by Frank Ryan
At the time, Franklin was preparing to leave King's to join the staff at the Biomolecular Research Laboratory at Birkbeck College, London, where she would work under the directorship of J. D. Bernal. To her credit, in her two years at King's Franklin had made a series of original discoveries about DNA. Her research included revealing that DNA existed in two different forms, which she had labeled A and B; that one form could readily turn into the other; and that she had hard proof that the phosphate spine was on the outside. This latter revelation established that it was readily exposed to take up water molecules which wrapped the molecule in a protective sheath within the nuclear environment, keeping it relatively free from the interaction of neighboring molecules while making stretching of the molecule easier.
Once ensconced at Birkbeck, Franklin appears to have settled into a fruitful and amicable working routine with her boss, Bernal, and graduate student Aaron Klug. Here she ceased to work on DNA fibers and instead focused on the molecular probing of viruses, producing some of her finest work. On her later tragic and untimely death, when she left her worldly possessions to Klug and his family, her scientific obituary was admiringly and respectfully written by Bernal in the Times and the scientific journal Nature:
Her life is an example of single-minded devotion to scientific research…As a scientist Miss Franklin was distinguished by extreme clarity and perfection in everything she undertook. Her photographs are among the most beautiful X-ray photographs of any substance ever taken.
Neither Franklin nor Wilkins was aware at the time when Watson stormed in with the Pauling paper, that he and Crick were now determined to construct a new model of its three-dimensional structure. Following the triple-helix debacle, Bragg had forbidden them doing any more work on DNA. Through all the emotional ballet, recalled so vividly by Watson, we should acknowledge that Watson did keep the King's group informed about his and Crick's thinking, and he had attempted to acquaint Franklin with a relevant publication, coming from a major potential rival. We might also note that up to the final decipherment exercise, Watson, Crick, and Wilkins had communicated openly with one another. If Franklin was not privy to these discussions, it was at her choosing. In neither of the biographies of Franklin is there mention of her being inspired by Schrödinger's book or his theory of an aperiodic crystal. She had not chosen DNA as her research theme, it had been suggested to her by Randall—though she evidently saw it as a challenge befitting her growing expertise and fascination with X-ray crystallography.
In their enthusiasm for the model-building approach, Watson and Crick had explained all about it to Wilkins. In passing over the reins of the DNA research to him, they even lent him their jigs for making the necessary parts of the model. But not only had Franklin rebuffed cooperation with Wilkins, the King's group had eschewed the opportunity of taking up the Pauling-inspired modeling approach. And now, at what must have appeared a critical moment in time, what were Crick and Watson to make of the fact that Franklin was leaving King's, abandoning her work on the DNA fiber, and at the same time Wilkins had also stopped working on DNA, waiting, as he confessed, for the dust of Franklin's departure to settle before vaguely starting anew.
Watson had every reason to assume that Pauling, bruised by his own published error of a triple-helix structure for DNA, must now be more intensively engaged than ever with the problem—he must surely be formulating a new molecular approach. After the heated encounter at King's, Watson and Wilkins shared a meal and a bottle of Chablis. But their conversation over dinner produced no new inspiration. For Watson, the key theoretical difficulty was not whether the DNA molecule was a helix, but whether the helix was a triple or a double chain. Wilkins still favored three chains over two, but in so far as Watson could tell, Wilkins's reasoning was not foolproof. By the time he had cycled back from the station in Cambridge and climbed over the back gate to make a late return to college, “I had decided to build two-chain models.” He must have chuckled at a humorous inspiration he would subsequently pass on to Crick the next morning. Francis would just have to agree. “He knew that important biological objects come in pairs.”
This inspiration—and there appears to be no other word for why Watson decided to focus on a double helix—would prove to be exactly what was required to fit the Chargaff data and Crick's ideas on how DNA might replicate itself. Given the new state of affairs at King's, even Bragg saw the sense of allowing his unruly young scientists to return to the mystery of the gene, most particularly so since it might give his group the advantage of a triumph over his academic rival, Pauling.
