Obituary: Lord Phillips of Ellesmere
Friday 26 February 1999
In 1966 he and his team, working at the Royal Institution in London, solved the first structure of an enzyme, lysozyme. From the structure they were able to demonstrate the relationship between enzyme structure and biological function. The work opened the way to the explosion in the numbers of protein structures that are now being determined with modern technology and for the insights that these structures provide for the benefit of fundamental research, medicine and agriculture.
Phillips was born in 1924 in Ellesmere, Shropshire, and educated at Oswestry Boys High School. His father was a master tailor and an active Methodist lay preacher. He fostered a lifetime interest in history; for David's 15th birthday he gave him Gibbon's Decline and Fall of the Roman Empire.
Despite his interest in history, Phillips read Physics for his first degree at University College, Cardiff. His degree course was interrupted (1944-47) for service in the Navy as a radar officer on HMS Illustrious, a fleet aircraft carrier. He remained at Cardiff for his PhD and began work in crystallography under the supervision of A.J.C. Wilson, a noted contributor to the theory of intensity statistics of X-ray diffraction patterns. In those days crystallography involved the elucidation by X- ray diffraction methods of small molecule structures, such as ephedrine hydrochloride, a component of anti-decongestant nasal drops.
After a post-doctoral period at the National Research Laboratories, Ottawa (1951-55), Phillips was attracted home in 1956 to the Royal Institution of Great Britain in London by Sir Lawrence Bragg.
Bragg had recently retired from the Professorship of Physics at the Cavendish Laboratory, Cambridge. There he had encouraged fundamental studies by John Kendrew on myoglobin and Max Perutz on haemoglobin, the first protein crystal structures to be solved by X-ray diffraction methods. Bragg was keen to set up a protein crystallography laboratory in London and began to attract several crystallographers. Among these, in addition to Phillips, were Colin Blake, Tony North and Roberto Poljak, who came in late 1960 from the United States bringing crystals of lysozyme.
Phillips realised that automating the collection of diffraction data was a prime objective for studies of large protein molecules. One of his first tasks was to join Uli Arndt in the design and construction of an automated diffractometer. This instrument, adapted to make multiple simultaneous measurements of intensities, was to have profound consequences. With the linear diffractometer Phillips and his team were able to achieve data of high accuracy that in turn led to precise structures. The instrument was first used to extend the data of the myoglobin crystals to 1.4A resolution.
Work on lysozyme started in 1961, a time that Phillips described as the spring of hope. In 1922, seven years before his more famous discovery of penicillin, Alexander Fleming had published a paper on his discovery of lysozyme entitled "On a Remarkable Bacteriolytic Element Found in Tissues and Secretions". Fleming had been excited by lysozyme because the enzyme showed antibacterial activity. Unfortunately lysozyme was active only against certain bacteria and it was not pursued as an antibacterial agent, although it is widely used today as a tool in molecular biology.
The solution of the X-ray structure of lysozyme was achieved in 1965, a time for a dual celebration with Bragg's 75th birthday. The structure showed the complete path of the polypeptide chain (129 amino acid residues) folded into both alpha-helices, that had previously been recognised in myoglobin, and beta-sheet, a structure that had been predicted by Linus Pauling but not hitherto observed in three dimensions.
I joined the Royal Institution in 1962 as a graduate student working under the supervision of David Phillips and in 1964 began crystallographic studies on lysozyme complexed with sugar molecules that were inhibitors the enzyme's reaction. We hoped by this method to locate the catalytic site; a procedure that Bragg described as "throwing a sop to Cerberus". By 1966 these experiments had led to a detailed interpretation of the lysozyme- inhibitor complex and the key elements of recognition at the catalytic site.
The next step was to work out how lysozyme recognised its substrate, part of the polysaccharide component of the bacterial cell wall. By molecular model building and by a series of logical arguments that brought to bear all the available biochemical evidence, Phillips was able to produce a proposal for the way in which a substrate must bind and to make proposals for the catalytic mechanism.
This was the first time that it had been possible to explain how an enzyme speeded up a chemical reaction in terms of the structural constraints and physical chemical principles. The extrapolation from inhibitor binding to the substrate binding was a remarkable leap of deductive reasoning, achieved in three days. Phillips described these three days as the most rewarding that he had ever spent.
