In the 1890s, a surgeon named William B. Coley injected cancer patients with dead Streptococcus bacteria in hopes of coaxing the people’s immune systems to attack their tumors. Although these so-called Coley’s toxins had some success, doctors largely ignored them in favor of radiation and other therapies.
But the idea of enlisting bacteria to fight cancer lives on. In recent years, researchers have tried to exploit bacteria’s affinity for tumors’ low-oxygen and immune-cell-free environments, engineering the microbes to attack the malignant cells.
Now a team of synthetic biologists has designed bacteria that grow and die in programmed cycles, allowing for a controlled release of anticancer molecules and preventing unchecked bacterial growth (Nature 2016, DOI: 10.1038/nature18930).
“This is a fascinating paper that blows me away,” says Martin Fussenegger, a bioengineer at the Swiss Federal Institute of Technology, Zurich, who was not involved in the work. “It describes an unconventional, completely novel, yet highly promising strategy to use synchronized bacteria that invade and kill cancer cells by rhythmic ‘explosions.’ ”
If bacterial anticancer therapies ever make it to the clinic, such synchronized explosions would help avert harmful uncontrolled growth of bacteria, Fussenegger says.
To program Salmonella bacteria to execute these cycles, the researchers, led by Jeff Hasty at the University of California, San Diego, designed a genetic circuit with two basic functions. First, the circuit tells the microbes to produce an anticancer molecule as they grow. “Then we program them to commit suicide to deliver the drug,” Hasty says.
That second step involves quorum sensing, a process in which bacteria communicate via molecules to coordinate their actions, such as forming biofilms. In this case, the engineered circuit instructs the bacteria to make a small molecule called N-acyl-homoserine lactone. Once the bacteria reach a certain threshold population, the molecules activate quorum-sensing pathways in the genetic circuit and trigger the cells to lyse, or break open, spilling their anticancer cargo.
About 10% of the bacteria survive the resulting wave of destruction and go on to restart the cycle. In cultures, each cycle lasts about four to five hours and the bacteria keep cycling for 15 to 18 days, Hasty says. “There is a strong selective pressure for the bacteria to beat this cycle, and eventually they do,” he says.
The researchers tested three strains of these bacterial suicide squads in mice with metastasized liver cancer. Each strain synthesized one of three anticancer payloads: a molecule that lyses mammalian cells, a cytokine that initiates an immune response against the tumor, or a protein that triggers cancer cells to kill themselves.
After 12 days, tumors in mice receiving the engineered bacteria were about one-quarter the size of those in mice treated with normal Salmonella. And when the researchers treated mice with the cycling Salmonella and the chemotherapy drug 5-fluorouracil, the mice survived 50% longer than animals receiving either the drug alone or just the bacteria.
Hasty considers this study a proof of principle and cautions that before any bacteria therapy can be tested in people, researchers must understand how the immune system will respond to the engineered microbes.
Still, “it’s forward-thinking and novel and worth exploring more,” says Shibin Zhou of Johns Hopkins Medicine. Zhou also wonders if the bacteria’s controlled release of therapeutic payloads could be exploited to treat chronic diseases such as hypertension or diabetes.