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David C. Phillips

Anthony C.T. North

There were two major aspects to the sci- Helen Scouloudi were already at the tribution in myoglobin in order to build entific career of David Phillips. The first Royal Institution and were joined in late a molecular model of the protein. It was was his crystallographic research, most 1955 by David Phillips, David Green, decided to represent the density values notably the role that he played in Jack Dunitz and myself. David Phillips by means of colored clips attached to studies of lysozyme, the first enzyme to began by finishing off his acridene struc- steel rods. Our initial calculations have its three-dimensional structure and ture. Despite initial uncertainty as to showed that we would require about six mechanism determined by X-ray crystal- whether to continue with small mole- miles of steel rods. This estimate was lography. This led to international recog- later lowered when it was realized that nition, with the consequent award of there would be no space for people to many prizes and medals, honorary doc- put their hands into the resulting forest. torates and fellowships. The second was I was deputed to go to Hamley’s toyshop the part that he played in scientific orga- in London, where I bought out their nization both within the UK and inter- entire stock of Meccano clips. Such nationally. improvisation was a characteristic of the David was born in Ellesmere in early days of protein crystallography! Shropshire on the 7th of March, 1924; David Phillips was keen to improve his father was a master tailor who was our methods of data collection and, also a Methodist lay preacher. He attend- jointly with Uli Arndt, whose life inter- ed Oswestry Boys High School and then est has been in instrument design,

http://structbio.nature.com • studied physics at University College, embarked upon building a ‘linear Cardiff. After taking the reduced two- diffractometer’, a mechanical analog of year degree course that had been mount- the crystal reciprocal lattice. Equipped ed to provide graduates for wartime with a proportional counter, this device service, he became a radar officer on the produced a direct printed output of the aircraft carrier Illustrious, experiencing intensity of each diffraction spot and the the dangers of carrying out experiments intervening background. David’s clear with high voltage equipment on the understanding of the principles of X-ray ship’s metal deck. diffraction led to a later version of this

After his naval service, he returned to Stephen Lee, Oxford University machine with which three X-ray reflec- 1999 Nature America Inc.

© Cardiff to work for a Ph.D. in the labora- tions were measured simultaneously tory of A.J.C. Wilson. This led to the 1924–1999 with high precision, and punched out well-known paper describing a statistical the results on paper tape which could be method of distinguishing between cen- fed directly into a computer. In 1960, the tro-symmetric and non centro-symmet- cules or to embark upon protein struc- structure of myoglobin was determined ric crystals by their X-ray intensity tures, he decided to collaborate with at high resolution and that of hemo- distributions. He then went to the Kendrew, taking charge of the ‘London globin at a lower resolution, which National Research Council laboratories office’ of the myoglobin project. The nevertheless showed how the four myo- in Ottawa for four years where he data for the myoglobin work were col- globin-like subunits were arranged. worked on the structures of organic lected photographically on precession David, with Colin Blake who had now molecules, including the carcinogen cameras and the films were scanned joined the Royal Institution team, then acridene. manually by use of a microdensitometer embarked upon a study of radiation In 1954, Sir Lawrence Bragg had taken which produced traces of the photo- damage to the myoglobin crystals. up the appointment of Director of the graphic density along the lines of spots In late 1960, Roberto Poljak also had Royal Institution. While in Cambridge, on the film. These traces had to be mea- come to the Royal Institution, having Bragg had encouraged the work of Max sured manually and several helpers were decided to take up protein crystallo- Perutz and John Kendrew, who were recruited to assist with this work. David graphy, and he brought with him crystals attempting to determine the three- Phillips, David Green and I traveled reg- of hen egg-white lysozyme. Lysozyme dimensional structures of hemoglobin ularly to Cambridge in order to discuss had been discovered by Fleming and it and myoglobin. Bragg needed to revital- the progress of the work and to use the had been shown to have anti-bacterial ize research at the Royal Institution and EDSAC computer, one of the first two activity, causing disruption of the bacte- gained the support of the Medical digital computers to be available in the rial cell wall. With the encouragement of Research Council to appoint a group of UK. I recall one hilarious visit when we Bragg and Phillips, Poljak embarked young workers who would collaborate were discussing how to represent the upon a systematic search for heavy atom with Perutz and Kendrew. Uli Arndt and three-dimensional electron density dis- derivatives. By October 1961, when I

