Mirror-Image Cells Could Transform Science — or Kill Us All
By John Bohannon
Photo: Spencer Higgins; Buckyballs courtesy getbuckyballs.com
Dmitar Sasselov was at the end of a long day of having his mind blown when the really big idea hit him. Sasselov, an astrophysicist and head of the Origins of Life Initiative at Harvard, was sitting in the front row of a packed lecture hall at the university last spring, listening to the famous human genome sequencer J. Craig Venter talk about his efforts to synthesize new forms of life. Sasselov had introduced the bald, perpetually sunburned biotech entrepreneur at another lecture that morning, and he’d spent the day squiring Venter around campus.
But Sasselov’s thoughts were light-years away. Two months earlier, a Delta II rocket had blasted off into the darkness above Cape Canaveral carrying the Kepler space telescope; Sasselov is on the team using Kepler to hunt for Earth-like planets around the Cygnus constellation—looking, ultimately, for extraterrestrial life. And he was frustrated. Because no matter how much data he and his colleagues collect—gases in the atmosphere, a fingerprint of color on the surface—they’ll never actually see aliens themselves. And that makes it impossible to answer one of the most basic questions of astrobiology: How diverse is life in the universe? If there is life somewhere other than here, does it look like earthly life, with DNA and protein? Or could it run on something else? Venter’s lecture about artisanal bacteria mapped suddenly onto Sasselov’s frustration. Why not just do what Venter was doing? If Sasselov wanted to study aliens, why not just make them himself—or at least the next-best thing? He imagined himself looking at synthetic aliens on a lab bench, “gazing at the other,” as he puts it, “similar to us but not the same.” He uncapped his red pen and scribbled a note: “Arrange a mtg/chat w Jack & GMC,” it read. “Chiral E. coli w GMC and put it into a vesicle w Jack & subject two cultures to planetary environments.”
Translation: Go to the synthetic biologists Jack Szostak and George Church. Ask them to create a life-form that runs on an operating system different from our own, based on mirror-image versions of earthly proteins and DNA. Let these alien cells grow and mutate, and see how they survive. If it worked, those new cells—Church called them “mirror life”—could answer one of the deepest questions about the origin of life, not just here on Earth but everywhere in the universe. They might also open up new avenues of discovery in materials science, fuel synthesis, and pharmaceutical research. On the down side, though, mirror life wouldn’t have any predators or diseases to limit its reproduction. They would have to keep an eye on that.
Four billion years ago was a hellish time on planet Earth. It was the end of the aptly named Hadean eon: Volcanoes spewed lava across rock baked by ultraviolet radiation; asteroids blasted craters into the landscape. But the worst of the bombardment—including the colossal impact that knocked loose the chunk that became our moon—was over. There were oceans of water and plenty of complex organic chemicals. So in some wet place, maybe near an undersea hydrothermal vent, maybe in the clay on the shore of a shallow pond, organic molecules started to replicate. No one knows exactly where or when or how, but life began.
It was nothing fancy at first. But soon those replicating molecules clothed themselves in a skin of fat, a membrane to keep their complex chemistry from diluting away. And with surprising speed, those bubbles of goop gave rise to a living, functioning cell, the Last Universal Common Ancestor of everything alive today—LUCA. Using the genetic differences between today’s living things as a molecular clock, we can calculate when that ancestral cell first emerged: about 3.5 billion years ago.
Since then, life has been busy. At last count, there were as many as 100 million species on the planet, and billions more have gone extinct. And yet, at the most basic level of biochemistry, it has just been more of the same. Every organism runs on the same operating system that LUCA invented. Peel back a cell’s membrane and you’ll find a blur of activity, thousands of chemical reactions taking place all at once. The conductors of this biochemical ballet are the proteins, nano-size building blocks and machines that control the speed and timing of every reaction. From breaking down sugars to clearing waste to repairing the membrane, the unique shape of each protein determines its job, as specifically as a lock to its key.
The LUCA operating system was an ingenious solution to keeping track of all those thousands of proteins. Biochemists call it the central dogma: Genetic material, in the form of a long nucleic acid polymer called DNA, stores a digital record of every protein’s design. Another nucleic acid, RNA, carries the information to a molecular machine called a ribosome, which reads the RNA and strings together amino acids to form the protein. Once the string is complete, the protein snaps itself into the right shape and gets to work.
