OOH...ONWARD!

OOH, THE COMPETITION :

I will pass a few clue words this time, so hopefully, you can Guess-Who (in case you couldn't, scroll down for the answer)! ¹

         1. The concepts of resonance and electronegativity were developed by him. 

         2. Sickle cell Anaemia 

         3. By folding a paper on which he had drawn a chain of linked amino acids, he discovered a cylindrical coil-like configuration- the alpha helix. The most significant aspect was its determination of the number of amino acids per turn of the helix. 

        4. (I mean, this clue just gives it away :\ )" The Nature of the Chemical Bond, and the Structure of Molecules and Crystals "; 2 unshared Nobel prizes! 

The American had done quite a bit and was now attempting to resolve the structure of DNA! Half of them who were attempting the problem were unnerved and the rest figured that he would obviously solve it- he had already cracked the model of the alpha helix and knew DNA was a helix too- so it was pointless to try right? WRONG. Or so thought the protagonists of this story- brash, DNA-obsessed James Watson, brilliant Francis Crick, shy and diffident Maurice Wilkins, and the sharp, no-nonsense Rosalind Franklin. 

ITTY BITTY PERSONALITY PROFILES ON THE 4: 

-----> New Zealander Maurice Wilkins:

                Team: King's College 

                Initial Work: Manhattan Project, but with the development of the atomic bomb, turned to biophysics, working with his mentor- John Randall. 

                Trivia: Franklin arrived when Wilkins was away, and on his return, the confusion about their roles created friction, a bad start to a relationship that never got better.

                Later Career Path: applied X-ray techniques to the structural determination of nerve cell membranes and of ribonucleic acid, rising in rank at King's. 

------> English legend Rosalind Franklin:  was the only one out of the key 4 who actually had any degrees in chemistry. 

              Team: King's College- offered a scholarship to set up and improve the crystallographic unit, 

              Initial Work: Her x-ray crystallographic work and her clear and accurate diffraction images were the stuff of legend. Produced papers on the chemistry of coal, went to Paris and improved her crystallography. 

             Trivia: A Francophile! Adored Paris and enjoyed some of her happiest years there. 

             Later Career Path: Birkbeck College, London; Made important contributions to the X-ray crystallographic analysis of the structure of the tobacco mosaic virus, a landmark in the field.

-----> Scientist to the very end, Francis Crick: 

              Team: Cavendish Laboratory, Cambridge

              Initial work: Another physicist; however, moved to DNA work after realizing its significance. 

              Trivia: Born in the middle of WW1, affected by WW2. 

              Later Career Path: Made fundamental contributions to unlocking the genetic code. He and Sydney Brenner demonstrated that each group of three adjacent bases on a single DNA strand code for one specific amino acid. Correctly hypothesized the existence of tRNA, which mediates between mRNA and amino acids.

-----> "Brat genius"of DNA, James Watson:

                Team: Cavendish Laboratory, Cambridge ² 

                Initial work: entered the University of Chicago at age 15, secured his doctorate from the University of Indiana at just 22, and had a Ph.D. in zoology.

                Trivia: performed on the national radio show “Whiz Kids" & grew up in Chicago 

                Later Career Path: Went to Cold Spring Harbor Laboratory (CSHL)and he headed the National Center for Human Genome Research at the National Institutes of Health.

THE RACE: 

DNA is quite elusive- it takes different forms in water and without, cannot be observed by a normal microscope, and definitely requires some complex chemistry to understand. So scientists came up with a new way of peering at it. X-rays bounce off atoms, and their pattern gives information about their location. One of the pioneers in this field called 'X-ray crystallography' was (you guessed it!) Pauling at Caltech, as well as Rosalind. 

IN 1951, a young man- a 23-year-old, with a Ph.D.- sauntered into the Cavendish Laboratory, having an obsession with DNA. He quickly hit it off with Francis Crick- a 35-year-old graduate student- and they shared an interest in the fundamental problem of learning how genetic information may be stored in molecular form. Neither had a degree in Chemistry, so they had to use standard texts as references. About this time, Watson attended a lecture given by Rosalind Franklin. He apparently did not pay close attention. Later on hearing the results of the Hershey- Chase experiment ³, Watson became convinced that DNA was the molecule responsible for transmitting genetic information. Watson was supposed to be working on viral structure, and Crick on protein structure, but DNA called.

About 50 miles from Cavendish were the minds at King's. The relationship between Franklin and Wilkins was fraught with tension. Wilkins thought that Franklin was his assistant, whereas she had been called to set up the crystallographic unit and focus on the DNA problem. Her images were constantly getting better, and the ones at Cavendish were urged to make progress. Watson and Crick hurried to produce a model, driven by the fact that they were competing with Pauling, but that turned out to be a disaster. Watson and Crick built a three-stranded helix with nitrogen bases on the outside of the structure. Franklin pointed out that, when her research was applied correctly, the hydrophilic phosphate-containing backbones of the nucleotide chains of DNA should be positioned so as to interact with water molecules on the outside of the molecule, while the hydrophobic bases should be packed into the core. 

