The Mysterious World of the Human Genome

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.

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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.’