In 2008, researchers built the first artificial genome, a wonder of synthetic biology in which scientists generated all 582,970 base pairs of the bacterium Mycoplasma genitalium's genome entirely from scratch. It was an unparalleled scientific achievement, requiring scientists to carefully design 101 unique DNA fragments so that their codes would overlap and stick together, then bind those fragments piece by piece. It was also small potatoes, one of many steps along the way to eventually creating a synthetic eukaryotic organism.
The humble baker's yeast. Image: Wikimedia
A new breakthrough now takes humankind closer than ever to developing the first complex artificial life.
In a suite of seven new studies published Thursday in the journal Science, researchers from the Synthetic Yeast Genome Project report that they have successfully synthesised six of the 16 chromosomes that comprise the entire genome of yeast. That puts them more than a third of the way to generating made-from-scratch designer yeast.
Biologists now regularly genetically engineer large swaths of DNA, achieving such triumphs as non-browning apples and correcting mutations that cause deadly disease. But synthesising an organism's entire genome could represent an unprecedented level of human control over nature.
"This is very exciting," said George Church, the Harvard geneticist whose own lab is working on synthesising the human and pig genomes, peptide by peptide. "They have tackled some of the hardest things. The other two-thirds of the yeast genome is going to happen much, much faster."
So why all the fuss over a few million artificial base pairs of a simple, single-celled fungus? The humble baker's yeast plays a crucial role in synthetic biology. Not only is it a single-celled eukaryote that shares many important cellular processes with humans, in recent years synthetic biologists have engineered it to function something like a living factory for biofuels and drugs. In addition to shedding light on important basic biology questions and acting as a stepping stone to one day synthesising genomes of more complex organisms, a full set of synthetic chromosomes might allow scientists to create designer versions of yeast that are far more useful and efficient. Scientists might, for example, one day engineer a strain of yeast optimised to survive in high-alcohol environments to more efficiently produce ethanol.
"When you can replace all of yeast's chromosomes with synthetic ones, you can do so much with it," said Eric Topol, a geneticist at the Scripps Research Institute who was not involved with the research. "It's a big advance in biology. We use yeast for everything."
To pull this genome synthesis off, the many researchers from around the world working on the Synthetic Yeast Genome Project first used specially-designed software to create synthetic versions of five yeast chromosomes. The software, dubbed BioStudio, is almost as big an accomplishment as the synthetic chromosomes themselves — it will likely make genome synthesis much, much easier in the future.
In BioStudio, researchers made many small tweaks to existing yeast DNA, things like removing areas of genetic repetition, and swapping DNA from one chromosome to another in order to create new chromosomes optimised for both research and industry. That designer DNA was then chemically synthesised in small chunks, assembled into bigger chunks and then finally into an entire chromosome. The researchers are reporting the synthesis of five new chromosomes today, bringing the total number of synthetic yeast chromosomes to six. (Yeast chromosome 3 was synthesised from scratch back in 2014.)
Each of those individual chromosomes were then placed into a living yeast cell, swapping the new, synthetic chromosome out for a single wild-type one. In the end, the researchers wound up with six partially-synthetic yeast cells, each with a single synthesised chromosome. In order to create a cell with 16 synthetic chromosomes, those partially synthesised yeast cells will be mated with one another, eventually producing a cell with an entirely synthetic genome. So far, three new synthetic chromosomes have been integrated into a single cell.
"We had two design goals in mind," said Joel Bader, a biomedical engineer at Johns Hopkins and one of the authors of the new studies. "We wanted to be able to answer biological questions, like, 'How do you make a chromosome? and 'Why are genes organised the way that they are?' And we wanted to design them for applied research, like making small molecule drugs."
For thousands of years, humans have manipulated yeast to turn wild strains into the stuff that gives us things like beer and bread. The goal now is to untangle and reorganise yeast's genetic blueprint, eventually creating a cell that has been optimised to remove all the redundancies and faulty design elements that nature endowed it with.
There is one paper for each new chromosome, in addition to one that provides a broad overview of the progress, and another that details the physical, three-dimensional structure of the synthetic yeast.
So far, the synthetic chromosomes are not entirely without error — there were a few off-target effects. The new chromosomes, though, functioned mostly as researchers hoped they would. Bader said than in two to three years they expect to have all 16 chromosomes synthesised and assembled.
"Now that we've figured out how to do it, the research is moving very fast," he said.
To be clear, even once researchers have accomplished the incredible feat of synthesising the entire yeast genome, they will not have created an entirely synthetic organism. That's because there is more to life than a genome. DNA is the molecule that encodes hereditary material. There are other parts to the cell, like the cytoplasm. Think of the genome like operating instructions for a computer — you still need the rest of the machine to actually get your program to run.
Topol said that the advance — less than three years after scientists announced they had synthesised a single base-pair of yeast's genome — underscores just how quickly the field is moving.
"When I started my career, I was thinking of one day being able to read DNA, and dreaming of just maybe one day being able to edit it," Topol said.
In the short term, a synthetic yeast genome could lead to the creation of designer yeast for manufacturing of vaccines, medicines and more sustainable biofuels. Further down the line, it could lead to custom-built designer organisms — perhaps even designer humans one day.
Hank Greely, a bioethicist at Stanford, said that it still isn't clear whether whole genome synthesis will be a more efficient way of making the desired changes to genomes than editing existing genomes.
"Ten years from now, will it be easier and cheaper to change thousands of base pairs using CRISPR or make to make a genome from scratch?" he said. "That's a question that depends on technologies that are still being invented."
Bader, though, said we should view the two approaches as complimentary.
"Sometimes you see something someone has written and it has some mistakes, so you want to edit it," he said. "Sometimes it's so far off you need to start from scratch."
Either way, genome synthesis is likely to be plagued by the same sort of ethical questions that have surrounded CRISPR. Just how far should we take humankind's meddling with nature? If we can create truly synthetic organisms, should we? And how do we make sure our technologies are used for good, rather than bad?
"We live in a world where already everything we eat was engineered by our ancestors and we regularly, easily talk to people hundreds of miles a way," Greely said. "Civilisation is about playing god. The question is not whether to do it, but how to do it in smart ways. We need to figure that out."