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Maurice had had a natural scientific curiosity even as a boy, and it was this curiosity that led to his studying physics as part of his BA at Cambridge University, after which he worked for his PhD under John Turton Randall (later knighted), a physicist who played a leading role in the development of radar during the war.
As a postgraduate, Wilkins moved to the University of Birmingham, following the posting of his Cambridge tutor, Randall, where the two scientists continued their collaboration on radar. But then, out of the blue, Wilkins found himself dispatched to the United States to work on the Manhattan Project. His purpose was to figure out how to purify suitable isotopes of uranium from impure sources, to make them suitable for the atomic bomb. In February 1944 Wilkins crossed the dangerous waters of the Atlantic on the Queen Elizabeth, heading for the University of Berkeley, California. Here he made a modest contribution to the development of the atomic bomb. However, the subsequent destruction of Hiroshima and Nagasaki by the very weapons that he had worked on left Wilkins somewhat unsettled in conscience.
After the war Wilkins returned to England, where he ended up as assistant director of the new Biophysics Unit at King’s College London, funded by the Medical Research Council, and where his former boss, Randall, was now the Wheatstone Professor of Physics. The new departmental remit was to apply the experimental methods of physics to important biological problems. This would result in Wilkins developing a relationship with Watson and Crick and joining the search for the molecular code of DNA. It would also involve him in a somewhat infamous strained working relationship with the X-ray crystallographer Rosalind Franklin.
Given this developing history, we might pause a moment or two to consider Wilkins’ personality, and its relevance to the com-ing storm. From what one can gather from his belatedly published biography, and the memory of those who knew him and worked with him, Wilkins was a quiet, highly moral man, somewhat Quaker-like in social attitudes. As a boy he enjoyed a close emotional relationship with his elder sister, Eithne, who taught him to dance. But this intimacy was torn apart when Eithne developed a bacterial infection that turned into a septicaemia, the blood-borne infection provoking septic arthritis in multiple joints. This would have been a shockingly painful and disabling condition, which, prior to antibiotics, might have proved fatal. She spent months in a hospital bed, with her limbs dangling from hoists, her joints lanced open to drain the pus. The unfortunate Eithne survived but the intimacy with her younger brother ended. The trauma of this experience may well have affected his self-confidence, particularly in his relationships with women.
While an undergraduate at Cambridge, he fell in love with a woman called Margaret Ramsey, but he ‘was incapable of making a suitable advance to her’. After he told her of his love, there was a short silence after which she walked from the room. During his stay in Berkeley, Wilkins was attracted to an artist named Ruth, who had shared lodgings with him. She conceived a child and they subsequently married, but when, as the war was ending, he informed Ruth that he intended to return to the UK, she refused to accompany him. ‘Ruth told me one day that she had made an appointment for me with a lawyer and when I arrived at his office I was shocked to hear that Ruth wanted to end our marriage.’ Shortly after the divorce, Ruth gave birth to a son. Wilkins went to see her, and their baby, in the hospital ward, before returning to the UK alone.
Wilkins would admit to difficulty overcoming an innate shyness, and he would require periodic psychotherapy in his time working at King’s, but he subsequently found a wife, Patricia, who appreciated the sensitive soul behind the diffident exterior, and he enjoyed a happy marriage and the joys of rearing a family of four children. There was also a fruitful outcome of his unsettled conscience following his work on the Manhattan Project. Before leaving Berkeley, one of his working colleagues came to his rescue … ‘Seeing I wanted to find some new direction, he lent me a new book with the rather ambitious title, What Is Life?’
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A Couple of Misfits (#ulink_2a07bc6a-42b5-5437-9335-fbe67e5a89a5)
Francis likes to talk … He doesn’t stop unless he gets tired or he thinks the idea’s no good. And since we hoped to solve the structure by talking our way through it, Francis was the ideal person to do it.
JAMES WATSON
It is somewhat ironic that Maurice Wilkins only arrived in Naples by happenstance, since he was substituting for Randall, who had agreed to present the talk but had been unable to attend. It seems unlikely, had Randall himself presented the lecture, that he would have included the DNA slide, or that he would have spoken of what it portrayed with such clear reference to Schrödinger’s book. This lecture, which so excited Watson, was on the physico-chemical structure of big biological molecules, mostly proteins, made up of thousands of atoms. The key photograph had been taken by Wilkins, working together with a graduate student called Raymond Gosling while using a technique called X-ray diffraction.
One of the things this technique was particularly good at was finding the sort of repetitive molecular themes you found in crystals, hence the other term for it: X-ray crystallography.
‘Suddenly,’ as Watson would later recall, ‘I was excited about chemistry.’
Up to this moment Watson had had no idea that genes could crystallise. To crystallise, substances must have a regular atomic structure – a lattice-like structure of atoms at the ultramicroscopic level. The youthful Watson appears to have been a wonderfully free spirit journeying from one interesting encounter to another. Impulsive, impatient, egregiously direct, yet all the while on the hunt for new adventure.
‘Immediately I began to wonder whether it would be possible for me to join Wilkins in working on DNA.’ But Watson never got to work with Wilkins. Instead, happenstance headed him in the direction of another X-ray crystallographer called Max Perutz, who was working at the Cavendish Laboratory at Cambridge University.
