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Reshaping the Limits of Synthetic Biology

Patient DNA data

Ever think you could have built something better if you had a hand in the design? Sometimes people just have a desire to make, after all the maker movement is huge for a reason. Well geneticists have a new toy tool to play with —dubbed “the telomerator”—that could redefine the limits of synthetic biology and advance how successfully living things can be engineered or constructed in the laboratory based on an organism’s genetic, chemical base-pair structure. How cool is that?!

The point of it all, or at least what synthetic biologists aim to do, is to be able to use such “designer” microorganisms to produce novel medicines, nutrients, and biofuels.

Scientists say the telomerator should also improve study of yeast genetics, which (and this might sound strange) is the model microorganism for human genetics, and help researchers determine how genes, as well as the chromosomes housing them, interact with each other.

The research team built the telomerator to convert circular chromosomes into linear ones. The big reason, this better resembles the natural structure of more complex organisms, including humans. Comprising about 1,500 chemical base pairs linked together, the man-made piece of telomerator code can be inserted as a single unit at any position on circular DNA and almost anywhere among a chromosome’s other genes — whose base pairs can number into the hundreds of thousands.

“Our new telomerator resolves a serious and practical issue facing biologists everywhere by helping us experiment with synthetic genes in ways that are more realistic and more closely aligned to the biology of higher organisms, such as humans,” says Jef Boeke, PhD, lead researcher.

“Until now, we’ve relied on synthesizing functional and stable yeast chromosomes in a circular format—with their telomeres cut off—so they can be uniformly reproduced for easy experimentation within bacteria, whose chromosomes are circular in shape,” he says.

What makes the telomerator particularly effective is its precise capacity to add buffering chromosome endings, or telomeres, to newly linearized yeast chromosomes.

A scientific schematic of the telomerator in action.  Image credit goes to: PNAS

A scientific schematic of the telomerator in action.
Image credit goes to: PNAS

Moreover, the telomerator, which took the team two years to construct and test, allows researchers to study how a gene’s position or placement on a chromosome affects the gene’s function.

The key components of the telomerator are its telomere seed sequences, which are exposed when the telomerator “cassette”— or its packaged components—is activated.

To test the device, researchers inserted a telomerator “cassette” at 54 different locations on a circular synthetic yeast chromosome of about 90,000 base pairs and tested whether the chromosome could be segmented and straightened at each position. Researchers compared the process to a clock dial, in which they could insert the telomerator at any “hour” on the clock face to break the circle and yield 12 different timelines, but all of equal length.

The telomerator can reformat the “clockface” of a synthetic yeast chromosome into 12 unique linear “timelines,” or chromosomes of equal length.  Image credit goes to: Courtesy of NYU Langone.

The telomerator can reformat the “clockface” of a synthetic yeast chromosome into 12 unique linear “timelines,” or chromosomes of equal length.
Image credit goes to: Courtesy of NYU Langone.

The results, researchers managed to see colonies grow for 51 of the linear yeast chromosomes, failing only in chromosomes where essential genes were placed too close to the telomere ends.

Additional testing confirmed that the modified yeast chromosomes were in a linear format and of the precise length predicted by researchers.

The research is just a small part in an international effort to manufacture all the yeast chromosomes, threadlike structures that carry genes in the nucleus of all plant and animal cells, and move genetic research one step closer to constructing the organism’s entire functioning genome. Earlier this year, this same team reported building the first of the 16 yeast chromosomes, which they call synIII, and successfully incorporating it into brewer’s yeast, known scientifically as Saccharomyces cerevisiae.

The point being, of course, to better understand human genetics and to find better ways to produce synthetic organisms. As mentioned before the end goal is to create novel medicines and even biofuels. In other words, this is a large step toward that end goal and exciting to think about all the implications this might have for the future.

J. Boeke et al (2014). Circular permutation of a synthetic eukaryotic chromosome with the telomerator Proceedings of the National Academy of Sciences : 10.1073/pnas.1414399111

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