DNA and the Cavendish Laboratory James Watson and Francis Crick discovered the structure of DNA at the Cavendish Laboratory in Cambridge in 1953. Their discovery illustrates the leading role played by the Cavendish Laboratory in biological fields such as structural biology and molecular genetics. It was a major factor in the scientific revolution that focused much of the scientific world on biological issues over the past 50 years. Why was this important discovery made in the Cavendish Laboratory? Figure 1: The old Cavendish Laboratory, Free School Lane, Cambridge. The Cavendish Laboratory was founded in the late 19th century to encourage the development of experimental physics in Cambridge. The Laboratory was designed and built under the direction of James Clark Maxwell, who was well regarded for his work on thermodynamics and electromagnetism. He was succeeded as head of the Cavendish Laboratory by Lord Rayleigh, who was then succeeded by J. J. Thomson. Before World War II, under the leadership of J. J. Thomson, and then Ernest Rutherford, the Cavendish Laboratory dominated the development of atomic and nuclear physics. Many great discoveries in physics were made at the Cavendish Laboratory, increasing its strong reputation in experimental physics and attracting many of the best physicists to come and work in Cambridge. This resulted in a stimulating intellectual environment which led to the further development of new ideas and experimental techniques. For example, in 1912 a young research student at the Cavendish Laboratory, William Lawrence Bragg, realized the simple way in which the diffraction of X-rays by crystals could be understood. He described this as reflection by sheets of atoms within the crystal, known as ‘Bragg planes’. Bragg planes can diffract strongly at specific angles that are dependent on the separation between the planes. This understanding led William Lawrence Bragg and his father, William Henry Bragg, to invent the technique of X-ray structural analysis (X-ray crystallography). For this work they shared the Nobel Prize in Physics in 1915. © University of Cambridge, Cavendish Laboratory, 2003. X-ray crystallography has since been used by several members of the Cavendish Laboratory. In the early 1930s John Desmond Bernal and Dorothy Crowfoot (later Hodgkin) used the technique to study crystals of the protein pepsin. They got excellent results by studying the crystals while they were still in the liquid from which the crystals had formed. This was the first use of the X-ray technique to study biological molecules at the Cavendish Laboratory. In the late 1930s Max Perutz used the technique to study haemoglobin and the enzyme chymotrypsin. The technique was deeply involved in the discovery of the structure of DNA at the Cavendish Laboratory, decades after the technique was first developed. Figure 2: X-ray diffraction image of ‘Btype’ DNA taken by Rosalind Franklin. William Lawrence Bragg became the head of the Cavendish Laboratory in 1937, following the unexpected death of Ernest Rutherford after a fall from a ladder in his garden. Before he returned to the Cavendish Laboratory, William Lawrence Bragg was professor of physics in Manchester. While in Manchester he had continued to develop and use X-ray analysis, applying the technique to complex problems. He spent a lot of time working on silicates, but his ideas for these compounds were overshadowed by the work of Linus Pauling in the United States. The rivalry that was thus established between William Lawrence Bragg and Linus Pauling continued throughout their careers. When William Lawrence Bragg returned to the Cavendish Laboratory he was intrigued by the beautiful X-ray diffraction patterns from haemoglobin that Max Perutz showed him. He recognized that the importance of interpreting the patterns correctly, and obtained enough money to pay for Max Perutz to stay in Cambridge and his family to join him from Austria. This work was interrupted by World War II, during which Max Perutz was interned and then deported to Canada for a time because he was an Austrian national. Although work at the Cavendish Laboratory was interrupted by World War II, the people who had worked there continued to think about the problems they were working on. John Desmond Bernal had left the Cavendish Laboratory and taken a job at Birkbeck College in London before the start of the war, but he was still using the X-ray technique to study proteins. During the war John Desmond Bernal met John Kendrew when they were both working in the jungles of Ceylon (now Sri Lanka). They talked about X-ray diffraction by proteins, and John Kendrew decided that he would like to work at the Cavendish Laboratory when the war was over. © University of Cambridge, Cavendish Laboratory, 2003. Towards the end of the war, Max Perutz returned to the Cavendish Laboratory and resumed his studies of haemoglobin. John Kendrew came to the Cavendish Laboratory in late 1945 and joined Max Perutz in studying haemoglobin. The following year William Lawrence Bragg convinced the Medical Research Council (MRC), that their work should be supported, and The MRC Unit for Work on Molecular Structure of Biological Systems was created at the Cavendish Laboratory. At first only the crystalline proteins haemoglobin and myoglobin were