The god of small things

January 26, 2007

After unlocking the secrets of the human genome, the controversial scientist Craig Venter now is trying to engineer a microbe to liberate us from our dependence on oil. Ross Douthat reports. Back when Craig Venter was the bad boy of science, racing the US Government to sequence the human genome - and using some of his DNA to do it - he kept his face cleanshaven, and often posed for photographs in suits or medical coats. With his high forehead, bald scalp and laboratory pallor, he looked more like central casting's idea of a respectable scientist than the self-promoting egomaniac that his enemies labelled him, or the surf bum and Vietnam War medic that, as journalists never failed to point out, he had been as a younger man. These days Venter has the air of a richer, less-rumpled Steve Zissou, the Jacques Cousteau-like oceanographer played by Bill Murray in The Life Aquatic. He sports a white beard and has the persistent tan of someone who's spent much of the past few years at sea, having circumnavigated the globe on a yacht, Sorcerer II. His office in Washington seems to boast a model ship for every distinguished-scientist citation, and screens on the walls display a rotating series of photos from his voyage - deep-sea creatures alternating with shots of a windblown Venter at the helm. Not that Venter has settled into retirement. The voyage may have helped him relax and blow off steam after several years in the eye of a scientific, political, and media hurricane. But it was primarily a Magellan-meets-Darwin expedition in which Venter and his crew sifted the sea for enough biological material to map the genome of, well, the entire planet, collecting millions of microbes on filter paper and shipping them back to Rockville, Maryland, for analysis. Venter's labs once broke apart human DNA and put it back together again; now they're attempting the same thing with microbial genes. But this time, Venter is out to build new genomes, not just to analyse existing ones. He's not just trying to understand how life works; he's trying to make it work for him, and us. The race to map the human genome, in its headier moments, promised cures for Parkinson's, Alzheimer's, cancer. Venter's undertaking shows promise for something no less ambitious: a cure for our dependence on oil. The scientific consensus on global warming and the role of carbon-dioxide emissions in heating up the earth is stronger than it has ever been. Concern is growing that the world might be nearing "peak oil" - the moment at which supply starts to decline (leading, some say, to the collapse of industrial civilisation). Ironically, though, the most-talked-up oil alternative in this alternative-energy moment is a fuel that's long been called a boondoggle: ethanol, a form of alcohol produced through the fermentation of sugar derived from plant matter, usually corn kernels. Like most alternative fuels, ethanol has problems on both the demand and supply sides of the equation. So why the excitement over ethanol? The answer isn't in corn kernels, but in the stalks, roots and leaves of corn and other plants - "cellulosic" material that's been difficult to break down into sugars efficiently, but that now may be only a few breakthroughs away from becoming the source that makes ethanol available on the cheap. Cellulosic ethanol could be made from agricultural waste, so we need not rob our food supply for our energy supply. Better, it could be derived from non-food-producing plants grown on land otherwise unsuitable for cultivation.

All that's needed is the right science. This is where Venter comes in - though arguably, he's been there all along. Genomic research, after all, doesn't just offer scientists an opportunity to take apart the genome of a human being, a mouse, or a bacterium to see how it works and what it does. It offers them a chance - if they're sufficiently ambitious, or hubristic - to change what a genome does, and to make the organism do what we want it to do. And one of the obvious things we might want organisms to do for us -they already do it for their own purposes - is produce energy. Venter took a roundabout route to scientific prominence. After growing up in a working-class neighbourhood in the San Francisco area, he drifted through junior college, spending most of his time on boats and surfboards, and then enlisted in the navy to avoid being drafted. After training as a medic in San Diego he was sent to Vietnam, where he spent a year in a field hospital in Da Nang during the Tet offensive. After surviving Vietnam, Venter never drifted again. The brashness remained, and the surfer's disrespect for authority, but they were channelled into a fierce ambition and a desire to make a difference in the world. He got married, went back to community college, and then enrolled in the University of California, San Diego, where he earned a joint doctorate in physiology and pharmacology, choosing research over medicine. It was followed by a junior faculty position at the State University of New York, Buffalo, where he drove a baby-blue Mercedes, favoured garish shirts and bell-bottoms, split with his wife, and married one of his students, Claire Fraser. In 1984 he took a position at the National Institutes of Health. There he would first impress and then clash with James Watson, the co-discoverer of the molecular structure of DNA, who took over the leadership of the institutes' branch of the nascent Human Genome Project in 1990. After Venter developed a quick-and-dirty method of identifying genes, Watson, with Venter present, told a 1991 senate meeting that the technique "isn't science" because the machines "could be run by monkeys". By the following northern summer, Venter had quit the health institutes and raised enough venture capital to found the Institute for Genomic Research, or TIGR, where he would have control of all research, although any marketable discoveries would belong to the commercial wing of the enterprise, a company called Human Genome Sciences; this was his initial step on to the nonprofit/for-profit tightrope he has walked ever since. In 1995 his team published the decoded genetic script for the bacterium Haemophilus influenzae; it was the first time the complete genome of a living organism had been mapped. Later that year, a team led by Fraser published the genome for the parasite Mycoplasma genitalium, a far simpler organism, with only about 500 genes to H.influenzae's 1800. So began the quest for the "minimal genome", the bare-bones genetic material necessary for life to sustain itself and reproduce. This required dismantling M.genitalium, which suggested another possibility: if you could take a genome apart bit by bit, why not put one together in the same way, creating "life from scratch", as Venter puts it, with a genome of your choice? Meanwhile, Venter sequenced a third microbe, Methanococcus jannaschii, an organism found deep in the Pacific Ocean. "That organism," Venter says, was responsible for "stimulating our thinking, or my thinking, on the energy front". But then the human genome beckoned. In 1998 the biotech firm PerkinElmer persuaded Venter to head a new company that would use a technique called "whole-genome shotgunning" to try to speed up the genome-mapping process. At that point the government's Human Genome Project, using a slower, more painstaking method, was seven years away from its projected date of completion. The new company, eventually

