Engineering Clostridium sporogenes to fight cancer

Image: Clostridium sporogenes. Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #15884 (public domain).
 

Researchers are engineering bacteria to invade tumors and consume them from the inside. Because tumor cores lack oxygen, they’re the perfect breeding ground for these microbes. The team added a genetic tweak that helps the bacteria survive longer near oxygen-exposed edges — but only once enough of them are present to trigger the change. It’s a carefully programmed biological attack that could one day offer a new way to destroy cancer.

The engineering of living cells and microbes is ushering in a new era of cancer therapy.

Scientists at the University of Waterloo (Canada) are working on a new cancer treatment that uses specially engineered bacteria to consume tumors from the inside. The strategy relies on microbes that naturally thrive in oxygen-free environments, which makes the interior of many solid tumors an ideal target.

Clostridium sporogenes is a species of Gram-positive bacteria that belongs to the genus Clostridium. Like other strains of Clostridium, it is an anaerobic, rod-shaped bacterium that produces oval, subterminal endospores and is commonly found in soil. The organism is being investigated for its cancer cell killing properties. 

Bacteria spores enter the tumor, 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.

At the centre of this approach is Clostridium sporogenes, a bacterium commonly found in soil. It can survive only in places that contain absolutely no oxygen. The inner core of solid tumors is made up of dead cells and lacks oxygen, creating the perfect conditions for this microbe to multiply and spread.

Difficult challenge

There is a challenge, however. As the bacteria expand outward and reach areas of the tumor exposed to small amounts of oxygen, they begin to die off before fully eliminating the cancer.

To address this limitation, the team inserted a gene from a related bacterium that is more tolerant of oxygen. This modification allows the engineered microbes to survive longer near the tumor's outer regions.

The researchers also needed a way to control when that oxygen-tolerance feature turns on. Activating it too early could allow the bacteria to grow in oxygen-rich areas such as the bloodstream, which would be unsafe. To prevent that, they used a natural bacterial communication process called quorum sensing.

Quorum sensing relies on chemical signals released by bacteria. As their numbers increase, the signal grows stronger. Only after enough bacteria have accumulated inside a tumor does the signal reach a level that switches on the oxygen-resistant gene. This timing ensures the bacteria activate their survival mechanism only when it is needed.

Synthetic Biology and DNA Circuits

In an earlier study, the team showed that Clostridium sporogenes could be genetically altered to better withstand oxygen. In a follow-up experiment, they tested their quorum sensing design by programming bacteria to produce a green fluorescent protein, allowing them to confirm that the system activated at the intended moment.

The next step is to combine both the oxygen-tolerance gene and the quorum-sensing control system into a single bacterium and evaluate it against tumors in pre-clinical trials.

Research paper 

The research appears in the journal ACS Synthetic Biology, titled " Construction and Functional Characterization of a Heterologous Quorum Sensing Circuit in Clostridium sporogenes."

 

 

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)