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returned from a year in the USA, had to be distorted slightly to fit into the oration was established through David’s progress appeared to be promising and a groove and flanking the distorted unit creation of the Oxford Enzyme Group low resolution map of lysozyme was were two acidic side chains. Just a few with the enthusiastic participation of obtained in 1962. Unfortunately, unlike days later, a Royal Society discussion Rex Richards and Bob Williams, among the low resolution maps of hemoglobin meeting was to be held at the Royal others. This group brought together and myoglobin which had clearly Institution on the subject of lysozyme chemists, biochemists and biophysicists shown rod-like features characteristic of and its activity. One of the speakers was and set in motion powerful collabora- -helices, features of the lysozyme map to be Charles Vernon as an expert on tions leading in the course of time to the were much less well defined; this was not enzyme mechanisms, and he visited the formation of the Oxford Centre for entirely surprising as it was known that Royal Institution to discuss the structural Molecular Sciences. the proportion of helices in lysozyme work in preparation for giving his talk. After the move to Oxford, work con- was much smaller and that it contained He was able to identify the type of mech- tinued on various aspects of the lysozyme four disulfide bridges linking parts of the anism that would be consistent with the project. These included the first example chain together. Nevertheless, the result location of the features defined by the of protein modeling by homology, with added to fears expressed in the USA by structural studies. the construction of a model of -lactal- Joe Kraut that maps of proteins with low Three components were considered bumin based on the close similarity of its helical content might be uninterpretable. important in the mechanism — the two amino-acid sequence to that of lysozyme. The Royal Institution team was, how- acidic groups on either side of the sub- Other firsts in the early days of the ever, undeterred and set out to improve strate and the distortion caused by fitting Oxford laboratory included the use of the instrumentation and computational the substrate into the groove2. The role of molecular replacement approach pio- methods and to obtain better heavy atom the acidic groups was verified fairly soon neered by Michael Rossmann and David derivatives. At this stage, Roberto Poljak by chemical modification, but the role of Blow to solve the structure of the triclinic left London for Cambridge and, then, distortion remained a matter of contro- form of lysozyme, and the first use of moved to the USA and David inherited versy for some years. The inherent plas- computer graphics to interpret both the the leadership of the lysozyme project. In ticity of protein molecules means that the electron density maps of proteins and those days, protein crystallography was enzyme itself could possibly be distorted NMR spectra. very much a matter of teamwork, with in order to accommodate the undistorted New projects soon arose, with David the need to write computer programs substrate, but more recent structural leading the determination of the structure

http://structbio.nature.com 3 • from scratch, to design and build instru- studies by Strynadka and James and by of the enzyme triose phosphate isomerase ments for collecting data and to synthe- NMR have verified the presence of dis- (TIM), the first example of what has size novel compounds for possible use for tortion in the bound substrate. All three proved to be a very common protein chain heavy atom derivatives. Spurred on by features identified from the crystallo- fold (the TIM barrel). The laboratory in these challenges, the lysozyme team con- graphic studies have thus stood the test of Oxford has continued to flourish, with the tinued happily under the benign guid- time. They were well illustrated by the determination of many structures of pro- ance of Sir Lawrence Bragg and in 1965 pictures by Irving Geis in David’s much- teins and viruses. obtained a 2 Å resolution map of cited article in Scientific American, David was initially a slightly diffident lysozyme from which an atomic model November 1966, in which he also put for- lecturer, but he rapidly became a most was built. The structure was determined ward a possible folding pathway for the proficient speaker with a precise and very 1999 Nature America Inc. th

© in time for Sir Lawrence’s 75 birthday protein. clear style, perhaps inherited from his party. The completed lysozyme model Sir Lawrence Bragg was due to retire in father. He gave the Royal Institution showed that the molecule did contain 1966 and it was decided, with the Christmas lectures in 1980 and of course some -helices and it also contained - promise of renewed support from the many invited lectures at home and strands, with the four disulfide bridges Medical Research Council, that the abroad. This led to a number of close linking parts of the chain together into a lysozyme group should move to the friendships, for example with Fred rather complicated fold1. University of Oxford, to establish a new Richards, who spent a sabbatical in Meanwhile, Louise Johnson had Laboratory of Molecular Biophysics with Oxford during which he constructed the embarked upon a Ph.D. under David’s David as Professor. The move was not ‘Richards optical comparator’, a device to supervision; she determined the struc- entirely welcomed by the Oxford estab- aid the construction of molecular models ture of one of the bacterial cell wall sac- lishment, some of whose members could of proteins, which became known as charide components that had been not see the need for knowing the three- ‘Fred’s folly’ as it assumed alarmingly shown to be a competitive inhibitor of dimensional structure of biological mol- large proportions in the laboratory. the enzyme’s activity and had therefore ecules, but it was strongly supported by Soon after the determination of the been thought to bind in the enzyme’s Sir Hans Krebs, John Pringle (the lysozyme structure, David was elected a active site. Low resolution studies of crys- Professor of Zoology) and not least by Fellow of the Royal Society and not long tals into which this and related molecules Dorothy Hodgkin. Pringle’s strong after he became a member of the Council had been diffused did indeed locate bind- encouragement, coupled with the fact of the Society. This began the second ing sites in a groove on the surface of the that his department was about to be phase of his career. He served as molecule. A high resolution map clearly given a new building, led to the Biological Secretary of the Royal Society showed the binding site for a trisaccha- Molecular Biophysics Laboratory being from 1976 to 1983. This period was one ride molecule in half of the groove and, established rather surprisingly within the of considerable difficulty for universi- by model building, David showed that Department of Zoology. ties, with financial stringency all but three additional saccharide units would Political fences were gradually mended halting the appointment of new younger fill the rest of the groove; one of the units and a very major step forward in collab- staff. David was involved with the intro-

