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Biotech / Medical : Celera Genomics (CRA)

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To: allen menglin chen who wrote (342)5/10/2000 11:44:00 PM
From: gao seng  Read Replies (1) of 746
 
yep.

DNA: It's war (part one)
Decoding the human genome will change the world. But, says Kevin Toolis, it's not just about science; it's UK vs US; public spirit vs private enterprise. And it's personal

Saturday May 6, 2000

It should have been the grandest of scientific occasions. On stage at the world-renowned Pasteur Institute in Paris, Craig Venter, one of the world's foremost biological scientists, announced he was just weeks away from completing the greatest scientific endeavour that mankind has ever known: the human genome, the book of life of Homo sapiens . It should have been a victory lap, applause, praise, talk of Nobel prizes, and commendations from his peers.

But instead there was silence. For most of the 600 academics in the audience, gathered from research institutes across the globe, Venter was the traitor; a ruthless competitor who sold his soul to American business and who now plans to charge the rest of the human race a fortune to read our own genetic code. "I was totally against him being invited to speak," said one of the conference organisers bitterly. "His first announcement when he created his company, Celera, was to attack the publicly-funded Human Genome Project. He wanted the public project to be closed so he would have a monopoly. He is extremely aggressive in his statements because, of course, he is speaking not to scientists but to his shareholders."

To his critics, the American scientist is "Darth Venter", an evil monopolist. To his admirers, he's a genius - "the Alan Turing [conqueror of the Enigma code] of his generation" - who more than anyone has revolutionised the field of genomics but, through the jealousy of scientific pygmies, has been unjustly denied credit. "You cannot repeal the laws of human nature," says Dr Sam Broder, a former director of the US National Cancer Institute and now chief medical officer at Celera. "It would be appropriate if someone said, 'I'm angry, I'm jealous, I can't stand this.' It would be better if people had the courage to come out with it."

Beneath the venom towards Venter lies another human emotion - fear. "Everyone is frightened of losing," said a senior scientist from the Pasteur Institute. "The human genome is only going to be sequenced once and it will never need to be done again. There are Nobel prizes riding on this. It's a big, big prize and it's technology driven. Craig is in cahoots with the American makers of the DNA sequencers we all use. He is also a self-aggrandising pain in the arse."


But the race for the code of the human genome is not just another arcane battle between boffins to see who wins the prize, even if it is a Nobel. It's a race for the future, a war being fought in science laboratories across the world, with battalions of $300,000 DNA sequencing machines that chunder out, in order, the four base letters of the human code - ccacatgatatctatccaacccatgtcc . . .

On one side is the publicly-funded Human Genome Project (HGP), which is decoding the human genome data and releasing it free of charge on the internet each night. And on the other is Celera, Venter's private upstart company founded in May 1998, which says its has decoded the genome cheaper and quicker than its slow-coach public rivals.

Celera does have a built-in advantage. Its scientists can access the two billion-plus letters already decoded by the Human Genome Project by simply looking it up on the HGP's websites. Celera's own data is strictly private, but Venter says he will also publish their human genome data on Celera's own website. His critics ask "when?" and "how much will it cost?" Inevitably, Celera will place some restrictions on the use of its data.

The race for the code is not just about science, it's also a tale of dirty tactics, brilliant scientific innovation, emotional insecurity, vicious bureaucratic in-fighting, black propaganda, rare joint presidential and prime ministerial statements, $225-a-share stock offerings, law suits and plain old-fashioned human goodness.

The Human Genome Project, largely funded by US tax dollars but with a third of the money from the British medical charity the Wellcome Trust, is vast, and there are many key scientists involved. But it has ultimately become a fierce personal battle between two men, the would-be American billionaire, high-school drop-out, ex-surfer and Vietnam War veteran, Craig Venter, and his runner-bean-growing, Oxfam-supporting, second-hand car driving, bearded British academic opponent, John Sulston, of the Wellcome Trust. And instead of academic papers, both men now trade insults such as "slimy" and "con job".

"The people from the Wellcome Trust do not believe this shit that they are saying," says Venter, leaning back on the chair in his office at his Rockville headquarters, near Washington. "It's much easier to demonise us than justify the hundreds of millions of dollars they have wasted. I have been a thorn in their side for some time because I keep coming up with breakthroughs. Having a rival in any sense is unacceptable to them. They are trying to destroy someone they view as a serious competitor. We did not set out to sequence the human genome just to make John Sulston and the Wellcome Trust look bad. What is it about Celera that has to be stopped - because we are trying to treat cancer, find treatments for disease?"

