Second genesis

  • Life as we know it, represented by the familiar double helix of DNA, or deoxyribonucleic acid "“ the hereditary material in humans and almost all other organisms. Nearly every cell in a person"â„¢s body has the same DNA. Image credit: iStockphoto/David Marchal
  • Gearge Church
  • Darwin
Date:31 May 2009 Tags:, , ,

One kind of life is all we know, but that’s about to change, right here on Earth…

When the Nobel prizewinning physicist Richard Feynman died in 1988, his blackboard carried the inscription, “What I cannot create, I do not understand”. By that measure, biologists still have a lot to learn, because no one has yet succeeded in turning a chemical soup into a living, reproducing, evolving life form. We’re still stuck with Life 1.0, the stuff that first quickened at least 3,5 billion years ago. There’s been nothing new under the Sun since then, as far as we know.

That looks likely to change. Around the world, several labs are drawing close to the threshold of a second genesis, an achievement that some would call one of the most profound scientific breakthroughs of all time. David Deamer, a biochemist at the University of California, Santa Cruz, has been saying that scientists would create synthetic life in “five or 10 years” for three decades, but finally he might actually be right. “The momentum is building,” he says. “We’re knocking at the door.”

Meanwhile, a no less profound search is on for a “shadow biosphere” – life forms that are unrelated to the life we know because they are descendants of an independent origin of life. We know for sure that life got going on Earth once, so why couldn’t it have happened twice? Many scientists argue that there is no reason why a second genesis might not have taken place, and no reason why its descendants should not still be living among us.

So the appearance of an “alien” organism seems imminent – we may find one that arose naturally, or engineer one in the lab. Either way, it’s a momentous step. Until now, biologists have had to base their understanding of life on the plants, animals and microbes that surround us, which all share a common ancestor. That doesn’t give much perspective.

“When you have a single example, it’s very hard to know whether it’s representative,” says Carol Cleland, a philosopher of science and astrobiologist at the University of Colorado in Boulder. “If you were an alien biologist who’s interested in understanding what a mammal was, and all you had was zebras, it’s very unlikely that you would focus on their mammary glands, because only half the specimens have them. You’d probably focus on the stripes, which are ubiquitous.”

Discovering – or engineering – a second genesis wouldn’t just broaden our view of life. Alternative life forms could supply biotechnologists with fresh molecules and new functions that they could apply to practical problems. A synthetic, made-to-order living system might even serve as a self-maintaining, self-improving, adaptable assembly line for producing everything from pharmaceuticals to petrochemicals. Over the next few pages, we first report on rapid progress in the lab, and then bring news from the field as researchers race to make what could be one of science’s most far-reaching breakthroughs.

The name most often associated with the quest to breathe life into inanimate matter is the pioneer of genomesequencing, 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 fi rst 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).

Four years ago, the magazine New Scientist profiled one such effort, led by Steen Rasmussen

of Los Alamos National Laboratory in New Mexico. 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 informationcarrying 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 halfmolecules 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 crossreplicators 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. “That’s the fi rst 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.

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. 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 forego 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 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 fi rst time in a synthetic system – a feat Church’s team has yet to accomplish. “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 non-living chemicals is now less a vague possibility than a defi nite target with clear roadmap leading to it. “I’m getting more confi dent in my fi ve to 10 year prediction,” says Deamer.

While some researchers are attempting to create brand new life in the lab, others are searching for alien life on Mars and, eventually, elsewhere in the solar system. This burgeoning field of astrobiology has a less well-known offshoot right here on Earth: the search for a “shadow biosphere” – a second, independent form of life unrelated to sort we know.

After all, many astrobiologists now think that given the right conditions, any suffi ciently complex molecular soup has a good chance of generating life if it simmers long enough. If that’s so, it seems plausible that life may have arisen on Earth not once, but several times. New origins of life are unlikely today, because existing life would gobble up any aggregations of prebiotic molecules before they could edge over the threshold.

