Genetically-Engineered Aliens?

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.

By John Bohannon for Wired Magazine

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.