Venkatraman Ramakrishnan, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
Thomas A. Steitz, Yale University, New Haven, CT, USA
Ada E. Yonath, Weizmann Institute of Science, Rehovot, Israel
The Science Nobels of year 2009 of come with recognition of beautiful symphony of discoveries and inventions which lifted each other to understand mysteries of life so as to strengthen our capabilities for realising the dream of long life which is full of vibrant communication in the shrinking world of relationships and expanding world of social networking technologies.
----------------------------------------------------------------------------------------------------------------------------In the 200th year of celebration of Darwin`s birth and 150th anniversary of publication of ‘On the Origin of Specis’, the cross-collaborative and unrelented effort "for studies of the structure and function of the ribosome" have translated into Nobel. The three Nobel Prize Laureates in chemistry for 2009, Ada E. Yonath, Thomas A. Steitz and Venkatraman Ramakrishnan, are rewarded for mapping the ribosome –one of the cell’s most complex machineries – at the atomic level. The ribosome reads the information in messenger RNA, and based upon that information, it produces protein. Scientists refer to this as translation. It is during this translation process, when DNA/RNA language becomes protein language, that life reaches its full complexity. The knowledge that this year’s Nobel Laureates provide us with can thus be of substantial value for the development of new antibiotics.
In early part of 20th century the majority of the scientific community thought that the proteins were the carriers of hereditary traits, since they are more complex than DNA. On 28 February 1953, James Watson and Francis Crick at the Cavendish Laboratory at Cambridge University, UK, assembled the pieces of the DNA puzzle. For several years they had tried to understand how the DNA molecule’s four nucleotides could be assembled into a three-dimensional structure.The scientific community then realized that the genetic code is contained within the nucleotide sequences on each of the strands. But questioned remained how?
One part of this question was answered by the scientists who won 2006 Nobel prize in Chemistry. He is credited for his fundamental studies concerning how the information stored in the genes is copied, and then transferred to those parts of the cells that produce proteins. Kornberg was the first to create an actual picture of this process at the molecular level, in the important group of organisms called eukaryotes (which, as opposed to bacteria, have well-defined cell nuclei). Mammals like ourselves, as well as ordinary yeast, belong to this group of organisms.
The truly revolutionary aspect of the picture Kornberg has created is that it captures the process of transcription in full flow. What we see is an RNA-strand being constructed, and hence the exact positions of the DNA, polymerase and RNA during this process.
Let us turn towards Symphony: The founding belief behind the development of different labs by John Szostak (one of the winners of Nobel Medicine 2009) is elaborated by himslef in these words: “We are interested in the chemical and physical processes that facilitated the transition from chemical evolution to biological evolution on the early earth. To explore these processes, we are trying to build a system that undergoes Darwinian evolution. Such a chemical system would concentrate on model of a primitive cell, or protocell, that consists of two main components: a self-replicating genetic polymer and a self-replicating membrane boundary. The job of the genetic polymer is to carry information in a way that allows for both replication and variation, so that new sequences that encode useful functions can be inherited and can further evolve....Such a system begin to evolve in a Darwinian fashion, potentially leading to the spontaneous emergence of genomically encoded catalysts and structural molecules.”
Moving to link next melody in symphony; One would not wonder why Ada Yonath was given The First European Crystallography Prize in 2000. She is strong-willed pioneer, no doubt! Often a ground-breaking discovery comes from a pioneer who investigates new uncharted territory.1 In this case, that pioneer was Ada Yonath. At the end of the 1970s, she decided to try to generate X-ray crystallographic structures of the ribosome. At this time, however, most people considered that this was impossible. In X-ray crystallography, scientists aim X-rays towards a crystal of, for example, a protein. When the rays hit the crystal’s atoms they are scattered. On the other side of the crystal, scientists register how the rays have spread out. Previously, this was achieved by using photographic film, which was blackened by the rays. Today one uses CCD detectors, which can be found in digital cameras (and are a focus for the 2009 Nobel Prize in Physics). By analyzing the pattern of dots, scientists can determine exactly how the atoms are positioned in a protein.
Many people were skeptical of Ada Yonath’s vision. In 1980, she had already managed to generate the first three-dimensional crystals of the ribosome’s large subunit. This was a great achievement, although the crystals were far from perfect.
