Researchers at the University of California San Diego and the Massachusetts Institute of Technology (MIT) have come up with a strategy for using synthetic biology in therapeutics. The approach enables continual production and release of drugs at disease sites in mice while simultaneously limiting the size, over time, of the populations of bacteria engineered to produce the drugs. The findings are published in the July 20 online issue of Nature.
UC San Diego researchers led by Jeff Hasty, a professor of bioengineering and biology, engineered a clinically relevant bacterium to produce cancer drugs and then self-destruct and release the drugs at the site of tumors. The team then transferred the bacterial therapy to their MIT collaborators for testing in an animal model of colorectal metastasis. The design of the therapy represents a culmination of four previous Nature papers from the UC San Diego group that describe the systematic development of engineered genetic clocks and synchronization. Over the years, the researchers have employed a broad approach that spans the scales of synthetic biology,
The new study offers a therapeutic approach that minimizes damage to surrounding cells.
“In synthetic biology, one goal of therapeutics is to target disease sites and minimize damage,” said UC San Diego bioengineering and biology professor Jeff Hasty. He wondered if a genetic “kill” circuit could be engineered to control a population of bacteria in vivo, thus minimizing their growth. “We also wanted to deliver a significant therapeutic payload to the disease site.”
In order to achieve this, he and his team synchronized the bacteria to release bursts of known cancer drugs when a bacterial colony self-destructs within the tumor environment. The use of bacteria to deliver cancer drugs in vivo is enticing because conventional chemotherapy doesn’t always reach the inner regions of a tumor, but bacteria can colonize there. Importantly, the researchers observed that the combination of chemotherapy and the gene products produced by the bacterial circuit consistently reduced tumor size.
“The new work by Jeff Hasty and team is a brilliant demonstration of how theory in synthetic biology can lead to clinically meaningful advances,” said Jim Collins, a professor at MIT who is known as a founder of the field of synthetic biology. “Over a decade ago during the early days of the field, Jeff developed a theoretical framework for synchronizing cellular processes across a community of cells. Now his team has shown experimentally how one can harness such effects to create a novel, clinically viable therapeutic approach.”
Limiting the bacterial population
In order to observe the bacterial population dynamics, the researchers designed custom microfluidic devices for careful testing before investigations in animal disease models. Consistent with the engineering design, they observed cycling of the bacterial population that successfully limits overall growth while simultaneously enabling production and release of encoded cargo. When the bacteria were equipped with a gene that drives production of a therapeutic, the synchronized lysis of the bacterial colony was shown to kill human cancer cells. It is the first engineered gene circuit in synthetic biology to achieve these objectives.