studied, but it was planned that the X-ray technique would later be used to study other interesting and suitable biological materials. In 1949 Francis Crick joined the MRC Unit in the Cavendish Laboratory. His job was to continue the X-ray analysis of haemoglobin, but he was always eager to absorb and understand new areas of science. He liked to discuss ideas, and was not afraid of speaking his mind. He had a penetrating voice and laugh that annoyed William Lawrence Bragg, and they did not have a good relationship. William Lawrence Bragg was particularly annoyed by his impression that Francis Crick thought that he knew more about X-ray crystallography (the technique that William Lawrence Bragg had invented) than William Lawrence Bragg himself did. James Watson came to the Cavendish Laboratory in the early autumn of 1951 to learn more about X-ray crystallography and its application to biological materials. Francis Crick welcomed intelligent discussions about structural biology and was soon working with James Watson to try to discover the structure of DNA. James Watson and Francis Crick worked together very well because they were interested in the same problem, and each of them had a different background experience and area of expertise. Figure 3: A model of the alpha helix. Francis Crick explained to James Watson how Linus Pauling had found the structure of the alpha helix by applying the laws of structural © University of Cambridge, Cavendish Laboratory, 2003. chemistry and building models of possible structures based on a small amount of X-ray diffraction results. They agreed to use a similar approach to try and discover the structure of DNA. Their early attempts to build models of the structure of DNA were not successful. As the head of the Cavendish Laboratory, William Lawrence Bragg was humiliated when James Watson and Francis Crick showed one of their incorrect models of DNA to Maurice Wilkins and Rosalind Franklin, who were using X-ray crystallography to study DNA at King’s College in London. Following this embarrassment William Lawrence Bragg banned James Watson and Francis Crick from continuing to work on DNA. Even though they could not continue to work on DNA Francis Crick and James Watson continued to think about and discuss the problem of how to find the correct structure. After many months, James Watson and Francis Crick found out that Linus Pauling had also created an incorrect model of the structure of DNA. They realized that Linus Pauling would soon recognize the mistakes that he had made, and would then be inspired to discover the correct structure of DNA. They told William Lawrence Bragg of his rival Linus Pauling’s work on DNA, and in February 1953 they were allowed to resume their own work on DNA. Making use of the X-ray diffraction work of Maurice Wilkins and Rosalind Franklin at King’s College in London, James Watson and Francis Crick discovered the structure of DNA just a few weeks later in spring 1953. Figure 4: The DNA Double Helix A second immensely important discovery was made at the Cavendish Laboratory a few months later in 1953. Max Perutz realized that attaching a single large atom (e.g. Mercury) to a haemoglobin molecule would change the X-ray diffraction pattern obtained from the crystal, making it possible to completely solve the structure of haemoglobin. He realized that this doping technique could be applied to a wide range of complex biological materials. Experimental techniques had to be developed over several years, organized by Max Perutz and John Kendrew, to put Max Perutz’s idea into practice. Eventually the correct structures of both haemoglobin and myoglobin were discovered. Their work was dependent upon tens of thousands of highly accurate measurements and interpretations of X-ray diffraction images. It was greatly assisted by the building models of possible structures and the use of early model computers housed nearby. The importance of this work was quickly recognized, and led to a massive expansion in the number of people studying the structure of complex biological materials. Although the Cavendish Laboratory provided the simulating environment in which new ideas were explored and developed, the successful discovery of the structure of DNA was also dependent on fortuitous circumstances and the personalities of the people involved. The entire field of structural biology can be traced back to the development of X-ray crystallography by William Lawrence Bragg and his father William Henry Bragg. In particular, the insight of William Lawrence Bragg that led to the development of Bragg’s Law for X-ray diffraction was crucial to the continued interest in the use of X-rays to study materials. The discoveries of the structure of DNA and the structures of complex biological materials were recognized in the same year (1962) by the award of a Nobel Prize in Physiology or Medicine to James Watson, Francis Crick and Maurice Wilkins, and a Nobel Prize in Chemistry to Max Perutz and John Kendrew. Rosalind Franklin had died of cancer in 1958. These discoveries are the basis of many areas of modern biology and medicine and are considered to be amongst the most important discoveries made at the Cavendish Laboratory since it opened over 100 years ago. © University of Cambridge, Cavendish Laboratory, 2003.