Scientists create first 'designer chromosome'

Researchers have chopped, spliced and manipulated DNA to craft the first extensively modified "designer chromosome," a genetic structure carefully engineered to spur scientific discovery.

The work is being hailed as a bioengineering feat and an important step toward producing a complex organism -- in this case brewer's yeast -- with a custom-made synthetic genome, or genetic blueprint. The research paves the way for producing new medicines and even biofuels from life forms with artificial chromosomes.

Artificial chromosomes have been built before. But those were relatively faithful copies of natural chromosomes, the tiny thread-like structures made of tightly packed DNA that serve as the body's blueprints. By contrast, the new chromosome is a product of purposeful tinkering, but the yeast that carry it act like normal yeast.

Previous artificial chromosomes were "copy-and-paste, more or less. It was plagiarism with a few edit marks in it," says Adam Arkin of the University of California-Berkeley and the Lawrence Berkeley National Laboratory, who was not involved in the research. The new structure is "a serious redesign of a chromosome with lots of very clever ways of … making it more engineerable and more understandable."

The result "is a tour-de-force in synthetic biology," Boston University's James Collins, another outside researcher, says via e-mail.

The chromosome in question belongs to the humble species known as brewer's yeast, crucial for beer, bread and biotechnology. Yeast don't look much like us, but at the deepest levels of biology we belong to the same category. Both yeast and humans store their chromosomes in cellular depots called nuclei; other organisms don't. Until now, the only synthetic DNA structures were designed for bacteria and viruses, which don't belong to the grouping that includes humans and yeast.

To build the first artificial copy of an entire yeast chromosome, an international team of researchers produced a modified version of yeast chromosome III. It's small, making it easier to copy, and it's "something of a sentimental favorite" for its role in understanding basic biology, says Jef Boeke of NYU Langone Medical Center, one of the leaders of the effort.

Starting with commercially available snippets of DNA, Boeke's team stitched together ever-larger DNA fragments, then added them to yeast cells. In the end, all the yeast carried a bioengineered version of chromosome III. The researchers named the artificial chromosome, described in this week's edition of Science, synIII, derived from the word "synthetic." When they tested the synIII-carrying yeast, they found it was as strong and vigorous as ordinary yeast.

In making the souped-up yeast chromosome, the researchers altered roughly 15% of the original. They deleted sections of chromosome that seemed unnecessary, and they spliced in bits of DNA that allow them to scramble the yeast's genes on command. Such scrambling generates a batch of yeast with enormous genetic variation, allowing researchers to fish out the strains that grow best or fastest or have gained a particular ability.

"That's where the real power of synthetic biology is going to come in," Boeke says. "It's evolution on hyperspeed."

Yeast are already used to manufacture biomedical products, and the ability to alter their chromosomes with such precision presents new possibilities, says Farren Isaacs of Yale University, who was not involved in the research.

Some of the design features of synIII allow for "really new and fundamental changes to these organisms," he says. "That could be important in, for example, using (them) as a factory or living foundry for producing entirely new types of drugs. … It's really exciting."