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Constructing Synthetic Biology, One Breadboard at a Time

If there’s a point that may be lost in my recent take on synthetic biology, published this week in The Chronicle Review, it’s this: Once you get past the inflated rhetoric, synthetic biology still oozes a revolutionary vibe.

Last year, when I visited the lab of Jim Collins, one of the field’s founders, his team was coming off the creation of a plug-and-play “breadboarding” system for microbes. It’s an idea inspired by electrical engineering, where plastic “breadboards” serve as experimental bases for tweaking circuits without the permanence of soldering. Collins’s method allows much the same, but in bacteria.

There are plenty of tools around for inserting bits of DNA into bugs with some precision. But given the messiness of life, things rarely work out right the first time around. The team’s method makes pulling biological parts out of the DNA much easier, said Raffi B. Afeyan, an author of the study describing the system, which appeared this past November in Nature Methods.

“There’s a very long post-construction process of making things work the way you want them to,” Afeyan said. “We sort of tried to attack that by making constructed circuits very accessible.”

It gets complex quickly, but essentially the team inserted 31 unique DNA signatures into the genome of an E. coli bacterium, each matched up to a protein known to cut DNA only at one targeted site. They then developed a suite of gene parts that could be swapped in and out of those 31 slots, allowing quick modification of genome designs gone awry. And as a demonstration, they modified Collins’s classic “toggle switch” design—its creation is detailed in the article—into a four-part loop in only five days.

Now they’re developing a similar tool set for human-style cells.

“We found that it really speeds things up for us,” Afeyan said.

In my reporting, one eminent scientist compared synthetic biology to the early days of organic chemistry. It’s an apt analogy, and one you can see in Collins’s plug-and-play system, or the “switchboard” that his lab also created recently. Work regularly appears defining how synthetic biology should be conducted, as much as it is creating applications that benefit society.

Another example: Just last month, Timothy K. Lu, an assistant professor at MIT and one of Collins’s former students, published work describing bacteria that can run simple Boolean logic—AND, OR, NOT, etc.—and then stash the results in their own DNA, treating their genetic code like a personal hard drive, its memory lasting for at least 90 generations. (Here’s more detail.) Such logic-and-memory systems will be crucial for persistent computing to become a reality in synthetic biology, Lu told Nature.

“To make this a really rigorous engineering discipline, we need to move towards frameworks that allow you to program cells in a more scalable fashion,” he said. “We wanted to show you can assemble a bunch of simple parts in a very easy fashion.”

Of course, Collins and Lu have applications in mind, too.

Right now, Lu is collaborating with the Walter Reed National Military Medical Center in hopes of treating combat veterans plagued with antibiotic-resistant skin infections. Several years ago, Collins and Lu developed modified viruses that raise the efficacy of antibiotics. Perhaps they can help end festering pain that can accompany blast wounds; right now, though, the work is limited to animal models.

Meanwhile, Collins is eyeing engineered probiotics, the beneficial bugs that sit in the human gut. He has a grant from the Bill & Melinda Gates Foundation to arm those bugs with a trigger that will detect the bacteria that cause cholera, spitting out amino acids to attack the microbe. The culture would be introduced every few days, through yogurt.

It would be “a synthetic self-sentinel,” Collins said, “sitting there waiting to detect and respond to a cholera infection, hoping to fight back the cholera before it took over your gut.”

The eventual goal, many years away, is the possibility of modifying the gut’s bacteria permanently, eliminating the need for regular doses. Then you can start to modify microbiomes in the gut or lung to deal with allergies, asthma—maybe even dietary issues.

After all, even the toolmakers must dream.

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As an addendum, for those adventurous souls looking for a deep dive into the tools available to synthetic biology, this open-access review, published in Molecular Systems Biology in January, provides an incredible state of the field. Beware: Jargon ahead.

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