We have even further to go to understand life than we thought.
The world’s first minimal genome, whittled down by gene elimination to the tiniest possible stash of DNA capable of supporting life, suggests that we don’t know the functions of almost a third of those essential genes.
The discovery comes from a team led by Craig Venter, founder of the J. Craig Venter Institute in La Jolla, California. He has long hoped to unravel the essential kit of life – something that may be common to all free-living creatures on Earth, including humans.
A creature formed of a minimal cell – simpler than any existing in nature – could help in studying the core functions of life, and allow us to work out the function of every gene that keeps it alive. That could yield insights into how genes can be repurposed, or let us design genomes from scratch, for applications in fields as diverse as medicine, energy and combating climate change.
“What we’ve done is important because it is a step toward completely understanding how a living cell works,” says Clyde Hutchison, who co-led the study. “If we can really understand how the cell works, then we will be able to design cells efficiently for the production of pharmaceutical and other useful products.”
Bioengineers have applauded the feat, but some are sceptical about how much minimal cells will tell us about what genes do, and about their commercial potential.
“It’s a milestone,” says George Church of Harvard Medical School. “But the market will tell you if it’s valuable.”
With 473 genes, the newly created minimal cell, JCVI-syn3.0, has at least 50 genes fewer than nature’s record holder for the shortest genome in self-sustaining living organisms, Mycoplasma genitalium – which has 525 genes.
The minimal cells were shown to live, grow and divide, forming clumps of cells in a lab dish containing nutrients to supply them.
The feat builds on a study by Venter’s team in 2010 that unveiled JCVI-syn1.0, the first living bacterium reliant on a synthetic copy of an existing genome. That genome was designed in a computer, before assembly and insertion into cells.
He and his colleagues at the institute, co-led by Hutchison, sought to whittle down the 901 genes in JCVI-syn1.0 to the minimum for supporting life. They started with a version of JCVI-syn1.0, the 2010 synthetic bug they made by transplanting a computer-generated copy of the entire genome of Mycoplasma mycoides, a natural bacterium comprising some 900 genes, into an empty host bacterial shell.
With the help of transposons – “jumping genes” that insert themselves into sections of DNA and disrupt individual genes – the team tested which genes the bacteria could do without.
Their first stab at a minimalist cell failed. “Every one of our designs failed because we based these on our existing knowledge base,” says Venter.
It later turned out that some genes they had thought were not essential were crucial – but because these came in pairs, the organism could still survive if only one of them was removed. When they realised this, they could more reliably whittle down the genome and still maintain a living, growing cell.
“To get a viable cell, the researchers needed to make discoveries about many essential and semi-essential genes that we did not know about,” says Steven Benner of the Foundation for Applied Molecular Evolution in Alachua, Florida.
Biology’s dark matter
The big surprise was the discovery that some 31 per cent of the essential genes have no known function.
“We discovered some essential facts of biology by doing this,” says Venter. “It means we know about two-thirds of essential biology, because we are missing a third, which is a very important lesson.”
Hutchison says it is an “exciting possibility” that some of the genes perform essential biological functions that are currently unknown.
It’s unclear how genes of such universal importance have ducked under biology’s radar for so long. It could simply be that they code for known functions, but are just not similar enough to equivalent genes from other organisms to be recognised as such yet.
“Finding so many genes without a known function is unsettling, but it’s exciting because it’s left us with much still to learn,” says Alistair Elfick, a bioengineer at the University of Edinburgh, UK. “It’s like the ‘dark matter’ of biology.”
Their discovery is the first step in revealing what they do, says Benner. Indeed, Venter’s team now wants to determine the functions of those mystery genes.
Drew Endy of Stanford University in California says the study has revealed things about the essentials of life that would otherwise have gone unnoticed, and that we should now try and close those gaps in our knowledge. “We simply have to finish understanding a cell – every atom and every molecule,” he says. “This has to be a top priority of biology as a science’.”
The bare essentials
Most of the known essential genes that were identified read DNA to make proteins vital for the organism’s survival, or check the fidelity of genome duplication when the cell divides.
The other two main groups of identified essential genes with a known function make proteins that work in the cell membrane – admitting vital nutrients such as glucose and excluding waste products – or enable the organism to turn nutrients into energy.
Elfick says the definition of essential could however change markedly, depending on an organism’s environment or lifestyle.
Venter’s new bug was produced in a bacterial Eden with every comfort provided – including a plentiful supply of energy-rich glucose. In a harsher environment, such as soil or water, they would need extra genes to fight off rivals for the same resources and manufacture essential building blocks of life from scarcer sources of “food”. “It’s likely that their degree of ‘essential-ness’ will be environment-specific,” says Elfick.
Paul Freemont, co-director of the Centre for Synthetic Biology and Innovation at Imperial College London, says it would now be useful to compare JCVI-syn3.0 with the smallest naturally known genome – of M. genitalium — to see which genes overlap.
Such efforts to design synthetic life forms are often referred to by mass media as humans playing God, and frequently raise fears about their possible impact on the environment and human health.
“If we’re already playing God, we’re not doing a particularly good job of it,” Elfick says. “Simply streamlining what’s already in nature doesn’t seem very God-like and, if anything, is a very humbling exercise.”
And he says we should not worry about this synthetic cell. “There are plenty of bugs already out there we should be much more worried about.”