SAN DIEGO — Here in a laboratory perched on the edge of the continent, researchers are trying to construct Life As We Don’t Know It in a thimbleful of liquid.
Generations of scientists, children and science fiction fans have grown up presuming that humanity’s first encounter with alien life will happen in a red sand dune on Mars, or in an enigmatic radio signal from some obscure star.
But it could soon happen right here on Earth, according to a handful of chemists and biologists who are using the tools of modern genetics to try to generate the Frankensteinian spark that will jump the gap separating the inanimate and the animate. The day is coming, they say, when chemicals in a test tube will come to life.
By some measures, Gerald F. Joyce, a professor at the Scripps Research Institute here, has already crossed that line, although he would be the first to say he has not — yet.
Biologists do not agree on what the definition of life should be or whether it is even useful to have one. But most do agree that the ability to evolve and adapt is fundamental to life. And they also agree that having a second example of life could provide insight to how it began and how special life is or is not in the universe, as well as a clue for how to recognize life if and when we do stumble upon it out there among the stars.
“Everything we know about life is based on studies of life on Earth,” said Chris McKay, a researcher at NASA’s Ames Research Laboratory in Mountain View, Calif.
Dr. Joyce said recently: “It drives me crazy when astronomers say, ‘Surely the universe is pregnant with life.’ If we have an Earthlike planet, what are the chances of life arising? Is it one in a million? Is it one in two? I don’t see how you can say.”
He continued, “If you had a second example of life, even if it were synthetic, you might know better. I’m betting we’re just going to make it.”
Four years ago Dr. Joyce and a graduate student, Tracey A. Lincoln, now a researcher at the University of Massachusetts Medical School, evolved a molecule in a test tube that could replicate and evolve all by itself, swapping little jerry-built genes in a test tube forever, as long as it was supplied with the right carefully engineered ingredients.
An article in the Joyce Laboratory newsletter called it “The Immortal Molecule.” Dr. Joyce’s molecule is a form of RNA, or ribonucleic acid, which plays Robin to DNA’s Batman in Life As We Do Know It, assembling proteins in accordance with the blueprint encoded in DNA. Neither RNA nor DNA is alive by itself, any more than any other chemical, like bleach, or a protein. But in Dr. Joyce’s test tube, his specially engineered RNA molecule comes close, copying itself over and over, and evolving.
But, Dr. Joyce says, “We really would hope for more from our molecules than just replicating.”
Reproduction is the job of any life, he explained, but Earthly organisms have evolved a spectacular set of tricks to improve the odds of success — everything from peacock feathers to whale songs. Dr. Joyce’s molecules have not yet surprised him by striking out on their own to invent the molecular equivalent of writing a hit pop song.
It is only a matter of time, he said, before they do.
“Our job is to give them the running room to do that,” Dr. Joyce said.
The deeper philosophical and intellectual ramifications of test tube life are as enormous as they are unknown. The achievement would probably not come with sci-fi drama, say scientists who are squeamish about such matters anyway, saying such speculation is beyond their pay grade. No microbe is going to leap out of the Petri dish and call home, or turn the graduate students into zombies. Indeed, given the human penchant for argument and scientists’ habit of understatement, it could be years before everybody agrees it has been done.
“The ability to synthesize life will be an event of profound importance, like the invention of agriculture or the invention of metallurgy,” Freeman Dyson, a mathematician and physicist at the Institute for Advanced Study in Princeton, wrote in an e-mail. “Nobody can tell in advance what will come of it.”
On Earth, all life as we know it is based on DNA, the carbon-based molecule that contains the instructions for making and operating living cells in a four-letter alphabet along its double-helix spine.
The possibilities of a second example of life are as deep as the imagination. It could be based on DNA that uses a different genetic code, with perhaps more or fewer than four letters; it could be based on some complex molecule other than DNA, or more than the 20 amino acids from which our own proteins are made, or even some kind of chemistry based on something other than carbon and the other elements that we take for granted, like phosphorous or iron. Others wonder whether chemistry is necessary at all. Could life manifest itself, for example, in the pattern of electrically charged dust grains in a giant interstellar cloud, as the British astronomer and author Fred Hoyle imagined in his novel “The Black Cloud”?
Dr. Joyce said that his RNA replicators would count as such a “second example, albeit one constructed as a homage to our ancient ancestors.”
So far, he said, his work with Dr. Lincoln has shown that manmade molecules can evolve over successive generations. “They can pass information from parent to progeny, they can mutate,” Dr. Joyce said. “They can win or die. The molecules are doing it all. We’re just keeping the lights on.”
Dr. Joyce’s molecules may not be clever enough yet to qualify as life in his view, but all sorts of alternatives are being explored in other labs.
Some researchers, like Steven Benner of the Foundation for Applied Molecular Evolution in Florida, are constructing and experimenting with forms of DNA that use coding alphabets of more than four letters. J. Craig Venter, who helped spearhead the decoding of the human genome and now works as president of the J. Craig Venter Institute, recently used store-bought chemicals to reconstruct the genome of a bacterial goat parasite and put it in another bacterium, where it took over, churning out copies of itself with Dr. Venter’s watermark inscribed in its gene code.
