Nobel Prize in Chemistry 2009

At the end of the 1970s, Yonath was a young researcher at the Weizmann Institute with an ambitious plan to settle one of the major outstanding questions concerning living cells: She wanted to determine the three-dimesional structure of the ribosome – the cell’s factory for translating into proteins the instructions written in the gene code – and thus to reveal the mechanics guiding the process. This was the beginning of a long quest – one that would take decades and in which she would be met with reactions of disbelief and even ridicule in the scientific community. In her Nobel lecture, Yonath compared her journey to climbing Mt. Everest “only to discover that a higher Everest stood in front of us.” She began her work in collaboration with Prof. H. G. Wittmann of the Max Planck Institute for Molecular Genetics in Berlin, who supported her studies academically and financially, in parallel to maintaining her modest lab at the Weizmann Institute with an even more modest budget. Yonath came, over the years, to lead a large team of researchers from all corners of the globe. Though her research began as an attempt to understand one of the fundamental components of life, it has led to a detailed understanding of the actions of some of the most widely prescribed antibiotics. Her findings may not only aid in the development of more efficient antibacterial drugs, they could give scientists new weapons in the fight against antibiotic-resistant bacteria – a problem that has been called one of the most pressing medical challenges of the 21st century

 

Almost all the functions of every living organism are performed by proteins, which carry out the daily processes of life. Each protein is made up of a sequence of building blocks called amino acids, and their sequence, which is encoded in the genes, determines how that protein will fold up into the three-dimensional structure it needs to carry out its assigned task. The ribosome is a sort of machine that can make any protein, fashioned according to the code fed into it. The machinery is composed of two subunits – one large and one small – that exist independently but come together to form a functional complex specifically for the task of producing proteins.
 

Because the ribosome is so central to life (not to mention interesting), scientists around the world had been trying for many years to figure out how it works; but without an understanding of its spatial structure, there was little hope of forming a comprehensive picture of its actions. To reveal the three-dimensional structure of such small entities as biological molecules – too small to be seen even under an electron microscope – scientists first turn them into crystals and then bombard the crystals with powerful X rays. The shapes of the crystallized compounds are revealed in the patterns of radiation scattered from them, each unique pattern resulting from the compound’s internal chemical composition. With such X-ray crystallography techniques, one can “map” the distribution of the electrons in the investigated molecule and deduce its structure. But when dealing with ribosomes, there are additional challenges: The ribosome is a complex of proteins and RNA; its structure is extraordinarily intricate; it’s unusually flexible; it’s unstable; and it lacks internal symmetry, a feature that makes the crystallization of even the subunits an extremely formidable task.

 

 

Yonath was also the first to visualize the tunnel running through the active ribosome, through which the nascent protein progresses as it’s being formed – until it’s big enough to take on a three-dimensional structure and “look after itself.” In the course of her research she developed a number of new techniques that are today widely used in structural biology labs around the world. One of these is cryo bio-crystallography, which involves exposing the crystal to extremely low temperatures – -185° Celsius – to prevent the structure’s disintegration under the X-ray bombardment. She also developed a unique experimental system based on ribosomes taken from the hardy bacteria living in the extreme environments of the Dead Sea, thermal springs and atomic piles.
 

By the end of the 1990s, Yonath had succeeded in breaking the resolution barrier, thanks to improvements both in the crystals and in the facilities for detecting the X-ray diffraction. The result was the first “electron density map” of the ribosome’s small subunit. This is the piece of the ribosome that does the actual job of decoding the gene code, which it reads from a strand of messenger RNA. Her findings were published in 1999 in the Proceedings of the National Academy of Sciences (PNAS), USA. Then, in 2000 and 2001, Yonath published the first complete three-dimensional structure of both subunits of a bacterial ribosome – work that was hailed by Science magazine as one of the ten most important breakthroughs of the year.
 

These discoveries were clearly a high point in 20 years of research. But Yonath’s quest to understand the ribosome was far from complete. Armed with new insight into ribosomal structure, she moved on to revealing what that structure can tell us about its actions and, especially, how antibiotic drugs block those actions in bacterial ribosomes. Another challenge Yonath and her research team undertook was to try to understand how cellular factors initiate the process, “telling” the ribosome that it must begin protein assembly. To produce an image of the contacts with one such cellular factor, Yonath and her colleagues inserted a component into the crystal that attaches to the ribosome and activates it.