It would actually take another 20 years of hard work before Ada Yonath managed to generate an image of the ribosome where she could determine the location of each atom. Step by step, Ada Yonath got closer to the goal. Eventually, it was realized that the ribosome’s atomic structure could be mapped, and more scientists joined in the race. Among them were Thomas Steitz and Venkatraman Ramakrishnan.
In 1998, Thomas Steitz published the first crystal structure of the ribosome’s large subunit. It resembled a dim photograph, and had a resolution of 9 Ångström (one Ångström equals one tenth of a million of a millimetre). It was not possible to see individual atoms, but one could detect the ribosome’s long RNA molecules. This was a decisive breakthrough.
The role of the large subunit in the ribosome is primarily to synthesize new protein. To obtain a step-by-step image of the chemical reaction is very difficult, as it occurs at the atomic level and at a daunting speed. In a single ribosome, about 20 peptide bonds can be formed every second. Thomas Steitz managed to freeze different moments of the chemical reaction. He crystallized the large subunit with molecules resembling those that are involved in peptide bond formation. With the help of these structures, scientists have been able to determine which of the ribosome’s atoms are important to the reaction, and how the reaction occurs.
A fascinating property of the ribosome is that it seldom makes any errors when it translates DNA/RNA-language into protein language. If an amino acid is incorrectly incorporated, the protein can entirely lose its function, or perhaps even worse, begin to function differently. Venkatraman Ramakrishnan’s crystal structures of the ribosomes have been crucial for the understanding of how the ribosome achieves its precision. He is great example of how he traversed acrooss three fundamental sciences before moving to life long devotion to Structural Biology. Ramkrishnan, a Ph.D. In Physics from Ohio University, gratuate in Biology(University of California, San Diego) and later worked as post doctoral fellow in department of Chemistry in Yale University for four early years of his career.
Ramkrishnan shares his reflections about the challenges this research faced during the two decades starting from 80s.2 The development of synchrotron radiation sources to provide intense beams of X-rays was crucial to provide sufficient signal from these weakly diffracting crystals. An other advance was the development of cryocrystallography as a general tool to minimize radiation damage from these intense X-ray beams , which was quickly adapted for data collection on ribosomal crystals. Advances in computing, detectors and crystallographic software were also essential. The unending efforts by scientiifc community are commended by Ramkrishnan in following word, “The high resolution structure of of 30S ribosomal subunit is significant for several reasons. It will allow the rationalisation in structural terms of four decades of biochemical efforts to elucidate the mechanism of protein synthesis.“ 3
An immediate consequence of the determination of the high-resolution structure of the subunits was the ability to determine the structures of complexes with antibiotics. The high resolution structures of ribosomal subunits have shed considerable light on specific aspects of ribosome function one of them being decoding and antibiotic binding. A large number of questions about translation still remain unanswered. These problems will require years of effort by the community to unravel. 4 Here I find it appropriate to mention the concluding lines of of Dr. Roger Kornberg from his acceptance speech of Nobel Chemistry 2006: “ Even as we celebrate, and savor this moment, the work goes on. I am reminded of some lines from the American poet, Robert Frost. During the long, arduous effort of the past 20 years, I often repeated these lines to myself. I view them as a kind of metaphor for science and our ongoing commitment to it.
The woods are lovely, dark and deep,
But I have promises to keep,
And miles to go before I sleep,
And miles to go before I sleep.”
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1THE ROYAL SWEDISH ACADEMY OF SCIENCES , Scientific Background on the Nobel Prize in Chemistry 2009, STRUCTURE AND FUNCTION OF THE RIBOSOME, 7th Oct. 2009
2 V. Ramakrishnan, Heatley Medal Lecture, Delivered at the University of Manchester on 26 March 2008 & Biochemical Society Transactions (2008) 36, 567–574
3 Brian T. Wimberly, Ditlev E. Brodersen, William M. Clemons Jr, Robert J. Morgan-Warren, Andrew P. Carter, Clemens Vonrhein, Thomas Hartschk & V. Ramakrishnan; Structure of the 30S ribosomal subunit, NATURE, Vol. 407, Sept. 2000
4 ibid
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