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Classic Texts: Watson & Crick - A structure for Deoxyribose Nucleic Acid
« on: 2004-07-29 18:51:55 » |
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A structure for Deoxyribose Nucleic Acid
The year 1953 could be said to mark, in biology at least, the end of history. Here is James Watson and Francis Crick's paper on the structure of DNA, which ushered in the new era with the celebrated understatement near the end. (as published in NATURE magazine)
MOLECULAR STRUCTURE OF NUCLEIC ACIDS
A Structure for Deoxyribose Nucleic Acid
2 April 1953
We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest.
A structure for nucleic acid has already been proposed by Pauling and Corey (1). They kindly made their manuscript available to us in advance of publication. Their model consists of three intertwined chains, with the phosphates near the fibre axis, and the bases on the outside. In our opinion, this structure is unsatisfactory for two reasons: (1) We believe that the material which gives the X-ray diagrams is the salt, not the free acid. Without the acidic hydrogen atoms it is not clear what forces would hold the structure together, especially as the negatively charged phosphates near the axis will repel each other. (2) Some of the van der Waals distances appear to be too small.
Another three-chain structure has also been suggested by Fraser (in the press). In his model the phosphates are on the outside and the bases on the inside, linked together by hydrogen bonds. This structure as described is rather ill-defined, and for this reason we shall not comment on it.
We wish to put forward a radically different structure for the salt of deoxyribose nucleic acid. This structure has two helical chains each coiled round the same axis (see diagram). We have made the usual chemical assumptions, namely, that each chain consists of phosphate diester groups joining ß-D-deoxyribofuranose residues with 3',5' linkages. The two chains (but not their bases) are related by a dyad perpendicular to the fibre axis. Both chains follow right- handed helices, but owing to the dyad the sequences of the atoms in the two chains run in opposite directions. Each chain loosely resembles Furberg's2 model No. 1; that is, the bases are on the inside of the helix and the phosphates on the outside. The configuration of the sugar and the atoms near it is close to Furberg's 'standard configuration', the sugar being roughly perpendicular to the attached base. There is a residue on each every 3.4 A. in the z-direction. We have assumed an angle of 36° between adjacent residues in the same chain, so that the structure repeats after 10 residues on each chain, that is, after 34 A. The distance of a phosphorus atom from the fibre axis is 10 A. As the phosphates are on the outside, cations have easy access to them.
The structure is an open one, and its water content is rather high. At lower water contents we would expect the bases to tilt so that the structure could become more compact.
The novel feature of the structure is the manner in which the two chains are held together by the purine and pyrimidine bases. The planes of the bases are perpendicular to the fibre axis. The are joined together in pairs, a single base from the other chain, so that the two lie side by side with identical z-co-ordinates. One of the pair must be a purine and the other a pyrimidine for bonding to occur. The hydrogen bonds are made as follows : purine position 1 to pyrimidine position 1 ; purine position 6 to pyrimidine position 6.
If it is assumed that the bases only occur in the structure in the most plausible tautomeric forms (that is, with the keto rather than the enol configurations) it is found that only specific pairs of bases can bond together. These pairs are : adenine (purine) with thymine (pyrimidine), and guanine (purine) with cytosine (pyrimidine).
In other words, if an adenine forms one member of a pair, on either chain, then on these assumptions the other member must be thymine ; similarly for guanine and cytosine. The sequence of bases on a single chain does not appear to be restricted in any way. However, if only specific pairs of bases can be formed, it follows that if the sequence of bases on one chain is given, then the sequence on the other chain is automatically determined.
It has been found experimentally (3,4) that the ratio of the amounts of adenine to thymine, and the ration of guanine to cytosine, are always bery close to unity for deoxyribose nucleic acid.
It is probably impossible to build this structure with a ribose sugar in place of the deoxyribose, as the extra oxygen atom would make too close a van der Waals contact. The previously published X-ray data (5,6) on deoxyribose nucleic acid are insufficient for a rigorous test of our structure. So far as we can tell, it is roughly compatible with the experimental data, but it must be regarded as unproved until it has been checked against more exact results. Some of these are given in the following communications. We were not aware of the details of the results presented there when we devised our structure, which rests mainly though not entirely on published experimental data and stereochemical arguments.
It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.
Full details of the structure, including the conditions assumed in building it, together with a set of co-ordinates for the atoms, will be published elsewhere.
We are much indebted to Dr. Jerry Donohue for constant advice and criticism, especially on interatomic distances. We have also been stimulated by a knowledge of the general nature of the unpublished experimental results and ideas of Dr. M. H. F. Wilkins, Dr. R. E. Franklin and their co-workers at King's College, London. One of us (J. D. W.) has been aided by a fellowship from the National Foundation for Infantile Paralysis.