But there is at least one viable alternative to LUCA: the mirror image of the entire system. Biochemistry is the story of shapes, and this is its strange plot twist. Lots of molecules come in multiple conformations—sticking together the same atoms can sometimes yield different three-dimensional structures that are the mirror images of each other, a property called chirality. Indeed, most of the basic molecules of life—from the nucleic acids of the genome to the amino acids of the proteins—have mirror-image versions. And all cells have enzymes called isomerases, which flip certain molecules into their mirror versions. But for some reason, in the machinery of living things on Earth, one side of the mirror goes almost wholly unused. All of us earthlings, from algae to elephants, have proteins made of left-handed amino acids and a genome of right-handed nucleic acids. (When chemists say handed, they’re generally referring to the direction that polarized light skews when beamed through a pure solution of the molecule.) No one knows why LUCA picked one side of the mirror and not the other.
Theoretically, a cell could be based on “wrong-handed” molecules. Its biochemistry would work just like ours—DNA to RNA to proteins—but it would be completely incompatible with earthly life, its chiral twin. And now, thanks to recent advances in genomics, cell membrane science, and synthetic biology, an ambitious researcher could go beyond theory and build it from the ground up. The tools are here (well, almost here) to make mirror life from scratch.
Photo: Spencer Higgins
Sasselov is the ultimate talent scout for a problem like this. Because of his job at the Origins of Life Initiative, he knew George Church was already trying to build mirror-flipped molecular machines that could translate genes into proteins, and he knew that Church didn’t have anything to put them in. The membranes of earthly cells are built of fat and protein molecules with the wrong chirality. But Sasselov also knew that if there was anyone in the world who could create a membrane that would work, it was Jack Szostak. “They’re both pioneers, but in different ways,” Sasselov says. “They are my favorite people, and my mentors.”
So he brought them both to a café in Cambridge and made his pitch: Build a fully functioning mirror cell made of molecules they themselves would synthesize. Or, to put it another way: Don’t just create new branches on the tree of life, as Venter was doing with his tweaks of existing cells. Instead, create an entirely new tree.
Church went for it immediately. He’d been looking at similar ideas for years. But Szostak didn’t think it would work. “I’m not saying it’s impossible,” he says, sitting in his office at Massachusetts General Hospital a year after that first meeting. “I’m just saying it requires a lot of hard steps.” Nevertheless, he agreed to support the project.
A soft-spoken 58-year-old Canadian with boyish good looks, Szostak won the Nobel Prize last year for his work on telomeres, the protective end caps of chromosomes. He also created the artificial yeast chromosome, critical to advances in DNA cloning and gene mapping. Lately, Szostak has been working on the origin of those membranes that somehow came to enclose and protect LUCA and every cell since. Inside test tubes in his lab float microscopic, hollow spheres of fat—primitive membrane bubbles. Given the right molecular ingredients, they spontaneously self-assemble, grow, and divide, but they’re much simpler than a naturally occurring cell membrane. The fatty acids have no chirality; their mirror image is the same molecule. So if they were injected with, say, the guts of mirror life, there would be no wrong-handedness to get in the way.
And that’s where Church comes in. He’s 6′5″, with a gnarly beard and a science fiction fan’s optimism. It’s his job to build the genome and protein infrastructure for mirror life. But … could mirror cells actually survive on Earth? “Everything I know from chemistry and physics says that this should work,” he says. Then he gets a little silly: “Hey! I know a great shortcut to get our mirror ribosome! I just need a four-dimensional being to pick me up, rotate me in 4-D, and put me back as my mirror self.”
Szostak still says he’d bet against their success. The cautious scientist in him can’t see how the mirror cell, once full of chirally flipped molecular machinery, will come to life. “Forget about all the technical issues of making mirror ribosomes, mirror peptides, and mirror DNA,” he says. “The complexity of reconstituting a normal cell, or even a simplified cell with 1,000 components, is mind-boggling. You don’t just mix these things up and get it to work.” Still, he agreed that if Church got his part figured out, they could use his membranes to keep everything in. Szostak hopes that even attempting to make mirror life could lead to a better understanding of how ribosomes work and cells evolved. He doesn’t mention the possibility that mirror life could earn someone serious money.