The Cavendish Laboratory is a world-famous department of physics. First established in the late nineteenth century to celebrate the work of British chemist and physicist Henry Cavendish, one of its founders and the first Cavendish Professor of Physics was James Clerk Maxwell, famous for his development of electromagnetic theory. The fifth Cavendish Professor and the director of the laboratory at the time of Watson’s arrival was William Lawrence Bragg, who was the successor, as director, to Lord Ernest Rutherford, another Nobel Prize-winner and the first physicist to split the atom. Bragg was an Australian-born physicist who, jointly with his father, had been awarded the Nobel Prize in Physics in 1915 for establishing the use of X-rays in analysing the physico-chemical structures of crystals. X-ray beams are bent when they pass through the orderly atomic lattice of crystals. What is projected onto the photographic plate is not the picture of the atoms within the structure but the refracted pathways of the X-rays after they have collided with the atoms. This is called ‘diffraction’ and is similar to how light is bent when it passes through water. In a structure with haphazard positioning of atoms in space, the X-rays will be scattered randomly and form no pattern. But in a structure that contains atoms in a repetitive atomic lattice – such as a crystal – the X-rays are deflected in a recognisable pattern of blobs on the X-ray plate. From this diffraction pattern, the atomic structure of the structure can be deduced.
The two Braggs – father and son working as a team at the University of Leeds – had constructed the first X-ray spectrometer, allowing scientists to study the atomic structure of crystals. At the age of 22, Bragg Junior, now a Fellow of Trinity at Cambridge, had produced a mathematical system, Bragg’s Law, that enabled physicists to calculate the positions of the atoms within a crystal from the X-ray diffraction pictures. At the time of Watson’s arrival into the laboratory, Bragg’s main focus of study was the structure of proteins. It was this potential for the X-ray diffraction of proteins that had attracted Max Perutz to the Cavendish Laboratory.
Born in Vienna of Jewish parentage, Perutz was another enforced exile who had settled in England and become a research student at the Cavendish Laboratory. He completed his PhD under Bragg and subsequently devoted most of his professional life to the analysis of the macromolecule of haemoglobin, the pigment that colours the red cells in our blood, enabling them to carry oxygen around the body. Also working at the Cavendish was an unusual young scientist, Francis Crick. The English-born scientist had graduated with a BSc in physics from University College London aged 21, but thanks to war duty and a profound antipathy to his PhD project (he was supposed to be working on the viscosity of water at high temperatures) he, like Watson, found an alternative source of inspiration in Schrödinger’s book. In Crick’s own words, ‘It suggested that biological problems could be thought about in physical terms.’
But what terms?
At the time Crick wasn’t as convinced by Avery’s discovery as Watson was. Like Schrödinger himself, Crick was more inclined to the protein hypothesis. But he was every bit as impressed with Schrödinger’s ‘code-script’ idea as Watson. What then could he possibly make of Schrödinger’s conception of an aperiodic crystal?
Simple crystals such as sodium chloride, the basis of common salt, would be incapable of storing the vast memory needed for genetic information because their ions are arranged in a repetitive or ‘periodic’ pattern. What Schrödinger was proposing was that the ‘blueprint’ of life would be found in a compound whose structure had something of the regularity of a crystal, but must also embody a long irregular sequence, a chemical structure that was capable of storing information in the form of a genetic code. Proteins had been the obvious candidate for the aperiodic crystal, with the varying amino acid sequence providing the code. But now that Avery’s iconoclastic discovery had been confirmed by Hershey and Chase, the spotlight fell on DNA as the molecular basis of the gene. Suddenly new vistas of understanding the very basics of biology, and medicine, appeared to be beckoning.
It was through a mixture of luck and the gut reaction of Perutz that the dilettantish Crick was taken into the fold of the Cavendish. In Perutz’s recollection, Crick arrived in 1949 with no reputation whatsoever in science. ‘He just came and we talked together and John Kendrew and I liked him.’ And so the likeable Crick ended up, in such an idiosyncratic process of selection, working on the physical aspects of biology – what today we call molecular biology – under the guidance of Bragg, Perutz and Kendrew, at the Cambridge laboratory.
In 1934, John Desmond Bernal, an Irish-born scientist with Jewish ancestry and a student of Bragg Senior, had shown for the first time that even complex organic chemical molecules, such as proteins, could be studied using X-ray diffraction methods. Bernal was a Cambridge graduate in mathematics and science, who was appointed as lecturer to Bragg at the Cavendish in 1927, becoming assistant director in 1934. Together with Dorothy Hodgkin, Bernal pioneered the use of X-ray crystallography in the study of organic chemicals – the chemicals involved in biological structures – including liquid water, vitamin B1, the tobacco mosaic virus and the digestive enzyme, pepsin. This was the first protein to be examined at the Cavendish in this way. When, in 1936, Max Perutz arrived as a student from Vienna, he extended Bernal’s work to the X-ray study of haemoglobin.
By the time Crick joined the laboratory, Sir William Bragg had been replaced by Sir Lawrence Bragg, and John Kendrew and Max Perutz had taken Bernal’s findings further to become bogged down in a ‘disastrous paper’ on the chain structures of proteins. And now we discover something distinctly unusual about Francis Crick, something that Perutz may have intuited at their meeting. He had an avid curiosity about science, reading very widely, and he was equipped with a mind capable of amassing a formidable knowledge base across different disciplines. One of the first things he did after his arrival into the Cavendish was to acquaint himself with everything his bosses had achieved. Junior as he was, Crick now took it upon himself to undertake a long, critical look at their work. This he then proceeded to criticise from basic principles. At the end of his first year in the department, Crick presented his criticisms in the form of an ad hoc seminar, borrowing his title from Keats as ‘What Mad Pursuit’. He began with a twenty-minute summary of the deficiencies in the departmental methods before pointing out what he saw as the ‘hopeless inadequacy’ of their investigation of the structure of the haemoglobin molecule. The X-ray analysis of haemoglobin was of course Perutz’s main objective. Bragg was infuriated by the cocky behaviour of this upstart junior colleague, but Perutz would subsequently admit that Crick was right and proteins were far more complicated in their structures than they had initially assumed. Restless and ever-inquisitive, Crick proved to be an uneasy, sometimes downright embarrassing import into the scientific pool of the laboratory. And while Bragg and Perutz saw proteins as the great unsolved puzzle, Crick was more interested in the mystery of the gene.
