We most often think of bacteria as tiny imperceptible organisms that often cause us to become irritatingly sick or as the origin of terrible disease epidemics. At best, some may view microbes as quasi-helpful when they are packaged in the form of probiotic food or supplement. What if, however, we were able to use bacterial species as a diagnostic tool to detect disease?
To that end, researchers from the French Institute of Health and Research and the French National Centre for Scientific Research (CNRS) in Montpellier believe they have assembled the appropriate synthetic biological systems within bacterial hosts to detect disease biomarkers.
The findings from this study were published recently in Science Translational Medicine through an article entitled “Detection of pathological biomarkers in human clinical samples via amplifying genetic switches and logic gates.”
The investigators had the idea of using concepts from synthetic biology that utilized electronics in order to construct genetic systems, making it possible to program living cells like a computer.
“We report that bacterial biosensors with genetically encoded digital amplifying genetic switches can detect clinically relevant biomarkers in human urine and serum,” the authors explained. “These bactosensors perform signal digitization and amplification, multiplexed signal processing with the use of Boolean logic gates, and data storage.”
Using the transistor as a model, which can act as both a switch and as a signal amplifier, the researchers quickly realized that they could construct logic gates within microorganisms. Logic gates respond to signal combinations according to a predetermined judgment, for example a dual input “AND” logic gate will produce a signal only if two input signals are present.
The CNRS teams inserted genetic transistors, or transcriptors, into live bacteria. Transcriptors are transistor-like devices composed of DNA and RNA rather than a semiconducting material such as silicon. Insertion of one or more transcriptors into bacteria transforms them into microscopic calculators, where the electrical signals used in electronics are replaced by molecular signals that control gene expression—allowing for the implantation of simple genetic programs into living cells in response to different combinations of molecules.
“We have standardized our method, and confirmed the robustness of our synthetic bacterial systems in clinical sample,” stated Alexis Courbet, graduate student at CNRS and lead author on the current study. “We have also developed a rapid technique for connecting the transcriptor to new detection systems. All this should make it easier to reuse our system.”
The researchers were able to exploit the transcriptor's amplification abilities to detect disease markers, even when present in minuscule amounts. Moreover, they also succeeded in storing the results of the tests in the bacterial DNA for several months. Additionally, the investigators connected the transcriptor to a bacterial system that responds to glucose and were able to detect slight elevations of glucose within the urine of diabetic patients.
“We have deposited the genetic components used in this work in the public domain to allow their unrestricted reuse by other public or private researchers,” says Jérôme Bonnet, Ph.D., research investigator at Montpellier's Centre for Structural Biochemistry (CBS) and lead author on the current study. “Our work is presently focused on the engineering of artificial genetic systems that can be modified on demand to detect different molecular disease markers.”