On the other side of the Atlantic, in his bare office in the shiny new Sanger Centre near Cambridge, Sulston takes an implacably hostile view of his enemy. "Global capitalism is raping the earth, it's raping us. If global capitalism gets hold of complete control of the human genome, that is very bad news indeed, that is something we should fight against. I believe that our basic information, our 'software', should be free and open for everyone to play with, to compete with, to try and make products from. I do not believe it should be under the control of one person. But that is what Celera are trying to do as far as they can. They want to establish a monopoly position on the human sequence. Craig has gone morally wrong."

The two men are roughly the same age - Venter is 54, Sulston, 57 - but could not be more different. Venter is brash, aggressive, egotistical. His list of considerable achievements trip off his tongue like a pre-printed CV. "Is my science of the level, with the breakthroughs, consistent with other people who have gotten the Nobel? Yes."

The walls of his office are covered in trophies, magazine covers of Venter, pictures of his naval graduating class and time in Vietnam, honorary degrees, and signed photos from Bill Clinton. During our interview, when he was not taking calls from Wall Street analysts, he was on the line to Business Week talking up Celera's stock price, or to his financial backers. He had a gold Rolex on his wrist, and sprawled at his feet were three huge black poodles, whom he calls "his children". When Venter is not darting around in the company Lear Jet, he is on his 84ft yacht, The Sorcerer, or flying to Saudi Arabia to pick up some prize, or attending the White House Correspondents dinner. He is now a player, lobbying his Congressional allies hard, up there in the big league in Washington. Fifteen years ago, microbiologists had to beg for grants. On February 29, 2000, Celera raised $1billion in one day on the New York Stock Exchange.

Venter likes to stand out from the dull pack of his fellow scientists. At one point he is called down to Celera's computer room, "whose Compaq computing power is rivalled only by the Pentagon", to pose for a New York photographer. He sits happily for 15 minutes, like a movie star. In more friendly times, Venter was once invited to a Wellcome Trust genomics conference in the Cotswolds. At Heathrow, the Trust laid on a bus to take arriving scientists directly to the conference. Venter was on the flight, but never took the bus - he turned up later in a hired Jaguar.

In contrast, the bearded Sulston is a model of quiet British understatement. Instead of a Rolex he was wearing a pair of old leather sandals. His wild beard and hair give him the air of being an ex-hippy professor. Sulston's father was a vicar and he has the same ideals of public service and social compassion. "The only thing I have retained from my upbringing - I did not retain the religious element - is the idea that you do not do things for money."

Sulston's office is lined not with power trophies but his old notebooks, filled with hand-drawn pictures of the dividing cells of the 1mm nematode worm he studied for years. He gets around in the family car and second class on Great North Eastern Railways. Sulston is, he says, a Guardian-reading political liberal, whose wife Daphne took part in the Greenham Common anti-missile protests. He did not get to the top rungs of British science, and the forefront of a world scientific revolution, by being a laid-back guy. By chance, I had to ask him something on Easter Sunday; he was there at his desk. The Wellcome Trust may be a charity, but it is the most powerful independent scientific institution in Europe, if not the world. Its œ300m purpose-built Sanger Centre is a big, big sequencing machine with one objective in mind - to clobber the opposition.

The battle between Venter and Sulston is more than a personal clash. Once the human genome is decoded, it will begin to transform medicine, science, human fertility, archaeology, genealogy, the insurance trade and the whole of human society. Knowledge of the human gemone, the code of life, will allow us to determine exactly what it is that makes us human. The code may give us the cure for cancer, heart disease, a thousand genetic human frailties. It will tell us who has a predisposition to be gay, to be depressed, to be good at metabolising oxygen and hence good at sport, to get Alzheimer's, to die of bowel cancer at 53. We are aware of some of these things already; clever parents generally have clever children; heart attacks, like some breast cancers, run in the family. But the difference is that we will know. You can alter your behaviour, but you cannot alter your genes, yet. It will give you, and other powerful institutions in society such as insurance companies, the power to read the unique genetic bar-code that is contained in every cell of your body. Scientists have already identified 289 genes, mutations to the normal code, that directly cause diseases in humans. Soon we will know an awful lot more. We may not like the answers but we will have them.

