decided to raise the money for a new company.
I now have TIGR, my original institute, and the new Venter Institute, both not-for-profit laboratories funded through the Venter Science Foundation into which I put most of my stock from Celera. I didn't make much personally but my foundation got a windfall. I have over 500 people working for me at the two research institutes. Then recently I raised $30m to start a new company called Synthetic Genomics. Its goal is to build on our basic research and find new commercial energy alternatives that do not cause global warming and will end the massive dependence on imported energy. The problem with trying to find novel sources of energy is that governments in the US, Britain and the rest of Europe aren't supporting that kind of research. Our governments should be spending 10 per cent of their budgets on trying to find new energy sources that don't add carbon to the atmosphere. It is vital for national security—we are fighting all these wars over energy sources instead of developing independent sources. It is also a priority for the health of the planet. Climate change is real and if we don't find alternatives to burning coal and oil we are going to be in trouble.
AA: You are thinking about using bacteria to produce fuels like hydrogen. But you need to create a new life form to do it?
CV: People have been looking for naturally occurring organisms to produce hydrogen or methane. But it does not make sense that anything would evolve naturally to produce commercial amounts of methane or hydrogen. Organisms would use the energy themselves. But if we can design synthetic cells then we can make them put all their energy into pathways that will drive methane or hydrogen production.
DuPont is a world leader in using modified bacteria on an industrial scale to transform renewable natural resources into products that would normally have to come from oil. They are building a $100m plant in Tennessee that will turn corn sugar into propanediol, a key polymer for making plastics, but it has taken them over five years to modify a bacterium so that it will turn the sugars into the polymer efficiently. Most of the work involved shutting down existing pathways in the bacterium so that the sugar would end up as the polymer and not be used for something else. The result showed that huge gains in efficiency are possible. My approach starts from a different place. I think that if we can build a cell from scratch with only the very minimum of processes it needs to survive, we won't need to go through this long process of modifying an existing bacterium to shut down all the pathways you don't want. Instead, you can add to this "minimal cell" the pathway you need in order to make a specific product. I have been trying to understand the minimum a cell needs to survive for the past ten years, as part of a basic research project; the fact that it has commercial and social applications is wonderful. We sequenced a bacterium called Mycoplasma genitalium which has the smallest genome of any known free-living organism and have modified it to make it simpler and find the minimum set of genes an organism needs.
At the same time, we've been finding ways to build genomes artificially. The first time a team built a simple virus genome from scratch, it took three years. Using new techniques we did it in two weeks. The genome of the simplest bacterium is around 60 times bigger so it is much more difficult, but we are moving towards creating the first very simple living organism.
AA: And that ties up with the project that has taken you right around the world in your yacht.
CV: Yes, I'm just back from a 40,000-mile trip around the globe on Sorcerer II. I bought the yacht in New Zealand and converted it, adding microscopes and sampling gear. All across the oceans we have been extracting unknown micro-organisms from sea water, sending them to my laboratory in Maryland and sequencing their DNA. The new discoveries are stunning. We only have the data from the first quarter of the expedition but we have already found 1.2m new genes—more than in the whole history of molecular biology. Among them are almost 800 genes involved in converting sunlight into energy.
AA: So the oceans could provide a huge stock of new genes that you could slot into your "minimal cell," like reprogramming a computer to do different things?
CV: That's the idea.
AA: To do all this you are once again running both non-profit and for-profit organisations. That means you have to be scientist and businessman, what Francis Collins described as a "Faustian" situation that doesn't work. Isn't there a risk that you'll hear those words "you're fired" again?
CV: This time I'm making sure to keep control of it. We have picked people as investors who all share the long-term view that this is a national and international priority. I want to change the world. A bacterium that makes gasoline from sugar in an academic lab doesn't change the world unless someone develops it commercially. If, all of a sudden, oil and energy could be produced locally and we were no longer reliant upon oil, global politics would be transformed. Sugar cane becomes a major source of energy—all of a sudden Latin America and Cuba look very attractive. It changes the security landscape and it changes how much carbon we are putting into the atmosphere. There is a unique opportunity here, so let's try it. This is my third company and I think this will be the one that really works. Basic research and commercialisation sit well together. They are not separate worlds: in fact, the more they get together, the better for society. People make a distinction between business skills and science skills, but if you can run a science programme and inspire people you can lead a business.
AA: You have set yourself big goals. Is part of that conditioned by your experience in the Vietnam war?
CV: I left home when I was 17 to surf and explore life. Instead, I got drafted into the war so I turned 21 in Vietnam. Being faced with the death of thousands of people your own age and younger, and trying [as a medical orderly] to save as many as you could are tough lessons for someone at the end of their teens. Everybody that was there had their lives changed. Many people changed for the negative and did not recover from the war, but I was changed in such a way that I wanted to go on and make a difference. I thought it was wrong, politically, that we were in Vietnam, but none the less, 30 years later, we are back in an almost identical situation.
AA: Many people say you have a very big ego. After all, the DNA you sequenced was mostly your own.
CV: You have to have a strong sense of self to get things done. I believe in myself and my team and our ideas and making history.
Will Venter succeed in making history? He's already made quite a bit of it through his enviable scientific publication record. That's quite separate from the notoriety which he acquired at Celera. But the impression you get on meeting Venter is that he always needs to move on to the next project.
If his audacity works, and he and Hamilton Smith succeed in creating a synthetic bacterium, then they will start a vast new field. The capacity to build genomes opens up so many possibilities, both in understanding life and in using bacteria as chemical factories. There will be new worries too: the technologies will make biological weapons easier to make.
Whether bugs can provide the next energy supply is controversial. There are plenty of simple creatures that make hydrogen as a by-product of their usual metabolic processes but can anyone make them do so efficiently enough to drive a switch to a non-polluting hydrogen economy?
Venter is certainly right about one thing. Governments aren't spending enough to find alternatives, or even to implement the solutions they already have.
