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Rewriting Life

Designer Chromosomes Point to New Synthetic Life-Forms

An international effort aims to create baker’s yeast with laboratory-made DNA.

Scientists are attempting to create yeast cells, shown above, with fully artificial DNA.

An international team of scientists is closing in on its goal of replacing all the genetic material in a yeast cell with designer DNA printed in a lab. The effort to endow baker’s yeast with artificial chromosomes signals a step toward what biologists say is technology for printing out improved, or entirely new, life-forms in the laboratory.

The project, dubbed Synthetic Yeast 2.0, or Sc2.0 for short, involves about 200 scientists at 10 universities. As reported today in Science, they painstakingly replaced five of yeast’s 16 chromosomes with artificial copies, which had been engineered with changes that could make them more suitable for producing drugs or biofuels.

“What we’re doing is essentially speeding up evolution,” says Jef Boeke of New York University’s Langone Medical Center, who has led the ongoing project.

Combined with the first synthetic yeast chromosome, previously created by the same team, the structures make up more one-third of the yeast genome.

The work relies on technology for manufacturing DNA strands in the laboratory. Boeke said his team had purchased DNA from commercial suppliers, spending about 10 cents for each DNA letter. At that rate, it would cost about $1.25 million to cover the full yeast genome, but the full cost of the effort, including labor, is far higher.

The synthetic-yeast project is the foundation of a much more ambitious effort called Genome Project-Write, of which Boeke is also a part. It aims to create a fully synthetic plant or animal genome, possibly that of a human, although it has not yet obtained the necessary funding. Last year these plans provoked strong criticism from other scientists, who said such an undertaking was unrealistic, would raise ethical questions over “designer” humans, and had not been fully thought out.

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The effort to create synthetic life-forms builds on ideas first demonstrated in 2010 by researchers at the J. Craig Venter Institute in Rockville, Maryland, who replaced the genome of a bacterium called Mycoplasma mycoides with a copy they built in the lab.

But yeast represents a tougher challenge. The single-celled organisms contain far more DNA than bacteria, and it is twisted into chromosomes, each containing several hundred to thousands of genes. Leaders of the effort, including Boeke and Joel Bader of Johns Hopkins University, estimate that within two years they will replace all 16 chromosomes in yeast with artificial copies and will also create an extra, 17th chromosome.

To create the artificial chromosomes, the Sc2.0 scientists have proceeded in a stepwise fashion, gradually replacing chunks of genetic material with DNA strands synthesized by machine and then checking to see if the yeast remain healthy. Their work, including their efforts at “debugging” rebuilt chromosomes, is described today in seven research papers.

Although Boeke and his team mostly copied the DNA sequence already present in yeast, they also changed it in several ways, including removing “junk” genes that have no apparent function and transferring large stretches of DNA from one chromosome to another. Surprisingly, the yeast still grew normally, even after significant changes. The scientists also added genetic “back doors” to create yeast that will be easier to manipulate in the future.

Daniel Gibson, a scientist at Synthetic Genomics in La Jolla, California, believes the techniques used by the yeast team are not yet advanced enough to build an artificial human genome. For one thing, the necessary DNA would cost around $300 million, according to some estimates. He also downplayed concerns over the potential environmental effects of man-made organisms. For now, says Gibson, “the purpose of these organisms is for them to be grown in a laboratory environment.”

Someday, however, designer human chromosomes could have a role in advanced gene treatments, according to some researchers. Currently, gene therapies usually involve replacing a single gene in a person’s body. But scientists believe a small artificial chromosome might be used to replace whole networks of faulty genes.

Pamela Silver, a bioengineer at Harvard whose lab is seeking to build an artificial human chromosome, says she hopes scientists may one day be able to easily design and build chromosomes without the need for a huge team of researchers.

But that day remains far off, she says: “Regardless of what you’re going to synthesize, you’re going to need a technological leap in order to make it faster and better than what it is today.”

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Scientists are attempting to create yeast cells, shown above, with fully artificial DNA.
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