biological circuits

Hacked E. Coli Shows the Promise of Programmable Biology

Researchers turn living cells into biological sensing and computing platforms.

Michael Byrne

Michael Byrne

Wyss Institute/Harvard

The preferred term is "ribocomputing." Take a molecule of RNA, the "messenger" chemical that carries instructions from a cell's DNA to the rest of the cell, and basically rewire it. By hacking the RNA, it's thus possible to take command of the processes of the cell, particularly that of protein synthesis. It's also possible to rewire the RNA to respond to specific stimuli, offering an engineered microbiological system that reacts to inputs in the same way that an embedded computer might respond to a temperature sensor of accelerometer.

Synthetic biology or "hacked" biology is a quickly growing field, but the term ribocomputing is scarce, mostly limited to a single 2016 study. That was the case at least until this week and the publication of a paper in Nature describing RNA-based synthetic biological circuits that are capable of implementing just what I described above: sensing external signals and directing cellular machinery to respond to those signals in programmed ways. It's fascinating but also a bit spooky.

Many efforts in synthetic biology involve compiling catalogs of biological "parts" that can be assembled into function bio-circuitry. These are consistent, modular building blocks that provide a basic Lego set for building biological machines. The downside of the modular approach, as explained in the current paper, is that the resulting circuits are complex and overly sensitive to their surrounding context. A cellular machine assembled in a test tube from prefab components is by nature a bit rickety. And, unfortunately, a living cell is a crowded, noisy environment.

Here, however, the machine's parts are naturally a part of the cell. It's just the RNA itself that's rewired. This is done with help from what's known as a Toehold switch. The switch is basically a small hairpin-shaped RNA nanostructure that gets inserted into a cell. The RNA of the switch is capable of inducing the cell to create a specific protein, but first it has to match with complementary RNA that already exists naturally within the cell. When the natural RNA and the RNA of the Toehold switch meet, the switch's RNA becomes exposed and the cell starts kicking out the prescribed protein.

"Once we had worked out how to use Toehold Switches and RNA molecules to encode the basic logic operations―AND, OR, and NOT, we were able to condense this functionality within a carefully designed molecule that we call a gate RNA," study co-author Alexander Green explained in a statement. "Use of a gate RNA makes the Ribocomputing Devices much more genetically compact and helps with scaling up the circuits so that the cells can make more complex decisions."

Green and colleagues were able to implement two independent gate RNAs that worked together within an E coli cell to produce fluorescent proteins―they were able to make the cell glow, in other words. It's not hard to imagine such cells being injected into the body as sensing units, alerting doctors to the presence of cancer cells or whatnot.

What's more, it's likely that that same technique could be extended beyond bacteria to other microorganisms, according to the study, and even perhaps beyond living cells. It may even be possible to freeze-dry hacked RNA and print it onto paper, where the same basic functionality could be implemented. Imagine test strips of paper capable of serving as dynamic sensing platforms for medical diagnostics.