Another step forward has just been taken in the area of synthetic biology. Research teams from Inserm, CNRS (French National Centre for Scientific Research), Montpellier Regional University Hospital and Stanford University, 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. The team state that this is the first step in the use of programmable cells for medical diagnosis. The study is published in the journal Science Translational Medicine.
The team note that bacteria have a bad reputation, and are often considered to be the human race’s enemies, causing many diseases such as tuberculosis or cholera. However, state the team, 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.
The researchers explain that 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, previous studies show that 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 in the current study. The team go on to explain that 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 group 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 team explain that 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. All calculations completed by the electronic instruments used every day, such as smartphones, rely on the use of transistors and logic gates.
In earlier studies the team invented a genetic transistor, the transcriptor. The team did this by inserting of one or more transcriptors into bacteria to transform 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 using this method.
The current study 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 team 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 data findings showed that 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.
The researchers have now standardised their method and confirmed the robustness of their synthetic bacterial systems in clinical samples. They have also developed a rapid technique for connecting the transcriptor to new detection systems, making it easier to reuse their system. As a proof of concept, the team 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.
The team state that their work is presently focused on the engineering of artificial genetic systems that can be modified on demand to detect different molecular disease markers. In future, this work might also be applied to engineering the microbial flora in order to treat various diseases, especially intestinal diseases.
They have also deposited the genetic components used in this work in the public domain to allow their unrestricted reuse by other public or private researchers.