The week that Sasselov met with Szostak and Church to discuss mirror life, a catastrophe was under way across the Charles River at Genzyme, one of the largest biotech companies in the world. Two of its top sellers—medicines for treating the rare genetic disorders Gaucher’s disease and Fabry disease—are proteins. In people with these maladies, fats accumulate in the blood, organs, and brain, causing symptoms from burning pain to kidney failure—unless they get the drugs, produced by genetically modified cells suspended in giant nutrient pools called bioreactors. But that week, a virus that disrupts cell reproduction infected one of the bioreactors. The entire plant had to be shut down.
It was a hard summer for Genzyme, as well as for the people who rely on its medications. While the company decontaminated its bioreactors, thousands of patients around the world rationed their drug supplies. Genzyme’s stock price dropped 20 percent.
When Church talks about mirror life’s quirky advantages, invulnerability to this kind of mishap is high on his list. “Viruses can’t touch a mirror cell,” he says. No virus has evolved to infect it. And even if a normal virus did figure out how to get past the membrane of a mirror cell—which usually requires a mechanism that would be thwarted by wrong-handed molecules—the mirror genome would be unreadable to the attacker. Viruses work by hijacking their victims’ genomes, taking over the cellular machinery for making proteins to build more of themselves; a normal virus wouldn’t have any effect on a mirror cell’s factory. This makes mirror life a potential workhorse for biotech.
As it happens, the cell that Sasselov ultimately wants to create—a chiral twin of E. coli—couldn’t make proteins like Genzyme’s cells. It would make the chirally flipped versions, which would almost certainly be useless.
But that’s not the sort of mirror cell Church has in mind. The problem, he says, is that billions of years of evolutionary R&D have made today’s bacterial cells tough, adaptable, and very good at making more of themselves—but inefficient at spitting out designed-to-order molecules in a bioreactor. Church wants a “minimal mirror cell” to produce specific proteins: mirror, normal, and even mixes of the two but far more efficient than a bioreactor full of finicky, genetically engineered cells.
Mirror Life: A Recipe
When scientists set out to invent a new kind of life on Earth—one that runs on DNA and proteins that are chirally “flipped,” mirror images, molecularly speaking, of everything already alive—they knew it wouldn’t be easy. Some of the ingredients are already in their labs, and some have yet to be invented. Here’s how they’ll do it.
—J.B.
Find a factory.
The cellular machine that assembles amino acids into proteins is called a ribosome. Biologist George Church’s lab is scanning its library of mutant ribosomes, looking for the ones best at connecting wrong-handed amino acids.
Build an assembly line.
Church’s lab will feed the mutant ribosome 150 genes—the minimum number believed to be necessary for a living cell—and wrong-handed amino acids. The ribosome will translate these genes into mirror proteins.
Use the assembly line to build a mirror.
With mirror proteins in hand, Church can build a completely mirrored ribosome. If it works, it’ll be able to copy itself and make other proteins. In other words: self-replicating mirror biochemistry in a test tube.
Make the packaging.
Mirror-life guts won’t survive inside a normal cell membrane. The researchers plan to use a synthetic one made from achiral fatty acids—they don’t have all the ingredients of a natural membrane, but they should work.
Put together the final product.
Assuming all those other steps succeed, the researchers will inject Church’s mirror biochemistry into protocell membranes. Theoretically, the cell will boot itself up and begin dividing and replicating. Voilà: mirror life!
Illustrations: Luke Shuman
The problem for now is that Church’s entire lab is tuned to the wrong chiral setting. Every step on the path to making a mirror cell is blocked by the absence of the right protein tool. The molecule that makes DNA, called DNA polymerase, isn’t the right shape to string together wrong-handed nucleic acids. Want to translate those mirror genes into enzymes? The protein machine that makes RNA copies of DNA—it’s called RNA polymerase—can’t latch onto mirror DNA. And normal ribosomes can’t read mirror RNA or string together mirror amino acids.
That’s why Church has been hacking the ribosome, the master tool that makes all the rest. His plan is to make one that reads regular RNA transcripts of genes but can string together wrong-handed amino acids to form mirror proteins. “It would be a bridge between our world and the mirror world,” Church says. With it, he’d be able to pick a known gene from a library and build mirror protein tools. Chief among them will be a full-on mirror ribosome—no easy task, since the ribosome is a mountain of a molecule, protein and RNA, dating from a time before LUCA. But with a set of mirror proteins, Church thinks he could build one.
