The first microbe to live entirely by artificial genetic instructions began proliferating in a test tube in late March at the J. Craig Venter Institute in Rockville, Md. Venter and his colleagues built a synthetic genome for a strain of the Mycoplasma mycoides bacterium. The feat made headlines because it marked a major step in the creation of life in the laboratory. But it also demonstrated a refinement of the tools of genetic engineering that, the researchers hope, will eventually offer new insight into basic genetic processes and revolutionize biotechnology and drug development.
To make a working genome, Venter and his team stitched together various short iterations of man-made versions of nuclei bases (adenine, cytosine, guanine and thymine). They then inserted the final synthetic genome—a bit more than one million base pairs long but still simpler than the M. mycoides’s natural genome—into an existing M. capricolum cell. It booted up the natural cell’s machinery and busily set to work making proteins and, ultimately, dividing and thriving. Within three days the researchers found a blue colony of M. capricolum living as synthetically driven M. mycoides. “This is the first self-replicating cell on the planet to have a computer for a parent,” Venter quipped during a press briefing on May 20, the day the research was published online by Science.
Getting to this point took at least $40 million in investment into relevant experiments during the past 15 years, which were primarily funded by Venter’s private company Synthetic Genomics and the U.S. Department of Energy. The researchers also had to overcome several other challenges, including one that needed three months of cross-checking to find a single missing base that prevented life. “Accuracy is essential,” Venter said. “There are parts of the genome where it cannot tolerate even a single error.”
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The genome also included four “watermarks” to distinguish the synthetic microbe—dubbed M. mycoides JCVI-syn1.0—from natural organisms. The watermarks are distinct genetic codes that include quotes: “To live, to err, to fall, to triumph, and to recreate life out of life,” from James Joyce; “see things not as they are but as they might be,” from J. Robert Oppenheimer; and “what I cannot build, I cannot understand,” from Richard Feynmann. (In less than two weeks since the announcement of the achievement, 26 scientists had cracked the watermark codes, according to Venter.)
Synthetic biologists have lauded the work. “It is a big deal,” says George M. Church, a geneticist and technology developer at Harvard Medical School. “It’s not incremental, but it’s not final either,” he adds. Biological engineer Drew Endy of Stanford University thinks of the creation this way: “It’s not genesis—it’s not as if mice are coming from a pile of dirty rags in a corner,” he says. “The correct word is poesis, human construction. We can now go from information and get a reproducing organism. It lays down the gauntlet for us to learn how to engineer genomes.”
Going forward, Venter hopes to hone the techniques to begin synthesizing new vaccines for viruses as well as to be able to make them in days, rather than weeks or months. One of the group’s long-term goals, Venter said at a June 1 Cold Spring Harbor Laboratory symposium, is to develop a universal recipient cell, into which researchers can plug a variety of synthetic genomes and see how they run. And someday, he surmised, it might be cheaper for scientists to synthesize simple organisms than to grow them.
The creation of an artificial genome, however, still has not demystified the origin of life. Investigators built much of the bacterium’s genome without fully understanding the function of many of the million-plus base pairs involved.
But not unlike the way complex erector sets can elucidate some of the basic rules of physics and engineering, constructing—and deconstructing and reconstructing—whole genomes might help clarify genomic principles. Scientists, for instance, do not yet know what role or importance the order of genes in the genome plays. In some cases, genes can have their order swapped with little visible outcome on life, whereas a specific sequence might be more important elsewhere on the genome.
To decipher such basic genetic puzzles, one of Venter’s co-author, Daniel G. Gibson, an institute molecular biologist, says that the researchers will also attempt to create the simplest genome possible that can still permit life. “This will help us to understand the function of every gene in a cell and what DNA is required to sustain life in its simplest form,” he explains. He guesses this genome will be half as big as the bacterial genome they created.
As for those first synthetic cells, their time in the spotlight has ended for the moment. Currently they lie dormant in a Venter Institute freezer.