As 1949 elided into 1950, Crick would subsequently confess that he still did not realise that the genetic material was DNA. But he knew that genes had been plotted out in linear arrays along the chromosomes by people like Barbara McClintock, and that proteins, which had to be the expression of the genes, were also being plotted out as linear arrays, however lengthy and complicated. There had to be some logical way in which one translated into the other. By 1951, two years after his arrival into the Cavendish Laboratory, Crick perceived that these were two different, if necessarily related, puzzles – the mystery of how genes appeared able to copy themselves, and the mystery of how the linear structures of genes translated into the linear structures of proteins.
The wide-reading, voraciously inquisitive Crick needed what Judson termed a catalyst. This arrived in the form of the gangly, equally inquisitive Watson that same year, 1951. From their first meeting, it would appear that here was one of those rare working conjunctions of two odd-ball personalities that, when they come together, make an extraordinary creative whole that is more than the sum of the individual ingenuities. And yet it very nearly didn’t happen.
*
We should recall that Watson was extremely junior within the department. A recent PhD graduate, he had arrived into Kalckar’s laboratory on a Merck Fellowship funded by the US National Research Council. The terms and conditions were laid down and signed for back home, but now here he was abandoning those carefully laid intentions to gallivant from the work in Denmark to follow some giddy new inspiration in England, a place he had never visited in his life and where he knew absolutely nobody. Impulsive and single-minded, Watson would subsequently confess that his head was filled with curiosity about that single DNA photograph. He had tried to engage with Wilkins in Naples after the lecture, at a bus stop during an excursion to the Greek temples at Paestum. He had even tried to take advantage of a visit from his sister, Elizabeth, who had arrived to join him as a tourist from the States. Now here were Maurice Wilkins and Watson’s sister, Elizabeth, finding a common table to take lunch together. Watson sensed an opportunity and barged in, with the intention of ingratiating himself with Wilkins. But the self-effacing Wilkins excused himself, to allow brother and sister the privacy of the table.
His plans foiled, Watson refused to let go of this exciting new avenue of interest. ‘I proceeded to forget Maurice, but not his DNA photograph.’
He stopped over in Geneva for a few days to talk to a Swiss phage researcher, Jean Weigle, who provoked yet more excitement by informing Watson that the eminent American chemist, Linus Pauling, had partly solved the mystery of protein structure. Weigle had attended a lecture by Pauling, who like Bragg in Cambridge had been working with X-ray analysis of protein molecules. Pauling had just made the announcement that the protein model followed a uniquely beautiful three-dimensional form – he had called it an ‘alpha-helix’. By the time Watson arrived back in Copenhagen, Pauling had published his discovery in a scientific paper. Watson read it. Then he re-read it. He was confounded by his lack of understanding of X-ray crystallography. The terminology, in physics and chemistry, was so far beyond him that he could only grasp the most general impression of its content. His reaction was so childishly naïve as to be touching: in his head he devised the opening lines of his own imagined paper in which he would write about his discovery of DNA, if and whenever he discovered something of similar portent.
But what to do to get on board the DNA gravy train?
He needed to learn more about X-ray diffraction studies. Ruling out Caltech, where Pauling would react with disdain to some ‘mathematically deficient biologist’, and now ruling out London, where Wilkins would be equally uninterested, Watson wondered about Cambridge University, where he knew that somebody called Max Perutz was following the same X-ray lines of investigation of the blood protein molecule, haemoglobin.
‘I thus wrote to Luria about my newly found passion …’
The world of science was smaller in 1951 than it is today. Even so, it would appear a hopelessly optimistic ambition for this impulsive young graduate to merely ask his mentor to fix his arrival into a leading laboratory in England to engage in a line of research that he knew absolutely nothing about.
The amazing outcome was that Luria was able to do so. By happenstance, he met Perutz’s co-worker, John Kendrew, at a small meeting at Ann Arbor, in Michigan, where, by a second and equal happenstance, there was a meeting of minds – both scientific and social. And by a third happenstance, Kendrew was looking for a junior to help him study the structure of the muscle-based protein myoglobin, which contained iron at its core and held on to oxygen, just like the haemoglobin in the blood.
Twice in his short career the young American scientist had leapt into the unknown and landed on his feet. First it had been through Luria’s patronage in Bloomington, and by extension also Delbrück’s, two of the co-founders of the phage group; and now the gift of happenstance extended further, again through Luria’s patronage, to Kendrew, and by proxy to the Cambridge laboratory and Max Perutz. Watson’s arrival into the laboratory would bring him under the ultimate tutelage of Sir Lawrence Bragg, a founder of X-ray crystallography. It would connect him directly to his future partner in DNA research, Francis Crick, and further afield – through the connection between the Cambridge laboratory and the X-ray laboratory at King’s College London – with Maurice Wilkins and a young female scientist, Rosalind Franklin, who were working on the X-ray crystallography of DNA.
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The Secret of Life (#ulink_191c9ae8-887d-5869-af27-b063095aa353)
I think there was a general impression in the scientific community at that time that [Crick and Watson] were like butterflies flicking around with lots of brilliance but not much solidity. Obviously, in retrospect, this was a ghastly misjudgement.
MAURICE WILKINS
In the opening pages of his brief, witty and brutally candid autobiography, James Watson recounts a chance meeting in 1955 with a scientific colleague, Willy Seeds, at the bottom of a Swiss glacier. It was two years after the publication of the discovery of DNA. Watson and Seeds were acquainted, Seeds having worked with Maurice Wilkins in probing the optical properties of DNA fibres. Where Watson had anticipated the courtesy of a chat, Seeds merely remarked, ‘How’s Honest Jim?’, before striding away. The sarcasm must have bitten deep for Watson to not merely remember it distinctly, but even to consider the term ‘Honest Jim’ as the initial title of his life story, before being persuaded to adopt the more descriptive alternative, ‘The Double Helix’. It was as if the former colleague was questioning Watson’s right to be recognised as the co-discoverer of the secret of life.
