A Short Account of the Impact of SRS Daresbury on UK Structural Biology
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The SRS Daresbury was the first dedicated X-ray synchrotron radiation source to be constructed in the world. Initial experimental facilities were brought into operation in 1981 and since then the SRS has provided an excellent resource for structural biology as well as other scientific disciplines. This document covers some of the most important method (instrumentation, analytical and theoretical) developments and scientific highlights, which demonstrate that the laboratory has played a leading role in structural biology in the UK. It draws comments from several recent independent reviews where appropriate.
It is clear that synchrotron radiation has transformed the scope for structural analysis of biological molecules1-3. Synchrotron radiation has many different applications in the Life Sciences but quantitatively the dominating use is in X-ray protein crystallography. It is widely recognised that this is likely to remain so for a foreseeable future. The needs in other applications of synchrotron radiation are also growing1 e.g. in non-crystalline diffraction (NCD), small angle scattering, X-ray absorption spectroscopy (XAS & XAFS), microscopy and medical applications. SRS has played a major role in each of these areas. In the non X-ray region (e.g. circular dichroism CD) also, SRS has played a leading role and been recently recognised for this by the establishment of one of the highly prized BBSRC’s Structural Biology centre at Daresbury.
1. Protein Crystallography
Science & Output
In a recent review (1996) conducted by BBSRC, it was found that UK had a "greater research output in Structural Biology than any other country except the USA". The review acknowledged that the UK owed "its leading position in Structural Biology to SRS Daresbury" (see enclosed pages from the review). The number of crystallographic structures determined by using the SRS Daresbury has been extremely high and has remained so during the last three years despite the emergence of three hyper SR facilities. The following table compares the output of SRS Daresbury compared to other major centres around the globe.
The SRS occupies a VERY high position with an extremely high output for each experimental station; on per station basis IT HAS THE HIGHEST OUTPUT LEVEL. The quality of the research is also high with 24 of the structures being reported in the most prestigious scientific journal Nature; many of these have been of groundbreaking importance and have been used to illustrate the front cover of prestigious scientific journals. In addition the Nobel Prize was awarded to John Walker in 1997 for determining the structure of F1 ATPase and the insight into the mechanism of this important enzyme. A large amount of use of the SRS Daresbury was made in order to investigate crystal quality and collect the necessary data to solve the structure. There have been many highlights, some of these are shown on the front cover of this document.
Method developments
It is difficult to do justice to many of the highlights in this brief document. Some of the major achievements have been:
2. Fibre Diffraction, Small Angle Scattering and Circular Dichroism.
Daresbury Laboratory has taken a world leading role in the development of facilities for x-ray time-resolved fibre diffraction and small angle scattering studies in biology. Investment from MRC in 1985 to build a dedicated x-ray small angle scattering facility at the SRS initiated a dramatic growth in time-resolved studies of biological systems. Continued Research Council investment facilitated significant advances in detector technology for this area culminating in the successful establishment of the RAPID detector as a users’ facility in 1998. This detector is state of the art and is ca. 50-100 times better than any other multi-wire system available world wide. Consequently, science at the SRS is still at the cutting edge for time-resolved studies in the micro to milli-second time regime. Areas of particular interest have been fibre diffraction studies from living muscles during contraction resulting in several papers in Nature, self assembly of complex protein systems such as tubulin and clathrin.
An area that is gaining increasing interest is protein folding and is of much interest to the structural biology community. Staff at Daresbury in conjunction with academic collaborators have developed the use of VUV Circular Dichroism and stopped-flow technology to put the SRS at the fore-front in this area. CD in conjunction with x-ray scattering offers a powerful tool for understanding the initial stages of protein collapse and secondary structure. This has enormous practical implications for example for the biotechnology industry where mis-folded over-expressed proteins frequently accumulate in inclusion bodies, resulting in expensive loss of product. The power of CD as a technique has been recognised by the award of one of only six UK BBSRC Centres for Structural Biology to develop a dedicated beamline for this work at SRS Daresbury.
