The Mysterious World of the Human Genome. Frank Ryan
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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,