The modeling went into overdrive, with Watson putting together scale models of the different chemicals involved in the structure of DNA, the four nucleotides—G, A, C, and T—the phosphate molecule, and the sugar molecule, deoxyribose. Obstinate in his notion that the spine, which probably involved the phosphate and sugar, had to be internal, Watson attempted to construct a new model with the phosphate-sugar spine still on the inside. But Crick, playing symbiotic devil's advocate, insisted this just did not fit the X-ray data. Indeed, Franklin and Gosling had both insisted that the phosphate spine must be on the outside. Watson now confessed that he had simply refused to take this into account because it made the modeling too easy and introduced an enormous variety of possibilities. But now, persuaded by Crick, he switched to putting the phosphate-sugar spine on the outside—as an exoskeleton, like one sees in the insect world—and then attaching the nucleotides so they projected into the middle of the double helix made by the spiraling phosphate-sugar spines. In spite of Chargaff's work, and in spite of Griffith's advice to Crick, Watson persisted in attempting to attach like with like, for example A to A, G to G. It just didn't work.
In the middle of all this, happenstance again contributed to the story. An American scientist, Jerry Donohue, a former protégé of Pauling's, paid a visit to the Cambridge lab. An expert on hydrogen bonding, Donohue now corrected their models to suit the quantum implications.
Watson and Crick now felt more confident that it had to be a double-stranded helix, with the two strands reading in counter directions—the sense and anti-sense we take for granted today. The two strands had to line up, with the complementary nucleotides linking to one another through hydrogen bonding. Watson sat down at his desk and cut out pieces of stiff cardboard in the shape of the nucleotide molecules, looking at how the actual shapes fit with one another, hoping to see some pairing possibilities.
Suddenly I became aware that an adenine-thymine pair held together by two hydrogen bonds was identical in shape to a guanine-cytosine pair held together by at least two hydrogen bonds.
Today we recognize that the latter is held together by three hydrogen bonds. If we peer at the basic shapes in the figure below we can see what became obvious to Watson.
The skeptical Crick, on arrival at the lab to examine Watson's matching shapes of cardboard, almost immediately agreed with Watson's brainwave. The complete model could now be assembled in three-dimensional space—a conflagration of bits of wire, cut to the right lengths to represent covalent and hydrogen bonds, the molecules constructed of the composite atoms, and the whole assemblage suspended by clamps from tall vertical steel rods. The resulting double helix coiled around the central rods, rising in a spectacular conflation of wires and hand-cut, molecular-shaped plates from the lab bench upward to the ceiling.
Everybody who saw the subsequent model reacted with awe. It was as if in the briefest look at it they saw immediately that it had to be right. It wasn't merely right: it was a spectacularly gorgeous creation—a beauty to behold. All the more so since it was immediately obvious to everybody who saw it that it explained all that was demanded of the mystery of the gene, in terms of chemical memory and the copying necessary for the gene to reproduce itself, from cell to cell, from parent to offspring. It was capable of providing the coding that was necessary to pass the secret on, generation after generation, for the immense complexity of biodiversity and for the complex evolving lineages of evolut
ion. It truly was the secret of life.
Watson and Crick's first paper on the structure and function of DNA appeared in the journal Nature on April 25, 1953, and was accompanied by two papers in the same issue from the crystallographers at King's College London—the first by Wilkins, Stokes, and Wilson; the second by Franklin and Gosling. Nobody's contribution was excluded. Five weeks later, Watson and Crick published a second paper, again in Nature, on the genetic implications of the structure of DNA. A short sentence in the April 25 edition would capture the attention of scientists throughout the world: “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”
Those papers would inevitably change the world of biology, evolutionary biology, and medicine. Indeed, the ramifications are still echoing through our world and penetrating much wider and deeper into society than Watson and Crick could have possibly imagined.
