Prof. Ada Yonat works in her laboratory on deciphering the structure of the ribosome - the intracellular organelle responsible for protein production. Her work, which among other things paved the way for understanding how antibiotics work, earned her the Israel Prize
Uri Nitzan
At least, some microbiologists believe so. Bacteria have a higher chance of surviving the harsh conditions of an ecological disaster, but the diseases they cause could hasten the coming of the apocalypse.
The war against bacteria is fought first and foremost with antibiotics. When the first types of antibiotics were developed, in the 40s, they revolutionized the life expectancy and quality of life of millions. It seemed to be found
The cure for deadly diseases such as pneumonia and meningitis, but not everyone predicted the "backlash" of the bacteria. The antibiotics act against mechanisms that are essential to the life or reproduction of the bacteria, and it turned out that in the process of natural selection, the bacteria change their properties, and are able to develop resistance to the effects of the antibiotics.
Intensive use of antibiotics accelerates the development of resistance, and today there are species of bacteria that doctors have no way of dealing with. Pharmaceutical companies are investing billions in researching the resistance mechanisms of bacteria, and there is a constant race for the "next antibiotic", which may give scientists the necessary breathing space to develop a super drug that will finally eliminate the bacteria.
Professor Ada Yonat from the Weizmann Institute won the Israel Prize this year for her major contribution to the description of the structure of the ribosome - an important intracellular organelle used as a factory for the cell's protein production. These proteins catalyze the thousands of reactions we call life. It is no coincidence that more than 40% of antibiotic drugs are aimed at acting on bacterial ribosomes. In the ribosomes, the genetic code in the DNA is translated into a protein; The paralysis of the production line of the proteins means the end of the life of a single-celled creature such as the bacterium.
The developers of the antibiotic drugs attach great importance to understanding the mode of operation of the ribosome and describing its spatial structure. The accepted method for determining the three-dimensional structure of molecules and biological structures is X-ray crystallography (X-rays). "In the first step, they produce a crystal of the material whose structure they are trying to decipher," Yonat explains. The production of the crystal is essential, because only in the solid state can the crystallography technology be applied. "In the next step, the crystal is irradiated with X-rays. The radiation hits the crystal, and from the measurement of the reflected radiation we can calculate the distances between the atoms that make it up and the nature of the chemical bonds between them," Yonat says.
The structure of the ribosome is extremely complicated, and it includes dozens of proteins and several long chains of RNA-type nucleic acids. All components are packed in two subunits; One is responsible for reading the hereditary material and its decoding, and the other is responsible for the production of the protein.
Yonat's research group is the only group in the world that deciphered the exact structure of the two subunits. "Deciphering the structure of the ribosome is a complicated task both because of its size and complexity, and also because of the organelle's sensitivity to radiation," Yonat says. "In order to produce the density map of the atoms at a good level of separation, high levels of radiation must be used. But radiation at high levels damages the stability of the ribosome and disrupts its structure. In fact, the conditions of the experiment distort the results."
In the 80s, Yonat was the only researcher who succeeded in producing ribosome crystals, but deciphering their structure was only partially possible. The quality of the crystals was not good enough, and the technological tools that would have made it possible to increase the sensitivity of the crystals to X-rays had not yet been invented. Despite the skepticism of the best scientists in the world, Yonat worked hard to develop the laboratory tools that eventually paved the way for describing the structure of the ribosome at the desired level of separation.
One of the ways to deal with the problem of the instability of the ribosome was to work with the ribosomes of bacteria living under stressful conditions. "Reuven Wimer, a Tel Aviv advertiser and amateur scientist, drew my attention to the fact that the bacterium DeinococcusRadiodurans is the ultimate survivor," says Yonat. "He remained alive even after several days of starvation, and he can be found in the desert, the North Pole, and also in the sewers of nuclear facilities. Relying on the bacterium's robustness, we assumed that its ribosome would also demonstrate stability, and that the bacterium would know how to deal with the damage that would be caused to it by exposure to high levels of radiation."
This bacterium was grown in Yonet's laboratory and eventually produced excellent crystals of the large subunit of the ribosome. In an article published in October 2001 in the journal Nature, Yonet presented a breakthrough in understanding the structure of the ribosome and how antibiotic drugs affect it. "Working together with a research group from the Max Planck Institute in Germany, we tried to find out how different antibiotic drugs paralyze the ribosome," she says, "in the first step, we prepared crystals of ribosomes from bacteria that were treated with known antibiotic drugs. After that, we deciphered the spatial structure of the ribosome units, and were able to locate the antibiotic drugs when they are associated with their sites of activity. It turns out that some of the antibiotic drugs block the site where the hereditary material is translated into protein, while other antibiotic drugs block the tunnel from which the newly synthesized proteins are ejected."
The results of the study have important implications for the improvement of antibiotic drugs and the deciphering of the bacteria's resistance mechanisms. "Since then, we have been able to describe the mechanisms of action of more advanced antibiotic drugs, some of which have not yet entered the market," says Yonat. "At the same time, we began to characterize the resistance mechanisms developed by bacteria against the antibiotics." The bacteria will continue to develop resistance mechanisms, but through technologies such as X-ray crystallography, it will be possible to locate new weak points in the defense system of the stubborn enemy.
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