In a related vein, George Church and Farren Isaacs of the Harvard Medical School recently reported that they had reprogrammed the genome of an E. Coli bacterium, opening up the possibility of incorporating new features into the ubiquitous little bug. Dr. Joyce called the work “really macho molecular biotechnology.”
Jack Szostak of Harvard Medical School and his collaborators have embarked on an ambitious project to build an artificial cell that can replicate and presumably evolve. Dr. Benner wrote in an e-mail, “In my view, a terran laboratory will make synthetic life before NASA or the E.S.A. finds it elsewhere,” referring to the European Space Agency. He added, “And a lot before, given the disassembling of NASA by the current administration.”
According to modern science, life on Earth originated about 3.8 billion years ago, perhaps in a warm pond, as Darwin speculated, or perhaps in a boiling, bubbling mud bath or a scorching volcanic vent way under the sea. The first inhabitant of this Eden, chemists suspect, was RNA.
In today’s world RNA runs errands for DNA. Like DNA, RNA encodes genetic information. Unlike DNA, however, RNA can also catalyze chemical reactions between other molecules, chopping them up or binding them together, a task mostly performed by proteins in modern organisms.
In 1962, the M.I.T. biologist Alexander Rich suggested that RNA could have played both roles — blueprint and machinery — at the beginning. Scientists cannot prove that this is how life arose on Earth, but they can do the next best thing. They can make their own RNA and see if they can then breathe life into it.
Enter Dr. Joyce, who says he came to his vocation by reading “Gravity’s Rainbow,” Thomas Pynchon’s 1973 novel about rockets and death in World War II, while he was a student at the University of Chicago. The last section of that book, he pointed out, is called “The Counterforce,” about pockets of life and love carving order out of the rubble of wartime Europe. For biologists the counterforce creating order and life out of chaos is simply Darwinian evolution, Dr. Joyce explained. “I wanted to be a member of the counterforce.”
At the center of the Joyce lab experiments is a T-shaped piece of RNA that has the ability to glue together other molecules of RNA. In 2002, Dr. Joyce and a postdoctoral fellow, Natasha Paul, configured it to recognize and glue together a pair of smaller molecules, essentially an L and a straight piece. When joined, those molecules would form a new copy of the original T-shaped molecule. It worked; the RNA was able to manufacture new versions of itself, but not fast enough to keep up with the original RNA’s natural tendency to fall apart. Essentially it was dying faster than it was reproducing. Dr. Joyce and Dr. Lincoln found a way to speed the process up, by having two complementary versions of the RNA manufacture each other.
“There was a day that it all happened,” said Dr. Joyce, namely Oct. 1, 2007, when as he puts it, the replicators “went critical,” and their population began growing exponentially.
The game, as he likes to say, was on. And it has never stopped. Dr. Joyce and his colleagues next proceeded to engineer a sort of March Madness for molecules. They synthesized 12 versions of the replicators, which could mutate and evolve to improve their ability to reproduce. The experimenters threw these into the pot, along with the appropriate “food” segments, to compete. “They just go at it,” Dr. Joyce explained.
By the end, the winning molecules were doubling their numbers every 15 minutes. Mistaken swaps had produced combinations, mutations, that had not been in the mix at the start. Most of the original versions almost completely disappeared. In short, the molecule evolved.
“Evolution is not a theory for us chemists,” Dr. Joyce said. “It’s what molecules do when they have the property to replicate and transmit information from parents to progeny.”
In a separate experiment the molecules were redesigned so that they would replicate only when another chemical was present. “That’s the app that’s going to pay for this,” said Dr. Joyce, explaining that the replicating molecules could be fashioned into sensors to detect pollutants or dangerous toxins in the environment. Dr. Joyce and his collaborators are now starting to run the same tournament with 256 versions of the replication enzyme. “We are pipetting madly,” he reported recently.
That means that there will be about 65,000 possible gene combinations that can emerge and try out their wings, which means things are getting interesting. As Dr. Lincoln said, “We’re knocking on the door, but we’re not quite there yet.” Sidney Altman, a Yale professor who shared a Nobel prize for discovering some of the talents of RNA, said that true test tube life could still be years away. “Gerry Joyce’s replicators are very clever molecules,” he said, but added that they were not self-sufficient enough to be alive.
Dr. Joyce said his team was working on having the replicating molecule invent a new ability, but he would not say what it was. Asked for an example of the kind of things he could teach his RNA to do, Dr. Joyce suggested it could take part in creating one of the ingredients for its own replication by adding together a pair of smaller molecules. “What would be cool,” he said, “would be if they could make their own food.” The key to more ability, he said, is complexity. His molecule has only two genes, compared with 25,000 in human beings, and experiments involved fiddling with four letters of these genes. The human genome has three billion letters.
“We have a little toy genome where we can have the complete book of life,” he said, “but the sentences only have two words.”
Dr. Joyce’s molecules will never catch up to the biosphere. But someday their genome may surprise their creator with a word — a trick or a new move in the game of almost life — that he has not anticipated. “If it would happen, it would do it for me, I would be happy,” Dr. Joyce said, adding, “I won’t say it out loud, but it’s alive.”
