Scientists Build a Yeast Chromosome From Scratch. Next Up? Designer Genomes

Creating synthetic organisms with specially-tailored genomes is a long way off, but the first synthetic eukaryotic chromosome is a big step forward

Scientists made synthetic version of a chromosome found in brewer's yeast, pictured above, a fungus commonly used to make beer. Courtesy of Flickr user Chris Campbell

Humans have been using what they know about the biological world to make stuff for centuries—from beer to antibiotics. But, what if you could manipulate that world at a very basic, genetic level to make something you needed? Programming a cell to produce a drug, generate energy, or attack a pathogen in the body seems like the stuff of science fiction, but that’s what the emerging field of synthetic biology promises.

On a very basic level, synthetic biology is sort of like building a complex structure out of Legos. Just as the Lego engineer must figure out how all the little blocks fit together, scientists have to figure out exactly which genetic elements they need and how those elements fit together to build these biological structures, whether it's a gene, a pathway involving a few genes, or even a full chromosome—a structure that contains hundreds of genes.

For the past seven years, an international team of researchers has been figuring out how to construct a yeast chromosome from the ground up. Now, they've successfully built one and integrated it into a living yeast cell. Their work, published today in Science, marks a significant advance in the field of synthetic biology—and cautious step toward the ability to create designer genomes for plants and animals.

"It is the most extensively altered chromosome ever built. But the milestone that really counts is integrating it into a living yeast cell,” Jef Boeke, a geneticist at NYU’s Langone Medical Center and a co-author on the study said in a statement.

Why yeast? For one thing, humans have a long relationship with the fungi. Brewer’s yeast (Saccharomyces cerevisiae) has been used to make beer and bake bread since ancient times. Today, the modern industrial biotechnology field is starting to use yeast to make vaccines, medicines, and biofuels. In the modern biology lab, yeast is also a model organism because its cells function similarly to human cells. Both humans and yeast are eukaryotes, meaning their cells contain a central hub called a nucleus that stores DNA in tightly wound chromosomes. As a result, we know a lot about yeast biology and genetics.

Yeast Boeke
Geneticist Jef Boeke examines a plate of yeast colonies containing a synthetic version of a specific chromosome Photo: NYU Langone

For organisms without a cell nucleus, synthetic biology has already produced entire genomes, though. Scientists have engineered and reproduced viruses for about a decade. In 2008, researchers at the J. Craig Venter Institute in Maryland built a full bacterial genome and have gone on to produce the first living organism with a synthetic genome (a single-celled bacterium). But such a microbial genome only contains one chromosome, whereas humans have 23 pairs and brewers yeast has 16. Having so many genes in play can mean a lot more variability, such that tweaking one gene could have far reaching implications across the genome.

One of yeast's chromosomes, for example, contains a gene for yeast mating type (sort of like gender)  which in itself governs several other genes across the genome. That made it an attractive starting point for Boeke and his colleagues. On a computer, they designed what they wanted their synthetic version of this chromosome to look like. Then at Johns Hopkins University in Baltimore, Boeke's team needed DNA, so he began enlisting the help of undergraduate students through a “Build-A-Genome” course in 2007. Students stitched together nucleotides, the compounds that form DNA strands, to make short snippets of genetic sequence or "building blocks".

To glue those building blocks into larger "minichunks", the researchers used different enzyme treatments and even used the yeast's own genetic assembly machinery. Finally, they took advantage of yeast's tendency to recombine pieces of DNA into its own genome to assemble, chunk by chunk. Eventually, the yeast replaced the original chromosome selected with the synthetic version. Boeke likens the whole process to building a book: you start by making words, then paragraphs, pages, chapters, and finally the book itself.

Once they built it, Boeke and his colleagues wanted to test the functionality of the synthetic chromosome in yeast cells. The researchers designed the chromosome to include special markers on genes thought to be nonessential—the markers were engineered so that they could be triggered by an enzyme to scramble, delete, or duplicate genes.

The team then triggered the markers systematically to make more than 50,000 changes to the synthetic chromosome at specific points in the code—risky business because random changes could easily kill the yeast cell. "It’s a very pervasively edited chromosome," says Boeke. When they changed or deleted genes, some cells grew better than others in varied conditions, but all the cells grew.

Further, no matter how the researchers tweaked growing conditions, the cells with the synthetic chromosome still spawned yeast colonies. "In spite of all these changes, we’ve actually got a yeast that looks like a yeast, smells like a yeast, and makes alcohol like a yeast, says Boeke. "We can’t really tell it apart, and yet it's so different." This means that the yeast genome—at least the portions that the researchers triggered to change—is highly resilient and can handle a lot of mutation, a finding that is pretty impressive from a genetic engineering perspective.

Yeast chromosome map
A map of the designer yeast chromosome built by Boeke and his colleagues. Image: Boeke et al.

“This work reports the first designer eukaryotic chromosome that has been synthesized from scratch, which is an important step toward the construction of a designer eukaryotic genome. It opens doors to address many scientific and technical questions,” says Huimin Zhao, a biomolecular engineer at the University of Illinois at Urbana-Champaign.

For example, the synthetic chromosome made by Boeke’s team is 14 percent smaller than the normal chromosome they sought to duplicate. So, what’s the smallest genome one would need to make a functioning yeast cell? Based on the methods applied here, they can start testing those questions in the lab. And although the research pathways abound, Boeke says that the next step for his team will be to use these techniques to synthesize the entire yeast genome.

After synthesizing the genome, researchers could, in theory, use the markers to tweak different genes on a grander scale. This could allow them to customize yeast cells with synthetic genomes suitable for specific purposes. 

For example, some biotechnology firms have already inserted genes into rapidly-replicating yeast cells to produce large quantities of a synthetic version of the malaria drug artemisinin, and engineering a designer genome could improve the manufacturing process. How would engineering a designer genome improve the manufacturing process? What new kinds of medicines could be made with specially tailored yeast? Or on a less altruistic level, what new kinds of beers? Whether you're looking to treat human diseases or just want a satisfying cold one at the end of the day, synthetic biology is now a step closer to helping you out. 

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