He had been taken aback, reflecting on meetings with the same colleague in London a few years earlier, at a time when, in Watson’s words, ‘DNA was still a mystery, up for grabs … As one of the winners, I knew the tale was not simple, and certainly not as the newspapers reported.’ It was a more curious story, one in which his fellow-discoverer, Francis Crick, would freely admit that neither he nor Watson was even supposed to working on DNA at the time. Equally curious was the fact that up to the day of the discovery, neither Watson nor Crick had contributed anything much to the many different scientific threads and themes that, when finally put together, like the pieces of a remarkable three-dimensional jigsaw puzzle, laid the molecular nature of DNA bare for the first time in history.
Watson’s welcome into the Cambridge laboratory was quintessentially English in its lack of formality. He arrived in Perutz’s office straight from the railway station. Perutz put him at his ease about his prevailing ignorance of X-ray diffraction. Both Perutz and Kendrew had come to the science from graduation in chemistry. All Watson needed to do was to read a text or two to become acquainted with the basics. The following day Watson was introduced to the white-moustached Sir Lawrence, to be given formal permission to work under his direction. Watson then returned to Copenhagen to collect his few clothes and tell Herman Kalckar about his good luck. He also wrote to the Fellowship Office in Washington, informing them of his change of plans. Ten days after he had returned to Cambridge he received a bombshell in the post: he was instructed, by a new director, to forgo his plans. The Fellowship had decided he was unqualified to do crystallography work. He should transfer to a laboratory working on physiology of the cell in Stockholm. Watson appealed once more to Luria.
As far as Watson was concerned it was out of the question to follow these new instructions. If the worst came to the worst, he would survive for at least a year on the $1,000 still left to him from the previous year’s stipend. Kendrew helped him out when his landlady chucked him out of his digs. It was just another indignity when he ended up occupying a tiny room at Kendrew’s home, which was unbelievably damp and heated only by an aged electric heater. Though it looked like an open invitation to tuberculosis, living with friends was preferable to the sort of digs he might be able to afford in his impecunious state. And there was a comfort to be had:
‘I had discovered the fun of talking to Francis Crick.’
And talk they did.
In Crick’s own memory: ‘Jim and I hit it off immediately, partly because our interests were astonishingly similar and partly, I suspect, because a certain youthful arrogance, a ruthlessness, and an impatience with sloppy thinking came naturally to us both.’ That conversation, lasting for two or three hours just about every day for two years, would unravel the most important mystery ever in the history of biology – the molecular basis of heredity.
We need to grasp a few fundamentals to understand how this happened. Firstly, we have two young and ambitious men – in Watson’s case aged just 23, in Crick’s, aged 35 – who were both exceptionally intelligent and surrounded by the ambience of high scientific endeavour and achievement. We need to grasp that Watson’s interest, intense and obsessive, was the structure of DNA in its potential to explain the mystery of the workings of the gene, and thus the storing of heredity. We also need to grasp the slight, but important, difference with Crick’s interest, which was not DNA, or even the gene in itself, but the potential of DNA to explain how Schrödinger’s mysterious molecular codes – his aperiodic crystals – had the potential not only for coding heredity but for translating from one code to another, from the gene to the second aperiodic crystal that must determine the structure of proteins.
Crick would subsequently recall Watson’s arrival in early October 1951. Odile, his French second wife, and he were living in a tiny ramshackle apartment with a green door that they had inherited from the Perutzes. Conveniently situated for the centre of Cambridge and only a few minutes’ walk from the Cavendish Laboratory, it was all they could afford on Crick’s research stipend. The ‘Green Door’, as it was thereafter called, consisted of an attic over a tobacconist’s house, with ‘two and a half rooms’ and a small kitchen that was reached by climbing a steep staircase off the back of the tobacconist’s house. The two rooms served as living room and bedroom for Crick and Odile, with the half room providing a bedroom for Crick’s son, Michael – born to his first wife, Ruth Doreen – when Michael was home from boarding school. The wash-room and lavatory opened halfway up the stairs and the bath, covered with a hinged board, was a feature of the tiny kitchen.
One day, out of the blue, Perutz brought Watson to the flat. Crick was out. But he would recall Odile remarking that Max had come round with a young American who ‘had no hair’. The newly arrived Watson was sporting a crew-cut – a hairstyle uncommon in England at the time. They met within a day or two … ‘I remember the chats we had over those first two or three days in a broad sort of way.’
Both men were impecunious, but it hardly mattered since they were uninterested in money. What mattered was that the deeply personal, deeply intellectual, symbiosis had begun. Crick brought a rowdy enjoyment of problem solving, together with the hubris, born out of his background in physics, to believe that the big problem facing them – the mystery of the gene – was indeed solvable. Watson, who had little knowledge of physics or X-ray crystallography, brought a mine of knowledge about the way in which genes worked – the fruits of the bacteriophage researches of Luria and Delbrück. Perutz would subsequently confirm that the arrival of Watson, at that particular moment of time, was opportune for the workings of the Cavendish Lab, where his enthusiastic personality appeared to have galvanised Crick, and where his knowledge of the field of genetics added an exotic aspect to the structural physics and chemistry that otherwise prevailed. Moreover, different as their backgrounds were, Crick and Watson shared a deep, insatiable level of curiosity about the puzzle that lay at the very root of biology: they were determined, almost from their first meeting, that they would solve the mysterious nature of the gene.
