Microbes will make a diagnosis

Kirill Stasevich, Science and Life 

To find out what is wrong with our health, we measure the temperature, measure the pressure, take tests. The more information the doctor gets, the better for the patient, but it's impossible to walk with a thermometer all the time or donate blood every minute. In addition, even the most modern diagnostic methods do not give a complete picture of what is happening – some molecules that could indicate unhealthiness remain unnoticed either because of a small concentration, or because they managed to appear and disappear between the next samples for analysis.

Therefore, now more and more attempts are being made to develop such a biosensor that could, roughly speaking, be stuck on a person and take readings continuously, 24/7. Of course, such a sensor should be small so as not to cause any inconvenience, and at the same time sensitive enough. First of all, a variety of microelectronics comes to mind here, but researchers from the Massachusetts Institute of Technology have proposed a more radical and ingenious solution – they tried to turn an intestinal bacterium into such a biosensor. 

Oddly enough, the famous E. coli is not quite suitable here: there are not as many of it in the intestine as there are other types of bacteria. The sensor should serve as a microbe that all people have stably and in sufficient quantity. A group of Bacteroides belongs to such universal bacteria; one of them was chosen, called Bacteroides thetaiotaomicron (in the picture from the website enews.membs.org – VM), which was equipped with the ability to remember changes in the environment with the help of molecular genetic manipulations. It should be said here that this work is a continuation of another one that we wrote about last year, when the same research group led by Timothy Lu managed to turn bacterial DNA into a kind of hard drive.

The genetically modified E. coli received a signal from the external environment, which was picked up by specially tuned proteins that triggered the synthesis of a DNA fragment.

A special enzyme, with which the bacterium was provided ahead of time, embedded the newly synthesized DNA into the genome, and in a strictly defined place set by the researchers themselves. It was possible to read this information by sequencing the genome of the bacterium. Or, if a piece of DNA was embedded in some important gene, the bacterium itself let it know that it remembered something - simply because the gene with the insertion stopped working for it. For example, if the embedding occurred in a gene that provides resistance to an antibiotic, then the E. coli became sensitive to it and began to grow and multiply poorly. 

Then, in an article in Science, the authors wrote that they managed to make bacteria remember the lighting around them, as well as the presence of two molecules in the medium, a lactose derivative and a modified antibiotic. It should be emphasized that neither the light nor the substances used by themselves could have made any modifications to the Escherichia coli DNA – they simply did not have mutagenic power. However, with the help of a molecular system embedded in a bacterial cell, even such "unobtrusive" signals from the outside were able to leave their mark in DNA. Moreover, by measuring the number of cells in the culture that had the corresponding changes, it was possible to conclude what intensity the signal was and how long it lasted. 

The medical prospects of such a bacterium are obvious: program it to sense inflammatory molecules, or some kind of toxins, and you have a diagnostic biosensor in your hands. But for this, firstly, a universal bacterium is needed - as we said, B.thetaiotaomicron was chosen with it. Secondly, you need to make sure that the new candidate will tolerate the necessary genetic operations well and will work as it should. 

Obviously, the main thing here is sensitivity: the sensor should feel the smallest possible changes in the measured parameters. In an article in Cell Systems, the authors write that they have managed to repeatedly, hundreds and thousands of times increase the sensitivity of B. thetaiotaomicron to certain signals, as well as make it more resistant to antimicrobial protective agents that can work in the intestine (after all, an important quality of a microbial sensor is its more or less constant amount). Four varieties of modified bacteria sensed four different signals, and, most importantly, they worked in the intestines of mice. Sensing a change in the host's biochemistry, the bacteria embedded a fragment in their DNA, which served as a sign that something had happened in the intestine - by such inserts it was possible to judge what kind of changes had happened there and how strong they were. 

This is the main point of the work: that a sensory system can be introduced into a human bacterium, and that such a bacterium will work in the body. True, so far the mouse remains such an organism, but in the near future, I think, the method will be tested on humans – although the authors themselves say that it will not come to clinical trials soon. 

They want to make the bacterium itself feel not one, but several signals, and ideally it will not only diagnose, but also synthesize some medicine, so that a real diagnostic and therapeutic module can be planted in the body. It sounds fantastic, but science is the science to make a fairy tale come true. 

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13.07.2015