" Game of DNA replication, transcription, translation and recombination towards functional protein..."

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.

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In the 200^th year of celebration of Darwin`s birth and 150^th 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 20^th 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, 7^th 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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From Photophone of 19th Century =>The masters of light: 20th Century Ambassador of Collaboration, Networking and Communication in 21st Century !!!

Two Revolutionary Optical Technologies: "for groundbreaking achievements concerning the transmission of light in fibers for optical communication" + "for the invention of an imaging semiconductor circuit – the CCD sensor"

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Question for online poll on the sidelines of this year`s Physics Nobel announcements was asked is this: “Did you know that this question comes to you via glass fibre?” The mere words reflecting the kind of revolutionary character the invention Charles K. Kao gifted to this world ! He initiated search for and the development of the low-loss optical fiber presently used in optical fiber communication systems. On the other hand ‘The Sailer Man’ George E. Smith who submitted thesis of three pages to University of Chicago says that ideas of the charged couple devices actually came from his head when he was deleivering one lecture on invention. He even don`t remember exactly how many patents he held with his colleague Willard S. Boyle at Bell Labs in 60s , 70s, 80s. Willard S. Boyle and George E. Smith invented the charge-coupled device (CCD) presently used in many digital cameras and in advanced medical and scientific instrumentation.

These three who are recipient of this year`s Physics Nobel are the people who are responsible for shaping modern information technology to present stage. Kao’s discoveries have paved the way for optical fiber technology, which today is used for almost all telephony and data communication. Boyle and Smith have invented a digital image sensor – CCD, or charge-coupled device – which today has become an electronic eye in almost all areas of photography.

Underlying the historical feature of the Kao`s work Nobel Foundation says, “When the Nobel Prize in Physics is announced in Stockholm, a large part of the world receives the message almost instantly. At almost the speed of light, the highest of speeds, the message is spread around the world. Text, images, speech and video are shuffled around in optical fibers and through space, and are received instantly in small and convenient devices. It is something that many people have already come to take for granted. The optical fiber has been a prerequisite for this extremely rapid development in the field of communications, a development that Charles Kao predicted over 40 years ago.”

Kao worked for Standard Telecommunication Laboratories Harlow, United Kingdom and Chinese University of Hong Kong. Charles K. Kao was a young engineer at STL working on optical communication. Kao was born in 1933 in Shanghai, China, educated in Hong-Kong and graduated in Electrical Engineering in 1957 at University of London and got a PhD at the University of London in 1965. With the help of colleague Hockham whose work on the analysis of the effect of waveguide imperfections lead them to a thesis defended in 1969. They investigated in detail the fundamental properties of optical fibers with respect to optical communication.

Just around that time, Willard Boyle and George Smith radically altered the conditions for the field of photography, because film is no longer needed in cameras where the images can be captured electronically with an image sensor. The electronic eye, the CCD, became the first truly successful technology for the digital transfer of images. It opened the door to a daily stream of images, which is filling up the optical fiber cables. Only optical fiber is capable of transferring such large quantities of data that electronic image sensor technology yields.

100 years ago, G. Marconi and K.F. Braun were awarded the Nobel prize “in recognition of their contributions to the development of wireless telegraphy”. 50 years ago, electronic and radio communications were in rapid expansion. The first transatlantic cable was installed in 1956 and satellites would soon allow even better coverage. The first communication satellite was launched in 1958. Research in telecommunication concentrated mainly in shorter radio waves, in the millimeter range, with the aim to reach higher transmission speeds. These waves could not travel as easily in air as longer waves, and the research focused on designing practical waveguides. The invention of the laser in the early 1960s (Nobel Prize in 1964 to C.H. Townes, N.G. Basov and A.M. Prokhorov) gave a new boost to the research in optical communication. ¹ Previous use of optical fibres was limited to medical use for industrial manufacturing of instruments for gastroscopy and other medical uses.

Global communication, and in particular internet and long-distance telephony, is now based primarily on optical fiber technology. The main advantage of optical waves compared to radio waves is the high frequencies that allow high data transmission rate. Nowadays, several terabits per second can be transmitted in a single fiber which represents an increase by a factor of one million to what could be achieved fifty years ago with radio signal transmission. The number of optical fiber cables being installed all over the world is increasing rapidly. Fiber optics has also been important for a huge number of other applications, in medicine, laser technology and sensors.