called Celera, vowed to finish the work in three years. The pledge, and the race that followed, made Venter famous. It also cemented the reputation for egomania he had developed and added a multitude of government scientists and officials to a substantial list of enemies. The Human Genome Project's custodians would probably have resented any private-sector rival, but Venter made himself easy to loathe. In May of 1998, when he met the project's scientists to outline his company's plans, he suggested that while his team polished off the human genome, they might consider turning their attention to another creature. Specifically, the mouse. Venter's rivals in government predicted that his method would deliver a patchy, error-ridden product, and warned that if he succeeded in sequencing the genome first, Celera could enjoy a dangerous monopoly over information that rightly belonged in the public domain. They were wrong on both counts, in part because the Human Genome Project, spurred on by the competition, finished about the same time as Celera. A tie was announced in June of 2000; shortly thereafter Celera's stock collapsed, and Venter was forced to resign as president. He had money, though, from stock in various companies, and he had freedom. Using $US100 million of his own funds, he started three non-profit research centres, which are now consolidated under the J. Craig Venter Institute. One of the new centres, the Institute for Biological Energy Alternatives, took up the challenge of creating the minimal genome. Because a minimal genome has no nonessential pathways, it is the ideal template for the creation of designer organisms. By inserting "cassettes" of engineered genes into a stripped-down genome, Venter hoped to construct organisms that would do exactly what he wanted, and nothing else - organisms, for instance, that could serve as "biofactories", carrying out energy-generating functions that had been written into their genetic code. In 2005 he founded Synthetic Genomics, a company that would build on the minimal-genome research. Meanwhile, he was making his ocean-sifting trip on Sorcerer II. The first third of the material from the voyage (the rest is still being sequenced) has yielded 6 million genes. Somewhere in this wealth of material, perhaps, are the keys to better living through ethanol - the genes that, inserted into a minimal genome, could produce an organism able to break down cellulose quickly and cheaply. Or at least that's one possibility. Venter is already looking beyond ethanol. It may well be that a gene from the ocean, or elsewhere, will enable a synthetic organism to break down cellulose quickly and cheaply - but that's only the first step to real independence from oil. "Ethanol's not an ideal fuel," Venter said. In the long run, you want fuels that burn hotter and that don't require long-distance transportation, vast tracts of land, and huge biorefineries. Fuels, perhaps, that you could make at home. ("Everybody would have their own little bath in their backyard and fuel their car from it.") Natural gas from sewage sludge. ("Pretty badsmelling stuff coming out of septic tanks. If you could convert it into something useful and burn it methane is natural gas, you know.") And hydrogen, the cleanest fuel, from sunlight. ("We're working on modifying photosynthesis to go directly from sunlight into hydrogen production.") But research needs steady support, and investors tend to move in cycles. Consequently, Venter believes, the US Government needs to make a steady commitment to alternative energy. But not with props like its 51 cents-a-gallon (a US gallon is 3.78 litres) ethanol subsidy. The Government should be funding research rather than products, he says, so as not to create "a false industry that collapses once the subsidies collapse". Venter wants to see the

Government fund a variety of competing companies and research projects. "I'd rather see a thousand points of light than one dull bureaucracy," he says. "We don't have to have a single industrial-complex solution to this problem." A thousand points of light. A thousand Craig Venters. "I'm hoping our research teams come up with the breakthroughs," he says, "but I think as a society, we need those breakthroughs, and there's no guarantee we'll make them. So I'd be almost as happy if somebody else makes those breakthroughs." Almost. Atlantic Monthly

