In what is being called a major step forward in genetic engineering, scientists have built a customized copy of an entire yeast chromosome. Experts say it may lead to a better understanding of how the thousands of genes contained in these packages of genetic material work together in everything from yeast to humans. And it may make it easier to make designer yeast, creating living factories that churn out everything from antibiotics to biofuels.
Geneticist Jef Boeke says it started with a coffee shop conversation with a colleague.
“I mentioned casually to him that, of course we could make the yeast chromosome if we wanted to, but why on Earth would we want to do that? And he practically literally started jumping up and down with excitement when I told him that,” he said.
So Boeke, the colleague, Srinivasan Chandrasegaran and a third partner, Joel Bader, spent the next year discussing how they could engineer the chromosome to make it worth the enormous investment of time and money it would take.
Working at Johns Hopkins University, they decided to create an artificial version of chromosome III, one of the smallest of yeast’s 16 chromosomes. It carries about 100 genes. Boeke says scientists have studied it for years, adding “It is the sentimental favorite of yeast geneticists.”
Block by block
Boeke and his colleagues recreated their favorite chromosome, gene by gene, with synthetic chemical building blocks. They included molecular seams, so they could cut the chromosome apart, take some genes out, add others, rearrange them and stitch it back together in ways that would help them understand how different combinations of genes work together.
Since yeast genes are a lot like ours, Boeke says the research could lead to a better understanding of human genetics.
“And perhaps most interesting of all, we think it will be useful for actually improving the strain under certain conditions of growth or production of some useful product,” he said.
Different strains of yeast are already used to produce antibiotics, antimalarial drugs, vaccines, biofuels and much more. The ability to custom-tailor chromosomes could give the biotech industry a boost.
And Boeke says the same process his group used to build a new yeast chromosome could be used in plants and animals and even humans as well.
Boeke, now at New York University,
says they are all aware of the ethical issues that possibility raises.
“We have a card-carrying bioethicist who is part of our team,” he pointed out, adding, “And we think a lot about these things. In fact, our whole field is infused with a passion for doing the right thing.”
He says every member working on the project has to sign an agreement not to do what he calls “bad things” with it.
Experts note that this is not the first time researchers have built a big chunk of genome from scratch. A group at the J. Craig Venter Institute synthesized an entire bacterial genome in 2008.
Paying for research
Ventner’s group was funded entirely with private money. Boeke’s group relied on a single, relatively small government grant. Virginia Tech professor Jean Peccoud notes that undergraduate students did much of the actual work.
“There is a lot of significance in terms of engaging students and using a research project like this as a training opportunity," he said. "But in terms of the kind of infrastructure and the kind of intensity you need for a project like this, is it really something that is fundable through public sources, or is it something that is going to be in the hands of commercial interests?”
Peccoud notes that Craig Venter also used private money to sequence the human genome faster than the publically-funded project.
Meanwhile, researchers have 15 more chromosomes to build in order to reach their goal of constructing an entirely custom-made yeast genome.
The work appears in the journal Science