The first creative step was to realise that the answer lay with DNA. To be more accurate, they realised that somehow chemical structure must parallel function: so the answer to the great conundrum lay in the three-dimensional chemical structure of DNA. But nobody really knew what shape or form this structure took. To the minds of Crick and Watson at that particular moment in time, it would have seemed nothing more than a ghost in the mist.
New discoveries in science will usually involve a lengthy period of laboratory labour, with knowledge growing by hard-won increments, often involving contributions from several, or a good deal more than several, different sources. In many ways the struggle to get to grips with the mysteries of heredity followed exactly such a course. But the mundane sweat of the laboratory aspects, the growth of knowledge by hard-won increments, would not fall to Watson and Crick. These would be left to others. The Crick–Watson symbiosis would be founded on a second, equally important ingredient of scientific advance, and one that has commonalities with the advances in the arts and humanities: this is the quintessentially human gift we call ‘creativity’.
Within the hierarchy of the lab, Crick and Watson were the lowest contributing level. In Crick’s words, ‘I was just a research student and Jim was just a visitor.’ They read very widely, imbibing the fruits of the hard work of others. They talked and talked, thinking out loud, probing one another’s ideas and knowledge, often with Crick playing devil’s advocate. In fact they gossiped and argued so much they were given a room to themselves – to avoid their interrupting the thoughts of their more senior colleagues – within the crowded structure of the old Cavendish Laboratory. The X-ray laboratory, with its heavy machinery and radiation dangers, was located in the basement. Jim and Francis would also share a cheap and cheerful lunch, of shepherd’s pie or sausage and beans, at the local pub, the Eagle – a grubby establishment in a cobblestoned courtyard – where the creative debate would simply continue.
What little they knew about DNA was made even more uncertain by the fact that Crick believed that much of what was generally assumed to be the case with DNA and heredity was almost certainly wrong. It had been this attitude that had got him into trouble with Bragg. It meant that he didn’t even trust the work of his seniors here in the lab. But the real reason behind Bragg’s anger was his resentment of the fact that the chemist, Pauling, had discovered the alpha helix of protein. Meanwhile, Crick was convinced that the reason why the Cavendish had missed out on this was because they were assuming the accuracy of some earlier experimentation on the X-ray interpretation of the skin protein, keratin, which is the main ingredient of our human nails and a raptor’s claws. The way in which Crick’s mind worked can be gleaned from a remembered conversation:
‘The point is [so-called] evidence can be unreliable, and therefore you should use as little of it as you can. We have three or four bits of data, we don’t know which one is reliable … [What if] we discard that one … then we can look at the rest and see if we can make sense of that.’
*
Watson joined the Cavendish in the same year, 1951, in which Linus Pauling published his paper on the protein ‘alpha helix’. This discovery so rattled Watson that all of the time he was working with Crick on the structure of DNA, he was looking over his shoulder in Pauling’s direction.
He had good reason for seeing Pauling as the supreme rival in such an exploration; awarded the Nobel Prize in Chemistry in 1954, Pauling was already being hailed by scientific historians as one of the most influential chemists in history. His master work, though he contributed a great deal more, was to apply a quantum theory perspective to the chemical bonds that bind atoms within the structure of molecules, extending this basic science to the complex organic molecules that are the chemical building blocks of life.
The twentieth century has amazed us with its achievements in astronomy, in which scientists have plotted the stars and galaxies, and the forces, such as black holes, that govern the Universe. Equally important, though not so easily recognised as such by the ordinary man and woman, have been the achievements of the chemists and biochemists in exploring the micro-universe of atoms and molecules. Two forces in particular play a key role in the way that atoms bind to one another to make up life’s particular molecules. One of these is called the covalent bond; the other is called the hydrogen bond. Pauling applied the science of quantum mechanics to the forces involved in these two very different chemical bonds.
We have no need to concern ourselves with the complex mathematics of the applied physics. We just need to grasp the basic mechanics. And where better to look than at the familiar molecule of water.
Everybody knows that the chemical formula for water is H
O. This tells us that a molecule of water comprises one atom of oxygen and two atoms of hydrogen. But how do they link with one another to form the stable compound that we handle and consume every day of our lives? The molecule of water might be compared to a planet, oxygen, with two encircling moons of hydrogen. In such a situation, we can readily imagine how the force of gravity would hold the hydrogen moons to their orbits around the oxygen planet. In molecular terms, the forces holding the two hydrogen atoms to the oxygen atom are called ‘covalent bonds’. At the ultramicroscopic level of atoms, the nucleus of each hydrogen atom contains a single positively charged proton while circling around the nucleus is a single negatively charged electron. Meanwhile, the oxygen atom has eight positively charged protons within its nucleus and eight balancing, negatively charged electrons in orbits around it. These electrons occupy two orbits – two electrons taking up an inner orbit and six taking up an outer orbit. In coming together to form a molecule of water, the two electrons in orbit around each of the two hydrogen nuclei have paired with two of the six electrons of the oxygen outer orbits. The paired electrons share their attraction to the protons of the two parent nuclei, so the paired electrons are now equally attracted to the oxygen nucleus and the hydrogen nuclei. This sharing of attraction creates a stable ‘covalent’ bond between the three atoms, just as gravity created stable orbits for the two moons rotating around our imaginary planet of oxygen.
Hydrogen bonds are something else.
Once again, we might take water as our example. But here we are looking at the chemical interactions between whole water molecules – the H
Os reacting with one another. There are forces of attraction, albeit rather weaker and less stable than covalent bonds, between certain molecules that contain both hydrogen and heavier atoms such as nitrogen, oxygen or fluorine. Since water contains hydrogen and oxygen, these hydrogen bonds can form between molecules of water – it is this sticking together of water molecules that explains the difference between water vapour, or steam, liquid water and solid water, or ice. In ice most of the molecules are attached to one another by hydrogen bonds, to form something like a crystal; in liquid water varying amounts are attached to one another; and in steam, as a result of the addition of energy through heating, the hydrogen bonds linking water molecule to water molecule are broken down but the covalent bonds linking atoms to atoms remain intact.
