By Angus Dalton
Dr Hugh Goold once earned a living delivering cheese to Buckingham Palace. Now he’s unlocked the final stage of a daring two-decades long research mission aimed at giving life to the first multicellular organism with entirely synthetic DNA.
The groundbreaking international project paves the way for building “designer” microorganisms that could kill cancer or better create biofuels and, eventually, the creation of plant and animal cells with fully customised human-made genomes.
Since 2006, scientists have worked to painstakingly assemble the 16 chromosomes that make up the yeast genome from scratch for the Synthetic Yeast Genome Project – a quest to create “Yeast 2.0”.
Scientist Hugh Goold has completed the final stage of an international effort to create a synthetic yeast genome.Credit: Janie Barrett
Researchers unveiled the first synthetic bacteria, a simple single-celled organism called Mycoplasma mycoides, in 2010. But Yeast 2.0 will be a synthetic eukaryote; the first lab-made organism in the vast domain of multicellular life that includes all plants, fungi, animals, and us.
Goold and a team of scientists spent years assembling the 16th and final synthetic chromosome. The synthetic biologist working at Macquarie University, who spent a stint in London as a cheesemonger to the royal family, was hired by the NSW Department of Primary Industries and Regional Development a decade ago to work on the project.
“The thing about DNA is it’s common to all living organisms,” Goold said, holding a petri dish hosting beige stripes of yeast spliced with the synthetic chromosome he built. “So the implications of this kind of technology are huge.”
Brewer’s yeast (Saccharomyces cerevisiae) under an electron microscope. It’s set to become the first multicellular organism replicated from entirely synthetic DNA.Credit: Getty Images
The yeast is soon bound for the New York lab of the project’s mastermind, Professor Jef Boeke, who will unite all 16 lab-built chromosomes into fully synthetic yeast.
“We didn’t know we could do this kind of stuff 20 years ago,” said Goold, the first author of a Nature Communications paper hailing the completion of the chromosome, called SynXVI.
“This was a fantasy. And now it’s happened.”
Key to the design of Yeast 2.0 is a system called “SCRaMbLE” (Synthetic Chromosome Rearrangement and Modification by LoxP-mediated Evolution).
It’s an “evolution button”, said Goold; when triggered by a certain chemical, the yeast rapidly reshuffles its DNA. That produces millions of genetically tweaked yeast cells, like evolution at warp-speed, to produce a flurry of variants that mightn’t arise naturally for millions of years.
Most of the mutations result in death. But some are valuable; perhaps producing a more heat-tolerant yeast or one that could make higher yields of ethanol or medicine. Yeast is also used for making HPV and hepatitis B vaccines.
“If we’re using yeast for bio-manufacturing, like the next COVID vaccine, this is a really important step to being able to do that in Australia, in NSW,” Goold said.
He’s most excited by Yeast 2.0’s potential to accelerate research into the secrets of plant life. Synthetic chromosomes can be neatly organised into sections, unlike in nature, where genes are “splooshed” randomly across the genome like files across a chaotic computer desktop.
Sydney’s skyline depicted in fluorescent bacteria designed by Goold in the lab, using methods adapted from yeast art techniques developed in Boeke’s lab.Credit: Dr Hugh Goold
That modular design of Yeast 2.0 will allow scientists to swap in genes from other organisms and study which exact strands of DNA are key to a crop’s heat tolerance or the deadly effect of a fungal pathogen, for example.
This visionary project found an Australian home in a serendipitous meeting of microbial minds.
In 2013, Professor Ian Paulsen introduced himself to Macquarie University’s new deputy vice-chancellor of research, Professor Sakkie Pretorius, a fellow microbiologist with “connections in the yeast world”.
The talk turned to synthetic biology, a field going gangbusters overseas that had little presence in Australia. The pair resolved to change that.
“We didn’t want to dip our toes in the pond. We wanted to do something big,” Paulsen said.
Pretorius reached out to Boeke, who told him a team tasked with building one of the chromosomes for Yeast 2.0 had folded due to funding woes. The Australians picked up the torch.
Their first question: how the hell do you build a synthetic chromosome?
Paulsen sat with the project’s first employee, Natalie Curach, and pored over the single paper available at the time that described how to do it. The paper was “incomprehensible”, so Curach was dispatched to labs in New York and London to study the process first-hand. She returned with a million-dollar equipment wishlist.
Dr Hugh Goold at his lab within the ARC Centre of Excellent for Synthetic Biology at Macquarie University.Credit: Janie Barrett
NSW’s inaugural chief scientist, Mary O’Kane, and the NSW Department of Primary Industries came aboard with funding, recognising the potential of the tech to enhance agriculture. The department hired Goold and the project began in earnest.
The synthetic DNA strands were designed digitally and then made by a company that chemically crafts custom DNA.
Then, one chunk at a time, Goold replaced the genome of normal lab yeast with the artificial DNA by culturing a concoction of yeast, lithium acetate, polyethylene glycol and herring sperm. The sperm protects the yeast’s genetic matter from agents that break down DNA, said Paulsen, who is a co-author of the paper.
“By putting in a lot of other DNA, it protects the DNA we’re trying to get into the cell, like the chaff you fire out of planes to protect them from anti-aircraft missiles,” Paulsen said.
Once the yeast accepted a synthetic section of DNA it was tested for viability. Many of the changes interfered with the organism’s mitochondria or caused cellular proteins to go astray. Goold then hunted the wayward DNA behind the faults, a gruelling process called debugging.
Two plates of yeast, one with fluorescent proteins which help researchers confirm cells have incorporated synthetic DNA.Credit: Dr Hugh Goold
“We had no clue it would take 10 years,” Paulsen said. “Hugh’s been heroic, he’s been in there since the start. At times it’s been soul-destroying to keep going.”
As the chromosome took shape, Australia’s capabilities in synthetic biology grew around it; the ARC Centre of Excellence in Synthetic Biology, which Paulsen leads, was established partly off the back of the project.
“Now we’ve spun out nine start-up companies that raised $200 million in venture capital. From $21 million investments from the government we’ve got a tenfold return,” Paulsen said.
While microorganisms and agriculture are the immediate focus for these researchers, the underlying science could – in future decades – allow for the complete redesign of plants and animals.
“You’ll get to a point where, literally, people sit at a computer, design an organism, order the DNA, put it in their organism of choice, and then they’ve got a new, designer organism,” Paulsen said.
“As you get closer to humans, of course, you get more ethical issues. But the yeast chromosome has taken us 10 years. It’s not going to be routine tomorrow. This is the proof of principle that we can do it.”
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