The Mysterious World of the Human Genome

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.

five

The Secret of Life

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.’

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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 H2O. 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.