"Our long-term vision has been to design and build synthetic organisms on demand where you can add in specific functions and predict what the outcome is going to be."
If synthetic biology has a rockstar, it's Craig Venter, and he's back with a new hit. Venter and his team say they've created one of the simplest organisms theoretically possible using a combination of genetic engineering techniques, in-lab DNA-synthesis, and trial-and-error.
The work, published Thursday in Science, describes a self-replicating bacterium invented by Venter and his team that contains just 437 genes, a "genome smaller than that of any autonomously replicating cell found in nature," according to the paper. The work sheds light on the function of the individual genes necessary to have life, and it also shows us just how little we actually know about specific gene functions.
"We have long been interested in simplifying the genomic software of a bacterial cell by eliminating genes that are nonessential for cell growth under ideal conditions in the laboratory," Venter wrote in the paper. "This facilitates the goal of achieving an understanding of the molecular and biological function of every gene that is essential for life."
A study published by the National Center for Biotechnology Information in 1995 suggested that a genome that coded the most basic lifeform would be roughly 256 genes. Venter said in a conference call with reporters that "everybody was off—by a third." The team says that 149 of the genes have unknown functions, but were nonetheless necessary for the organism to grow and replicate. For comparison, E. Coli and other well-understood genes have roughly 5,000 genes.
"We now know, in the end result, that 32 percent of the genes required for life in this most simple of all organisms are of unknown function," Venter said. "If we don't understand the functions of a third of those genes—you know we're also involved in depth in analyzing the human genome with 20,000-some-odd genes, most of which we have no known function for. So I think these findings are very humbling in that regard."
So what does this all mean? Venter says his team and others will now work on identifying the purpose of some of the genes with unknown functions, and Daniel Gibson, a researcher who works at the J. Craig Venter Institute said that this work will ultimately lead to the creation of synthetic life with specific purposes, such as producing cheap biofuel and creating new medicines.
"Our long-term vision has been to design and build synthetic organisms on demand, where you can add in specific functions and predict what the outcome is going to be," Gibson said.
You may remember Venter as one of the leaders of the Human Genome Project, or the first scientist to ever transfer a synthetic genome into a living cell and have it continue to function (the first synthetic life ever, many argue). He's also friends with Elon Musk, with whom he casually talks about printing synthetic life on Mars to terraform the planet, and he's cofounder of Human Longevity, which is dedicated to extending the human lifespan using genetics.
These new findings make his more outlandish claims seem ever so slightly more attainable, but it's important to recognize just how painstaking and slow this work was. Venter says he's been working on the project off and on for 20 years, and that, essentially, the organism he's dubbed JCBI Syn 3.0 was the result of some very sophisticated trial-and-error.
At first, the team tried to model life using computer software alone, but found that when they actually went to synthesize the organism, it never worked.
"Every one of our designs failed," he said.
And so the team took its original synthetic life, called SYN 1.0, and started knocking out and adding back in genes as necessary. The team found that it would regularly knock out a gene it thought to be "inessential," only to find that, when they knocked out an analogous gene, the bacterium couldn't survive. Venter likened it to a Boeing 747 plane—you can take out one engine and have it still fly, but if you take out both, the plane crashes.
"That's what happened over and over again, where we would have what appeared to be a non-essential component until we removed its counterpart," he said.
Only genes that were required for the bacterium to survive—not those that are required for it to thrive, such as specific growth genes—were included. Venter noted that, though this is a "minimal" bacterial genome, it is not necessarily the minimum, because other types of life may exist, and a couple of growth-related genes were kept in because it "had to grow at a sufficient pace to be a good experimental model."
"A typical experiment took three months, and so this study would have taken probably another five years if we didn't insist on rapid growth," he said.
We're still in the early days of synthetic biology, and it's anyone's guess when truly synthetic life will be used in an applied sense versus a lets-learn-more-about-the-basics-of-life sense, but increasingly impressive feats are being accomplished on a semi-yearly basis at this point. Venter created the first artificial life in 2010; in 2014, Floyd Romesberg of the Scripps Research Institute created synthetic life using DNA base pairs that are not found in nature; and genetic editing tools like CRISPR-Cas9 are being used in laboratories big and small to fundamentally alter DNA.
These findings suggest that the definition of "life" is actively changing as we manipulate its code. It's no surprise, then, that in the paper Venter regularly refers to the "genome" as "a piece of software."
"We view life as DNA software-driven," Venter said. "And we're showing that by trying to understand that software, we're going to get better understandings of life."