Over ten years ago, Jef Boeke embarked on a research project to understand what might be the most important microorganism to human civilization, Saccharomyces cerevisiae, also known as baker’s yeast or brewer’s yeast. For millennia, we’ve used yeast for feasts and festivities, but we didn’t really know how it worked. Even today, the critter remains something of an enigma. Boeke, who is a professor at Johns Hopkins University, wanted to make one, from scratch. Well, at least its genome.
The project, dubbed Synthetic Yeast 2.0, was excruciatingly slow-going at first. So Boeke and his team decided to abort the mission in favor of a simpler approach centered on yeast chromosome number 3, which contains the code to the fungus’s sexual behavior. Through a course at Johns Hopkins called “Build a Genome,” Boeke and his colleagues enlisted the help of undergrads, who collectively synthesized the regions of the chromosome that code for proteins, the compounds that perform actions with a cell. At 272,871 base pairs long, this “abridged” version represents only 2.5 percent of the entire yeast genome.
Why would scientists chop away at DNA like this? Over the course of yeast’s evolution, it acquired extra sequencing—accessories, if you will—that optimize its ability to function but aren’t essential to its survival. One way of getting clarity on how an organism works is to eliminate these extra variables and structure your prototype around the genetic information you can control: the stuff that actually makes proteins. It’s like a minimum viable chromosome, giving scientists access to the spine of the genetic skeleton.
Ewen Callaway reporting for Nature, describes how the project worked:
Each student makes their own stretch of the yeast genome, which involves stitching together very short lengths of DNA created by a DNA-synthesis machine into ever-larger chunks. These chunks are then incorporated into the yeast chromosome, a few at a time, through a process called homologous recombination. Eventually, this results in an entirely synthetic chromosome. Many of the students are co-authors on Boeke’s Science paper, which details the synthesis of S. cerevisiae‘s chromosome III.
The Synthetic Yeast 2.0 project isn’t the first to replicate a major portion of an organism’s genome—that honor went to researchers at the J. Craig Venter Institute who synthesized the genome of Mycoplasma mycoides, a relatively simple bacterium. But it is the first time we’ve been able to do it with a chromosome. David Biello reporting for Scientific American, has more:
This marks the first time scientists have synthesized the genetics of a complex organism, a landmark achievement in the field of synthetic biology, and given the college kids involved, a triumph for the new movement known as “DIY biology.” Prior specialist work had succeeded in synthesizing the entire genetic code of simpler microbes, such as the goat pathogen Mycoplasma mycoides, renamed JCVI-syn1.0 by its creators, which has been lying dormant in a freezer since 2010.
The synthetic Mycoplasma mycoides genome was nearly identical to the original. The synthetic chromosome in yeast isn’t. By excluding the noncoding regions, Boeke hopes to create an experimental platform that will allow researchers to test the function of various genes in a highly controlled fashion. It’s the sort of undertaking that could allow us to finally get a handle on what, exactly, yeast does to turn malt and hops into beer or flour and water into bread.