In just a few years, scientists will unveil a creature whose every letter of DNA was written by a human being. It will be a yeast cell with a fully designer genome, and biological capabilities seen nowhere else in nature.
Recently, a global team of scientists announced a major milestone in their decade-long quest to create a fully synthetic yeast genome. As described in the journal Science, the hundreds of scientists have completed work on six of the yeast’s 16 chromosomes (the individual stands of DNA that make up a genome). Meanwhile, the remaining 10 chromosomes (plus one extra, not found in nature) have been designed and are awaiting production.
The synthetic yeast will be a huge advancement in bioengineering. It will be a proof of concept that scientists can design and implement genome-wide changes, tailoring microorganisms in major ways for further engineering and study. It means we may be able to create whole new species of microorganisms for industrial or scientific purposes.
No, this isn’t “playing God,” the scientists behind the project say. In their view, rewriting the yeast genome is more like domestication. “No one created a dog; they adapted a wolf,” says Sarah Richardson, a synthetic biologist who is the lead author on one of the Science papers describing the project.
Right now, biologists have a lot of genetic engineering tools at their disposal. CRISPR/Cas9 allows biologists to neatly snip out one single gene and replace it with another. Recombinant DNA is how we’ve coaxed bacteria to create human insulin — a treatment for diabetics. But those techniques are for tiny edits. This yeast project is a rewriting and reorganization of the whole genetic book.
Why redesign yeast?
The project, called Sc2.0 — as in the 2.0 version of Saccharomyces cerevisiae, a.k.a. household yeast — started 10 years ago. Now the end is in sight. In just a few more years, the researchers should be able to unite all 17 synthetic chromosomes in one cell.
Research efforts have developed synthetic bacteria genomes before. But yeast is vastly more complicated. The most commonly used bacteria in genetic engineering, Richardson explains, has about 4 million base pairs of DNA. (Base pairs — you might remember from high school — are the individual building blocks that make up DNA: adenine-thymine; cytosine-guanine. No shame if you’ve forgotten.) Yeast has around 12 million base pairs.
Building that all from scratch is an enormous task — which is why the Science papers describing the project have hundreds of authors.
But why all the effort? This project has two main benefits.
1) It helps scientists understand the fundamentals of life.
“If you know how a radio works, you should be able to take it apart and put it back together,” Richardson says. Same goes for genetics.
Already, the team has gained a huge understanding of what yeast genes are necessary for keeping it alive and which are bloatware. And they’ve learned a lot from trial and error: Small changes to the genetic code have made the difference between a cell that thrives and a cell that dies.
2) It paves the way for further genetically engineering yeast.
If you think of yeast as a factory, then its genome is the operating system. The engineered yeast will be a well-understood platform upon which to build extra functions, like generating biofuels or manufacturing pharmaceuticals.
Yeast is already extremely useful. Brewers use it convert sugar into alcohol in beer. Bakers use it to turn a mass of flour into pillowy, tender bread. If scientists can reengineer yeast from scratch, they can teach it a few more tricks.
“We wanted to make changes that are very difficult to make without rebuilding it from the ground up,” Richardson says.
The scientists have designed some new “programs” into the genome. One is called a “scramble” function. With a push of a button — essentially, this is a simplification — scientists will be able to instantly mutate their synthetic genome into a million new forms.
“The analogy is if you had a million decks of cards, there would be one that would give you the best hand at gin rummy, there would be another that would give you the best hand at Texas Hold’em, and so on,” says Jef Boeke, an NYU biochemist and one of the leads of the Sc2.0 project.
And then they could look through those randomized yeast cells for ones that might be handy. Some could, for instance, produce higher concentrations of alcohol from sugar (which is useful in producing biofuel, or beverages). Others could be more adept at breaking down certain proteins.
Also, in the Sc2.0 design, the biologists have done some tidying up of the genome. “Genes that do something similar often are not grouped together in one location — like someone organized would do it,” Joel Bader, a Johns Hopkins biomedical engineer who oversaw much of the project, explains.
How do you rebuild a genome from scratch? In five not-so-easy steps.
1) Design the chromosomes on computers.
The scientists are editing an existing genome, rather than dreaming up a genome from scratch.
So they start with the text of a fully sequenced yeast chromosome on a computer, and make little tweaks. Most of the changes are to make the genomes more resistant to mutations. That way nature won’t as easily erase any changes scientists engineer in the future.
The scientists also took out introns, filler regions of the DNA that don’t code for anything at all. And they took special pains to mark genes that yeast need to survive. “You have to be careful around them,” Richardson says.
2) Make sure the designs can actually be built.
An architect can draw the most beautiful building her mind can imagine. But if an engineer says it can’t be built, it can’t be built.
A similar thing happens with DNA design. The chromosomes have to be assembled from tiny pieces of DNA, and they have to get glued together at very specific points. “In your design, you want to plan ahead for where those junctions are,” she says. Or certain snippets of DNA just won’t stick together during assembly.
3) Manufacture the DNA
Each one of the 16 yeast chromosomes can contain 100,000 base pairs of DNA. But there is no DNA “printer” that can perfectly spit out that many in a stable chain.
So the scientists have to manufacture the DNA in small chunks — 60 or 100 base pairs. “Every letter has to be synthesized and then checked against our design to make sure we don’t have any mistakes,” she says.
Lab workers can then assemble around 10 or so of these chunks into 600-base-pair pieces of DNA. Then they glue those larger pieces together — and so on — until they have large 10,000 base-pair chains.
4) Replace natural chromosomes with synthetic ones
In a painstaking process that provides a critical safety check, the new synthetic chromosome is inserted in pieces rather than all at once. If any piece kills the cell, they know there’s a problem in that section of the code.
5) Combine all the synthetic chromosomes into one yeast cell.
The previous four steps are what it takes just to produce one chromosome. Yeast has 16 total.
For a time, each of those 16 chromosomes will live in a separate yeast strain. (That is, one yeast cell will have a synthetic version of “chromosome 1,” with the rest being natural. Another will have a synthetic version of only “chromosome 2” and so on).
In another painstaking process, the scientists will have to carefully breed the yeasts with each other so that all 16 synthetic chromosomes (plus one extra, completely new chromosome) all end up in the same cell together.
I asked several of the scientists if, when this is all done, they will have created a new species altogether. That’s up for debate, they say. The yeast 2.0 will look like and function like a normal yeast cell. But there’s a chance it won’t be able to mate with a naturally occurring yeast cell (reproductive compatibility is a traditional definition of a species).
Overall, the scientists stress the wrong conclusion is that they’re creating life.
“We’re not starting with a bunch of inanimate chemicals, mixing chemicals, and having life pop out,” Boeke says. “We start with a living cell, and we replace the DNA that is inside.”
But they’re doing something that’s just as intriguing. No, they’re not creating life. They’re transfiguring it.