We see that hydrogen bonds are weak, and thus unstable when heated, but covalent bonds are stable. These same two bonds, covalent and hydrogen bonds, are important ingredients in the structure of organic chemicals such as proteins. And they are also important in the structure of DNA.
Between 1927 and 1932, Pauling published some fifty scientific papers in which he conducted X-ray diffraction studies, coupled with quantum mechanical theoretical calculations, leading him to postulate five rules, known as Pauling’s rules, that would help science to predict the nature of the bonds that held together atoms within molecules. At least three of these rules were based on Bragg’s own work, the purloining of which provoked Bragg to fury. It was now inevitable that there would be ongoing scientific rivalry between the two scientists. Pauling’s work into the nature of chemical bonding was so original, and pioneering, that he was awarded the Nobel Prize in Chemistry in 1954. Meanwhile, this new level of understanding enabled Pauling to visualise the precise shape and dimensions of molecules in three-dimensional space. Working at Caltech, Pauling applied this to the huge molecules of proteins, using the techniques of X-ray diffraction analysis pioneered by the Braggs. He showed, for example, that the haemoglobin molecule – the focus of Perutz’s research – changed its physical structure when it gained or lost an oxygen atom. And Pauling continued to apply his rules to researching the molecular structure of proteins.
Pioneering X-ray pictures of fibrous proteins had been obtained some years before at the University of Leeds by William Thomas Astbury, the physicist who had attended Wilkins’ talk in Naples, but it was assumptions based on these X-ray diffraction pictures that Crick was now questioning at the Cavendish Laboratory. For many years Pauling had tried to apply quantum mechanics calculations to Astbury’s X-ray pictures, but he found that things just didn’t add up. It would take him and two collaborators, Robert Corey and Herman Branson, fourteen years before they made the necessary breakthrough.
All proteins have a primary structure that is made up of an amino acid code, with the letters made up of twenty different amino acids. The chemical bonds that join up the amino acids into the primary chain are called ‘peptide bonds’. Pauling and his collaborators now realised that peptides bonded together in a flat two-dimensional plane – they called this ‘a planar bond’. A problem with outdated equipment had caused Astbury to make a critical error in taking his X-ray pictures: the protein molecules became tilted away from their natural planes, skewing the mathematical extrapolations of their structure. Once they had corrected Astbury’s error, Pauling and co discovered that as the chain of amino acids grew, to form the primary structure of proteins, it naturally followed the shape of a coiled spring, twisting to the right – the so-called ‘alpha helix’. This was the discovery that had excited Watson on his return trip from Naples.
Back in Cambridge, Sir Lawrence Bragg was bitterly disappointed when Pauling’s group beat his to the discovery of the primary structure of proteins. But there was a silver lining to the cloud: Perutz now used Pauling’s breakthrough to reappraise his own work on the haemoglobin molecule, a reappraisal that would solve the structural puzzle of haemoglobin and garner his Nobel Prize in Chemistry in 1963. Pauling’s discovery also alarmed Watson who, from his arrival at Cambridge, had assumed that they had a very knowledgeable and powerful rival in what was now a race to discover the three-dimensional structure of DNA.
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But the problem, as Crick would point out in their day-to-day sharing of thoughts and incessant debate, was that they couldn’t even assume that Pauling’s data was right. In Crick’s words, ‘Data can be wrong. Data can be misleading.’ So Crick and Watson attempted to construct their physical model with a sceptical eye on prevailing experimental data. To put it another way, they relied just as heavily on creative leaps of their own imagination as on existing experimental data.
Crick and Watson were now asking themselves if DNA, like proteins, had a helical structure, and Watson in particular was convinced that they should also take their cue from Pauling, who liked to construct three-dimensional models of the molecules he was attempting to envisage. To do so they would have to think, as Pauling did, about the atomic structures that made up the chemistry of DNA – to fit the molecules, with their component atoms, and the bonds between them, into a complex three-dimensional jigsaw. They knew that they were dealing with the four nucleotides – guanine, adenine, cytosine and thymine – together with the molecule of the sugar, called ribose, and the inorganic chemical, phosphate, all of which, when correctly fitted together, must somehow make up the mysterious three-dimensional jigsaw puzzle.
Two relevant questions now loomed. Firstly, if the structure was helical, what kind of helix was involved? And secondly, where did the phosphate molecule fit into the structure? Calcium phosphate is the mineral of bones, of shells, of rocks formed from the remains of living marine organisms – limestone. The presence of phosphate suggested some kind of strengthening of the DNA chain – a chemical scaffold – maybe a spine? But where did this spine lie in relation to the presumptive and as yet unknown spiral? And where, or how, did the sugar fit in? The code itself must surely lie with the nucleotides, acting perhaps as something like letters. Each was a key ingredient, but how on earth did the whole thing assemble in a way that made sense?
An important clue must come from the X-ray diffraction patterns. That meant they needed the help of Maurice Wilkins and Rosalind Franklin – ‘Rosy’, as Watson referred to her in his autobiography – who were conducting X-ray analyses of DNA fibres at the King’s College London laboratory.
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Rosalind Elsie Franklin was born in London to a prosperous Jewish family in 1920. From an early age she showed both a brilliantly incisive mind and the stubbornness necessary to make a distinguished mark for herself. She also showed an aggressively combative side to her personality that might prove a mixed blessing in overcoming the prevailing prejudices against Jews in society, as well as against women being in higher education and the scientific workplace. It didn’t help that her father, who appeared to be a similarly combative character to his daughter, opposed her notion of a career in science. In her second year at Newnham College, Cambridge, he threatened to cut off her fees, urging that she switch to some practical application in support of the war effort. Only when he was dissuaded by her mother and aunt did he relent and allow her to continue her course.