It is extraordinary to realize that, less than two years after the start of their ad hoc partnership, Watson and Crick had correctly figured out the three-dimensional chemical structure of DNA. Crick was 37 and still had not completed his PhD, and Watson was still a postgraduate student, aged just 25. At a superficial glance, there would appear to be no logical reason why these two seeming misfits should be the discoverers of the three-dimensional chemical structure of DNA. They had done little or no lab work in the prelude to the discovery. They were lowly in their positions within the lab—Crick a research assistant and Watson a graduate student. They were impecunious, living in impoverished surroundings, yet uncaring about all that. They had only belatedly realized the relevance of discoveries made by other scientific contributors. Their official duties had nothing to do with DNA. Crick was still trying to complete his PhD thesis on the X-ray diffraction of polypeptides and proteins while Watson was supposed to be helping Kendrew to crystallize the molecule of myoglobin. The head of their department, Sir Lawrence Bragg, was, through most of their efforts, opposed to their work on DNA. In the manner in which science normally works, the pair should never have made their discovery. There were colleagues, like Willy Seeds who insulted Watson at the foot of the Swiss glacier, who thought that Watson in particular didn't deserve the acclaim. But the fact is, they both did.
The detractors are missing the point: what Watson and Crick achieved was an act of sublime creativity, like the plays of Shakespeare, Da Vinci's Mona Lisa, or Beethoven's Ninth Symphony. Admittedly this was not artistic creativity. Rather, like Newton's discovery of gravity, Darwin's discovery of natural selection and Einstein's theory of relativity, this was an act of scientific creativity that opened a new window of understanding onto our understanding of life itself—and, at the most profound of levels, what it is to be human.
In 1962, Crick, Watson, and Wilkins shared the Nobel Prize in Physiology or Medicine for the discovery of the structure of DNA. The only one of the three to mention Rosalind Franklin was Wilkins, who also acknowledged Alexander Stokes's 1/5000th contribution. Tragically, Franklin had died of ovarian cancer some four years earlier, at a time when her work on viruses was becoming globally recognized as among the finest achievements in X-ray crystallography. Some, including Sayre, have queried if Franklin might have taken Wilkins's place on the rostrum had she lived. It's a moot question, but I personally think it unlikely. Wilkins initiated the DNA research at King's, inspired, like Watson and Crick, by Schrödinger's book. His X-ray diffraction picture—actually taken by Gosling—inspired Watson's arrival into the Cambridge lab. His cooperation with Watson and Crick was so close and formative in the discovery that Watson wanted to include his name in the famous first paper. It was Wilkins's modesty and integrity that caused him to refuse the honor. This is why I doubt that Franklin would have replaced Wilkins on the rostrum in 1962. But I do believe that there might have been a second, rather more likely, opportunity for recognition of the contribution of Rosalind Franklin to X-ray crystallography, one that is suggested in the great admiration felt for her work by such an eminent figure as Bernal.
When she moved to Birkbeck College, Franklin found a happy working relationship with Lithuanian Jewish chemist and biophysicist Aaron Klug who, following graduation in South Africa, had arrived in the UK on a research fellowship to complete his doctorate in X-ray crystallography at Trinity College, Cambridge, in 1953. This was, of course, the year of publication of the DNA discovery. At Birkbeck, Franklin took Klug under her wing, forming a close working relationship and friendship that would continue for the rest of her life. We know that after Franklin's untimely death, Klug took her techniques further to be rewarded with the Nobel Prize in Chemistry in 1982. The official declaration of his meriting the prize was: “for his development of crystallographic electron microscopy and his structural elucidation of biologically important acid-protein complexes.” How likely is it that, had Rosalind Franklin lived, she would have shared the podium with Aaron Klug for their cooperative effort?
Some nine years earlier, on August 12, 1953, five months after Crick and Watson had first modeled the double helix, Francis Crick wrote a letter to Erwin Schrödinger in which he thanked him for the inspiration of his book. In the letter he described how, in the structure of DNA, they had indeed discovered the “aperiodic crystal” that he had predicted would be the molecular code for life.
I have the feeling that if your structure is true, and if its suggestions concerning the nature of replication have any validity at all, then all hell will break loose, and theoretical biology will enter into a most tumultuous phase.
