Imagine a bacterium that, when injected into the bloodstream, would travel to the site of a tumor, insert itself into the cancer cell, and then produce a cancer-killing compound. That’s exactly what scientists at the University of California, Berkeley (UCB) and University of California, San Francisco (UCSF) have set out to do.
Traditional cancer therapies are limited for two key reasons: little of the drug actually reaches the tumor and the drug is toxic to both cancerous and healthy tissues. Bacteria, however, have the potential to precisely target cells. “In a way, bacteria are the ultimate in smart drugs,” says George Church, a geneticist at Harvard Medical School in Boston (he was not involved in the current work, but will collaborate on the project in the future). “It’s hard to pack a lot of intelligence into a small molecule or protein; but bacteria can have sensors and actuators and can drill into a cell, like a submarine.”
To build a cancer-killing bacterium, biologists must create organisms that can perform a series of complicated functions – namely, when in the bloodstream, they have to sense and respond to the tumor environment. Once inside the tumor, the bacteria must infiltrate the cancer cell, and then – and only then – start producing a tumor-killing toxin. The researchers plan to engineer such super-organisms by co-opting parts from different types of bacteria and inserting them into Escherichia coli, a bacterium commonly used in research.
Tumor tissue has unique characteristics, including lower oxygen and higher lactic acid concentrations than surrounding tissue. To create a bacterium that can sense a tumor, Christopher Anderson, a postdoctoral researcher at UCB and UCSF, and colleagues took an oxygen sensor from E. coli and linked it to a special protein, called invasin, from another type of bacteria, which allows the organism to invade cancer cells. In a paper published earlier this year in the Journal of Molecular Biology, the researchers showed in a test tube that the engineered bacterium selectively invades tumor cells.
Anderson and colleagues are now working on making the system even more specific. To ensure that the bacteria invade only tumor cells, they will create a genetic mechanism that allows the invasin protein to be expressed only when two conditions are met, such as when both the oxygen and lactic acid concentrations are at a certain level. Essentially, it’s a genetic version of what’s known in engineering terms as an AND gate – a regulatory circuit that’s turned on only if two conditions are met.
“By using multiple cues, we can garner a great deal of specificity,” says Adam Arkin, a bioengineer at UCB and the Lawrence Berkeley National Laboratory, a TR100 recipient in 1999, and one of the senior scientists on the project. “After the bacteria sense the cues, they turn on the rest of the apparatus to do the job.”