There are a 100 trillion cells in the human body. In the nucleus of each of these cells are 46 chromosomes, 23 from your mother and 23 from your father. Those chromosomes are made of DNA, a long molecule of deoxyribonucleic acid, whose famous double helix shape was the greatest scientific discovery of the 20th century. There are six feet of DNA in each human cell. And DNA is composed of four chemicals, or bases, adenine (A), thymine (T), guanine (G) and cytosine (C).

It is these bases that are the digital code of life. Every living organism on earth, from microbes living in super-heated sulphur vents two miles down on the bottom of the ocean, to bacteria, roundworms, wheat, fish, trees, cows, chimpanzees (who share 98.9% of our human DNA) is composed of letters of the same A, T, G, C genetic code. It is the one and only alphabet of life - hence the ability of researchers to insert "fish" genes into plants.

There are 3.5 billion bases in the human genome. The human genome is, in effect, a single sentence: ccacatgatatctatccaacccatgtccccacatgatatctatccaacccatgtccccacatgata tctatccaacccatgtcc and so on until it would fill 500,000 pages of a telephone directory. It is equivalent to 750 megabytes of data and will fit on one DVD disk. Most of that genome is junk: between 95 and 97% is redundant, the left-over genetic instructions for what to do with our fins or tails; we still carry with us our evolutionary ascent from bacteria in the swamp. Scattered at random amid this genomic sentence are the 100,000 genes - active sequences - which code for the 20 amino acids that make up the body's proteins. Everything that we are as humans, from our toes to our hormones, to the synaptic gaps in our brains, muscles, bones, to when and how our cells divide, is, or is the product of, proteins. Our genes are the codes for these proteins. They are the telephone numbers that actually work.

Each of those genes can be thousands of letters long. Other parts of the genome, which do not code for genes, also act like a control mechanism and play a role in the way genes interact or the way a human foetus is formed. Our genome is the book of human life. "As long as there are humans in the universe, it will be essential," says John Sulston.

Decoding the human genome will increase our knowledge, a thousandfold times a thousandfold of the nature of Homo sapiens . And with that knowledge will come immense power. Before we create, we will almost certainly destroy, committing a new form of human selection, genomecide. Through systematic but simple foetal genetic tests in the next decade, we will ruthlessly search out and eradicate those human genes we regard as inferior, Trisonomy 21 or Down's Syndrome, Turner's Syndrome, Huntingdon's Chorea, Cystic Fibrosis; the list is as long as we want to make it. The difficulty we will have to face is where do you draw the line? Do you abort multi-celled foetuses because the tests show genes that code for Alzheimer's in later life? Would we now eradicate the former US President Ronald Reagan, whose Alzheimer's is genetically inherited, just after conception? What is the definition of an acceptable genetic human being? What is a valid human life? In America, where medical insurance is a key issue, the first cases of genetic discrimination are already appearing in the courts.

In time, we will begin to manipulate our genes, select the traits we want in our children, designer babies, just as we are now altering the genes of the plants and animals.

There will be great benefits, a cure for Aids, malaria, maybe eventually nearly all of the diseases that afflict humanity. Genomics is the future of a whole new set of pharmaceutical industries that will create thousands of individually tailored drugs.

We are at the beginning of a genomic century and in the midst of a biological gold rush. Every day, the US Patent and Trademark Office is flooded with new patent applications from US biotech companies such as Incyte, Human Genomic Sciences, and Celera, claiming patent rights - exclusive property rights - on the 100,000 genes in the human body. Celera alone is believed to have filed more than 20,000 provisional patents. Incyte aims to patent one million of what are known as ESTs, expressed sequence tags, snippets of the genetic code that identify genes, whose functions may be entirely unknown at the time of patenting.

Along with the benefits will come unparalleled profits, wealth beyond even the dreams of Microsoft's Bill Gates, as a few companies carve themselves monopolies from the code of human life. T
he first battles have already begun. Aids researchers have recently identified the pathway, or docking site, known as the CCR5 receptor, by which the Aids virus enters human cells. Block that doorway and, potentially, you have a cure for the most expensive disease in human history - a virus that has killed and lethally infected 30m people. But the gene for CCR5 is "owned" by Human Genomic Sciences Inc (HGS), of Rockville, Maryland, former collaborators of Venter, which is demanding royalties and licences from every drugs company that wants to work on CCR5, even though HGS admits it had no idea of the gene's function in Aids when it filed the patent application.