J. D. WATSON F. H. C. CRICK
Medical Research Council Unit for the Study of Molecular Structure of Biological Systems, Cavendish Laboratory, Cambridge. April 2.
1. Pauling, L., and Corey, R. B., Nature, 171, 346 (1953); Proc. U.S. Nat. Acad. Sci., 39, 84 (1953).
2. Furberg, S., Acta Chem. Scand., 6, 634 (1952).
3. Chargaff, E., for references see Zamenhof, S., Brawerman, G., and Chargaff, E., Biochim. et Biophys. Acta, 9, 402 (1952).
4. Wyatt, G. R., J. Gen. Physiol., 36, 201 (1952).
5. Astbury, W. T., Symp. Soc. Exp. Biol. 1, Nucleic Acid, 66 (Camb. Univ. Press, 1947).
6. Wilkins, M. H. F., and Randall, J. T., Biochim. et Biophys. Acta, 10, 192 (1953).
VOL 171, page737, 1953
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Re:Classic Texts: Watson & Crick - A structure for Deoxyribose Nucleic Acid
« Reply #1 on: 2004-07-31 18:35:48 » |
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Astonishing Mind: Francis Crick 1916 – 2004
By Michael Shermer
Science has lost one of its brightest luminaries on Wednesday, July 28, when Francis Crick died at age 88 after a long battle with colon cancer. Crick was co-discoverer of the structure of DNA, pioneer researcher on the neural correlates of consciousness, a powerful promoter of science and critical thinking, and a good friend of the skeptical movement in general and the Skeptics Society in particular. I did not have the opportunity to work with Francis, but every year he made a generous unsolicited donation to the Skeptics Society for no other reason than he believed all scientists should support science education and the scientific exploration of fringe and revolutionary science. I know because I called him once to thank him for a munificent check he sent; he responded by saying that such acknowledgments are unnecessary because he felt it was his duty in the name of sane science and a rational society.
Francis Harry Compton Crick was born on June 8, 1916 in Northampton, England. He attended Northampton Grammar School and later the Mill Hill School in North London, where he showed an early aptitude for science while receiving a basic education in chemistry, physics and mathematics. Upon graduation Crick attended University College in London where he received a bachelor of science degree in1937, majoring in physics. His Ph.D. work was interrupted by the outbreak of the Second World War in 1939, during which he helped to design magnetic and acoustic mines for the British Admiralty.
After the war Crick grew less interested in physics and began exploring other areas of science where major contributions could still be made. As he recalled for a Rutgers University honors seminar in 1997: “I used what I call the ‘Gossip Test’ to decide what I wanted to do. The gossip test is simply that whatever you find yourself gossiping about is what you’re really interested in. I had found that my two main interests which I discussed the most were what today would be called molecular biology, what I referred to as the borderline between living and the nonliving, and the workings of the brain.”
Crick’s “Gossip Test” led him in 1947 to the Strangeways Laboratory in Cambridge. Although he knew little biology and almost no organic chemistry or crystallography, Crick mastered both, and in 1949 he joined the Medical Research Council Unit as a laboratory scientist in the Cavendish Laboratory at Cambridge University. It was during these formative years that Crick and his collaborators at the lab worked out the general theory of x-ray diffraction by a helix, which ultimately led to the discovery of the double helix structure of DNA.
In what has become one of the most famous collaborations in the history of science, in 1951 Crick and an American postdoc named James Watson teamed up to crack this greatest mystery of biology. Crick and Watson (now as famous a duo as any two names in any field) were both convinced that DNA, not proteins, was the critical factor for passing on genetic information. “It was obvious that I knew more about x-rays and structures than Jim did and he had more background in biological things which I’d only toughly taught myself,” he said. “So you might have guessed that I did the structural part and he did the more biological aspect. That really wasn’t true. For example, Watson discovered exactly how the base pairs went together, which is structural. He made that discovery.” This led to the discovery in 1953 of the double helix nature of DNA, for which both men, along with Maurice Wilkins, received the Noble Prize (for which! Rosalind Franklin probably deserved equal recognition for her work on x-ray crystallography).
Their paper in the journal Nature, entitled simply “A Structure for Deoxyribose Nucleic Acid,” is now a classic of science literature. The paper’s opening line reveals the authors’ awareness of the importance of their discovery, albeit in the understated tone appropriate for such an august venue: “We wish to suggest a structure for the salt of deoxyribose nucleic acid (D.N.A.). This structure has novel features which are of considerable biological interest.” The novel feature, or what they also described as “a radically different structure for the salt of deoxyribose nucleic acid,” is that the “structure has two helical chains each coiled round the same axis.” The short paper (only one typeset page in the journal), ends, as it began: “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic mater! ial.” Indeed it does.
