Scientists from the University of California San Diego and their colleagues in Australia have created bacteria that can detect the presence of tumor DNA in a living organism. This innovative achievement is an insight into the development of revolutionary biosensors with the potential to diagnose various infections, cancers and other medical conditions.
On August 11, 2023, Science reports significant progress. Until now, bacteria have been modified for various purposes related to diagnostics and therapy, but they could not specifically detect certain DNA sequences or mutations outside their own cells. The new system called “Cellular Assay for Targeted CRISPR-discriminated Horizontal gene transfer” or “CATCH” was developed to perform exactly this function.
“When we started this project four years ago, we weren’t even sure that using bacteria as a sensor for mammalian DNA was possible. The detection of gastrointestinal cancers and precancerous lesions represents an attractive clinical opportunity to apply this invention,” said lead scientist Jeff Hasty, a professor in the School of Biological Sciences and the Jacobs School of Engineering at UC San Diego.
According to the researchers, tumors release or disperse their DNA into the environment. Although there are many technologies capable of analyzing purified DNA in the laboratory, they cannot detect the DNA at the sites where it was released. In the approach called CATCH (Cellular Assay for Targeted CRISPR-discriminated Horizontal gene transfer), the specialists manipulated bacteria using CRISPR technology to examine DNA sequences freely present in the genome and compare these samples with specific cancer sequences already known .
“Many bacteria can take up DNA from their environment, an ability known as natural competence,” said Rob Cooper, co-first author of the study and a scientist at UC San Diego’s Institute for Synthetic Biology.
Hasty, Cooper and Australian physician Dan Worthley worked together to explore the concept of using natural competence in the context of bacteria in relation to colorectal cancer, which is the third leading cause of cancer death in the United States.
These researchers began to develop the idea of modifying the bacteria already existing in the colon to turn them into innovative biosensors. The goal was to integrate these biosensors inside the intestine to identify DNA released by colorectal tumors. Their efforts focused on the bacterium Acinetobacter baylyi, where Cooper identified the essential components for DNA uptake and the use of CRISPR technology for analysis.
“Knowing that cell-free DNA can be mobilized as a signal or input, we set out to engineer bacteria that respond to tumor DNA at the time and place of disease detection,” said Worthley, a gastroenterologist and cancer researcher at the Colonoscopy Clinic in Brisbane, Australia.
Through their collaboration with Australian researchers Susan Woods and Josephine Wright, the scientists developed, constructed and tested the bacteria Acinetobacter baylyi to act as sensors capable of identifying DNA sequences in the KRAS gene. This gene is mutated in a variety of cancers. The team programmed these bacteria using a specially designed CRISPR system to distinguish between mutant and normal (non-mutant) copies of the KRAS gene. Thus, only bacteria that captured the mutant forms of the KRAS gene, as found in precancerous and cancerous polyps, survived to transmit signals or react to the presence of disease.
The new research builds on previous ideas related to horizontal gene transfer, a method by which organisms can move genetic material between themselves in a way distinct from traditional genetic inheritance from parents to offspring. Although horizontal gene transfer is mostly recognized in the context of bacteria, researchers have successfully extended this concept, this time applying it from mammalian tumors and human cells to bacteria.
“It was incredible when I saw under the microscope the bacteria that had taken over the tumor DNA. Mice with tumors grew green bacterial colonies that acquired the ability to grow on antibiotic plates,” Wright said.
Currently, researchers are fine-tuning their approach to using bacterial biosensors by implementing new configurations and various types of bacteria, with the goal of identifying and treating both cancers and human infections.
“There is vast potential in modifying bacteria to prevent colorectal cancer, a condition in which the tumor is surrounded by a community of bacteria that could positively or negatively influence the course of the disease,” Woods explained.
Associate Professor Siddhartha Mukherjee of Columbia University, who was not involved in this study, indicated that in the future, “diseases will be treated and prevented with cells, not pills.”
“A living bacterium that can detect DNA in the gut is a tremendous opportunity to act as a sentinel to seek out and destroy gastrointestinal cancers, as well as many other cancers,” added the professor.
Hasty, who is associated with UC San Diego’s Department of Molecular Biology as well as the Shu Chien-Gene Lay Department of Bioengineering and the Institute for Synthetic Biology, indicated that while this new innovation requires additional development and refinement, the team of synthetic biology at UC San Diego continues to work to optimize the advanced strategy of this biosensor.
“There is a future where no one has to die from colorectal cancer. We hope this work will be useful to bioengineers, scientists and, in the future, clinicians in pursuit of this goal,” Worthley believes.
2023-08-21 08:23:14
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