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To keep old trains running, operators had to keep a firm grip on a dead man’s switch. If the operator became incapacitated or, well, dead, his hand would loosen, the brakes would engage, and the train wouldn’t turn into a runaway—no active intervention required. That was 20th century engineering.
In the 21st century, where scientists are as likely to engineer microbes as locomotives, “Deadman” is a kill switch created by MIT biologists to prevent engineered microbes from running out of control in the wild. Deadman and another microbial kill switch called Passcode are the newest of the increasingly sophisticated ways biologists hope to control microbes they’re building to cure diseases or clean up oil and toxic spills. Without those controls, the bugs will never leave the lab. “The biggest enemy we have is uncertainty,” says Karmella Haynes, a synthetic biologist at Arizona State University. “We don’t have a practical way to prove tomorrow that GMOs are absolutely dangerous or absolutely safe. The appropriate response to uncertainty is, let’s arm ourselves with an engineering solution.”
The simplest kill switches simply deleted a gene that made some molecule critical to the life of the organism. Without scientists feeding that molecule to the microbe, it died. The risk was that microbes in the wild might find an unexpected source for it.
But earlier this year, scientists at Harvard and Yale described kill switches that force the engineered microbe to rely on lab-made molecules that do not exist in nature. “This year could be characterized as the year of the kill switch,” says James Collins, an MIT synthetic biologist who led the most recent study, published in Nature Chemical Biology.
Collins and his colleagues designed Deadman so that any microbe with it would need a small molecule—a drug, if you will—to repress a genetic circuit for suicide. No small molecule, and the bug goes kaput. Passcode, though, is even cooler. The microbe relies on some combination of three small molecules. It might need, for example, molecules A and B, but the complete absence of C. And you can change the combination. Hence: Passcode.
“That will allow you to really scale up the different combinations for small molecules—or cocktails, if you will,” says Farren Isaacs, a molecular biologist at Yale who was not involved in the research. The fact that Passcode is easily changed will make companies happy for another reason: Keeping engineered microbes secret is hard. Anyone who gets ahold of your proprietary microbe could sequence its genome and copy it. With Passcode, the real secret sauce is the cocktail of small molecules that keep your microbe alive.
In addition to his job at MIT, Collins is a cofounder and scientific advisor to Synlogic, a Cambridge-based company that wants to engineer microbes that can attack pathogens such as cholera. But you don’t want the engineered microbes to stick around forever in the body, and you especially don’t want them to stick around if the patient has an unexpected bad reaction. Collins’ kill switch technology seems to fix all that.
So far, Collins’ paper shows only that Passcode works in E. coli, but based on past experiments, it’s likely to work in other common bacteria as well. A potential roadblock, though, is that bacteria are wily: After four days, subsequent generations became adapted to escape the Deadman and Passcode kill switches. Collins says that a commercial kill switch would probably combine several different strategies and toxins for extra layers of security.
As paradoxical as it might sound, synthetic biology companies have good reason to want to kill their products under the right circumstances: protect the public from possible dangers and protect it from competitors. That’s two for the price of one technology, even better than the dead man’s switch of trains.
