Proteins are the most essential building blocks for 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 form the cell’s structure.
And because proteins are so important, clearly the “factory” that produces them in the cell is one of the pivotal stages of life. This factory, the ribosome, is a huge complex in itself composed of proteins and RNA. Its 3D structure is extremely important, since if disturbed, the entire cell shuts down. If, for instance, we aim 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 to 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.
A great mind, a tiny office
Ada Yonath (née Lifshitz) was born in 1939 in Jerusalem to a family of few financial means, sharing a cramped apartment with a several other families. Her father, whose health had deteriorated for many years, passed away when she was only 11 years old, and she began to work in order to help support the family – cleaning, babysitting, and teaching private lessons. From a very young age, her remarkable curiosity drove her to try to understand the world around her, in part, by measuring things and performing experiments.
Despite their financial circumstances, the family put education first, and Ada was sent to prestigious and expensive schools. After her father's death, the family moved to Tel-Aviv, where she graduated with a high school diploma. Following a military service in the Medical Corps, she studied at the Hebrew University, where she acquired her BSc in chemistry and MSc in biochemistry and biophysics.
During her PhD studies at the Weizmann Institute of Science, Yonath began investigating the structure of the protein collagen, and during her postdoctoral training in the US, expanded her studies to other proteins. In 1970, she joined the Weizmann Institute’s Department of Chemistry, where she established the country’s first laboratory for crystallography of biological materials and 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 the gold standard 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 a crystal is illuminated with strong X-rays, its structure can be deciphered from the scattered rays. The crystal structure sheds light on 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 received 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. In contrast, the ribosome 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 considered an all but 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 instrument used to solve molecular 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 ribosome crystallization feasible came to Yonath after reading a paper about polar bears, which showed that ahead of hibernation, the ribosomes in their cells assume a certain dense structure. This led her to examine the ribosome structure of organisms that inhabit extreme environments, such as bacteria from the Dead Sea or from hot springs, assuming their ribosomes would be more robust in the face of environmental changes. Using a method developed by a German colleague, Yonath managed to extract large amounts of ribosomes from such bacteria, sufficient for acquiring micro-crystals. While not enough for solving the structure of the ribosome, 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 applied to determine their structure. In order to prevent this disintegration, Yonath decided to snap-freeze the cells in -190 degrees Celsius, using liquid nitrogen, but the ribosomes were destroyed in the process. To deal with this, Yonath incorporated another organic chemistry technique, immersing the ribosome crystals in oil before snap-freezing them. The method Yonath developed, termed “cryo-bio-crystallography,” is in currently in wide use in solving the structure of numerous 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, once it was deemed possible, additional scientific groups throughout the world joined the race to the ribosome structure. After overcoming other intermediate stages and hurdles, Yonath and her students published a series of papers in 2000-2001 displaying the structure of the ribosome. Yonath likened her scientific quest to determine the structure of the ribosome to climbing the Everest: Time after time, she thought that she had finally reached the peak, only to discover beyond it an even taller summit.
The questions of life
Two other researchers, Venkatraman Ramakrishnan and Thomas A. Steitz, independently published data on the structure of bacterial ribosomes, with each adding a layer to the solution of the 3D structure. Yonath also continued to extensively research the structure of the ribosome and published extensively about 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 the 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 paves 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 answers to these intriguing questions will probably emerge from the groundbreaking achievement of the inquisitive child from Jerusalem.
Translated by Elee Shimshoni