A University of Waterloo team is reprogramming bacteria to invade and consume solid tumors from the inside out. Their synthetic biology approach could one day turn a common soil microbe into a highly targeted cancer treatment.
A team of researchers led by the University of Waterloo is turning a common soil bacterium into a potential cancer-fighting ally, engineering it to invade and literally eat tumors from the inside out.
The work, published in ACS Synthetic Biology, centers on Clostridium sporogenes, a bacterium that thrives only where there is no oxygen. That makes the core of a solid tumor, which is packed with dead cells and starved of oxygen, an ideal hiding place and food source.
“Bacteria spores enter the tumour, finding an environment where there are lots of nutrients and no oxygen, which this organism prefers, and so it starts eating those nutrients and growing in size,” Marc Aucoin, a chemical engineering professor at Waterloo, said in a news release. “So, we are now colonizing that central space, and the bacterium is essentially ridding the body of the tumour.”
For years, scientists have explored ways to use bacteria to target cancer, since microbes can naturally home in on hard-to-reach areas and grow where many drugs struggle to penetrate. But controlling where and when bacteria grow has been a major safety challenge, especially in oxygen-rich parts of the body such as the bloodstream and healthy tissues.
The Waterloo team’s approach tackles that problem head-on.
Clostridium sporogenes can only grow in environments with absolutely no oxygen, so it flourishes in the dead, oxygen-free center of a tumor. However, as the bacteria spread outward toward the tumor’s edge, they encounter low levels of oxygen and die off before they can finish the job.
To extend the bacteria’s reach just enough to attack more of the tumor, the researchers first added a gene from a related bacterium that can better tolerate oxygen. That genetic addition helps the engineered microbe survive longer near the outer regions of a tumor, where oxygen levels are higher but still lower than in normal tissue.
Simply making the bacteria more oxygen-tolerant, though, would raise the risk that they might grow in places they are not supposed to, such as healthy organs. To keep that from happening, the team turned to a natural bacterial communication process called quorum sensing.
Quorum sensing relies on chemical signals that bacteria release into their surroundings. When only a few bacteria are present, the signal is weak. As the population grows, the signal builds up. Many bacterial species use this system to coordinate group behaviors, such as forming biofilms or producing toxins, only when there are enough cells to make the effort worthwhile.
The Waterloo researchers harnessed this phenomenon as a genetic timing switch. They designed the engineered Clostridium so that the oxygen-resistant gene turns on only when many bacteria have already grown inside a tumor and the quorum sensing signal reaches a certain threshold. That way, the bacteria gain extra oxygen tolerance only after they have safely colonized the tumor’s interior, reducing the chance they will activate in oxygen-rich parts of the body.
In one study, researchers showed that Clostridium sporogenes can be modified to tolerate oxygen. In a follow-up study, the team tested their quorum sensing system by programming the bacteria to produce a green fluorescent protein when the signal turned on. The glowing protein served as a visible readout that the genetic circuit was working as intended.
“Using synthetic biology, we built something like an electrical circuit, but instead of wires we used pieces of DNA,” added Brian Ingalls, a professor of applied mathematics at Waterloo. “Each piece has its job. When assembled correctly, they form a system that works in a predictable way.”
That synthetic biology framework allows the researchers to treat genes and regulatory elements like modular components, combining them to create finely tuned behaviors in living cells. In this case, the behavior is a bacteria-based system that can sense its environment, communicate internally and respond at the right moment.
The next step is to bring all the pieces together. The team now plans to combine the oxygen-resistant gene and the quorum-sensing timing mechanism in a single strain of Clostridium sporogenes and test it on tumors in pre-clinical trials. Those tests, typically done in laboratory models before any human studies, will help determine how well the engineered bacteria can shrink tumors and how safely they behave in a living organism.
The project grew out of the work of doctoral student Bahram Zargar, who was supervised by Ingalls and Pu Chen, a retired professor of chemical engineering at Waterloo. It has since expanded into a broader collaboration that reflects Waterloo’s emphasis on interdisciplinary health innovation, bringing together engineers, mathematicians and life scientists to design technology-enabled solutions that can move from lab bench to bedside.
Waterloo researchers partnered with the Center for Research on Environmental Microbiology (CREM Co Labs), a Toronto company co-founded by Zargar. The group also includes Sara Sadr, a former Waterloo doctoral student who played a leading role in the research.
While this bacteria-based therapy is still in the early stages, it points to a future in which living, programmable microbes could complement surgery, chemotherapy and radiation. Because bacteria can be engineered to seek out specific environments and carry custom genetic circuits, they may one day deliver drugs directly inside tumors, activate immune responses or, as in this work, consume cancer tissue itself.
If the upcoming pre-clinical trials are successful, the engineered Clostridium sporogenes could move closer to becoming a new kind of precision cancer treatment — one that turns a once-feared microbe into a carefully controlled tool for healing.
Source: University of Waterloo