Five designer chromosomes bring synthetic life a step closer
Life 9 March 2017
By Bob Holmes
A challenge for bioengineers, but not an insurmountable one
Gene Cox/Getty
The goal of creating a complex organism with a genome designed and built from scratch in the laboratory has come a giant step closer.
The team that built the first synthetic yeast chromosome three years ago has now added five more chromosomes, totalling roughly a third of the yeast's genome. It's a dramatic scaling-up of our capabilities, and opens the door to large-scale genomic engineering.
The world has already seen one synthetic genome, that of the bacterium nicknamed Synthia. However, bacteria have much smaller and simpler genomes than higher organisms such as yeast and humans, known as eukaryotes. Synthesising a eukaryotic genome is thus a much more complex challenge.
In 2014, a team led by Jef Boeke, now at New York University Langone Medical Center in New York City, managed to construct a single yeast chromosome. They then replaced one of a living yeast cell's natural chromosomes with it – the first time this had been done in a eukaryote.
Boeke's team has since edited the entire yeast genome (see "Re-engineering yeast", below), before farming out the synthesis of the 16 rewritten chromosomes to an international consortium of geneticists and yeast biologists.
Read more: Artificial cell designed in lab reveals genes essential to life
This week, the consortium announced the completion of an additional five chromosomes. Each one was assembled from pieces of 30,000 to 60,000 DNA letters. This allowed the builders to "debug" each section as they added it, correcting for inadvertent errors that crept in during the editing process.
As a result of this careful debugging, yeast cells with the new synthetic chromosomes grow just as quickly as normal, wild, yeast in laboratory cultures, despite the wholesale alterations. "It is amazing how much torture the yeast genome can take and still be happy and healthy," says Boeke.
Other researchers say the health of the modified yeast is remarkable. "The fact that they were able to do this across five different chromosomes, and the fitness is still similar to wild-type cells, that's pretty impressive," says Dan Gibson at Synthetic Genomics, a biotech company in La Jolla, California, which is developing synthetic chromosomes in another yeast species.
"It now sets the stage for the ultimate, which is putting all 16 synthetic chromosomes into one cell," says Gibson. "I now have more confidence that they'll be able to achieve that."
If and when they do, researchers hope to learn a huge amount. "If you take a bicycle and break it down to its smallest parts in your basement, and reassemble it again, you know a hell of a lot more about your bicycle than you did before," says Boeke. Similarly, taking apart the entire genome and rebuilding it should yield new understanding of life and its processes.
The biotechnology industry, too, should see large payoffs. Yeasts are already biotech workhorses, producing products such as pharmaceuticals and even perfumes in vast fermenting vats.
Unprecedented control
A synthetic genome will give bioengineers unprecedented control over yeast metabolism. It would, for example, allow them to expand yeast's repertoire of molecules to be produced or degraded.
Researchers could also "humanise" the yeast by incorporating human versions of genes. Geneticists already do this for a few genes at once, but synthetic chromosomes would allow them to go much further – a big plus when it comes to testing new drugs and other therapies.
The biggest payoffs, however, may be ones that no one foresees. We tailor our ambitions to what's achievable. "The history of genomics is you do what you can do, and then you rationalise that that's all you wanted," says George Church, a geneticist at Harvard University. Once more is possible, we'll probably think of new things to do, he says.
Freed from the shackles of natural genomes, synthetic biologists may find they want a whole lot more.
Journal reference: Science, DOI: 10.1126/science.aaf4557
Re-engineering yeast
To synthesise the entire genome of the yeast Saccharomyces cerevisiae, Jef Boeke at the Langone Medical Center in New York City and his colleagues began by deleting unnecessary bits, making it about 8 per cent shorter to start with.
They also inserted labels and other tools to make later engineering easier, including a series of controllable cut-points scattered around the genome. This allows researchers to generate random rearrangements of the genome at will, deleting and duplicating portions of the chromosome or putting genes in different genomic neighbourhoods.
"This, I think, is our most innovative design feature," says Boeke. "It essentially shuffles the genome and makes millions of variants from one starter genome."
As the random variants compete, those yeast cells best adapted to the conditions will gradually dominate. This may eventually let researchers harness evolution to optimise the yeast genome for particular applications, although the approach remains unproven.
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