Crick’s restless mind led him in 1966 to turn his attention to embryology, and a decade later, in 1976, he moved to the Salk Institute in La Jolla, California, for a one-year sabbatical year that lasted three decades and gave him the opportunity to pursue research on the brain and consciousness. In his 1990 book, What Mad Pursuit: A Personal View of Scientific Discovery, Crick equated the brain sciences of today with the state of molecular biology in the 1920s and 1930s. “The brain sciences still have a very long way to go. But the fascination of the subject and the importance of the answers will inevitably carry it forward. It is essential to understand our brains in some details if we are to assess correctly our place in this vast and complicated universe we see all around us.”
Although Crick was best known for his co-discovery of the double helix structure of DNA, he stirred up both the scientific community and the general public in 1994 with the publication of his book, The Astonishing Hypothesis: The Scientific Search for the Soul, in which he called consciousness “the major unsolved problem in biology.” The “problem” is explaining how billions of neurons swapping chemicals give rise to such subjective experiences as consciousness, self-awareness, and awareness that others are conscious and self-aware; or as Francis wrote, “that ‘you,’ your joys and your sorrows, your memories and your ambitions, your sense of personal identity and free will, are in fact no more than the behavior of a vast assembly of nerve cells and their associated molecules.”
Crick wanted to ground the study of consciousness in solid experimental neuroscience. When I was a graduate student in experimental psychology in the 1970s neuroscience was a burgeoning rigorous science, but in the late 1970s and early 1980s “consciousness” was usurped by New Agers who turned it into an airy-fairy notion that drove scientists to avoid it in droves. When Crick took up the subject, however, the study of consciousness regained scientific respectability.
To me, the most astonishing aspect of Crick’s hypothesis is that it is astonishing to anyone. Where else could the mind be but in the brain? I was astonished, therefore, to receive numerous critical letters in response to several articles I wrote for Scientific American in which I supported Crick’s hypothesis, from correspondents who believe consciousness exists somewhere other than the brain. Part of the problem has been that finding the neuronal correlates of consciousness (NCC) has proved elusive, so instead of concocting a grand unified theory, Crick, and his young and brilliant collaborator Christof Koch of Caltech, undertook a very specific research program focusing on the visual system, to understand precisely how photons of light striking your retina become fully-integrated visual experiences.
One of the more interesting lines of inquiry pursued by Crick and Koch was tracking the neural pathways of facial recognition. It turns out, for example, that there is a single neuron that fires only when the subject sees an image of President Bill Clinton. If this neuron died would Clinton be impeached from the brain? No, because the visual representation of Clinton is distributed throughout several areas of the brain, in a hierarchical fashion, eventually branching down to this single neuron. The visual coding of any face involves several groups of neurons, one to identify the face, another to read its expression, a third to track its motion, and so on. This hierarchy of data processing allows the brain to economize neural activity through the use of combinatorics.
In Koch’s recently published book, The Quest for Consciousness: A Neurobiological Approach, with a foreword by Francis Crick, Koch explains what he and Crick deduced from their research: “Assume that two face neurons responded either not at all or by firing vigorously. Between them, they could represent four faces (one face is encoded by both cells not firing, the second one by firing activity in one and silence in the other, and so on). Ten neurons could encode 2 10, or about a thousand faces. It has been calculated that one hundred neurons are sufficient to distinguish one out of thousands of faces in a robust manner. Considering that there are around 100,000 cells below a square millimeter of cortex, the potential representational capacity of any one cortical region is enormous.” Given that the brain has about a hundred billion neurons, consciousness is most likely an emergent property of these hierarchical and combinatori! c neuronal connections. How, precisely, the NCC produce the subjective experiences of consciousness (called “qualia” by philosophers) remains to be explained, but Crick’s and Koch’s scientific approach, in my pinion, is the only one that will solve the “major unsolved problem in biology.”
Since Christof was such a close friend and collaborator of Francis, I asked him for a comment. Christof was understandably upset, but managed to compose this thoughtful observation: “ Francis Crick was a close personal friend and mentor to me for the past sixteen years. He was the living incarnation of what it is to be a scholar: brilliant, rational, dispassionate, and always willing to revise his own opinions and views in light of the actions of a universe that never ceased to astonish him. He was editing a manuscript on his death bed, a scientist until the bitter end.”
An end that is only a beginning.
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