MAX DELBRÜCK, WRITING TO WATSON
Judson, widely recognized as the historian of the DNA story, described the elucidation of its structure as “a siege, a conquest.” Given the discovery of the three-dimensional structure of DNA, with its four-letter code for the storing of heredity, one might have anticipated enlightenment, but instead the prevailing atmosphere was one of confusion. Watson and Crick's discovery had provoked a storm of new questions. To begin with, was DNA the answer to the coding of heredity to all of life? At least this question was already answered; Avery had set the ball rolling by discovering it in bacteria. The phage school worked on it in viruses. Chargaff had confirmed the same in a range of different life-forms. DNA was universal. The next major question was this: How did its incredibly simple four-letter code—G, A, C, and T—translate into the complexity of the estimated 80–100,000 proteins that were essential for the structure and functioning of our human bodies, and the bodies of every other living creature?
Crick would later recall that they already had an outline of the answer to the protein enigma. Since the spine of the helix was made up of sugar and phosphate repeats, the only chemicals capable of coding for heredity, and translating to proteins, were the four nucleotides—otherwise known as bases, or base sequences—GACT. Some advances had already been made into this mystery. Thanks to the pioneering evolutionary biologist Thomas Hunt Morgan, working in his fruit fly laboratory at Columbia University, we knew that the genome was divided into chromosomes. Thanks to Morgan, Muller, and others, we knew that the chromosomes were themselves parceled into discrete sections called genes. A further step, that a gene coded for a specific protein, was first postulated by a British doctor, Archibald E. Garrod, as early as 1908, when he figured out that the inherited illness known as alkaptonuria was probably the result of a defective enzyme. An enzyme is a protein that speeds up the rate of a chemical reaction in living systems. But Garrod couldn't take it that vital step further and prove that the defective enzyme was the expression of a defective gene. The essential link between genes and proteins was confirmed by two Americans—a geneticist, George W. Beadle, and a biochemist, Edward L. Tatum—who were working on the heredity of eye color in fruit flies. By 1941, shifting their focus to a fungus that infected moldy bread, they had showed that a single gene coded for a specific enzyme involved in the mold's living chemistry. It was this discovery that resulted in the maxim: “one-gene-one-p
rotein.” But how did the four-letter DNA code of the gene translate to the 20-letter amino acid code of the protein?
For Francis Crick, this was the very enigma that had inspired his own “mad pursuit” after reading Schrödinger's book. Following the discovery of the double helix, Watson would soon be forced to return to the United States, having run out of funding. But Crick would continue to investigate the extrapolation to proteins.
Since the DNA was contained in the nucleus of the cell and protein manufacture always took place in the region outside the nucleus, known as the cytoplasm, the code of the gene had to be copied in some way that allowed it to be sent out of the nucleus and into the cytoplasm. This made Crick consider a sister molecule of DNA known as ribonucleic acid, or RNA.
There are obvious similarities between the two molecules. Both are nucleic acids, made up of varying sequences of four nucleotides. Where DNA is made up of guanine, adenine, cytosine, and thymine, or GACT, RNA is made up of guanine, adenine, cytosine, and uracil—GACU. RNA also differs from DNA in the fact that it is not a double-stranded helix but, at least in most of its roles, is single-stranded. It also differs from DNA in its sugar, which is ribose where DNA's sugar is deoxyribose. At the time of Watson and Crick's discovery of the 3-D structure of DNA, molecular biologists and geneticists were also becoming increasingly interested in this sister molecule, RNA. Immediately prior to Watson and Crick's monumental discovery, many scientists were beginning to think that RNA must be playing an important role in the way living cells worked.
At the same time, there was something elusive about RNA. Where the amount of DNA in different cells of the body, say a brain cell or a liver cell, was always the same, the amount of RNA seemed to vary. To add to the confusion, DNA was only found in the nucleus, meanwhile RNA was found in both the nucleus and the non-nuclear territory, known as the cytoplasm—the part of the cell where most of the active biological chemistry takes place. To confuse things even more, the amount of RNA in a given cell also varied, depending on how active the cell was. A growing cell, or a cell that was producing lots of new protein, had more RNA than a cell that was mature and chemically quiet. Liver cells, for example, which were thought of as the factory for making proteins, were packed with RNA. Moreover, RNA was also found in the same parts of the cytoplasm—the small round bodies known as ribosomes—where protein was manufactured.