Franklin studied physical chemistry, which involved lectures, extensive reading and laboratory experience in physics, chemistry and the mathematics that applied to these disciplines. One of the mandatory texts she read was Linus Pauling’s The Nature of the Chemical Bond.
The youthful Rosalind Franklin was disappointed when she ended up with a good second, and not a first, ‘bachelor’s’ degree in 1941. Even then, such was the lingering prejudice against female graduates in science that she was forced to wait in an unseemly uncertainty, one shared with all previous female graduates of Newnham, until her due qualification was formally granted, retrospectively, in 1947.
Like Francis Crick, Franklin was seconded to National Service during the Second World War, studying the density and porosity of coal for a PhD, in which she helped to classify different types of coal in terms of fuel efficiency. Post-war, she followed this up with a research stint working under the direction of Jacques Mering at the Laboratoire Central des Services Chimique de l’Etat, in Paris. Here, Mering introduced her to the world of X-ray crystallography which he used to study the structure of fibres, such as rayon. ‘With his high tartar cheekbones, green eyes and hair combed rakishly over his bald spot’, Franklin was surprised to discover that Mering was Jewish, as well as being ‘the archetypal seductive Frenchman’. The still youthful, and perhaps naïve, Rosalind Franklin appears to have fallen in love with Mering, who was already married, but whose wife was ‘nowhere in evidence’.
Brenda Maddox, one of Franklin’s biographers, would draw attention to the fact that Franklin’s most imaginative and productive research was conducted when she was teamed up with male scientists of Jewish background. Mering also appeared to be attracted to the trim, slender young woman, with the lustrous dark hair and glowing eyes. They would spend entire days and on into the evenings deep in discussion and argument over likely meanings of X-ray plates and atomic structures.
However, Franklin’s infatuation with Mering would be painfully halted when, in January 1951, she took up a post as research associate at King’s College London in the Medical Research Council Biophysics Unit, directed by John Turton Randall. Her appointment happened to coincide with a major post-war rebuilding within the department, designed to accommodate new ambitions within the nascent field of biophysics. The precise nature and purpose of her appointment has since become the subject of debate. In part some confusion has arisen because Randall changed the scope of her appointment in between first confirming it and Franklin taking up the post. She had initially agreed to carry out X-ray diffraction studies of proteins, but Randall wrote to her before she took up her appointment, suggesting that she change direction to the study of DNA. According to Maurice Wilkins, this was at his suggestion. Whether at Wilkins’ suggestion or Randall’s own idea, Franklin agreed. She was offered the assistance of a promising graduate student, Raymond Gosling, to work with. But there was an inherent problem with this new direction.
Wilkins, who was Deputy Director of the MRC Unit based at King’s College, was the same scientist who had first lit the fuse of inspiration for Watson in the 1950 Naples lecture. Wilkins had initiated the research into DNA in the department, but happened to be deputising once again for Randall in America at the time of Franklin’s appointment. Up to now Gosling had been working with Wilkins on DNA; even after his return from America, Randall failed to inform Wilkins about the terms he now proposed for Franklin’s job description. This led to what Franklin’s later research colleague, Aaron Klug, would describe as ‘an unfortunate ambiguity about the respective positions of Wilkins and Franklin, which later led to dissension between them and about the demarcation of the DNA research at King’s’.
This is a short quote from the typed letter from Randall to Franklin, specifying her working conditions:
… as far as the experimental X-ray effort is concerned there will be at the moment only yourself and Gosling, together with the temporary assistance of a graduate from Syracuse, Mrs. Heller …
While this clearly suggests that Franklin was expected to take on the X-ray diffraction work, the qualification ‘at the moment’ is too vague to interpret. But there is nothing in this letter to suggest that Franklin should ignore the work performed by Wilkins, or that she should refuse to collaborate with the rest of the department in her approach to the DNA problem.
Wilkins, working with Gosling, had initiated the X-ray diffraction studies on DNA in the department, and in particular obtaining the best resolution diffraction photographs that existed up to this date. They had demonstrated a key property of DNA – that it had a regular, crystal-like molecular structure. In Paris Franklin had learned, and improved upon, X-ray diffraction techniques for dealing with substances of limited order. But even Klug, an ardent supporter of Franklin, admitted that in relation to the work conducted by Franklin in Paris, ‘It is important to realise … Franklin gained no experience of such formal X-ray crystallography.’
Back in early 1950 Wilkins had complained of poor-quality X-ray apparatus that was not designed for the scrutiny of exquisitely fine fibres. At his suggestion, the department had purchased a new and better-quality X-ray tube to be set up in the basement, but it had lain there for a year or more unused while Wilkins was distracted by the multiple tasks that fell to a busy deputy director of the unit. On her arrival, Franklin, not unnaturally, believed that she was there to take over the DNA work as her personal project. However, the returning Wilkins expected that Franklin had been brought in as his collaborator, to take up the research from where he had already developed it. He would subsequently admit that he was unqualified to take the X-ray diffraction work further and needed exactly such a dedicated and qualified collaborator. ‘That’s why we hired Rosalind Franklin.’
Unfortunately, Franklin and Wilkins now disagreed as to her role. Even so, rancour was neither necessary nor inevitable between the two scientists, personally or scientifically. These difficulties, provoked by Randall’s vagueness, might have been readily overcome with goodwill on both sides, but Franklin, in the opinion of both her biographers, was not inclined to cooperate.