3. X-ray Absorption Spectroscopy
The importance of this technique for studying metalloproteins which make up some 30% of the known proteins has been addressed recently by Johnson & Blundel and Hasnain & Hodgson in reference 3. Recently (June 1999) an international review panel chaired by Professor Roger Fourme (LURE) reported that Daresbury Laboratory "has played a very important and leading role in the development of X-ray spectroscopy. It has always been at the forefront and in fact is driving new developments. This is particularly true for the application of X-ray spectroscopy to questions in the field of structural biology, where major contributions and initiatives, covering both instrumental as well as theoretical aspects of this technique, originated at the SRS". They also stated "As far as beamline facilities are concerned, we feel that the general standards are very high but at the same time also reflect the age of the SRS. Despite this aging factor, the performance of monochromators, which are the key optical elements of any EXAFS beamline, is outstanding in terms of reliability, stability, as well as ease of use". "In addition, SRS continues to play a leading role in the development of new X-ray fluorescence detectors and this will contribute to keeping the two beamlines mentioned competitive with similar beamlines at other synchrotron facilities".
4. Summary
The above indicates that Daresbury laboratory has provided excellent facilities for structural biology to its USERS’ community. It has adapted over the years to respond to changing users’ requirements and has, in addition, driven many necessary developments. This has required a team of accelerator physicists, optics experts and scientists who understand the requirements together with the skills of many other supporting staff. This team has been built up over many years with excellent integration between the various disciplines. This team, together with the first class research of the users community, is responsible for the excellent scientific output from the SRS Daresbury. As a result, SRS Daresbury is a jewel in the British Science crown as we believe DIAMOND at Daresbury would be in the next century.
REFERENCES
Synchrotron Radiation
Other Central Facilities
University-based Facilities
UK Structural Biology research (1993-1995) was compared with that of the other 11 OECD countries (Figure 1). The UK was found to have a greater research output in Structural Biology than any other country except the USA. Note that Germany may be over represented because of EMBL.
The UK has 12 - 13% of world output in Structural Biology,compared with just under 9% for Biomedical Sciences in general. Indeed, the only other areas of UK biology which contribute over 11 % of world publications are tropical medicine and psychology/psychiatry ("Evaluation of National Biomedical Research Outputs through Journal-Based Esteem Measures"; Grant Lewison, PRISM).
The UK percentage share of Structural Biology Publications has increased steadily from 1988 to present (Figure 2).
When publication quality is considered (Figure 3), the strength of the UK is even more apparent. As a measure of relative paper quality, the ratio of the weighted value of papers published can be compared with the total number of papers published (unweighted value). The UK (ratio = 1.11) performs better than all countries except Switzerland (ratio= 1.19). Japan does most poorly (ratio = 0.81). Thus, the relative quality of UK output is high.
The research output in Structural Biology per million population is shown in Figure 4. The conclusions were not significantly different when weighted paper counts were used (data not shown). The UK is third in this ranking, after Switzerland and Sweden. However, Switzerland and Sweden have small populations and the values are significantly influenced by one or two very strong laboratories.
Importantly, on this analysis the UK appears stronger than all other countries including the USA, France and Germany.
Conclusion: UK Structural Biology is highly competitive internationally, in quality and quantity, and the UK proportional contribution has steadily increased over the last ten years.
Distribution of Structural Biology Research within the UK
Table I shows a geographical analysis of UK Structural Biology papers. Column 1 (Total) shows the total number of papers; column 2 (Non-collaborative) the number of non-collaborative papers; column 3 (Collaborative) the total number of papers weighted for collaborations (eg. if a paper involved two institutions it was accorded a half value for each institution). The % Total reflects the percentage contribution of a laboratory to total Structural Biology publications (after adjusting for collaboration with UK and overseas laboratories) .
Structural Biology research is distributed amongst a number of types of organisation; universities (70;2% of UK output), research council institutes (16.7%, industry (5.6%), hospitals (2.3%) and others (eg. cancer charities) (5.2%).
THE FUTURE OF SYNCHROTRON RADIATION
Access to a reliable source of synchrotron radiation is essential for the future of Structural Biology in the UK. The SRS based at Daresbury Laboratory will be upgraded over the coming three years. However, this represents the physical limit of the improvements that can be made to the SRS. Further improvements in the provision of SR can only be possible with a new SR source. The future provision of this SR source is currently being debated and a number of different options are being explored involving the public and private sector partnerships. The likely cost to BBSRC for a new synchrotron source is c. £15M over 5 years at current prices.
BBSRC must play a major and proactive role in ensuring that a new source is provided in the UK as soon as possible with the necessary specification and with adequate numbers of beamlines for structural biology research. The Chief Executive of BBSRC is urged to explore, with high priority and with the other research council chief executives, all possible opportunities to support a new SR source in the UK.
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