Friday, March 28 2014

Total Synthesis of a Functional Designer Eukaryotic Chromosome

Classification: Sciences @ 09:44:05

Synthetic biology has come a long way in recent years. In the last two decades alone, scientists have been able to go from synthesising the genome of a relatively small virus, Hepatitis C, to creating what researchers refer to as the “first synthetic cell” from a unicellular organism.

Yet until recently, researchers had been incapable of constructing one of the most emblematic symbols of our own genetic makeup: the eukaryotic chromosome. Now, a team of scientists has announced that the age of the synthetic chromosome is upon us, as a study published in Science reveals how the group was able to construct a yeast chromosome from scratch.

Although scientists have previously been able to construct viral DNA and bacterial DNA, the synthesis of a eukaryotic chromosome had not been achieved. So, when the scientists decided to generate a chromosome from scratch, they knew they had to plan it out carefully. “We didn’t make a carbon copy of an existing chromosome,” says Jef Boeke, a molecular biologist at New York University and co-author of the study, “but an extensively modified version designed on a computer, using a set of principles that were predicted to make happy, healthy yeast.”

This careful planning is what allowed the researchers, along with 60 undergraduate students, to painstakingly string chunks of DNA together and insert them into living yeast cells. It’s also what allowed them to introduce over 500 mutations to the chromosome’s native sequence – a process that yielded yeast cells endowed with what Boeke referred to as “unusual properties.”

One of the most significant changes they introduced was the addition of a gene called “Cre”. This gene is atypical because it produces a protein, also called “cre,” that can scramble the synthetic chromosome’s sequence when it comes in contact with estrogen. This technique is called “the scrambling approach,” and it allows the researchers to rearrange the structure of the designer chromosome “on demand” within the living yeast cells, just by adding various concentrations of estrogen to the growth medium, Boeke explains. “So, just like the shuffling of a set of cards, you can delete or duplicate any subset of genes and generate a whole new set of cards – or a whole new genetic sequence.”

The researchers hope to use the scrambling method to come up with yeast that can tolerate a wider range of environmental conditions, and that can carry out fermentation more efficiently. If they can do that, the applications will be countless, because these microorganisms do a lot more than help us make beer and bread. “I think we will see all kinds of biosynthetic products made in bacteria and yeast over the next 10 years,” Boeke says. This advancement will make the production of things like antimalarial drugs and diesel fuel-like compounds a lot more cost-effective, he says. “Pretty much anything made in yeast could benefit from this scrambling approach.”

But wholly engineered designer yeast isn’t on its way just yet. There is a lot more work to do before researchers can truly explore the treasure trove of applications that this technique will engender, because yeast has more than one chromosome. In fact, it has 16. “It’s unlikely that we will revolutionize an industry by rearranging a single chromosome,” says Boeke. But the scientists might be able to revolutionize a number of industries if they can synthesize the whole set. “Ultimately we want to do this with all 16,” Boeke says, which should take the researchers another two to three years. “That’s when it will become really interesting and powerful, because we will be able to do a lot more when we can control all of its genes.”

Boeke knows some people might question the wisdom of “controlling genes” in this manner, but he doesn’t take those criticisms very seriously. “Unless they subsist exclusively on fruits, nuts and fish, there is about a 100 percent chance they are enjoying the meddling done by our genetically oriented forebears who did selective breeding.” And in any case, he says, whenever the designer chromosome gets too scrambled, “it deletes itself out, self-destructs and the yeast dies,” so the dangers of these types of interventions are minimal.


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