Scientists Tap Into Biology’s ‘Mirror Dimension’ to Create Ultra-Strong Synthetic RNA

I get frustrated every time I grab a glove and realize it’s for the opposite hand.

But to synthetic biologists, this annoyance is a biological quirk that could help transform medicine. Think long-lasting medications that can be taken once a month rather than three times a day. Or biomolecule-based diagnostic tools that linger inside the body to keep a watchful eye on emerging cancers or other chronic illnesses, without fear of being prematurely cleared out by the body’s metabolism.

Even more daring, biology’s “mirror dimension” may be a springboard to engineer synthetic life forms that exist outside of nature, but are literal reflections of ourselves. To rephrase: building a mirror-image version of biology means rewriting the fundamental operating system of life.

Sound a bit too sci-fi? Let me explain. Similar to how our left hand can’t wear a right-hand glove, the building blocks of life—DNA, RNA, and proteins—are etched into specific 3D structures. Flip them around, as if reflected by a mirror, and they can no longer function inside the body. Scientists aren’t yet sure why nature picked just one shape out of two potential mirror images. But they’re ready to test it out.

A new study in Science made strides by reworking parts of the body’s protein-making machine into its mirror image. At the center is a structure called the ribosome, which intakes genetic code and translates it into amino acids—the Lego blocks for all proteins. The ribosome is an iconic cellular architecture, fused from two main molecular components: RNA and proteins.

The team, led by long-time mirror life enthusiast Dr. Ting Zhu at Westlake University in Hangzhou, China, tackled the RNA part of the puzzle. They re-engineered a workhorse protein that builds two-thirds of the structure so that the resulting RNA components are built in mirror form.

These structures aren’t capable of pumping out “reflected” proteins yet. But several tests found that the synthesized molecules were far more resistant to the cell’s normal “housekeeping” proteins that chew up natural versions of the same proteins.

“From a biotechnology perspective, a lot of applications would be enabled by having a mirror-image ribosome,” said Dr. Jonathan Sczepansk at Texas A&M University, who was not involved in the work. “It’s a really huge advance for the field of mirror-image biology.”

A Cabinet of (Bio)curiosities

The tale of life’s curious predilection for certain structures begins in 1848 with Louis Pasteur. You’ve likely heard of the French chemist—the father of vaccinations, microbial fermentation, and the pasteurization that still keeps our milk safe to drink. When peeking through his wine caskets, Pasteur found crystalline sediments of a tantalizing molecule. Although they had the same shapes and chemical properties, they formed mirror images of each other. One configuration was named “L” for leavus, or left in Latin; the other “D” for dexter, or right.

Scientists later found that L- and D-form molecules exist as a base code for biology. The building blocks of DNA, the blueprint of our genetics, are naturally in D form. Amino acids, in contrast, usually turn towards the left.

This bias is deeply rooted in a central tenet of biology. DNA is translated into RNA and subsequently shuttled to the ribosome to be further built into proteins that perform essential processes for life. But here’s the crux: at each step, the cell’s machinery pumps out molecules of a particular chirality. Our tissues and organs are programmed for a chiral world—that is, one in which the object in question can’t be superimposed on its mirror image, even if it’s rotated.

A few years ago, scientists asked: what if we could artificially put a mirror to this system and shatter it into a new synthetic dimension of life made from opposite chirality?

Through the Looking Glass

Rewriting life into a mirror-opposite version of itself is, to put it mildly, a tough task.

The new study focused on a mirror “reflecting” parts of the ribosome. Previous studies showed that it’s possible to replicate mirror-imaged DNA and even translate it into the messenger mirror RNA. “The next step is to realize mirror-image translation,” from RNA to protein, the authors explained.

It’s a high hill to climb. The ribosome is a massive structure with roughly 2,900 RNA letter building blocks and over 50 diverse proteins. Chemists have previously been able to synthesize the mirror image of RNAs into long chains. But it’s tedious, prone to error, and can only reach 70 letters at most.

If man-made chemistry doesn’t work, why not tap into nature? In cells, RNA letters are normally stitched together into biological data chains with an enzyme—a protein called an RNA polymerase. “Mirroring” the enzyme, could, in theory, also build a reflected version of RNA that builds the ribosome. Back in 2019, Zhu’s team took a stab at the idea by “flipping” a protein workhorse from a virus. It worked—but it was painfully slow and the resulting molecules were riddled with errors.

Rather than tackling the entire protein synthesis machinery, the authors zoned in on one critical member: the T7 RNA polymerase. The darling of the synthetic biology sphere, this enzyme is a hefty workhorse that can churn out long RNA chains—including those that make up protein-building ribosomes—with high efficiency.

Using X-ray analysis, the team found that T7 can be split into three segments, each well within the reach of traditional synthesis. By synthesizing each segment—a mirror version of their natural counterparts—the ultimate structure self-assembled into a mirror version of the T7 enzyme.

“It was a herculean effort to put together a protein of this size,” said Sczepanski.

Into the Unknown

Mirror T7 in hand, the team next began building a flipped ribosome. The protein-making factory is made of three major RNA chunks. When given mirror versions of DNA instructions for those components, the engineered T7 enzyme happily built all three segments in one go. Additional tests found that the mirror-flipped enzyme had similar error rates as its natural counterpart.

What’s more, the molecules pumped out by the mirror-imaged T7—mirror RNAs—were far more stable in cells than those naturally produced. It’s a potential boon for RNA-based vaccines or pharmaceuticals, which often get readily chomped up inside the body before taking effect. Because mirror-molecules are alien to the body’s biological processes, they could stick around for far longer, potentially increasing the effects of RNA or protein-based vaccines and drugs.

It’s a long road ahead. For now, the team hasn’t yet built a full mirror ribosome. The RNAs make up roughly two-thirds of the structure, with over 50 proteins remaining. Adding the protein components through genetic engineering is a feat in itself; whether they’ll assemble with the mirrored RNA into functional mirror ribosomes is totally unknown.

But the team have their eyes on the prize: “The realization of mirror-image translation will complete the mirror-image central dogma of molecular biology,” they wrote.

Image Credit: neo tam / Pixabay

Shelly Fan
Shelly Fan
Shelly Xuelai Fan is a neuroscientist-turned-science writer. She completed her PhD in neuroscience at the University of British Columbia, where she developed novel treatments for neurodegeneration. While studying biological brains, she became fascinated with AI and all things biotech. Following graduation, she moved to UCSF to study blood-based factors that rejuvenate aged brains. She is the co-founder of Vantastic Media, a media venture that explores science stories through text and video, and runs the award-winning blog Her first book, "Will AI Replace Us?" (Thames & Hudson) was published in 2019.
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