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- Labor in the colony: victory over the "egoism" of bacteria will help create new medicines
Labor in the colony: victory over the "egoism" of bacteria will help create new medicines
Russian scientists have developed a system that allows them to control the production of the necessary proteins in individual bacterial cells and increase the efficiency of the entire population. Technology helps to overcome "cellular egoism", when some microorganisms actively produce protein, while others hardly work under the same conditions. This heterogeneity reduces product yield and makes it difficult to scale production. The development may find application in synthetic biology and in the future will allow the creation of new drugs and biologically active additives. However, so far the results have been obtained only in laboratory conditions, and additional research will be required to move to industrial volumes, experts told Izvestia.
What is the "cellular egoism" of bacteria?
MIPT has developed an innovative system for controlling gene expression in bacteria, which makes it possible to control the production of target proteins at the level of individual cells. The creation of populations of microorganisms with a given intensity of protein synthesis opens up new possibilities for synthetic biology and industrial fermentation.
Bacteria are widely used as biological factories for the production of proteins, nucleic acids, organic compounds and other substances, the scientists said. However, the effectiveness of such processes is limited by the heterogeneity of the population. Researchers at the MIPT Laboratory of Molecular Genetics have proposed a solution to one of the problems of biotechnology — the so-called cellular egoism, when under the same conditions some bacteria actively produce the target protein, while others practically do not participate in synthesis.
"To force a bacterium to synthesize the necessary protein, engineers carry out genetic modification: they deliver instructions to cells in the form of DNA vector molecules containing genes that allow them to control the synthesis process," Sergey Bazhenov, senior researcher at the Laboratory of Molecular Genetics at MIPT, told Izvestia.
At the same time, different DNA vectors differ in their ability to regulate and maintain a given level of protein production. When researchers try to customize the synthesis of the desired compound, bacterial culture often behaves not as a single system, but as a collection of independent cells. After the addition of an inducer, a substance that triggers synthesis, part of the population begins to actively produce protein, while the other remains practically not involved in the process.
For biotechnological production, such heterogeneity means a decrease in overall productivity, an increase in the metabolic load on cells, and difficulties in scaling processes. Scientists have long been looking for a way to achieve the coordinated work of bacteria, and the key to the solution, as it turned out, was found in the marine environment.
The developers used the ability of bacteria to exchange chemical signals. To do this, the genes of the marine bacterium Aliivibrio logei, which lives in cold water, were added to the genetic structure. This communication mechanism is called quorum sensing, or quorum sensing. It allows bacteria to coordinate their behavior depending on the population density: when there are enough cells, they synchronously activate certain genes, such as those responsible for bioluminescence or biofilm formation.
"In our new work, we have shown that the launch of synthesis and regulation of its intensity occur in all cells in the same way and there is no division of culture into "hard workers" and "lazy people," noted Sergey Bazhenov.
The study helps to better understand how the bacterial population processes and distributes chemical signals. The developed system is a model platform for studying these processes under controlled conditions and can become an effective tool for bacterial biotechnology, the scientists concluded.
Biofactories for the production of additives and medicines
Bacteria have been working in biotechnology for a long time as microfactories for the production of medicinal proteins, but they have a weak point: in the same flask, some of the cells are working at full capacity, and some are inactive, molecular biologist Arina Kholkina explained to Izvestia. This reduces the yield of the product and makes it difficult to scale production.
"Scientists from MIPT solved this problem by embedding the genes of a cold—loving marine bacterium into bacteria," the expert said.
The principle of controlled gene expression itself is not new: there are chemical inducers that can be used to regulate the amount of protein synthesized, as well as temperature-sensitive systems. However, the peculiarity of the new work lies elsewhere, Albert Rizvanov, head of the Personalized Medicine Center of Excellence at Kazan (Volga Region) Federal University, explained to Izvestia.
"Scientists have shown that the system they developed allows you to smoothly change the expression level not just on average across the entire bacterial culture, but in almost every single cell," the scientist explained.
In practice, this approach provides an additional tool for precise control of the bacterial "factory". Protein synthesis can be automatically started when a certain culture density is reached, or regulated using a chemical signal, and then stopped quickly enough by increasing the temperature. This is especially useful when working with proteins, the excess of which is toxic to the cell, as well as in cases where it is necessary to obtain a strictly specified volume of the product, the expert noted.
According to Lyudmila Bystritskaya, a specialist in biomaterials and tissue engineering at NTI Helsnet, the technology can be used primarily where reproducibility of each batch is important: in the production of recombinant enzymes, components of diagnostic kits and protein antigens for vaccines. In fundamental biology, the advantage of this approach is the ability to specify a fixed number of protein copies in each cell. This allows us to correctly study the dose-dependent effects and functions of proteins.
"It should be borne in mind that the result was obtained on a laboratory scale, and the transition to industrial volumes will require a separate check of the stability of the structure during prolonged cultivation," she noted.
The article was published in the Biotech journal. The research was supported by the Ministry of Science and Higher Education and the Russian Science Foundation.
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