Intelligent Bacteria For Detecting Disease

Intelligent Bacteria For Detecting Disease
This image shows the principle of the use of modified bacteria
for medical diagnosis. (Credit: J. Bonnet/ Inserm.)
Researchers have transformed bacteria into "secret agents" that can give warning of a disease based solely on the presence of characteristic molecules in the urine or blood. To perform this feat, the researchers inserted the equivalent of a computer programme into the DNA of the bacterial cells. The bacteria thus programmed detect the abnormal presence of glucose in the urine of diabetic patients. This work, published in the journal Science Translational Medicine, is the first step in the use of programmable cells for medical diagnosis.
 
Bacteria have a bad reputation, and are often considered to be our enemies, causing many diseases such as tuberculosis or cholera. However, they can also be allies, as witnessed by the growing numbers of research studies on our bacterial flora, or microbiota, which plays a key role in the working of the body. Since the advent of biotechnology, researchers have modified bacteria to produce therapeutic drugs or antibiotics. In this novel study, they have actually become a diagnostic tool.
 
Medical diagnosis is a major challenge for the early detection and subsequent monitoring of diseases. "In vitro" diagnosis is based on the presence in physiological fluids (blood and urine, for example) of molecules characteristic for a particular disease. Because of its noninvasiveness and ease of use, in vitro diagnosis is of great interest. However, in vitro tests are sometimes complex, and require sophisticated technologies that are often available only in hospitals.
 
This is where biological systems come into play. Living cells are real nano-machines that can detect and process many signals and respond to them. They are therefore obvious candidates for the development of powerful new diagnostic tests. However, they have to be provided with the appropriate "programme" for them to successfully accomplish the required tasks.
 
To do this, the researchers had the idea of using concepts from synthetic biology derived from electronics to construct genetic systems making it possible to "programme" living cells like a computer.
 
The transcriptor: the cornerstone of genetic programming

The transistor is the central component of modern electronic systems. It acts both as a switch and as a signal amplifier. In informatics, by combining several transistors, it is possible to construct "logic gates," i.e. systems that respond to different signal combinations according to a predetermined logic. For example, a dual input "AND" logic gate will produce a signal only if two input signals are present. All calculations completed by the electronic instruments we use every day, such as smartphones, rely on the use of transistors and logic gates.
 
The researchers invented a genetic transistor, the transcriptor. The insertion of one or more transcriptors into bacteria transforms them into microscopic calculators. The electrical signals used in electronics are replaced by molecular signals that control gene expression. It is thus now possible to implant simple genetic "programmes" into living cells in response to different combinations of molecules.
 
In this new work, the researchers applied this new technology to the detection of disease signals in clinical samples. Clinical samples are complex environments, in which it is difficult to detect signals. The authors used the transcriptor's amplification abilities to detect disease markers, even if present in very small amounts. They also succeeded in storing the results of the test in the bacterial DNA for several months.
 
The cells thus acquire the ability to perform different functions based on the presence of several markers, opening the way to more accurate diagnostic tests that rely on detection of molecular "signatures" using different markers.
 
As a proof of concept, the authors connected the genetic transistor to a bacterial system that responds to glucose, and detected the abnormal presence of glucose in the urine of diabetic patients. In the future, this work might also be applied to engineering the microbial flora in order to treat various diseases, especially intestinal diseases.
 
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