Proteins are the most essential building blocks for the essential processes of life. We would not be able to breath, eat or fight infection without hemoglobin, digestion enzymes or antibodies – all of which are proteins. Tiny protein machines perform all life processes in the cell, from DNA duplication to waste removal, while other proteins provide structure to the cell.
If proteins are so important, it is obvious that the "factory" that makes them in cells is one of the pivotal processes of life. This factory, the ribosome, is a huge complex that is in itself composed of proteins, as well as RNA. Its 3D structure is extremely important, since if disturbed, the entire cell shuts down. If, for instance, we wish to develop an antibiotic drug that inactivates the bacterial ribosome, we need to know exactly how it is constructed, and how we can bind it and block its activity.
However, deciphering the 3D structure of such a large and complex, yet fragile and delicate, molecule is an incredibly complicated task. In fact, it is so complicated that many scientists deemed it impossible.
Research on the toilet
Ada Yonath (born Lifshitz) was born in 1939 in Jerusalem to a family of little means, sharing a cramped apartment with a few other families. Her father, which suffered from deteriorating health for many years, passed away when she was only 11 years old, so she began working in order to help support the family. She worked in cleaning, babysitting and in teaching private lessons. From a very young age she was a curious girl and attempted to understand the world around her by measuring things and performing experiments, among other things.
Despite the difficult financial situation, the family put education first, and Yonath was sent to prestigious and expensive schools. Following the father's death, the family moved to Tel-Aviv, where Yonath acquired her high school diploma. Following a military service in the Medical Corps, Yonath turned to the Hebrew University, where she acquired her B.Sc. in Chemistry and M.Sc. in Biochemistry and Biophysics.
During her PhD studies at the Weizmann Institute of Science, Yonath has begun examining the structure of the protein collagen, and during her post-doctoral training in the US, she expanded her studies to other proteins. In 1970, she was recruited to the chemistry department at the Weizmann Institute, where she established the laboratory for crystallography of biological materials, which was the only of its kind in Israel at the time. She led her research from a tiny office, which was no more than a bathroom, with its sink transformed into a desk and its toilet into a chair.
Crystallization has long been nearly the sole method for accurately solving the 3D structure of biological molecules. In this method, the molecules are turned into a crystal, i.e., a material comprised of identical repetitive units. When you illuminate the crystal with strong X-rays, its structure can be deciphered from the scattered rays. The crystal structure can be utilized to learn a lot about the structure of the units that comprise it.
One of the pioneers in this field was the British researcher Dorothy Hodgkin, who solved the structure of a number of important proteins, and even won the Nobel Prize in Chemistry for solving the structure of insulin. Another British researcher, Rosalind Franklin, used that very same technique to solve the structure of DNA. In those days, crystallography was limited to very specific types of molecules, relatively small ones that can easily be crystallized. The ribosome, as opposed to such molecules, is composed of dozens of different proteins and RNA sequences, and has a very unstable structure that tends to fall apart and lose its function in response to slight changes in the environment. Crystallizing the ribosome was very much considered to be an impossible task.
Yonath stated in her biography on the Nobel Prize website that "when I described my plans to determine the ribosome structure many distinguished scientists responded with sarcasm and disbelief. Consequently I became the World's dreamer, the village fool, the so-called scientist, and the person driven by fantasies."
I was the dreamer. Yonath with the equipment used for solving structures using crystallography | Photograph: Micheline Pelletier/Corbis, the Nobel Prize website
Polar bears and the Dead Sea
The inspiration for the idea that eventually made crystallization of ribosomes feasible came to Yonath from a paper about polar bears, which showed that the ribosomes in their cells become arranged in a certain dense structure towards hibernation. This led her to examine the structure of ribosomes of organisms that live under extreme conditions, such as bacteria from the Dead Sea or from hot springs, assuming their ribosomes would be more robust to environmental changes. Using a method developed by a German colleague of hers, Yonath managed to produce large amounts of ribosomes from such bacteria. This amount was sufficient for acquiring micro-crystals. It was not enough for solving the structure of the ribosome, but it was a beginning.
One of the problems with crystals of such a delicate material is that they tend to disintegrate when exposed to the radiation used for determining their structure. In order to prevent this disintegration, Yonath decided to snap freeze the cells in -190 degrees centigrade using liquid nitrogen, but this process destroyed the ribosomes. So, now Yonath incorporated another organic chemistry technique, and immersed the ribosome crystals in oil before snap freezing. This method, developed by Yonath, is now termed "cryo-bio-crystallography", and it is used for solving the structure of many biological materials.
The removal of this obstacle enabled Yonath and her colleagues to gradually solve the structure of ribosome crystals using strong X-rays. Soon enough, when it was deemed possible, more groups of scientists from all over the world joined the ribosome race. Here, there were additional intermediate stages and difficulties to overcome, up until Yonath and her students published a series of papers in 2000-2001 displaying the structure of the ribosome. Yonath compared her scientific quest to determine the structure of the ribosome to a climb of the Mount Everest. Time after time she thought that she had reached the peak, only to discover a taller summit.
The questions of life
Two other researchers, Venkatraman Ramakrishnana and Thomas Steitz, published independent data on the structure of bacterial ribosomes, with each study adding a layer to the solution of the 3D structure. Yonath has also continued to extensively research the structure of the ribosome and published many studies on the relationship between its structural components and how it functions in translating genetic information into a sequence of amino acids and in constructing the protein. In 2009, all three scientists were awarded the Nobel Prize in Chemistry "for studies of the structure and function of the ribosome".
Deciphering the structure of the ribosome enables development of more efficient antibiotics and novel drugs that bind different regions of the ribosome with higher affinity, thus shutting down protein production in the bacterium. Better understanding of the ribosome has paved the path to understanding diseases and human cell dysfunction.
Beyond its clinical importance, unraveling the secrets of the ribosome may shed light on some of the central questions of life itself: how did proteins become the most important molecules in the existence of life, and how has protein production been perfected throughout evolution. The curious girl from Jerusalem can very much account for the answers to these intriguing questions.
Translated by Elee Shimshoni