Having a monopoly on an individual gene is one thing, but controlling access to the human sequence itself would give the means of taxing every single biological research project for the next 20 years. Genes do not work in isolation. The 100,000 genes in every cell of our bodies interact in ways that are still unknown to us. To understand those interactions, scientists will have continually to return to the whole genome sequence. Whoever owned exclusive rights to the sequence could quite easily become the richest person in the world and stifle any research that threatened their monopoly. Controlling the sequence would be like owning copyright on the letters ABC of the alphabet. Celera's declared aim is to became the "definitive" source of genomic information, so definitive that drugs companies will pay millions for the data, even though HGP will provide a rival version for free. Being first in the race for the code would be a huge propaganda victory. But in Sulston's view, it also explains Celera's attacks on the publicly-funded project. Celera wants to undermine and degrade its only possible rival; for "definitive" read "monopoly".

For Craig Venter, the race for the code began during the 1968 Tet Offensive in a Da Nang field hospital in South Vietnam, where, as a medical corpsman, he was suddenly confronting thousands of casualties. The communist Vietcong launched a surprise offensive against US bases on the eve of the traditional Vietnamese holiday; there was bloody hand-to-hand fighting all over South Vietnam. "I had to learn, in real time, what triage actually meant. I dealt with the death of thousands of men my age. It was a life-altering experience. The biggest thing was the loss of my innocence. The loss of the sense of immortality that goes with being young. Life was so cheap in Vietnam. And that is where my sense of urgency comes from. Before that, I had no urgency at all."

Vietnam was the making of Venter. Although he came from a military family - his parents, John and Elizabeth, met in the Marines in 1943, in San Diego - he had dropped out of high school. Before he was drafted in 1965, he had been a beach bum, a champion swimmer, whose main occupation was surfing and sailing the waters of San Francisco bay. He originally intended to join the US Navy swim team, but ended up in the medical corps as a freak result of the IQ tests undertaken by every recruit. Venter had, out of 35,000 tests, the highest score, over 140, and was immediately offered a specialism. The medical corps, unlike nuclear engineering, was the only specialism that did not require signing up beyond three years. He trained as an army medic and found that he loved it.

After Vietnam, Venter returned to the US determined to get a medical degree and work in the developing world. In six years, he crash-coursed his way through a local community college to get basic qualifications, and then the University of California med school. Along the way, he shifted into medical research and began teaching at the State University of New York, where he met his future wife and collaborator, Claire Fraser.

Part of the key to Venter lies in this unorthodox academic ascent. Although the Community College of San Mateo - whose other most famous alumnus is John Belushi -and the State University of New York are competent institutions, they are far from being the great scientific centres of the West. Venter was never a traditional insider.

In the late 70s, he began working on the adrenalin receptor in the brain. Isolating genes, cloning them in sufficient quantities to engage in experiments, was a tedious, frustrating process. Sequencing was messy and cumbersome, involving radioactive dyes and X-ray film. It could take 10 years to isolate one gene. And everything depended on precious grants doled out by the scientific elite.

Now, Venter does little to mask his contempt for his scientific rivals who sat on grants committees and awarded each other the prizes. "I was not a molecular biologist, but you could not get a grant to do molecular biology unless you had trained with one of the few molecular biologists. It is part of the assumptions of science that I detest. It is part of the apprentice system that assumes you cannot go out and learn something on your own. In science, the same people, in a few powerful positions, control the input and the output. The same people get asked to review your grant - 'Should we give this guy the money' - then get asked to review the manuscript: 'No, it's trash, we don't like him.' It's more a way of controlling things than doing science."

In the 80s, Venter became a researcher at the prestigious US National Institute of Health (NIH), in Washington. He was an innovative scientist, who helped develop the technology for automated gene sequencing. Fifteen years ago, decoding just one base letter cost $10 and was a painstaking manual task. Today, both Celera and the Human Genome Project churn out millions of letters a day by using banks of sophisticated sequencers. Genomic science has become an industrial rather than a scientific process: it simply would not be possible to decode the 3.5 billion bases of the human genome without this automation. It was Venter, in 1987, who ordered the first automated gene sequencer and worked closely with the manufacturer, Applied Biosystems, to test and improve the nascent technology. It would prove to be the key relationship of Venter's scientific career. His company, Celera, is a sub-division of Perkin Elmer, the maker of the Applied Biosystems sequencers.

"The scientific community has never forgiven us for picking Craig," said one of the leading designers of sequencing technology. "They have never accepted Craig as one of their peers, never accepted that he was one of the best scientists in their midst. Sure, he is antagonistic, but Craig is prepared to take risks. Back in 1987, he bought the machine. All the others said, 'No, it's too risky, let's wait for a couple of years.' But you need someone like Craig to test and validate the system."