Subsequently the proposed mechanism has been validated by a host of biochemical and structural experiments. For this work and his later achievements in protein crystallography Phillips was awarded the Feldberg Prize, the CIBA Medal of the Biochemical Society, the Royal Medal of the Royal Society, the Charles Leopold Meyer Prize of the French Academy of Sciences, the Wolf prize, the Aminoff medal of the Royal Swedish Academy of Sciences and many honorary doctorates and fellowships.
Following Bragg's retirement in 1966, Phillips was appointed Professor of Molecular Biophysics in Oxford University, a move funded by the Medical Research Council and promoted by Hans Krebs (then Professor of Biochemistry in Oxford), Dorothy Hodgkin and John Pringle (then Professor of Zoology). Despite Krebs's enthusiasm for the newly created subject of molecular biophysics, there were several in biochemistry who were suspicious of the new group (a view which happily no longer prevails). The laboratory therefore became part of the Zoology Department where John Pringle had a vision of zoology that ran all the way from molecular structures to populations.
In Oxford there were new achievements in protein structures. In an article published in Scientific American, Phillips showed how knowledge of the lysozyme structure could predict possible folding pathways that the protein might adopt as it was being synthesised in the cell. In an early example of homology modelling, he was able to show how a protein distantly related in amino acid sequence (lact- albumin) might adopt the same structure as lysozyme.
With graduate students he solved the structure of glycolytic enzyme, triose phosphate isomerase. This was the first example of an eight-fold alpha-beta barrel protein, a fold now recognised as the most common fold for many different proteins.
Phillips was a gifted lecturer who spoke without notes, a capability that perhaps he inherited from his Methodist father and forebears. This caused some concern to the BBC when they were televising the memorable Royal Institution Christmas Lectures delivered in 1980 and in which he was ably assisted in the lecture demonstrations by his daughter Sarah, then aged 18. He was a fluent and eloquent speaker.
Phillips was elected to the Royal Society in 1967. From about the mid- Seventies he began his second career as an influential figure in the administration of science. From 1976 to 1983 he was Biological Secretary and Vice-President at the Royal Society and during this time was instrumental in introducing the Royal Society University Research Fellowships, a scheme that offers up to 10 years' support for talented young researchers and which has done much to promote the independent careers of gifted individuals.
In his 1991 Bernal lecture at Birkbeck College, Phillips put forward his view that scientific research must be organised so that, "combined with the provision of the necessary infrastructure, it can release individual scientists to display their critically important gifts of spontaneity and originality". These were his goals when for 10 years from 1983 he was Chairman (first part-time and then full-time) of the Advisory Council for the Research Councils (ABRC), the then intermediary body between government and the research councils set up to "advise the Secretary of State on the resource needs of the Research Councils, the Royal Society and the Fellowship of Engineering".
He also served as member on the Advisory Council for Science and Technology (Acost) and other advisory councils. His skills in committee were characterised by honesty, considerable oratory and a gift for friendships. He made a special plea for openness in the decision-making process and in the decisions taken.
His time at ABRC was not without controversy. On the one hand he needed to satisfy the increasing demands for funding from scientists faced with the continuing growth of scientific opportunities, the increasing need for more and more complex apparatus and facilities (often achievable only through international collaboration); the growing importance of interdisciplinary science, and the need for a variety of different organisations within which research can be conducted most effectively.
On the other hand, he fought to persuade government to deliver more money but recognising the necessarily limited resources and pressures for concentration. He won the respect of both sides, emphasising that only the best science should be funded, although some of his views on choices, selectivity and priorities, were not generally accepted.
As recounted to Max Blythe at the Oxford Centre for Twentieth Century Medical Biography, Phillips was once reprimanded for making a public statement concerning his view of the poor treatment of the science budget in the annual government statement on Public Expenditure. The Secretary of State conceded in private that the qualities required in a person in the advisory role on visionary uses of science resources would probably not be compatible with a person who would be willing to be snaffled and they came to a good understanding. The next year the Public Expenditure statement produced a much better settlement for science that recognised the need for a rising profile over future years.
David Phillips was knighted in 1989 and appointed to a life peerage as Baron Phillips of Ellesmere in 1994. His retirement from Oxford in 1989 led to a move back to London and further involvement in science and Westminster. He joined the House of Lords Select Committee on Science and Technology and became its chairman in 1997, contributing especially to a study of the information society and the needs of the UK and initiating important reviews, such as the Report on Resistance to Antibiotics chaired by Lord Soulsby.
