Synthetic Life Dies Without Mysterious Genes
One-third of the genes relate to unknown, but critical biological functions.
Five years after creating the first self-replicating, synthetic bacterial cell, biotech researcher and entrepreneur J. Craig Venter and colleagues have figured out the little guy can live a full and reproductive life with just 473 of its genes, a miniature biological code smaller than any known replicating cell found in nature.
But what most interests the researchers is not so much the actual number of genes this cell needs for life, but that about one-third of them relate to unknown, but critical biological functions.
Scientists from the J. Craig Venter Institute have produced a living cell powered by manmade DNA, creating what they call the world's first synthetic cell. Lead researcher Craig Venter talks about what this milestone means.
"If we take out any of those genes, the cell dies," Venter told DNews. "We expected some of those because we see them in every life form, but I expected 5 to 10 percent at most. The fact that we don't know this much biology is very humbling."
Using its first synthesized cell as a model, scientists at the La Jolla, California-based J. Craig Venter Institute and its commercial arm, Synthetic Genomics Inc., started with a set of genes they thought would be necessary for life.
The model cell, known as JCVI-syn1.0 and which has 901 genes, is nearly identical to the naturally occurring bacteria Mycoplasma mycoides, which has a short genetic code to begin with because it lives inside a host cell, a luxury lifestyle for an organism.
"Those (genome) are not small because they're primitive. They are small because they evolved from a cell that has a few thousand genes. They've lost genes they don't need in a mammalian host, which provides a very rich, uniform, constant environment. They've already evolved a long way toward a minimal genome. We're just helping them along to get rid of genes they don't need in the laboratory," said biochemist and microbiologist Clyde Hutchison, lead author in a paper describing the research in this week's Science.
Whittling away at syn-1 proved a laborious process.
Scientists devised a hypothetical genome they thought could produce life, organizing the genetic code into segments that could be tested one at a time so each could be classified as essential or non-essential.
"The goal was not to reduce the number of genes – it could have been twice as big. It's more important what the final number was," Venter said.
The team also wanted a cell that would replicate quickly, which added genes to the minimal code.
The design-test-build process, resulting in JCVI-syn3.0, ended up taking the better part of five years.
"This study would've taken probably another five years if we didn't insist on rapid growth," Venter said.
In addition to the 149 mystery genes, the team discovered that some genes initially classified as non-essential were responsible for the same tasks of a second gene, so the cell could live with one or the other, but not without both.
It's like flying an airplane, Venter explained.
"If you don't know what the different functions are ... you could knock out one engine and the airplane keeps flying and lands safely, so you could interpret that that engine isn't really important. You won't find that out until you knock out your second one," Venter said.
Chemist Steven Benner, founder of the Florida-based Foundation For Applied Molecular Evolution, which was not involved in the research, said that existing theories about which genes are needed for life could not produce a viable cell.
"Synthesis can drive discovery in ways that analysis and 'hypothesis-based research' cannot," Benner wrote in an email to Discovery News. "To get a viable cell, Hutchison et al. needed to make discoveries, here, about many essential and semi-essential genes that we did not know about."
Venter's team also discovered that environment plays a huge role in the genetic code for life. For example, test cells could feed on both fructose and glucose and had genes to metabolize both sugars.
"If you have both sugars in the media and you knock out the glucose transporter, the cell still lives and you can say the glucose transporter is not essential for life. But then if you knock out the fructose transporter, the cell dies," Venter said.
"The trouble with the whole field of biology, and we see it clearly with the human genome, is this notion that you can assign this single function to a gene or protein. And, some have multiple functions at different stages of biology," Venter said. "Life is much more like a symphony orchestra than a piccolo player."
Follow-on research is under way. Venter's non-profit research institute is tunneling down into the functions of life's mystery genes, while Synthetic Genomics Inc., and its partners are developing custom cells that can be used for a wide variety of medical and industrial applications, including biochemical, biofuels, nutrition and agriculture.
"We are getting close to fully understanding the number of genes and the set of genes that are required to make a cell grow and divide," said molecular biologist Daniel Gibson, vice president at Synthetic Genomics and an associate professor at Venter's institute.
"Our long-term vision has been to design, build and synthesize organisms on-demand where you can add in specific functions and predict what the outcome is going to be," he said.