Scientists build yeast with artificial DNA in a major synthetic biology advance

For more than 15 years, scientists have worked to build a complex cell with an entire genome built from scratch. This week they announced a major milestone: They've created synthetic versions of the 16 chromosomes in a yeast cell and successfully combined some of them in one cell.

Why it matters: The feat is revealing new information about fundamental processes in cells, and it is a key step toward some scientists' vision of creating programmable cellular factories to produce biofuels, materials, medicines and other products.

What's happening: International teams around the world each took the lead in creating a chromosome as part of the Synthetic Yeast Genome Project.

• "The building of each one of these chromosomes is an absolutely mammoth task," says Benjamin Blount, a synthetic biologist at the University of Nottingham in the U.K. and co-author of some of the scientific papers in a series published this week in Cell and Cell Genomics detailing the work.
• Researchers have built synthetic genomes for bacteria and viruses, which have smaller genomes than yeast cells, which — like animal and plant cells — are more complex. These eukaryotic cells have specialized compartments where different processes take place, and they contain longer genomes split up across multiple chromosomes.
• In the past, scientists modified individual genes, not entire chromosomes.

How it works: The changes researchers made to yeast chromosomes fall into three main categories: increasing stability of the genome, repurposing codons (genetic sequences that carry instructions for reading DNA or RNA) and introducing a system that allows scientists to make millions of cells, each with different genetic properties.

• "A big problem is a lot of the things you want to make are actually toxic to the cells," Blount says. With the system that reshuffles the genome and effectively mimics evolution, scientists can make many variants of yeast and pick the ones "that are really good at growing in the presence of what you're trying to make."
• Then, they're able to look at what's happened to their genomes to enable that particular strain to grow and make the desired product, and use that genetic information to develop strains of yeast suited for an industrial process.

What's next: The chromosomes still have to be combined in one cell that can survive, which means they have to be "basically indiscernible" from natural chromosomes in terms of the cell's fitness, Blount says.

• That requires a lot of debugging of the genome, similar to what's done for computer code.
• One team was able to combine multiple chromosomes in one cell and it survived and reproduced, demonstrating a mechanism for bringing them together.

The intrigue: Building the genomes — and seeing when the cell doesn't work as expected as the result of one change or another — has revealed fundamental information about genome biology, Blount says.

• For example, the team identified sequences in genes that interrupted a key process in the cell and led to mitochondria dysfunction, which is involved in some human diseases.

What they're saying: The research is "such a big deal because it's marching towards [a high] level of complexity," says Julius Lucks, a synthetic biologist at Northwestern University who wasn't involved in the project.

• Building synthetic chromosomes of yeast is "very complicated" and "conceptually and technically enabling," he adds.

The big picture: Some scientists are working to use synthetic biology to produce biofuels, materials, medicines and other products in cells.

• Products are starting to come online and "raise awareness for the technology," Lucks says.
• He points to LanzaTech, a startup in Skokie, Illinois, that is doing carbon negative manufacturing by harnessing the ability of some microbes that eat methane and other gases to make fuel molecules and materials for clothing, cleaning products and other applications.

What to watch: There are concerns about synthetic microbes being able to survive in the wild.

• Other scientists have modified cells so they can't survive outside the lab without supplementing them with something that doesn't exist in nature, or they have designed genomes so cells "can't pass their genetic information in any meaningful way to any other thing," Blount says.
• Some of the biggest challenges, though, are "societal scale," Lucks says, including a regulatory framework, ethical considerations and economic drivers for adoption.
• Others will be technical, including scaling up production, but also more fundamental, he adds.
• "You want systems that do what life does, but you don't want the complexity of life," Lucks says, adding it is essentially about taking the best of life's abilities and simplifying them so they work more robustly. "There are huge open questions on how to do that."