Different schemes for color photography were also explored during the 19th century. G. Lippman was awarded the 1908 Nobel Prize in Physics for his color photographic process based on interference effects. W.H.F. Talbot invented in 1841, thus initiating modern photography, light sensitive papers containing silver salts for first obtaining a negative image and thereafter, through contact copying with another light sensitive paper, a positive image. He described also the steps necessary to develop the latent images formed in the papers. Several developments followed regarding the substrate used for the light sensitive layers. The idea to use emulsions (silver salts in gelatin) to create negatives was conceived around 1870 and the replacement of glass plates with a celluloid film around 1880. The roll of film was invented 1887 by a priest, H. Goodwin, and explored by G. Eastman. In 1888 the Eastman Kodak box camera for roll film appeared on the market. Different schemes for color photography were also explored during the 19th century. G. Lippman was awarded the 1908 Nobel Prize in Physics for his color photographic process based on interference effects.


Willard S. Boyle and George E. Smith were both at Bell Laboratories, New Jersey when they conceived the CCD device. The CCD is a metal-oxide semiconductor (MOS) device that can be used as a detector to record images in electronic form, and thus it offers a modern alternative to the photographic film. A CCD can record a scene by accumulating light induced charges over its semiconductor surface, and by transporting them to be read out at the edge of the light sensitive area. The invention utilized the properties of the then new MOS (Metal Oxide Semiconductor) technology to create an integrated and simple device to record and read out a scene. The read-out is similar to a fashion often referred to as a “bucket brigade” as it shifts arrays of information by successive site shift.

The hour long discussion between Boyle and Smith in 1969 led to an enormous development of practical and scientific instrumentation based on CCDs: digital cameras, medical devices and high performance scientific instrumentation, not least for astronomy and astrophysics. There are several important medical applications for CCD cameras, e.g. for the study of tissues and cells as imaging devices in microscopes or for the recording of cells and tissue. Digital photography has also revolutionized almost all image based medical diagnostic tools. A large application is found in endoscopy for inspections inside the body and for guidance during micro- or ‘key hole’- surgery. There are many types of endoscopes, e.g. based on single optical fibers, optical fiber bundles or in the form of capsules possible to swallow with built in light source, CCD sensors and wireless signal transmission.

Solid-state image sensors and digital cameras have changed the role of images in our society, since they give electronic signals, digits, which can easily be transmitted and treated. In science, the possibility of transferring and processing images digitally is a real revolution. Digital image processing is now a global commodity which enables, for instance, the best international expertise to be involved in crucial diagnostic and even surgical situations, through remote control and feedback through digital cameras. Furthermore the evaluation of large amounts of data (e.g. created in mapping the universe) can be spread to many groups and even to volunteers from the general public; and no doubt this dissemination will take place of course due to the grace of Optical Fibres invented by Dr. Kao.

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1 THE ROYAL SWEDISH ACADEMY OF SCIENCES, Scientific Background on the Nobel Prize in Physics 2009, TWO REVOLUT IONARY OPTICAL TECHNOLOGIES, 6 October 2009

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"Abhi to main jawan hoon..." + "how chromosomes are protected by telomeres and the enzyme telomerase"

When Elizabeth Blackburn last visited India on a lecture tour, introductory note inviting for her lecture read: "Nehru Memorial Museum and Library: Award-winning biologist and professor at University of California Elizabeth Blackburn will speak on “Chromosome Ends and Human Health and Disease”, Teen Murti Auditorium, Teen Murti House, 4:30 p.m."After following this and her non-stop talk lasting above an hour, it was clear how she was successfull in radiating her energy in jargon-less presentation along with consistent enthusiasm to appeal girls and young minds to take a giant leap to study this area which ultimately marched towards Nobel of 2009.