None of this will be easy. Messing with the ribosomes inside a living cell can kill it, so Church is going to make ribosomes self-assemble and function in a test tube. And then he’ll have to find mutant versions that will accept wrong-handed amino acids. Think of it as switching the sockets on a wrench from standard to metric.
Church and his team have cracked the first step. Though they haven’t published their results yet, last year his team got a synthetic ribosome to self-assemble and produce luciferase, the protein that makes fireflies glow. And he has a library of mutant ribosomes that have the right kind of sockets—they’ll accept mirror amino acids.
This is where the money comes in. Some of the most valuable drugs are actually tiny proteins that include wrong-handed amino acids—like the immunosuppressant cyclosporine. To manufacture it, pharmaceutical companies have to rely on an inefficient and expensive fungus. A hacked ribosome modified to handle both normal and mirror amino acids could crank out the stuff on an industrial scale. And why stop at what we already know? Being able to produce unnatural proteins cheaply means you could synthesize billions of them and then test them in parallel for antitumor and antibiotic properties. Once you got a hit, Szostak says, you could generate trillions of variations on that molecule, “figure out which are the good ones, and evolve them.”
Church thinks even bigger. A manufacturing ribosome would be great, but a fully domesticated mirror cell—able to synthesize more-complicated stuff—would change everything. “All production will be biological,” he says. In that science fiction future, vats of virus-proof mirror cells could pump out biofuel, lay down nano-size organic circuitry, and even extrude organic cement foundations for skyscrapers.
Of course, mirror life could also kill us all. Synthetic biologists like Church have been thinking about doomsday scenarios for years—the idea that some synthetic super-pathogen will jump a fence. “But that’s the beauty of mirror life,” Church says. “It can’t infect us.” Just as viruses from our side of the mirror can’t infect it, mirror pathogens can’t infect us.
They might be poisonous, though. “I am reluctant to say that the mirror cells or their contents would be nontoxic,” says Jerry Kasting, a researcher at the University of Cincinnati who studies the way chemicals interact with human physiology. “But nor would I expect them to be highly toxic.” It took evolution millions of years to come up with snake venom proteins that shut down mammal organs. The same goes for microbes that produce toxins like anthrax and botulinum. Mirror molecules aren’t tuned to our biochemistry. That’s why the 1960s controversy over the antinausea drug thalidomide was such a surprise—the right-handed version calmed morning sickness in pregnant women, but the left-handed version caused birth defects. Usually, though, the mirror image of biological molecules are weaker or have no effect. They can’t shake hands with our proteins. And that would be one of the safety features of mirror life. To a mirror cell, Earth’s environment is mostly the equivalent of Olestra, the synthetic fat that human enzymes can’t break down. There’s just not enough nutrition for them in the wild.
On the other hand, if mirror cells somehow evolved—or were engineered—to consume normal fats, sugars, and proteins, we might have a problem. If a mirror cell got the right set of isomerases to break down these nutrients, that would be a mess. Mirror cells would slowly convert edible matter into more of themselves. Anything that ate them wouldn’t be able to digest the mirrored molecules—they’d pass right through predators’ guts. And as the mirror cells excreted waste and died, the accumulating material would be like a self-generating oil spill with nothing to clean it up.
It gets worse: If mirror cells acquired the ability to photosynthesize, we’d be screwed. “I suspect that all hell would break loose,” says Jim Kasting, a climate scientist at Penn State University and an expert on the global carbon cycle. (He is also Jerry Kasting’s chiral twin brother; Jim is right-handed, Jerry is left.) All it would take would be a droplet of mirror cyanobacteria squirted into the ocean. Cyanobacteria are at the base of the ocean’s food pyramid, converting sunlight and carbon dioxide into more of themselves. After doing some rough calculations on the effects of a mirror cyanobacteria invasion, Jim Kasting isn’t sure which would kill us first—the global famine or the ice age. “It would quickly consume all the available nutrients,” he says. “This would leave fewer or perhaps no nutrients for normal organisms.” That would wipe out the global ocean ecology and starve a significant portion of the human population. As the CO2 in the ocean was incorporated into inedible mirror cells, they would “draw down” CO2 from the atmosphere, Kasting says. For a decade or two, you would have a cure for global warming. But Kasting predicts that in about 300 years the bugs would suck down half of Earth’s atmospheric CO2. Photosynthesis of most land plants would fail. “All agricultural crops other than corn and sugar cane would die,” he says. (They do photosynthesis a little differently.) “People might be able to subsist for a few hundred years, but things would be getting pretty grim much more quickly than that.” After 600 years, we’d be in the midst of a global ice age. It would be a total evolutionary reboot—both Kasting and Church think mirror predators would evolve, but whatever life existed on Earth by that point wouldn’t include us.
