Synthetic Life Seeks Work

A startup company says it is expanding the language of DNA to create new tools for drug discovery.

Life isn’t limited to the DNA or proteins found in nature.

In the May 15, 2014, edition of the journal Nature, Floyd Romesberg’s chemistry lab at San Diego’s Scripps Research Institute published a paper titled “A Semi-Synthetic Organism with an Expanded Genetic Alphabet.” Romesberg and his colleagues had created a bacterium incorporating chemical building blocks that, as far as anybody knows, have never been part of any earthly life form.

There had been previous claims to “creating life.” Genome pioneer Craig Venter led a team that manufactured a genome for a germ that causes pneumonia in cows, but their effort used the familiar chemical bases of DNA, known by the letters A, G, C, and T. Romesberg’s group, on the other hand, added two additional letters, dubbed X and Y. When the bacteria successfully replicated X and Y in succeeding generations, Romesberg’s lab could claim to have made the first living thing with an expanded genetic code.

“People would ask what the big deal is, and I said, ‘Imagine you had a language with only four letters,’” Romesberg says. “‘It would be clumsy and would really curtail the kinds of stories you could tell. So imagine two more letters. Now you could write more interesting stories.’”

New drugs are the most obvious story that could be told with the technology. A startup company called Synthorx, created by Romesberg and the venture fund Avalon Ventures, says it has exploited E. coli bacteria containing X and Y to help manufacture a protein, a step the company’s president and CEO Court Turner describes as “our baby unicorn.” The company didn’t identify the protein, except to say it is “well studied” and that they’d added a new function to it, a way for another drug to attach to the protein at a specific site.

The technology might also pave the way to new biotech drugs. Nearly all such drugs, proteins like insulin or the blood cell-booster erythropoietin, are made inside a bacterium or other cell. But synthetic DNA could vastly expand what drugs are possible. That is because a normal cell builds proteins from just 20 amino acids, stringing them together into long chains. Exactly which amino acid gets added next is specified by three-letter sequences of DNA, called codons.

Although the math gets complicated, with the addition of the new bases X (chemical name d5SICS) and Y (chemical name dNaM), Romesberg approximately tripled the number of possible codons, and theoretically increased to 172 the number of different amino acids a cell could build a protein from (see this explanatory graphic).

Synthorx scientists work on a system to produce proteins using partially synthetic DNA.

That’s important because scientists have invented thousands of artificial amino acids. It just hasn’t been very easy to make proteins from them. Unlike conventional drugs, where chemists exert exquisite control over the position of every atom, with proteins they mostly still need a living thing to do their manufacturing for them. “When you get to whole proteins, chemists really lose the ability. Protein molecules are too complex, too big,” says Peter Schultz, a Scripps biologist. (Romesberg trained in Schultz’s lab.)

Eventually, there could be bacteria producing entirely new proteins. “To make a billion-dollar business, yes, we need a protein,” says Romesberg. “The home run is the ability to produce therapeutic proteins with unnatural amino acids in them.”

Synthorx’s achievement falls a bit short of that. It made its first protein by breaking up its E. coli and using their unnatural genes to make a novel protein molecule in a test tube reaction. Turner thinks the system could be of interest to drug companies who could use it to generate ideas for new drugs. “You could make a million proteins with unnatural amino acids,” he says.

Synthetic organisms could lead to other types of products, including new vaccines. It might be possible, for instance, to make a tuberculosis bacterium with unnatural DNA in it. It would be a real, living germ. But without any raw material to copy its genes (that is, no external source of the chemicals X and Y) you could give it to a person without worrying that it would make them sick. “If it was TB, but also benign, that would be the perfect vaccine,” says Schultz.

Court Turner, left, the CEO of Synthorx, looks at the results of a synthetic biology experiment.

Synthetic life forms have implications far beyond new products. Romesberg and Schultz are part of a cadre of scientists who have been asking the basic question of whether life could have evolved in ways other than the one we are familiar with. “Will life on Mars have a fifth and sixth base?” Steven Benner, a synthetic biologist and a founder of the Foundation for Applied Molecular Evolution in Gainesville, Florida, asks. Benner, who works with NASA trying to find life on other planets, suggests that synthetic biology might also improve the ability to detect new earthly life forms. “Maybe they exist on earth, but we just don’t know what to look for,” he says. “It forces you to ask unscripted questions to challenge your fundamental core hypotheses.”

Synthorx isn’t the only startup looking to expand upon the life code for commercial reasons. Ambrx, another San Diego company, uses unnatural amino acids in partnership with major drug companies like Eli Lilly and Merck. And last January, Harvard University scientist George Church and his former student, Farren Isaacs, of Yale, held a press conference to announce a breakthrough of their own. Isaacs and Church described how, in separate experiments, they created what they called a “genomically reordered organism,” or GRO. They hadn’t changed the DNA letters, but they had hijacked a few codons to make them use artificial amino acids.

Church and Isaacs recently announced they had formed a Boston-based company, enEvolv, to supply such GROs for use by industry to, say, clean up oil spills or even make cheese. During a January phone conference with reporters, Church declared that “we are aiming at modifying plant and animal cells, and maybe plants and animals.”

A potential objection to the technology is already apparent: nobody knows quite what these novel forms of life would do if released into the wild. Romesberg’s E. coli depend upon an external source of X and Y to stay alive. Church likewise argues that his GROs are safe because they depend upon unnatural amino acids that are only supplied in the lab. Withhold these and the bacteria die.

This sort of “kill switch” is meant to assuage anyone who wonders what happens if the bacteria escape. But it isn’t foolproof. Both Romesberg and Church reported a tiny fraction of the bacteria managed to slip the genetic handcuffs via mutation. That means if they were released outside the lab, an artificial organism might somehow scavenge up a substitute chemical from the environment to replace the critical one fed to it in the labs. Or it might exchange genes with other organisms it runs into outside a lab dish. Such an event could allow modified germs to live and reproduce.

Schultz thinks there will be medical uses of synthetic organisms long before they are released into the environment to eat oil or make cheese. And once synthetic biology leads to a new drug or vaccine, he thinks, we’ll get used to the idea of inventing life for our own good. “One has to pick the most near-term applications of this technology to show what [it] can really do for the good of mankind,” Schultz says. “I think medicine is one area of pretty obvious applications.”

This original version of this article incorrectly said tuberculosis is caused by a virus. It is caused by a bacterium.

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