Significance of the discovery made by Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak can be guaged from the starting words of the press release: "This year's Nobel Prize in Physiology or Medicine is awarded to three scientists who have solved a major problem in biology: how the chromosomes can be copied in a complete way during cell divisions and how they are protected against degradation. The Nobel Laureates have shown that the solution is to be found in the ends of the chromosomes – the telomeres – and in an enzyme that forms them – telomerase." (http://nobelprize.org/nobel_prizes/medicine/laureates/2009/press.html


This is the first time that two women are sharing the Nobel prize in entire history of Nobel prizes. The discovery is key in finding many answers of ageing and decay of immune system in cancer. As release further elaborates, "If the telomeres are shortened, cells age. Conversely, if telomerase activity is high, telomere length is maintained, and cellular senescence is delayed. This is the case in cancer cells, which can be considered to have eternal life. Certain inherited diseases, in contrast, are characterized by a defective telomerase, resulting in damaged cells. The award of the Nobel Prize recognizes the discovery of a fundamental mechanism in the cell, a discovery that has stimulated the development of new therapeutic strategies."


This award also reflects inspiring story of student and teacher sharing the hallmark of greatest glory in scientific acheivement. Carol Greider who is Proffessor of Molecular Biology in Johns Hopkins University and Genetics will be sharing prize with Szostak was graduate student of third co-winner Blackburn and she completed Ph.D. from California University, Berkeley.


The efforts directed at approaching path breaking solutions to cancers can be understood from her words: "To understand how telomere functions to provide chromosome stability and how telomerase might play a role in cancer, we generated a telomerase null mouse. Mice that lack the gene encoding the mouse Telomerase RNA (mTR) show progressive telomere shorting during successive breeding. The mice are viable for up to six generations although in the later generations there is severe reduction in fertility due to apoptosis in the germ cells. Crosses of these telomerase null mice to other tumor prone mouse models suggest that under some circumstances tumor formation can be greatly reduced when telomerase is absent. This suggests that telomerase inhibition may be a useful approach to cancer treatment." (http://www.hopkinsmedicine.org/pharmacology/research/greider.html)


Third legend in the group is Jack W. Sztostak in Department of Genetics & Molecular Biology at Cambridge St. A Ph.D. from Cornell University, this man is member of all premier acadamies like National Academy of Sceinces, American Academy of Arts and Sciences and New York Academy of Sciences.

"At the outset of his career, Szostak made pioneering contributions to the field of genetics. His discoveries helped clarify the events that lead to chromosomal recombination—the reshuffling of genes that occurs during meiosis—and the function of telomeres, the specialized DNA sequences at the tips of chromosomes. He is also credited with the construction of the world's first yeast artificial chromosome. That feat helped scientists to map the location of genes in mammals and to develop techniques for manipulating genes. " (http://www.hhmi.org/research/investigators/szostak_bio.html)

But a Nobel Prize–winning discovery in the 1980s by former HHMI President Tom Cech and Sidney Altman transformed Szostak`s research. This discovery demonstrated that RNA, the sister molecule of DNA, can catalyze certain chemical reactions inside cells, a job previously thought to be the exclusive domain of proteins. This new revelation about RNA's dual role suggested to some scientists, including Szostak, that RNA likely existed long before DNA or proteins because it might be able to catalyze its own reproduction. Their discovery made it easier to think about the origin of life. (life.http://www.hhmi.org/research/investigators/szostak.html)

Blackburn who is distnguished recipient of six honorary doctorates from renowned universities, not to mention the legendary awards and membership from across the world. Most importantly her research vindicates other scientist`s work focussing on potential of diet, exercise, stress reduction and other "lifestyle interventions" in reducing the risk of and reverse damage from coronary artery disease and stave off diabetes. She was consistently emphasising on this mind-body link now being fertile territory for prominent research scientists when she referred to her experience during the talk she delievered few months ago in India.
(Her major list of publications is available at http://cancer.ucsf.edu/people/blackburn_elizabeth.php.)


Fountain of Youth:
In a recent interview she says, "For now, the best defense is healthy living, she said. The goal should not be to live to 150 years old but to live well for 80 or 90 years. In an ideal world, people would protect their telomeres during the years they're normally susceptible to diseases of aging. Then they would "fall off the perch" and die, as genetically programmed, at 90 or even 100 years old. Scientists used to believe that everyone's telomere length shortened over time, the same way they used to think that brain neurons stopped growing in the elderly. But telomere length, while it does decline in general, fluctuates in individuals. Many older people have relatively long telomeres. Eventually she indicates towards a way where drugs will play a lesser role and study of our body's physiology should play a major role in enabling us to arrive at a age when we will sing "Abhi to main jawan hoon..." "(http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2009/01/02/CMBO14L1P9.DTL&type=health)

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