Much has been written about prejudicial attitudes to women in science at this time. In particular an American journalist, and personal friend of Franklin’s, Anne Sayre, would write a biography of her in which she suggested that King’s College was particularly unfriendly to female scientists, with Franklin struggling to assert her presence in a domain that was almost exclusively male. But when another American journalist, Horace Freeland Judson, looked into this claim, he discovered that of the 31 staff working at King’s at this time, eight were female, including some working in a senior position in Franklin’s unit. A second biography of Franklin, by Brenda Maddox, confirmed that women were, on the whole, well treated at King’s College. Crick made the same point in his biography – and Crick had come to know Franklin well in the years following the DNA discovery. Even in Sayle’s more trivial complaint – that the main dining room was exclusively forbidden to women, who were thus precluded from lunchtime conversation – is misleading. There were two dining rooms. One was limited to men, but this, in the main, was used by Anglican trainees. The main dining room, used by the departmental staff, including Randall himself, was open to all.
The frosty relationship between Wilkins and Franklin was not the result of anti-female prejudice – it even seems unlikely to be the result of Randall’s peculiar wording in the letter – but it appears to be more directly related to a personality clash between the two scientists. Of the two, only Wilkins ever seems to have made any attempt at compromising. He asked other colleagues what he should do, but Alexander (Alec) Stokes, his closest colleague, was even meeker than he was. In Brenda Maddox’s opinion, the two should have got on well; Wilkins was gentle in manner and, despite his lack of self-confidence, was attractive to women. He was mathematically fluent and immersed in the very problems that concerned Franklin. But ‘confrontation’, in Maddox’s words, ‘was Franklin’s tactic, whenever cornered’. In an earlier confrontation with her professor, R. G. W. Norrish, when working on a postgraduate research project at Cambridge, she would confide, ‘When I stood up to him … we had a first-class row … he has made me despise him so completely I shall be quite impervious to anything he may say in the future. He gave me an immense feeling of superiority in his presence.’
Sayre, who championed her friend, would admit that Franklin’s ogrish depiction of her professor was unkind and inaccurate. Professor Norrish was awarded the Nobel Prize in Chemistry in 1967.
Sayre had a correspondence with Norrish in which she described Franklin as ‘highly intelligent … and eager to make her way in scientific research’, but also ‘stubborn, difficult to supervise’ and, perhaps most tellingly, ‘not easy to collaborate with’. In Maddox’s opinion, ‘If Rosalind had wished, she could have twisted Wilkins around her little finger.’ The fact is she had no wish to collaborate with him. This left Wilkins isolated locally so instead he turned to Crick and Watson at Cambridge. It also meant that Franklin was equally isolated. To the commonsensical Crick, this may have been a crucial factor when it came to working out the molecular structure of DNA. ‘Our advantage was that we had evolved … fruitful methods of collaboration, something that was quite missing in the London group.’
In that same year of Franklin’s appointment, just before Wilkins headed for America, he asked his colleague, Alec Stokes – another Cambridge-educated physicist – if he could work out what kind of diffraction pattern a helical molecule of DNA would project onto an X-ray plate. It took Stokes just twenty-four hours to do the mathematics, largely figuring it out while travelling home on the commuter train to Welwyn Garden City. A helical model fitted very closely with the picture Gosling and Wilkins had obtained in their diffraction pictures of DNA. It would appear that if anybody first confirmed that DNA had a helical structure, the credits must surely include Wilkins, Gosling and Stokes – the latter would subsequently lament that, in retrospect, he might have merited 1/5000th of a Nobel Prize.
In November 1951, Wilkins told Watson and Crick that he now had convincing evidence that DNA had a helical structure. Watson had only recently heard Franklin say something similar in a talk about her research during a King’s College research meeting. This inspired Watson and Crick to attempt their first tentative three-dimensional model for DNA.
But where to begin?
Taking their cue from Linus Pauling, Watson and Crick decided that they would attempt to construct a three-dimensional physical model of the atoms and molecules that made up DNA with their covalent and hydrogen bond linkages to one another. On the face of it, the structure was made up of a very limited number of different molecules. There were the four nucleotides – guanine, adenine, cytosine and thymine – but they also knew that the structure contained a sugar molecule, deoxyribose, and a phosphate molecule. The phosphate was likely to be playing a structural role, perhaps holding the thread together, much as phosphate is a key structural component of our bony human spine. In the colloquium at King’s, attended by Watson, such was his lackadaisical absence of focus that he completely missed the importance of Franklin’s statement that the phosphate-sugar ‘spines’ were on the outside, with the coding nucleotides, the GACT, on the inside. As usual, he had eschewed making notes. All that seemed to intrigue Watson was the fact that the King’s people were uninterested in the model-building approach developed, with such aplomb, by Pauling.
In 1952 Franklin appears to have undergone a drastic change of heart in her own thoughts on the structure of DNA. She had in her possession a brilliantly clear X-ray picture of DNA, taken by Gosling, that clearly showed a helical structure to the molecule. She called this her ‘wet form’, and also her ‘B form’. But she had even clearer pictures of a different structure of the same molecule in its ‘dry form’, or ‘A form’, that did not appear to suggest a helix. The contrast between the two forms caused Franklin to dither as to whether the DNA molecule was helical. There is a suggestion that she may have asked the opinion of an experienced French colleague, who advised her to place her bets on whichever form gave the clearest pictures. She must have been altogether aware of the advice her ignored colleague, Wilkins, would have given. Unfortunately, she ended up putting the B form into a drawer, meanwhile focusing most of her research over that year into the A form.
Early that same year Watson and Crick made a first attempt at building a triple-stranded helical model of DNA, with a central phosphate-sugar spine. When Wilkins brought Franklin and Gosling up to Cambridge to view the model, they broke out into laughter. The model was absolute rubbish. It did not fit at all with the X-ray diffraction predictions. Thanks to Watson’s lackadaisical focus, and his failure to take notes at Franklin’s colloquium, he had made the cardinal error of putting the phosphate-sugar spine at the dead centre of their helix and not on the outside, as Franklin and Gosling had clearly deduced.
