The name most frequently associated with the quest to breathe life into inanimate matter is the pioneer of genome-sequencing, Craig Venter. He, however, begs to differ. “I keep trying to make it clear – we’re not creating life from scratch,” he says.
Venter’s team at the J. Craig Venter Institute in Rockville, Maryland, plans to remove the genome from an existing bacterial cell and replace it with one of their own design. If successful, this will indeed result in a novel life form, but it is a far cry from the ultimate goal of a second genesis, as Venter would be the first to admit.
Other teams, however, are striving directly for that ultimate goal. The most ambitious of them do not even rely on the standard set of molecular parts, but seek to redesign a living system from first principles. If successful, they would provide an entirely new form of life unlike any that exists today, an achievement comparable to finding alien life on other planets – but one which would raise novel ethical and safety issues (see box).
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“Producing synthetic life would be an achievement comparable to finding alien life on other planets”
Four years ago, Â鶹´«Ă˝ profiled one such effort, led by Steen Rasmussen of Los Alamos National Laboratory in New Mexico (12 February 2005, p 28). Instead of emulating the system used by existing cells – a watery soup of biomolecules enclosed in an oily membrane – Rasmussen’s “Los Alamos bug” consists of biomolecules studded into the surface of an oil droplet, like cloves stuck in an orange.
At the time, Rasmussen hoped success might be only a few years away. Today he’s more cautious. “No life yet,” he reports. “But we’re getting closer… we’re inching our way.” Rasmussen, now at the University of Southern Denmark in Odense, and his team, are steadily working through a checklist of intermediate goals. For example, they have persuaded their minimal DNA genome to direct the production of fatty acids, allowing the oil droplet to grow – a key step in their bug’s rudimentary biochemistry. They are now trying to prove that the genome can replicate while attached to the droplet, and that the droplet can be made to grow and divide in sync with the genome.
Meanwhile, another group has leaped ahead by developing an information-carrying molecule that can help make copies of itself. This is one of the biggest obstacles to synthetic life. Most experts assume that a self-replicating molecule – most likely RNA – must have played a role in the origin of life on Earth, but no one has been able to build one.
Tracey Lincoln and Gerald Joyce of the Scripps Research Institute in La Jolla, California, tried a slightly different tack. Instead of a single RNA molecule, they made two, each able to construct a copy of the other by stitching together two half-molecules supplied by the researchers.
Some think the earliest life forms may have replicated in a similar chunk-by-chunk way, with evolution gradually reducing the size of the chunks until it arrived at the DNA letter-by-letter replication we see today. If so, Lincoln and Joyce’s cross-replicators would be the closest anyone has got to recreating the origin of life. Indeed, the molecules worked so well that their population began to grow exponentially (Science, ). “That’s the first time that’s happened, except in biology,” says Joyce.
The RNAs even underwent a rudimentary form of evolution. When the researchers supplied them with varying precursor molecules, the replicators spontaneously selected a combination that worked most efficiently.
This, however, falls short of true Darwinian evolution. Selecting from a pre-ordained range of options is not the same as an open-ended capacity to create new variants by mutation. The cross-replicators cannot be considered alive until they meet this tougher test, says Joyce.
There are two other tests they would have to pass to cross the Rubicon from inanimate to animate: carry out some sort of metabolic processes and segregate themselves into some kind of package. Joyce’s team is trying to build new functions into the system in the hope of passing these tests – but that is probably a long way off. Other efforts to design living cells from scratch, notably those of Jack Szostak at Harvard University and Pier-Luigi Luisi at the Swiss Federal Institute of Technology in Zurich, are similarly unlikely to reach their goal soon.
There is, however, yet another approach that looks closer to paying off. Instead of going back to the drawing board and designing life from scratch, George Church of Harvard Medical School and Anthony Forster of Vanderbilt University in Tennessee are short-cutting the design process by using the familiar molecular tool kit of existing cells. Starting with a set of inanimate molecules, they intend to assemble a living, replicating system in much the same way as a hobbyist might assemble a kit car. “It’s complicated, but I think people are starting to realise that this may be the best chance we have to create a synthetic living cell,” says Forster.