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duction of the Royal Society Research and Scientific Committee, has recounted Technology, and became its chairman in Fellowship scheme which allowed the that politicians found David Phillips to be 1997, a post that he was forced to resign appointment of outstanding young sci- formidable, with a less than fully- with great reluctance because of his entists to positions in the universities. informed opinion from them resulting in increasing ill health. He contributed to For the 10 years from 1983 to 1993, a “direct, glacial interrogative stare”. Such debates on the role of women in science David served as Chairman of the a response was not unknown to his scien- and to a very important study of the Advisory Board for the Research tific colleagues and friends, though it ‘information society’ which he was Councils (ABRC), a body set up to advise quickly melted when a reasoned discus- pleased to see was rapidly made avail- the government on the apportionment sion ensued. I well knew that David’s able on the Internet. of funds between the several UK political views would not be exactly con- David married Diana Hutchinson in Research Councils, the Royal Society and gruent with those of Margaret Thatcher, 1960, and they had a daughter, Sarah; the Fellowship of Engineering. Initially a but he was as ever discrete when I asked always fond of children, he took great part-time position, it became full time in how he got along with her, and merely delight in his two grandchildren. 1989, when he returned to London from recounted that when they were discussing Diagnosed with prostate cancer 10 years Oxford. This brought him into close possible applications of genetic modifica- ago, a succession of treatments kept the contact with government and he found tion of cattle, she responded “the meat disease at bay and he was able to com- himself between the Scylla of Thatcherite would be tough”. Dalyell considered plete a lengthy historical account of funding restrictions and the Charybdis Phillips to be “the most effective of all “How the structure of lysozyme was of the ever-increasing cost of scientific operators in that world where science actually determined” only 10 days research. A particular difficulty was meets politics”, “making it abundantly before he died5. A highly talented scien- competition between the rapidly- clear that he considered it his duty to tist himself, a good listener with a prodi- increasing complexity of biological bring Members of Parliament face to gious memory and a great facility for research, involving demands for face with reality” with his incisive, ele- friendship, he was a fine representative advanced instrumentation, and the con- gant, often provocative, but always per- of UK science. tinuing need of physical scientists for tinent contributions to discussion4. expensive equipment. The advice of the After his retirement from the ABRC, Anthony C.T. North is in the School of ABRC to the government was normally when it was disbanded, he was elevated Biochemistry & Molecular Biology, made public and David was incensed to the House of Lords in 1994, where he University of Leeds, LEEDS LS2 9JT, UK.

http://structbio.nature.com • when, in a particularly bad year for took the title Lord Phillips of Ellesmere email: [email protected] funding, the government refused to pub- after his native town. In the current

lish the advice they had received. He was widespread discussion about the future 1. Blake, C.C.F. et al. Proc. Roy. Soc. B 167, 365–377 apparently admonished for making of the House of Lords, it seems to me (1967). 2. Blake, C.C.F. et al. Proc. Roy. Soc. B 167, 378–388 known his criticism of this decision, but that insufficient heed is given to the role (1967). the following year did see a better settle- that highly experienced people such as 3. Strynadka, N.C.J. & James, M.N.G. J. Mol. Biol. 220, 401–424 (1991). ment for the science budget. David Phillips can contribute in that 4. Dalyell, T. In The Independent, 26 February The veteran Member of Parliament forum in guiding the direction of the (1999). Tam Dalyell, who served for many years country. He joined the House of Lords 5. Blake, C.C.F. et al. International tables for crystallography, vol. .F in the press (eds M.G. on the House of Commons Parliamentary Select Committee on Science and Rossman & E. Arnold) 1999 Nature America Inc.

508 nature structural biology • volume 6 number 6 • june 1999