Syn3.0 has the fewest genes of any self-replicating creature on Earth. It’s a marvel of engineering, and it’s doomed. Photograph by Thomas Deerinck and Mark Ellisman / NMCIR / UCSD

When the theoretical physicist Richard Feynman died, in early 1988, he left behind a maxim scrawled on the blackboard of his office at Caltech: “What I cannot create, I do not understand.” The words have been repeated often by scientists in many fields, but never so indelibly as when researchers at the J. Craig Venter Institute, in Rockville, Maryland, encoded them into the genome of a living organism, in 2010. Venter and his colleagues called their new entity syn1.0. It was a replica, with a few extra snippets of DNA thrown in, of Mycoplasma mycoides, a parasite that causes pneumonia in goats. Syn1.0 was the first human-engineered genome to be capable of controlling a cell, and Venter’s group used a custom alphabet of nucleotides to weave messages into it marking their own success. Revealingly but unintentionally, they mangled the Feynman quote, rendering it as “What I cannot build, I do not understand.”

Last week, in a paper published in the journal Science, Venter’s group unveiled the next step in their Feynmanian quest: syn3.0. For this edition of the parasite, their goal was to assemble as streamlined a new genome as possible. Humans have somewhere in the region of twenty-two thousand genes—more than a chicken, which has about seventeen thousand, but fewer than a grape, which boasts more than thirty thousand. Syn1.0, by comparison, had only nine hundred and one genes, and syn2.0 had five hundred and sixteen. By paring down their original synthetic genome even further, to four hundred and seventy-three, the researchers were able to produce what the Venter Institute’s Web site calls the world’s “first minimal synthetic bacterial cell.” Syn3.0 has the smallest genome of any self-replicating organism on Earth—that scientists are aware of, anyway—with “only the machinery necessary for independent life.” Within the discipline of synthetic biology, there seems to be little doubt that it represents an impressive achievement. Harvard’s George Church called it “a tour de force,” and Eugene Koonin, of the National Center for Biotechnology Information, described it as “quite a technical feat” and an “immensely satisfying development.”

But, in certain ways, syn3.0 must be classified as something other than a complete success. For a start, as Venter and his colleagues explain in their Science paper, they were able to build the genome but not, in Feynman’s words, create it. Their original designs failed to result in a viable cell. Instead, the researchers took syn1.0’s genome and reshuffled it, producing a lightweight variation on the original. At the same time, syn3.0 is not as minimal as it likely could be. It has fifty-two fewer genes than its nearest natural competitor, M. genitalium, a bacterium that infects the human urinary and genital tracts, but is still well above the theoretical lowest point. Koonin suspects that a truly minimal cell is something of an asymptotic target, one that synthetic biologists will edge closer and closer to, without ever actually reaching. Different creatures fulfill life’s essential functions differently, some with more brevity than others. Cherry-picking the best of each would be a Sisyphean task.

These issues aside, just how useful is Venter’s pursuit of minimalism? According to Christina Agapakis, the creative director of Ginkgo Bioworks, a bioengineering startup in Boston, the Institute’s techniques—particularly its gene-shuffling methods—will have important applications in the lab. But she was less convinced that, as Venter and his co-authors suggest in the Science paper, syn3.0 will reshape the biotechnology industry, which already relies on engineered microbes to produce everything from pharmaceuticals and food flavorings to detergent enzymes. “People have been doing industrial biotechnology for decades without a minimal cell,” Agapakis said. Yeast, for instance, has a larger genome than syn3.0, but it has been harnessed by humans for millennia, is well understood, requires little upkeep, can be grown at scale, and is relatively easy to genetically modify. It’s hard to imagine how syn3.0, which is raised on an expensive diet of cow parts within the cushy confines of a petri dish, could compete.

What it could do, however, is help scientists understand some of life’s most fundamental processes more completely. In 1996, when synthetic biology was in its infancy, Koonin wrote a paper in which he theorized that a cell with just two hundred and fifty-six genes, almost half as many as syn3.0, could be viable. Extrapolating backward from such a cell, he wrote, “may lead close to the origin of life itself,” shedding light on the nature of Earth’s last universal common ancestor—the simplest, most minimalistic organism, with none of the clutter of aeons of natural selection. In the past two decades, Koonin told me, Venter and others have done about as much extrapolating as is possible this way. But syn3.0 could still expand scientists’ knowledge of how existing organisms function. “Anyone who claims that she or he understands how a cell works is either ignorant or ridiculously arrogant,” Koonin said. “They don’t.”

Syn3.0 itself provides ample evidence of this: Venter’s group doesn’t know what nearly a third of its genes do. “Our main interest now is investigating those,” Hutchison said. For some of the mysterious genes, the researchers have a general sense of their purpose—removing toxins from the cell, for example—but not which chemicals are involved or why syn3.0 could possibly need six different ways of taking out the trash. For other genes, Hutchison said, “We don’t have a clue.” Answering that question will help demonstrate what functions are fundamental to life, if not how many genes they require.

One of the curious things about syn3.0 is that its stripped-down genome, although a marvel of human engineering, is poorly suited to life on Earth. It appears capable of all the essential functions, including reproduction, but it is already “en route to extinction,” Koonin said. Its wild counterpart, M. genitalium, has such a shrunken genome because it is far along what he called “a path of dependency”—as a parasite, it has outsourced many of its functions to its hosts, becoming less and less self-sufficient. It has lost genes in the process, leaving it vulnerable to the tiniest shifts in environmental context. “These particular organisms—they will not be on this planet for many hundreds of millions of years,” Koonin said. And yet, in its free-living state, even M. genitalium has some redundancies—non-essential genes that are, in fact, essential if the species is to mutate, evolve, and become capable of new behaviors. A minimal cell like syn3.0 is, by definition, doomed. Its DNA provides just enough information for a single organism to sustain its own life, but too little to insure the long-term survival of the species.

The American painter Ad Reinhardt, whose work had a major influence on the Minimalist movement, once wrote that “art begins with the getting-rid of nature.” Trying to engineer a minimal cell cannot help but run up against this dichotomy, which Agapakis summed up as the “conflict between the emergence of evolutionary novelty and the construction of designed novelty”—in other words, between the logic by which we seek to alter biology and the logic by which it alters itself. From this perspective, syn3.0’s relationship to life begins to resemble the relationship of Soylent to food. Both are facsimiles that serve mainly to show us the richness of the original.