“People are starting to realise that this is the best chance we have to create a synthetic living cell”
Just as a first-time car builder might keep things as simple as possible by omitting cruise control and aircon, Forster and Church began by stripping their kit down to its barest bones. They ended up with a list of 151 essential biomolecules: the proteins and RNAs needed to replicate DNA, make RNA copies, and translate RNA into protein molecules (Molecular Systems Biology, ). The rest can be outsourced. For example, instead of having their cell extract energy from sunlight or turn food into the energy-carrying chemical ATP, the researchers supply them with ready-to-go ATP. They also plan to forgo a cell membrane for the time being, running the whole system as a loose soup in a test tube.
Many of the components of this minimal cell already work well together. Biotechnology companies routinely sell commercial kits to synthesise DNA, RNA or proteins to order in a test tube. But these kits only work for a few hours or days before the components are used up and the reaction grinds to a halt. To create a system that runs indefinitely, Forster and Church will also need to add a DNA molecule that encodes all 151 components, so that the system can make new ones as needed. Once they have combined this DNA with a starting set of components, they should in theory end up with a replicating, evolving – in short, living – system.
Putting together so many complex parts remains a challenge but, suddenly, the finish line may be in sight. At a synthetic biology conference in Hong Kong in October 2008, Church and his Harvard collaborator Michael Jewett reported that they had solved one of the biggest assembly problems: putting together a ribosome.
The ribosome is the cell’s protein-making machine and is one of life’s most complex molecular contraptions, consisting of 57 proteins and RNA molecules that all need to come together in exactly the right way. Many have tried to achieve what Church calls “the biggest assembly in biology”. Now that Jewett and Church have succeeded, there is ground for hope that the production of any complex molecular machine is possible.
At the time, the pair had only assembled the ribosome from components extracted from cells. Now they have succeeded in repeating the assembly using a synthesised version of the largest RNA component. Church sees incorporating the rest of the synthetic RNAs as a relatively minor challenge. “There’s nothing you’d expect to go wrong, the way we expected things to go wrong with the assembly,” he says.
Even after that hurdle has been cleared, unforeseen problems are likely to pop up when the researchers try to assemble all 151 genes and their products into a functioning whole. “Until you actually try this, you won’t know,” says Forster. “Having said that, we know cells can do it, so we should be able to do it – sooner or later.”
Already, some other subsystems are beginning to come together. A team led by Tetsuya Yomo at Osaka University in Japan has created a system similar to Church’s, but consisting of 144 parts instead of 151 – partly because he leaves out the DNA step. In Yomo’s system, a tiny RNA genome contains the directions for making a single protein which, in turn, helps the RNA molecule replicate. Gene makes protein makes gene, closing the loop for the first time in a synthetic system – a feat Church’s team has yet to accomplish (ChemBioChem, vol 9, p 2403). “We’ve spent 10 years to reach this level,” says Yomo.
Synthetic life is not yet a newspaper headline waiting to happen. But every research team that has embarked on the quest reports good progress, and the goal of creating a living being from nonliving chemicals is now less a vague possibility than a definite target with clear roadmap leading to it. “I’m getting more confident in my five to 10 year prediction,” says Deamer.
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Frankenstein’s microbe?
If scientists succeed in synthesising life from nothing, is there a risk that, like Frankenstein’s monster, their creation might run amok and cause incalculable damage? In the long run, perhaps. After all, evolutionary innovation is intrinsically unpredictable, and once a synthetic organism begins evolving on its own in the real world, it could spring surprises. But then again, so can normal bacteria and viruses – witness the former chimp virus we now call HIV.
In the short term, there seems to be little to worry about. Any synthetic life form now on the drawing board would be able to “live” only with massive life support. In the real world, without a steady diet of complex molecules and energy, an escaped “Frankenbug” would quickly perish. That means society will have plenty of time to grapple with safety issues, says Mark Bedau, a philosopher of science at Reed College in Portland, Oregon. And indeed, a European Union task force has already begun working on the topic.
At least a few critics – notably ETC Group, an activist organisation based in Ottawa, Canada – also worry that creating life from scratch might cross some moral line, though mainstream theologians seem unruffled. Humans creating life would just be a special case of life creating more life, which in a sense has been the norm for billions of years, says John Haught, a Catholic theologian at Georgetown University in Washington DC.