On a long, boring night-flight back from Tokyo, Venter also came up with a novel way - expressed sequence tags (EST) - of locating genes in the vast, bewildering genome. DNA is transcribed into protein via a slightly different compound Messenger RNA. By cloning this mRNA back into what is known as complementary DNA (cDNA), Venter short-circuited the laborious hunt for genes. ESTs are a clever, but patchy, way of using a cell's own mechanism to help find genes. ESTs, gene fragments, are like marker flags that identify individual genes and locate their position in the genome.

With his EST strategy and primitive but state-of-the-art gene sequencer, Venter was soon cranking out more human code, and locating more genes, in a day than other scientists had done over decades. But it was Venter's next move that shocked the scientific community. In 1990, the Human Genome Project, the international effort to decode the human genome, was finally launched after years of carefully-crafted international agreements with Britain, France and Japan. It was the biological equivalent of sending a man to the moon, with a budget of $3billion, and was expected to take until 2010 to complete.

In June 1991, in the US, the National Institute of Health (NIH), where Venter was still working, without warning filed 6,500 patents on Venter's ESTs. It seemed to be the opening salvo in a nationalistic biotech war. The harshest criticism came from the NIH bureaucracy itself, where James Watson, the Nobel Prize-winning co-discoverer of DNA and leader of the Genome Project, denounced Venter's patents as "monkey work". There was a damaging row. Venter's attempts to get more grant funding, despite his successful sequencing track record, were mysteriously rejected and the patent applications overturned. Stung by the personal criticism, Venter left NIH, and public science, in June 1992 to found a private research institute, The Institute for Genomic Research (TIGR). Although TIGR was run as a charity, it was funded by the aggressive patent-seeking biotech firm Human Genomics Sciences that had ownership rights over TIGR's discoveries. The real race for the code was just beginning.

DNA: It's war (part two)

Decoding the human genome will change the world. But, says Kevin Toolis, it's not just about science; it's UK vs US; public spirit vs private enterprise. And it's personal

Saturday May 6, 2000

The Vietnam war was also a pivotal point in John Sulston's life. After doing a PhD in chemistry at Cambridge, he was awarded a post-doctoral scholarship at the Salk Institute in La Jolla, near San Diego, just as the anti-war movement took to the streets. "I was absolutely a child of the 60s. I feel very strongly that I was on the side of people who opposed the war. I remember arguing with lots of right-wing people in the lab, people who believed it was a just war and the US was totally right to go there. I was a real lefty figure."
Sulston, whose father, Ted, worked for the Society for the Propagation of the Gospel, in London, and whose mother, Muriel, was a schoolteacher, fell into science after what he admits was a fairly undistinguished undergraduate degree at Cambridge between 1960-63. "I never regarded myself, and I'm not an especially bright person, more of an artisan than an intellectual. I tried to go off with VSO and was signed up for some programme that collapsed. So, at the end of the summer term, without any particular plan, I asked about doing a PhD. And they said, 'Oh fine, come along in' - this was the 60s. That was tremendous. I did not like book work, I never have liked book work. What I actually liked was being in the lab and playing with the toys. I just played and played and played."

Sulston's scientific awakening came in California. "I was spoilt at the Salk Institute. I was the post-doc who got all the goodies. You were invited to have dinner with Nobel prize winners, made to feel bigger than your boots. I was absolutely in love with California. I loved staying at home, having babies, going to the beach - we bought a pick-up and put the pram in the back - and growing runner beans."

In 1969, Sulston returned to Cambridge and its world-famous molecular biology laboratory, where DNA was originally discovered. In California, he had worked on nucleic acids - how genetic inheritance might get going - but techniques were primitive. He made his scientific name with a detailed study of a tiny worm, Caenorhabditis elegans.

There are thousands of these little worms, also known as ringworms, in every handful of soil, where they eat bacteria. As part of a research project examining the worm's genome, Sulston had the simple but audacious idea of tracing the "choreography" of the way the cells divided by just watching them hatch through a Nomarski light microscope, that magnifies at 2,000 times.

Every human starts off as one cell, a fertilised egg, but our cells soon divide, spine, bones, eyes, kidney, blood and hair. Understanding the lineage of how our cells specialise is fundamental to understanding genetics. Even in C. elegans, with just 1,000 cells, it is a complex process. For 18 months, Sulston shut himself in a small room and watched worms hatch. "No one thought it was possible. Various people had looked at taking photographs, cutting and staining. But the resolution was not good enough. I twigged I could do it just by sitting and looking, so I did."