“I would be the first to say that we shouldn’t make a photosynthetic mirror cell,” Church says. “But I’m reluctant to have a moratorium on something that doesn’t exist yet.” He says he’d build safeguards into his mirror cells so they’d perish without constant care. And the advances in synthetic biology required to transform those first delicate mirror cells into anything that could survive in the wild are even more remote.
Early Earth seems to have been covered in a soup of organic molecules with no chiral preference. One plausible theory for where they came from: space. In 1969, a meteorite fell on Murchison, Australia. The 4.6 billion-year-old rock is a sample of the solar system from before the birth of our planet. Not only does it carry both right- and left-handed versions of normal amino acids; it also contains dozens of exotic amino acids that life ended up not using at all. This material was pummeling the surface of Earth right through the Hadean era. But that doesn’t explain why LUCA chose our side of the mirror.
It could be that the primordial soup wasn’t equally spiced with both versions of the molecules. Stars sometimes emit polarized light that selectively breaks apart one version or the other of a chiral molecule. In fact, the Murchison meteorite contains a slight imbalance between the right- and left-handed amino acids, with an excess of the kind that got used by LUCA. (Scientists are convinced that it isn’t due to earthly contamination.) So it’s possible that the sun destroyed the wrong-handed amino acids, denying mirror life its construction materials before it could get a toehold on this planet.
Or the game may be rigged. There might be something more fundamental about our universe that prefers our side of the mirror. But if so—a possibility that thrills Sasselov—the physics behind it is unknown. His new cells will provide the test bed for that hypothesis. “We’ll use the mirror cells as the basis of the assay,” he says. “We can use them as an amplifier.” He’ll grow colonies of normal cells and mirror cells under the same conditions. If the mirror cells aren’t exactly as healthy or fertile as the normal ones, he’ll know something weird is going on. Even the tiniest bias in physics will show up as a big difference after thousands of generations.
Sasselov has another, even stranger experiment planned. If it works, it will ruin Church’s hopes for virus-free biotechnology but might earn all three researchers the Nobel Prize. “It’ll be a revolution in our understanding of life and its place in the cosmos,” Sasselov says. The short version: He’s going to try to find mirror life that’s already living on Earth.
In the traditional story of the origin of life, the chances of evolution producing a living cell are vanishingly small. LUCA was a lottery winner. But it could just as well be that life is easy—something that just happens in environments like those of early Earth. In this version of the story, the primordial soup was a party. There were plenty of resources, few rules, and all manner of bizarre cellular characters. LUCA was there—and so was LUCA’s mirror twin. And maybe even stranger versions of life, too.
We know how the party ended. LUCA went on to become the dominant colonizer of the planet, evolving into billions of species great and small, including a midsize naked ape that likes to read magazines. But what if some of those other partygoers stuck around? Strange life-forms might be living undetected because we’ve never thought to look for their chemical traces. They might live in extreme places, at the bottom of the ocean or inside the pores of rocks—a “shadow biosphere” that’s been here all along, eking out a quiet living. Just as Sasselov worries that astronomers have defined the signs of life too narrowly, maybe we don’t know what to look for right here at home.
If mirror life-forms do exist, Sasselov knows one thing for sure. “They must have their own viruses,” he says. “That’s just a fact of life.” And that’s how he’ll trap the shadow biosphere. “We can use mirror cells as a honeypot,” he says. Earthly mirror viruses might mistake synthetic mirror cells for their usual prey, come out of hiding to infect them, and then snap! He’d close the lid of the petri dish. Rather than going hunting for mirror life, Sasselov would coax it into the light.
Kepler has already spotted hundreds of Earth-like planets—Sasselov estimates that there are 100 million habitable worlds in our galaxy. Odds are we’ll never visit them. But if Sasselov is right, then the “aliens” could be here already, and they might be older than LUCA. If so, mirror life isn’t just here. It’s us.
John Bohannon (gonzo@aaas.org) wrote about a protein-folding game in issue 17.05
