Inside every living cell are molecule-building factories called ribosomes. These tiny machines read blueprints of genetic information and fabricate the molecules that make up all life. They are hugely important to genetic engineers and researchers, because controlling ribosomes could be the way to synthesize the custom-made biological nano-machines of the future—ones that could make anything from therapeutic human antibodies to the next generation of unfathomably complex super-materials.

There's a problem: Engineering a ribosome to do interesting tricks often means paralyzing and killing its parent cell. But today, a team of biologists and biological engineers at Northwestern University and the University of Illinois have made a fascinating breakthrough that could help scientists get around this roadblock. As they report in a new study in the journal Nature, the scientists have created unique, experimental ribosomes they're calling Ribo-T that are the first ever to passively co-exist with a living cell's natural ribosomes. It means that for the first time, researchers will be able to tinker with ribosomes in living organisms, such as bacteria, without worrying about killing the lifeforms they're studying.

"You can think of it like this: Imagine you only have one family car and you want to start modifying it, say, putting a truck bed in," says Alexander Mankin, a biologist with the team at the University of Illinois. "With each modification, you risk breaking down important processes, like losing the back seat your kids need. This is the same with these ribosomes. But here, [having Ribo-T] is a bit like having two cars, instead of one." So you can modify Ribo-T in any way you want without worrying about destroying the whole setup, he says.

The genetic lasso

What makes ribosomes so hard to work with is their fundamentally weird nature. Here's an oversimplification of the strange setup: In all living cells, ribosomes are broken up into two independently floating parts. There's a smaller "reader" half of a ribosome, which attaches to a strip of genetic data, and a larger half that assembles the molecules. Each cell is a sea of ribosomes halves. Those halves randomly join together to read and create a molecule, then split up and promiscuously recouple with totally different halves.

Based on what we know about cell biology, this really shouldn't have worked.

According to Mankin, that two-parted nature has made genetically engineering these molecules machines almost impossible. You either genetically engineer the whole sea, or nothing at all. But Mankin and his fellow scientists had an idea, one that totally went against what scientists thought they understood about ribosomes. Why not just tie the two halves of certain ribosomes together indefinitely?

Based on what we know about cell biology, this really shouldn't have worked. The reason is that the two ribosome halves need to move around relative to each other as they built molecules, which a tether might prevent. Researchers also didn't know how such a tied-together ribosome would find the strips of genetic data blueprints it reads.

For the most part, it didn't work. Mankin and his colleagues tried to tie the ribosome halves together tethers of basically nonsense sticky RNA. They tried 91 different combinations, and most of them failed. A few of them worked, albeit it very poorly. But here's where the team did something really clever: They let a cutthroat competition decide which tether was best.

By joining the RNA of the large and small ribosomal subunits into a unique chimaeric molecule, it was possible to engineer functional ribosome with tethered ribosomal subunits (Ribo-T) Eric Carlson

The researchers were thinking that the length of the tethers might impact how well the combined ribosomes were able to function, since the ribosome halves need to shift around without breaking their connection. So Mankin and his team genetically engineered a handful of bacteria with tied-together ribosomes, each with different tether lengths. Then the scientists let them compete on a petri dish with limited food for two days to see which bacteria out-competed the rest. "This way the cells told us themselves what was the best ribosome tether design in the smorgasbord of options we offered," he says. In the end, bacteria with two sticky tethers 8 and 9 RNA nucleotides long was the champion.

Having found the optimal length, the scientists did one last round of bacterial gladiator battle to se whether—with enough time—some bacteria might spontaneously evolve some trait that would make the combined ribosomes more efficient. "After several dozens of generations, a bacteria did," Mankin says, and it dominated a different petri dish with more gusto than any other strain. (Exactly why this random mutation allowed a bacterial with a combined ribosome to grow faster is still a mystery, he says.)

Scaffolds for the science of the future

"The answers to these questions will illuminate the basic mechanisms of molecule creation."

Finally, Mankin and his team had created a combined and tethered ribosome that works surprisingly well: Ribo-T. A bacterial cell using only Ribo-T ribosomes will grow normally, but at about 45 percent the speed of a non-engineered cell.

Joseph Puglisi, a biologist at Stanford University who was not involved with the project, says that figure is actually damned impressive. In an essay accompanying the Nature paper, Puglisi confirms that Ribo-T, while a bit slower, can create any of the molecules a normal ribosome can make. That makes Ribo-T—which can be genetically created to appear alongside a population of normal, halved ribosomes—the perfect scaffold for a new wave of genetic engineering experiments.

Better still, Puglisi says, because we now have the first platform where we can test and tinker with truly delicate and crucial ribosomal features (without worrying about killing our experiment), Ribo-T may offer new insights into the mysterious inner-workings of the ribosome—which, as Mankin admits, is still poorly understood. We can now ask basic questions like why ribosomes seem unable to create certain types of molecules.

"The answers to these questions will illuminate the basic mechanisms [of molecule creation] and will probably cause surprise," Puglisi says. "Armed with this knowledge, thoughtful engineers will continue to tinker with the ribosome.

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