In the last years of his life he was ill with cancer but took a keen scientific interest in the treatment that held the disease at bay for a considerable time. Before he died, he completed the final draft of a manuscript on how the lysozyme molecule was solved. It is a fitting tribute, assembled with historical accuracy and vision and containing much that is instructive to modern-day protein crystallographers.
He married Diana Hutchinson in 1960 and they had one daughter, Sarah. His two grandchildren gave him enormous pleasure in his later years. He once listed among his interests "talking to children". He had a simplicity and directness that was equally effective with children and with the most august members of his committees.
Odd though it may sound, many scientists profess themselves to be in awe of their encounters with politicians, writes Tam Dalyell. In the case of David Phillips, it was the other way round. Politicians found him formidable.
I was not alone in being just a little frightened; more than one Conservative minister confided to me, "I read my brief three times before Phillips enters my office and my normally placid civil servants are on tenterhooks." The less-than- informed opinion would be punished by that direct, glacial interrogative stare. Phillips was master of the stony short silence extracting a faltering answer.
Over my 33 years as a New Scientist columnist on Westminster/ Whitehall politics and policies relating to science and technology, Phillips was the most effective of all operators, in that world where science meets politics - clearer than Zuckerman, with fewer reservations about what he wanted done than Dainton. He displayed a certain somewhat mechant pleasure in presenting unpalatable sights and awkward views to politicians, spiced with "take it or leave it".
As Sir David Phillips, former Biological Secretary of the Royal Society and chairman of the ABRC, he appeared before a range of Commons select committees and made it abundantly clear that he considered it his duty to bring MPs face to face with reality. Asked by the able and scientifically numerate Conservative MP Spencer Batiste about the interaction between a co- ordinating committee and the chairmanship of the Chief Scientific Adviser in relation to top levels of the office of Science and Technology, "Where would you plug into that process?", Phillips replied:
The high-level committee would be of independent outsiders representing the interests of the world "out there". I am reminded of the Bromley joke about Washington being 100 square miles surrounded by reality. I think we have to remember that all of this is intended to serve reality out there. The top-level committee would have representatives of the public interest, if you like.
Or to Sir Trevor Skeet, veteran of innumerable scientific committees inquiring about the fast breeder reactor, somewhat tartly,
I would suppose that decisions have been taken as a result of discussions in what was the Department of Energy advised by Acord, their advisory committee. That is related to, I suppose, proposals within the Department of Trade and Industry which have now been announced as government policy. As for Robin [Nicholson] saying that is a question that has been rumbling for quite a long time, I do not doubt the ramifications of it will rumble even longer.
To get the full flavour of what Phillips meant, "I suppose" might mean "if only they knew clearly what they were talking about".
In his maiden speech in the House of Lords on 23 November 1994 we get an example of his brand of barbed humour:
My period as chairman of the Advisory Board for the Research Councils, which noble lords may remember was abolished at the end of last year, included many exciting developments in science and its application; but none more dramatic than the development of molecular biology and its application to medicine and to agriculture. Your lordships will remember, for example, the sheep named Tracy which was bred to produce in her milk the important anti-haemophilia drug Factor IX. Tracy is now a senior member of a small flock of sheep, whose members produce, among other things, alpha antitrypsin, which has great promise in the treatment of emphysema. Those of your Lordships who may be concerned about shortness of breath will no doubt take a great interest in that development.
Once a fortnight, the Parliamentary and Scientific Committee meets at 5.30pm in Westminster Hall for an hour and a half's lecture and questions. This is followed by a working dinner in a Commons dining room to which the two speakers and a score of peers, MPs, and scientists are invited. Phillips was a frequent invitee. His post-prandial contributions were elegantly incisive, cunningly provocative, often aggressive and always, always pertinent. David Phillips was one of nature's shakers.
David Chilton Phillips, biophysicist: born Ellesmere, Shropshire 7 March 1924; Research Worker, Royal Institution of Great Britain 1956-66, Fullerian Professor of Physiology 1979-85; Professor of Molecular Biophysics, Oxford University 1966-90 (Emeritus); Fellow, Corpus Christi College, Oxford 1966-90; FRS 1967; Vice-President, Royal Society 1972-73, 1976-83, Biological Secretary 1976-83; Kt 1979; Chairman, Advisory Board of the Research Councils 1983-93; KBE 1989; created 1994 Baron Phillips of Ellesmere; married 1960 Diana Hutchinson (one daughter); died London 22 February 1999.
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