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Take one genome…

Craig Venter plans to build a living organism from scratch. Is it a technological tour de force or is he just wasting public money on little more than a parlour trick?

SOME ideas are so audacious they might just work. So when genome guru Craig Venter unveiled a plan last week to create a new life form in the lab, it sparked a blaze of publicity and excitement.

Venter, of course, is the scientist whose American company Celera famously set out to sequence the human genome – mostly Venter’s own genome, as it turned out. Never known for modesty, he has set new heights of ambition with this latest project.

Its aim is no less than to build a new organism from scratch. Out of a selection of essential bits and pieces from existing life forms would emerge a primitive single-celled microbe, the simplest design that would still qualify as a living creature. And there would be checks and balances: no way, journalists were told, would this microbe be capable of surviving outside a lab. And no way would it be capable of infecting or harming people.

Quite the opposite. The long-term goal, Venter declared, will be to use the new organism as a blueprint for creating benevolent microorganisms for sucking unwanted carbon out of the atmosphere, excreting hydrogen fuel, and destroying toxic waste. In short, for saving the planet.

The “minimal microbe” project confirms Venter’s genius for creating headlines, but two crucial questions remain after last week’s media frenzy. Can his team really make a brand new organism? And would such a creature really transform our understanding of the basic mechanics of life, let alone our ability to engineer useful microbes?

Opinion is sharply divided. Venter has already recruited Nobel laureate and DNA expert Hamilton Smith, previously of Celera. He has also attracted a $3 million grant from the US Department of Energy (DOE) to fund the work at his newly formed Institute for Biological Energy Alternatives.

However, many scientists èƵ approached were sceptical. At best, one expert says, it is “a neat parlour trick”. Another expert said the scheme could become a technological tour de force. But he also feared that it could backfire and end up being used to make potent bioweapons.

As raw material for new life the project will use Mycoplasma genitalium, a bacterium with only 480 genes that lives in human genital tracts. The scientists will remove all the genetic material from the organism, then synthesise the smallest artificial M. genitalium genome needed to sustain life. This artificial chromosome will be inserted into the hollowed-out cell, which will then be tested for its ability to survive and reproduce.

The idea is not new. Venter sequenced the bacterium’s genome seven years ago, and in 1999 his team published a genetic analysis in the journal Science suggesting the bug could get by with less than 350 genes. It is these genes that will form the basis of a stripped-down genome.

Even so, the genome is still likely to contain more than 300,000 DNA letters. Synthesising it in the lab will be by far the most elaborate genetic construction project yet attempted. Recently, for example, researchers in New York were lauded for the remarkable achievement of assembling the 7500 DNA letters of the polio virus.

If Venter’s team succeeds, what’s the pay-off? As experts digest last week’s news, practical spin-offs such as hydrogen-producing microbes are increasingly being called into question (see “Why artificial microbes may be just a solution looking for a problem”).

Venter has been quoted as claiming that it might yield “a molecular definition of life”. But other experts say it will no more do this than an inventory of transistors and resistors defines a radio. “It doesn’t seem like a very direct way to answer any questions,” says Ford Doolittle, a biologist at Dalhousie University in Halifax, Nova Scotia.

Most biologists and philosophers agree that the essence of life has something to do with self-replication and evolution, but they have difficulty settling on a more precise definition (see èƵ, 13 June 1998, p 38). And a minimum parts list neither casts any useful light on the origin of life on Earth nor helps astrobiologists recognise life on other planets.

“It would be the neatest parlour trick you can imagine,” says Doolittle, “but it wouldn’t tell you how life started.” Life must have arisen from simple, self-replicating molecules, a far cry from even the simplest forms of modern life, with their intricate cellular structures and protein synthesis machinery.

Venter’s project might provide one indirect pay-off for researchers. If he can make a living, metabolising, reproducing cell, it would give biologists a brand-new experimental tool – an organism so simple it may soon be possible to model every aspect of its biology in a computer. “Once you mathematically capture the complexity of a simple cell, those equations form a foundation to understand all sorts of biochemistry in a fundamentally new way,” says Ari Patrinos, the director for biological and environmental research at the DOE office of science.

Worryingly though, the microbe’s simplicity might also appeal to would-be bioterrorists trying to reconstruct deadly pathogens. Raymond Zilinskas, director of the Chemical and Biological Weapons Nonproliferation Program at the Monterey Institute of International Studies in California, warns that the minimal genome represents a jump in technology that “raises some dangers”.

“This is something only the world’s most sophisticated labs can attempt right now,” he says. “Once it’s done, it will become easier and easier to replicate if the information gets out there.” A team of ethicists who studied the project argue that this is not a compelling reason to stop the work. But Venter himself has cautioned that some aspects will have to be kept secret to prevent terrorists picking up ideas.

Despite such concerns, Venter’s track record of delivering on outrageous claims makes everyone pause before dismissing the artificial microbe. “If it was anybody but Craig Venter, you’d say, ‘Well, that’s an interesting direction, good luck’,” says Bruce Logan of Pennsylvania State University in University Park, who engineers bacteria. “But if he can assemble a huge team and go after [it], it might show some interesting scientific results.”

Patrinos goes further. “Twenty to 50 years down the road, people will say that in 2002, we made the right bet.”

Additional reporting by Anil Ananthaswamy