Making a Safer Microbe

Laboratories can be designed to prevent the escape of potentially dangerous organisms. But there is always the chance that something or someone will fail--and that a few virulent bugs will slip through the safeguards to multiply in the outside world. Faced with this problem at the Asilomar conference. Geneticist Roy Curtiss III proposed an ingenious solution: Why not convert the standard genetic research organism, a strain of the E. coli bacterium, into a seriously weakened mutant variety that would quickly self-destruct if it escaped the laboratory? Curtiss volunteered to engineer the new bug, and his colleagues agreed to hold off on many of their recombinant DNA experiments until they could be supplied with it.

Returning to his laboratory at the University of Alabama Medical Center in Birmingham, Curtiss quickly hit on a way to keep E. coli under control. The microbes must be able to manufacture a protective membrane; without such an outer coat they would swell and burst during normal growth. To keep them from manufacturing a complete coat, Curtiss created an E. coli with a defect in a gene that makes diaminopimelic acid (DAP), an important ingredient of the membrane. The defect made the bugs dependent for their survival upon DAP supplied by scientists.

Unfortunately, the defect proved insufficient. Some of the descendants of the new microbe mutated naturally and began manufacturing their own DAP. So Curtiss went a step further and deleted another gene involved in DAP production. These newly designed bugs remained DAPless. But more frustration awaited Curtiss: the mutants managed to survive and multiply even without DAP. How? Dennis Pereira, a graduate student who worked with Curtiss on the project, discovered that they were producing a sticky substance called colanic acid that held them together in the absence of their normal outer coat. By manipulating still another of the microbe's genes, Curtiss and Pereira deprived the bug of its ability to make colanic acid. That change provided an unexpected dividend; it also made the already sickly microbe extremely sensitive to ultraviolet light. Any exposure to sunlight would kill it.

After a few more genetic refinements, Curtiss had developed what seemed to be a safe research bacterium. But a major problem remained. Even dying E. coli bacteria can conjugate with healthy ones, transferring their possibly dangerous genetic material in the process. Thus an escaped and dying bug might still pose a danger. Again Curtiss worked his genetic magic, this time taking away from the microbe the ability to produce the chemical thymine, which is a component of the bug's own DNA. Without thymine supplied in the lab, the E. coli could not pass its genes on to healthy outsiders.

Curtiss is still working to develop a more perfect--or defective--microbe for recombinant DNA research. But for the time being, genetic engineers have available a tailor-made microbe that cannot survive outside the laboratory and that cannot colonize or even live in the human intestinal tract. Nor is this the only indication that the bug would make a poor pathogen, or disease organism. Curtiss' handmade microbe will not survive in human serum--including that of cancer patients. It is also easily destroyed by common household detergents.

Curtiss named his transmuted bug E. coli x1776--in honor of the Bicentennial. In November 1976, the NIH certified it for use in genetic engineering experiments, removing one of the major obstacles to resuming recombinant DNA research.

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