The physicist Richard Feynman famously said, "what I cannot create, I do not understand." A new breakthrough has led scientists closer to understanding the true nature of life, by being able to custom-build an organism that has only the bare essentials for life and reproduction.
Silicon Valley entrepreneurs have a concept called "minimum viable product," or the product that contains the least amount features and still functions. J. Craig Venter, one of the scientists involved in the race to sequence the human genome, has led a team that just created a minimum viable product for a bacterium’s operating system: the minimum viable genome. Why? "We have discovered some essential facts of biology by doing this," Venter says.
With just 473 genes, the synthetic microbe, known as Syn 3.0, has the smallest genome of any free-living organism (some smaller lifeforms require the support of a host, for instance). What’s even more remarkable—and humbling to the researchers—is that even with only the genes that are needed for its survival, they still don't know the specific function of 149 of them. "It’s very exciting that they discovered this subset of genes," says Georgia Tech synthetic biologist Eric Gaucher, who was not involved in the work. "You don’t have to be a fortune teller to know that there’s probably going to be labs all over the world trying to understand what these genes do."
Researchers from two institutions Venter co-founded, the nonprofit J. Craig Venter Institute and the company Synthetic Genomics, Inc., collaborated on the paper, published in the journal Science on Thursday. The long-term purpose of the Syn 3.0 genome, which Venter says they’ve filed to patent, is in its commercial applications.
The genome is meant to serve as a "chassis" for building specialized organisms that can churn out useful products, such as medicines, vaccines, biofuels, and industrial chemicals. Today, scientists engineer microbes by adding or subtracting genes from the microbe’s existing genome, but it’s tricky and delicate work. Instead, one day, key genes could be added on top of the new minimalist genome, potentially allowing easier or more efficient customization. "I think it’s the start of a new era. It won’t happen overnight," Venter says.
The quest to create Syn 3.0 began more than two decades ago, with the sequencing of the genome of a Mycoplasma genitalium—a microbe with only 525 genes, the smallest genome of any existing free-living organism. But the project got started in earnest after a Venter team announced in 2010 that it had engineered the world’s first synthetic bacteria—a relative, Mycoplasma mycoides. Their initial approach to figuring out which of those its genes was essential was to compare the Mycoplasma genome to other viruses and bacteria. About 256 genes overlapped—and they thought those were probably the ones required for life. But that failed to produce a living organism. Instead, they had to go through many hundreds of rounds of trial and error, knocking out different combinations of genes and trying to figure out which combinations left could produce life. Venter explains it by using the analogy of an airplane: If you destroy the right-wing engine, the plane might still fly. But if you destroy both the right and left engines, it won’t get off the ground. Trying to understand which genes duplicated each other—especially when many were of unknown function—was a challenge.
"The whole idea of a minimal genome was not as clear cut as it seemed initially," says Clyde Hutchinson, who led the project at JCVI. "The finding of all these quasi-essential genes changes our perspective." What it made clear, also, was that the required survival genes are entirely context-specific, to the environment and to the organism. A different bacteria—or one living outside the nutrient-rich lab environment—would likely have a different minimum viable genome.
In the end, the final product, Syn 3.0, doesn’t look anything like a naturally-evolved genome. It is built for design and engineering. The team re-ordered all 473 genes so they are grouped by function. With this order, Venter says, "we can take designs to a whole new level."
In 2010, when JCVI announced the first synthetic life form, President Obama commissioned a bioethics panel to investigate the implications. Gaucher notes that Syn 3.0 is designed so that it wouldn’t survive outside of a lab environment, but it’s easy to worry about what happens when it’s easy to create life from scratch—and whether it can be used to produce a useful fuel or instead do something more nefarious, like act as a bioweapon. In many ways, the project shows that though scientists are getting better at designing life, there is still a long way to go in understanding what they are producing. But getting to a minimum viable genome for humans, who have about 19,000 genes, is still a long way off.