Embarrassed by this public failure, the director of the Cavendish told Watson- Crick to abandon their model-building efforts. Both men officially turned to other research but continued to think about the DNA problem. The failure of Wilkins and Franklin to cooperate was one of the reasons they resumed work towards finding a molecular model of DNA. 

Coming back to King's, Rosalind had come up with her best photo yet- the famous Photo 51. It has been described by some as "amongst the most beautiful X-ray photographs of any substance ever taken." This was the last piece of the puzzle- the structure it proposed was beautifully coinciding with fundamental chemistry. The progress she made on her own- isolated and without anyone to share her ideas with- is remarkable. 

She realised that:

1) DNA takes two forms (shorter-dryer and longer-wetter)

2) the sugar-phosphate backbones must be on the outside

3) the molecule looks the same upside down or right side up; double helical and the way the nucleotides connected meant the 2 strands were complementary. Franklin noted that ‘an infinite variety of nucleotide sequences would be possible to explain the biological specificity of DNA”- showing she had known that a combination of bases form genetic code. To prove this she had to convert this into a mathematical and chemical model, which she had not the time to finish as Watson and Crick, had rapidly interpreted the structure through spatial relationships & chemical bonds.

Wilkins removed the image from the lab without Franklin’s permission and shared the Photo with Watson and Crick, and they made use of it along with unpublished X-ray diffraction images of Franklin's, including preliminary accounts of Franklin's results of the X-ray images  in a written progress report for Randall from late 1952.  As Watson recounts in The Double Helix: 

                     "The instant I saw the picture my mouth fell open and my pulse began to race. The pattern was unbelievably simpler than those obtained previously" 

                     "Rosy (Franklin), of course, did not directly give us her data. For that matter, no one at King's realized they were in our hands." ⁴

Watson's crucial realization was that the base nucleotides must be linked in pairs to form the ‘rungs’ of DNA’s ladder. In a draft paper from March 17, 1953, Franklin also proposed a double chain helical structure for DNA. However, her model did not contain base pairing, nor did she realize that the two chains are antiparallel. (antiparallel is basically 2 parallel lines in opposite directions) 

Filled with excitement, James returned to the lab to draw plans for models that the machine shop would construct out of sheet metal and wire. They played around with the shapes of the bases, used paper models, and combined them in different ways. News reached them that Pauling had arrived at an answer, which fuelled them on. When they examined the model, they saw that it was clearly wrong. Relieved, they pushed on with the ordeal and finally visualized that if two of the bases were bonded in pairs (G with C), they took up the same space as the other pair (A with T). Hence, they could be arranged like steps on a spiral staircase inside of two strands of sugar phosphates running in opposite directions. Their model was one of the biggest breakthroughs in biology. 

Watson-Crick and their model

NATURE AND THE NOBEL⁵

On April 25, 1953, an issue of Nature published Watson-Crick’s 900-word article, “Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid” changing history forever. Their caution yet foresight is depicted in this sentence: 

              “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”

 Five weeks later, Crick- Watson published another article proposing the idea that, to make a copy, the double helix unzips, each sugar-phosphate with the four bases attached in some sequence. Then the cell uses each strand as a template to assemble another DNA strand from free-floating complementary bases: A-T; G-C, resulting in two identical DNA molecules. Occasional mistakes enable evolution, resulting in the uniqueness of each organism.

Wilkins, Crick, and Watson won the Nobel Prize in Physiology or Medicine in 1962 for their research on the structure of nucleic acids. Franklin was not conferred upon the Nobel, her part being overlooked, intentional or not. She died from ovarian cancer at the age of 37 on April 16, 1958, in London. However, there was no fixed rule on awarding Nobels posthumously till 1974. So this brings us to the end of partie-2 of our sojourn through the breakthrough which brought in the era of modern genetics- Onward!

 

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¹ It is seldom one sees such a star-studded career (there's a LOT more, wikipedia Linus Pauling and you can gush over that too). The man undoubtedly is Linus Carl Pauling.

² Also, at Cambridge near the same time, Max Perutz was investigating hemoglobin and John Kendrew was studying myoglobin. Perutz and Kendrew received the Nobel Prize in Chemistry for their work in the same year that the prize was awarded to the DNA researchers—1962.

³ Martha Chase was not included in the Nobel, whereas Hershey was. Well, the Committee is missing out I guess, with its Meitner's, Franklin's, and more. 

⁴ Crick acknowledged later: "I'm afraid we always used to adopt – let's say, a patronizing attitude towards her." The sexist atmosphere of that time often ignored women scientists- Both Watson, Crick, and many of their colleagues had the same attitude. Franklin was unhappy with the kind of treatment meted out and later shifted to Birkbeck.

⁵ Watson and Crick included a footnote in their article acknowledging that they were "stimulated by a general knowledge" of Franklin's unpublished contributions.