It was mind-numbing, fastidious work. Sulston fondly still keeps his old microscope in his office. In true British fashion, Sulston describes his work as "not the top stuff, the breakthrough that leads to Nobel prizes, but solid middle-of-the-road science". The results were published in 1983, and Sulston, with his US collaborator Bob Waterston, who heads the other major genome sequencing centre in the University of Washington, St Louis, moved on to map the worms' genes.

Although the nematode is tiny, its genome is still 100 million bases long. That is 100 million Cs, As, Gs and Ts. Decoding a genome is a bit like doing a very big jigsaw. In gene mapping, the genome is first divided up into big chunks - with the human genome there will be 22,000 segments, 150,000 letters long - and then each segment is analysed and their sequence, CATTGCC, read off. Because researchers know which big bit the individual sequence comes from, it's easier to put the whole jigsaw back together. Sulston and Waterston, viewed by James Watson at NIH as the best sequence team in the world, began sequencing the worm in 1990 as a test run for the human genome. The C. elegans genome was finally published in 1998. It was the first genome of a free-living animal ever decoded.

By then, a forerunner of the current war over the human genome between Sulston, his collaborator Waterston, and Venter had already broken out. At his research institute, TIGR, Venter was producing a library of ESTs - valuable biotech material indicating the site of potential human genes - and TIGR's funders, Human Genome Sciences, sold the exclusive rights to consult this library to big pharmaceuticals such as SmithKline Beecham. The five-year deal with SmithKline Beecham alone was worth $125m. HGS was effectively operating a monopoly and demanding "reach-through" royalties; anyone who used its material and subsequently came up with a commercial application for a drug had to pay HGS a royalty. Academic researchers unable to pay the fees were locked out. Most of the data was sitting in closed computer files, waiting for paying customers.

SmithKline Beecham's drug rivals, Merck, struck back. Rather than pay HGS fees, they gave Waterston a research grant to sequence a rival EST library and lodge them for free in Genbank - a public depository for genetic material and accessible to anyone. Overnight, it destroyed the economic value of HGS's precious library. "Everything they do seems to have more of a political lean to it than just science. Waterston was a willing employee, or just part of someone else's game plan, in the contest between giant pharmaceutical companies," says Venter provocatively.

But for Sulston, the open publication of the EST data was the ideal outcome. "The human genome is vastly more complex, and its implications far greater, than anything we have encountered before. There is no way it should be concentrated in the hands of the few - that is exactly where Bolshevism went wrong. The human genome should be spread out laterally. We want competition on the products, not on the information itself."

At TIGR, Venter had been developing a new way of sequencing genomes, called the "whole shotgun method" that relied on powerful computers and complex algorithms to reassemble tiny fragments without the aid of the gene-mapping sequences used by Sulston. Instead of first using big bits of the jigsaw, Venter just cloned the whole genome and then blasted it in small fragments. These fragments were then fed directly into sequencing machines and reassembled by concentrated computer power. In 1994, he used the shotgun method to sequence the micro-organism Haemophilus influenzae, the bug that gives children ear infection. It was the first actual organism, rather than an animal such as the worm, ever to be sequenced. Other bugs, syphilis and the bacteria that live in sulphur vents on the bottom of the ocean, followed.

Again Venter came under attack for his methods. Critics claimed the shotgun method was imprecise - shotgunning the human genome leaves you with 60 million gene fragments, 2,000-10,000 letters long, to put back together again. His opponents claimed shotgunning would leave gaps in the sequence data, and would be unable to cope with larger genomes. But again Venter was triumphantly vindicated when, in collaboration with public scientists from Berkeley in California, he published the 120-million base genome of the fruit fly - important in genetic research - in March 2000.

In 1997, Venter fell out badly with HGS's boss, Bill Haseltine, over the company's secretive business plan and ended their collaborative relationship. Haseltine and Venter swiftly became deadly rivals. Venter was out in the commercial cold again, lobbying for grants to sequence genomes from his academic enemies.

But then his old partners, Applied Biosystems, saved him. In 1998, Perkin Elmer finally completed a new sequencing machine, the AB3700, that could sequence at hundreds of times the rate of earlier machines. Sequencing the human genome was just a question of lining up enough AB3700s - Celera has 300 of them - and turning them on. Perkin Elmer's Mike Hunkapiller, who developed the machines from their infancy, called Venter to head the new company. Big business
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