Craig Venter um anti-heri da cincia. Apressado, sem falsas modstias, difcil de vergar, rico. Aos 63 anos colhe crticas e elogios com a mesma destreza, mesmo quando acaba de anunciar uma das tecnologias com mais potencial econmico dos ltimos anos. Nasceu em Salt Lake City, Utah. Em mido era mau aluno, trocava a escola por perseguir avies na pista do aeroporto mais prximo. com esta memria que arranca a biografia "A Life Decoded", publicada em 2007, porque a lembrana mais viva que tem da infncia uma liberdade absoluta, de onde nasceu a curiosidade na base do seu xito. Foi no Vietname que acordou para uma misso maior. Em 1967, com 21 anos, foi destacado para um hospital de campo em Da Nang. "Durante anos tentei perceber o significado das vidas que vi serem destrudas ou estropiadas devido s polticas que nos envolveram na guerra do Vietname", escreveu. "Havia to pouca considerao pela vida no Vietname... da que vem o meu sentido de urgncia." De regresso aos Estados Unidos estudou Medicina e especializou-se em biologia molecular. Elegeu como campeonato pessoal os genes, e conquistou o dio de estimao de cientistas conceituados como James Watson, um dos descobridores da estrutura do ADN, ao impulsionar um novo mtodo de leitura da informao gentica no organismo, a chamada "sequncia shotgun". O mtodo tradicional dividia o ADN em fragmentos muito grandes - pense-se na tarefa como uma biblioteca em que os livros esto escritos com um alfabeto de apenas quatro letras (A, C, G e T) e o desafio perceber a sequncia das letras ao longo de 46 livros (cromossomas), que tm cerca de 4000 a 3340 pginas (genes), e cada um deles com 48 a 250 milhes de letras. Venter props que os fragmentos fossem mais pequenos, pois as dificuldades de alinhamento poderiam ser resolvidas por tcnicas avanadas de computao. Largou o projecto pblico por falta de outros entusiastas da sua verso e fundou a empresa privada Celera Genomics. Em 2001, os dois projectos apresentaram os resultados em conjunto - pela importncia do passo cientfico. Celera a tarefa custou 300 milhes de dlares e demorou trs anos, enquanto no sector pblico levou dez anos e custou 3 mil milhes. Foi despedido um ano depois, em conflito com o principal accionista e por querer manter a sequncia do genoma humano em open source. Em 2006 fundou o Instituto J. Craig Venter, onde reuniu alguns nomes da nata da cincia - entre eles o Nobel que assina com ele a criao da primeira clula sinttica, Hamilton Smith. A meta agora criar um organismo vivo de raiz. Anda de iate e de jacto privado. Acha que est altura de um Nobel.

By Alasdair Palmer 5:41PM BST 22 May 2010

91 Comments Has Craig Venter created life? Much of the reporting last week certainly leaves that impression. One critic says Dr Venter's new technology is like "splitting the atom". Another insists that "its risks are unparalleled" because it could "be used to make the most powerful weapons imaginable. The challenge is to eat the fruit without the worm." And yet the reality turns out to be much more prosaic. Dr Venter has created an artificial version of the DNA the set of chemical instructions which determine what an individual cell will build and reproduce for a very simple form of bacteria, and has inserted this into a cell from which the original DNA had been removed. The bacterium reproduced itself normally, using Dr Venter's version of the DNA (from which he had removed about 100 genes), eventually creating more than a billion copies.

As Dr Venter's less hysterical colleagues have noted, that is not the same as creating life. It is more accurately described as "mimicking life". Given the complexity of achieving even that task (the very simple form of life Dr Venter copied has more than a million chemical "letters" in its DNA code), Dr Venter has certainly pulled off something substantial. But it may turn out not have any significant applications at all. It might be possible to use it to manufacture a form of algae which could absorb CO2 and produce oil but it might not. Although Exxon has invested money in just such a process, there isn't a lot of evidence that the project will succeed. Dr Venter's technique also could aid the production of vaccines. But other than increasing the potency of medicines used to fight infections, no one claims that there will be any specific medical benefits from it. Even Dr Venter thinks that using his technique on any cells other than the most primitive forms of bacteria is "a long way off". For the foreseeable future, it cannot be used on human cells, or even on more complex bacteria. So unlike stem-cell research, which hopes to find ways to make damaged human organs, nerves and tissue repair themselves, it does not hold out the promise of cures for dozens of presently untreatable diseases. So why all the fuss? I don't think it is because we need to be frightened of the prospect of terrorists getting hold of the technology and using it to create terrible new techniques of germ warfare. Replicating what Dr Venter's team has done is far beyond their capacity. No, the source of our anxiety about the work is rather the ruthless demonstration that the essence of life is simply a series of chemical reactions. You may say that we knew that already, and we did but only in theory. Now Dr Venter has shown it in practice. Copy the chemical code that controls cell reproduction the equivalent to a computer's software put that code into a cell, and voil! The cell reproduces itself. It is alive. And if it works for the cells of bacteria, it will work for our cells, too: with us, there are more components we have 25,000 genes in each of our cells, as opposed to the 500 that control the reproduction of the bacterium that Dr Venter used but the mechanisms are the same. The differences are a matter of quantity, not quality. That sends a shiver down the human spine. What has happened to the mystery of life, the intangible, miraculous glory that we think is somehow its essence? It has disappeared. There are only molecules and the void. As for anything more elaborate than a string of chemicals such as, for instance, the soul well: we "do not have need of that hypothesis", as the French mathematician Laplace famously replied when asked where God was located in his cosmological system. The universe is a bleak and comfortless place when life's essence is just a sequence of chemicals. The reason why Dr Venter's work has created alarm is that it holds up a vision of what we are that we do not want to accept. We can't bite his apple without eating its worm: and that leaves a very bad taste.