However, opportunities for the origin of life may well have existed for long periods on the early Earth. Some of these origins may have been dead ends, out-competed by other life forms – but others could still be living among us, unnoticed.

As big as Darwin
“I think if we found a second sample of life on Earth, it would be as big as Darwin’s theory of evolution,” says cosmologist and astrobiologist Paul Davies at Arizona State University in Tempe. “It would answer the most fundamental question we can imagine, which is: are we alone in the Universe?”

Sceptics might scoff that shadow life could pass unrecognised for so long, but Davies and his collaborators have a simple rejoinder: we’ve never looked properly. Such life would probably take the form of single-celled microbes, so we would not expect naturalists to spot it casually like some rare parrot. And the techniques microbiologists use to detect life – staining for DNA, sequencing DNA, and culturing microbes in the lab – assume that the target microbes have the normal biochemistry.

“They couldn’t detect an alternative form of microbial life,” says Carol Cleland, a philosopher of science and astrobiologist at the University of Colorado in Boulder. Given that fewer than 1 per cent of microbes have been cultured and described, there is plenty of room for shadow life to be living right under our noses.

However, the task of searching for shadow life on Earth is much tougher than looking for life on other planets. "This planet is heavily contaminated with life as we know it," says Shelley Copley, a biochemist at the University of Colorado. That means researchers can't just look for evidence of metabolism or the presence of large biopolymers, because ordinary life would swamp any signal from shadow life. Instead, shadow-stalkers have to get more creative.

One promising avenue is to explore extreme environments that are beyond the reach of conventional life, such as ultradry deserts, ice sheets, the upper atmosphere or the hottest hydrothermal vents. Another is to devise ways of detecting alternative biochemistries.

In the first and so-far only experiment of this kind, Richard Hoover, a microbiologist at Nasa's National Space Science and Technology Centre in Huntsville, Alabama, went looking for "mirror life". Normal organisms use right-handed sugars and left-handed amino acids almost exclusively, and eschew their mirror-image equivalents. But what if shadow life developed the opposite preference? Hoover and his colleague Elena Pikuta created nutrient broths containing only left-handed sugars and righthanded amino acids, inoculated them with unusual extremophile microbes and waited to see if anything grew.

"Much to our great astonishment, we found that we did have some micro-organisms that were capable of growing," Hoover recalls. But on closer examination, the shadow microbes turned out to be ordinary bacteria with unusual metabolisms. Cleland thinks there are other places to look. "What I think we should do is go out looking for anomalies," she says. For example, some researchers have reported nanobacteria that show some of the characteristics of life but are too small to be ordinary cells.

An even more promising anomaly, Cleland says, is "desert varnish" . a thin, manganese-rich layer that forms on the surface of rocks, especially in hot, dry places. "Everyone thinks they know what desert varnish is, but everyone disagrees," says Cleland. "There is no agreement on whether it is produced by living or nonliving processes."

The layered varnish looks a lot like the primitive microbial mats called stromatolites, but for the most part, microbes are absent. Bacteria-like objects are occasionally present, but have never been fully characterised. "What they really are, I have no idea," says Ronald Dorn, who studies rock varnish at Arizona State University.

In September 2008, Cleland and her colleagues took samples of desert varnish. They hope to fi nd unusual ratios of elements that might point to some sort of metabolic process, but with a signature that differs from that of familiar life. They hope to have some results later this year.

Not likely, says Norman Pace, a microbiologist at the University of Colorado who is one of the researchers Cleland has recruited to examine the desert varnish. "The only reason to invoke (shadow life) is that we don't know what causes desert varnish," he says. Still, he's willing to have a look.

Davies hopes that more researchers will start looking for shadow life. Even if they don't find it, the search could turn up previously unknown branches on the familiar tree of life. "So it's worth doing anyway," he concludes, "even if you've convinced yourself that we're alone in the Universe."

*First published in New Scientist.

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, although mainstream theologians seem unruffl ed. 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.

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