A clock made of genetically modified bacteria
Artificial biological clock counted down the first timeArtificially created genetic clocks, these microscopic "mechanisms", having essentially the same standard set of functions, can serve, for example, as sensors and help solve many problems of modern medicine, chemical and food industries.
Moreover, biological clocks do not even need any additional equipment, because their readings are light.
Scientists from the University of California at San Diego (UCSD) were the first in the world to create a stable, fast, genetically programmable biological clock. They count the time in a very unusual way: at certain intervals, the luminosity of fluorescent proteins inside the cells of Escherichia coli bacteria increases significantly (see how it looks on the video).
Biologists used a three-step approach for these purposes. First, the researchers built several computational models for a specific system (in this case, for a genetic clock), then based on the models they determined the design criteria and, finally, created genetic chains and checked their operability.
Apparently, the scientists meant that they first calculated what an E. coli colony should be, which could be called a "genetic clock". Then they figured out in their minds and, of course, on paper what this colony needed in order to flicker strictly according to schedule, provided the cells with everything they needed and checked whether what they saw corresponded to the model built at the very beginning.
"Instead of making countless adjustments and trying to figure out what is needed, we decided to first build a model, create a colony, and then in the process determine what is wrong," explains one of the researchers, graduate student Scott Cookson, in a university press release.
It cannot be said that scientists came to such a seemingly logical decision out of the blue. Team leader Jeff Hasty has been working on creating a more or less fully functioning genetic clock for the past eight years.
And only recently, Jeff and his colleagues in their Biodynamics Lab were able to create a very precise micro-jet system that controls the conditions in which E. coli multiplied. She helped biologists to determine exactly what changes in the state of the environment and how they affected the frequency of flickering.
The figure shows the dependence of the oscillation period (vertical scale, in minutes) on various factors. IPTG is an isopropylthiogalactoside that makes E. coli genes work in a certain way; G is the period of cell division, arabinose is a carbon source for bacteria (illustration by UC San Diego Jacobs School of Engineering).
The frequency of colony flickering in a test tube depends on many parameters: temperature, energy intake and other environmental factors. This leads to a logical conclusion – the new invention may well serve as a natural biological sensor that tells about the state of the surrounding space by blinking (practically Morse Code!).
Bioengineers provided data on the study in an article published in the journal Nature.
"We finally realized that the key aspect of the system was a small delay in the negative feedback loop in the built genetic network," says Hastie.
The diagram shows the circuit of the oscillator with double feedback, which provided such an important breakthrough in synthetic biology.
Let's try to explain: the flicker is caused by a two-minute delay between the synthesis of matrix RNA and functional proteins. Above the negative (virtually) there is a positive feedback loop, which makes the artificial clock more accurate and stable in time. Of course, the processes regulating the circadian rhythms of higher organisms are much more complicated. Nevertheless, scientists believe that the simplified scheme they created can be considered an evolutionary prototype of the modern biological clock of animals.
More and more studies indicate that the functions of genes fluctuate in natural conditions.
"Within individual cells, the activity of many genes increases and decreases," says Hastie. And after the conducted research (construction of simple circuits within which the functions of genes oscillate) he is no longer surprised that the whole genome is able to enhance or "suspend" its work in the same way.
Thus, this study closely linked synthetic biology and genetics. Observing the work of the network allows you to understand the basics of gene regulation.
"The assembly of genes into artificial chains, the behavior of which we can predict, significantly adds to the scientific world of knowledge about the fundamental principles of cell work," explains one of the experimenters James Anderson (James Anderson).
Of course, it is impossible to simulate all the nuances in the laboratory, but after thinking carefully, you can come to the conclusion – what needs to be taken into account and what not, concludes Hastie.
At the next stage of the work, biologists will try to make all E. coli located inside the test tube glow at the same time.
Jeff says about the future of such experiments and synthetic biology in general: "Sooner or later, gene therapy will outlast itself, researchers will learn how to manage gene sequences and build DNA for certain needs. The next goal will be to be able to read the cell states by sensors – only then will scientists be able to act in accordance with the data obtained. We strive to ensure that an artificially constructed chain of logical decisions inside DNA helps us learn more about the cell. But to do this, we need to conduct many more fundamental studies on the work of genes, which is what we are doing now."
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26.11.2008