❝ Peel away the layers of a house — the plastered walls, the slate roof, the hardwood floors — and you’re left with a frame, the skeletal form that makes up the core of any structure. Can we do the same with life? Can scientists pare down the layers of complexity to reveal the essence of life, the foundation on which biology is built?
That’s what Craig Venter and his collaborators have attempted to do in a new study published…in the journal Science. Venter’s team painstakingly whittled down the genome of Mycoplasma mycoides, a bacterium that lives in cattle, to reveal a bare-bones set of genetic instructions capable of making life. The result is a tiny organism named syn3.0 that contains just 473 genes. By comparison, E. coli has about 4,000 to 5,000 genes, and humans have roughly 20,000.
Yet within those 473 genes lies a gaping hole. Scientists have little idea what roughly a third of them do. Rather than illuminating the essential components of life, syn3.0 has revealed how much we have left to learn about the very basics of biology.
❝ “To me, the most interesting thing is what it tells us about what we don’t know,” said Jack Szostak, a biochemist at Harvard University who was not involved in the study. “So many genes of unknown function seem to be essential…”
❝ The seed for Venter’s quest was planted in 1995…when Venter’s researchers started work on this new project, they chose M. genitalium — the second complete bacterial genome to be sequenced — expressly for its diminutive genome size. With 517 genes and 580,000 DNA letters, it has one of the smallest known genomes in a self-replicating organism…
M. genitalium’s trim package of DNA raised the question: What is the smallest number of genes a cell could possess? “We wanted to know the basic gene components of life,” Venter said. “It seemed like a great idea 20 years ago — we had no idea it would be a 20-year process to get here…”
❝ …Rather than editing DNA in a living organism, as most researchers did, they wanted to exert greater control — to plan their genome on a computer and then synthesize the DNA in test tubes.
In 2008, Venter and his collaborator Hamilton Smith created the first synthetic bacterial genome by building a modified version of M. genitalium’s DNA. Then in 2010 they made the first self-replicating synthetic organism, manufacturing a version of M. mycoides’ genome and then transplanting it into a different Mycoplasma species. The synthetic genome took over the cell, replacing the native operating system with a human-made version. The synthetic M. mycoides genome was mostly identical to the natural version, save for a few genetic watermarks…
With the right tools finally in hand, the researchers designed a set of genetic blueprints for their minimal cell and then tried to build them. Yet “not one design worked,” Venter said. He saw their repeated failures as a rebuke for their hubris. Does modern science have sufficient knowledge of basic biological principles to build a cell? “The answer was a resounding no,” he said.
❝ So the team took a different and more labor-intensive tack, replacing the design approach with trial and error. They disrupted M. mycoides’ genes, determining which were essential for the bacteria to survive. They erased the extraneous genes to create syn3.0, which has a smaller genome than any independently replicating organism discovered on Earth to date.
What’s left after trimming the genetic fat? The majority of the remaining genes are involved in one of three functions: producing RNA and proteins, preserving the fidelity of genetic information, or creating the cell membrane. Genes for editing DNA were largely expendable.
❝ Venter’s minimal cell is a product not just of its environment, but of the entirety of the history of life on Earth. Sometime in biology’s 4-billion-year record, cells much simpler than this one must have existed. “We didn’t go from nothing to a cell with 400 genes,” Szostak said. He and others are trying to make more basic life-forms that are representative of these earlier stages of evolution.
“Not yet” applies to most of the unresolved questions about Venter’s research and exploration. It is, after all, how he set about to win the prize for sequencing the human genome. Ignoring accepted practices, he looked ahead to what he logically presumed would be the amount of computing horsepower that would be around at the end of the time-scale for his experiments. And calculated the management of his experiments on the basis of what hardware would be available to run whatever software he designed to analyze what he was building – when he got near the end of the whole timeframe.
He nailed it.
This time? He found more questions. Plus – he ain’t in a race either.