Synchrotron radiation biomedical imaging and radiotherapy: from the UK to the Antipodes.

Although the general public might think of 'X-rays' as they are applied to imaging (radiography) and for the treatment of disease (radiotherapy), the use of synchrotron radiation (SR) X-ray beams in these areas of science was a minor activity 50 years ago. The largest gains in science from SR were seen to be in those areas where signals were weakest in laboratory instruments, such as X-ray diffraction and spectroscopy. As the qualities of SR X-rays were explored and more areas of science adopted SR-based methods, this situation changed. About 30 years ago, the clinical advantages of using SR X-ray beams for radiography, radiotherapy and clinical diagnostics started to be investigated. In the UK, a multi-disciplinary group, consisting of clinicians, medical physicists and other scientists working mainly with the Synchrotron Radiation Source (SRS) in Cheshire, started to investigate techniques for diagnosis and potentially a cure for certain cancers. This preliminary work influenced the design of new facilities being constructed around the world, in particular the Imaging and Medical Beam Line on the Australian Synchrotron in Melbourne. Two authors moved from the UK to Australia to participate in this exciting venture. The following is a personal view of some of the highlights of the early-year SRS work, following through to the current activities on the new facility in Australia. This article is part of the theme issue 'Fifty years of synchrotron science: achievements and opportunities'.

Structure-guided fragment-based drug discovery at the synchrotron: screening binding sites and correlations with hotspot mapping.

Structure-guided drug discovery emerged in the 1970s and 1980s, stimulated by the three-dimensional structures of protein targets that became available, mainly through X-ray crystal structure analysis, assisted by the development of synchrotron radiation sources. Structures of known drugs or inhibitors were used to guide the development of leads. The growth of high-throughput screening during the late 1980s and the early 1990s in the pharmaceutical industry of chemical libraries of hundreds of thousands of compounds of molecular weight of approximately 500 Da was impressive but still explored only a tiny fraction of the chemical space of the predicted 1040 drug-like compounds. The use of fragments with molecular weights less than 300 Da in drug discovery not only decreased the chemical space needing exploration but also increased promiscuity in binding targets. Here we discuss advances in X-ray fragment screening and the challenge of identifying sites where fragments not only bind but can be chemically elaborated while retaining their positions and binding modes. We first describe the analysis of fragment binding using conventional X-ray difference Fourier techniques, with Mycobacterium abscessus SAICAR synthetase (PurC) as an example. We observe that all fragments occupy positions predicted by computational hotspot mapping. We compare this with fragment screening at Diamond Synchrotron Light Source XChem facility using PanDDA software, which identifies many more fragment hits, only some of which bind to the predicted hotspots. Many low occupancy sites identified may not support elaboration to give adequate ligand affinity, although they will likely be useful in drug discovery as 'warm spots' for guiding elaboration of fragments bound at hotspots. We discuss implications of these observations for fragment screening at the synchrotron sources. This article is part of the theme issue 'Fifty years of synchrotron science: achievements and opportunities'.

Small Angle Scattering: Historical Perspective and Future Outlook.

Small angle scattering (SAS) is a powerful and versatile tool to elucidate the structure of matter at the nanometer scale. Recently, the technique has seen a tremendous growth of applications in the field of structural molecular biology. Its origins however date back to almost a century ago and even though the methods potential for studying biological macromolecules was realized already early on, it was only during the last two decades that SAS gradually became a major experimental technique for the structural biologist. This rise in popularity and application was driven by the concurrence of different key factors such as the increased accessibility to high quality SAS instruments enabled by the growing number of synchrotron facilities and neutron sources established around the world, the emerging need of the structural biology community to study large multi-domain complexes and flexible systems that are hard to crystalize, and in particular the development and availability of data analysis software together with the overall access to computational resources powerful enough to run them. Today, SAS is an established and widely used tool for structural studies on bio-macromolecules. Given the potential offered by the next generation X-ray and neutron sources as well as the development of new, innovative approaches to collect and analyze solution scattering data, the application of SAS in the field of structural molecular biology will certainly continue to thrive in the years to come.

Impact of synchrotron radiation on macromolecular crystallography: a personal view.

The introduction of synchrotron radiation sources almost four decades ago has led to a revolutionary change in the way that diffraction data from macromolecular crystals are being collected. Here a brief history of the development of methodologies that took advantage of the availability of synchrotron sources are presented, and some personal experiences with the utilization of synchrotrons in the early days are recalled.

Notes of a protein crystallographer; our unsung heroes.

Dedicated to the people who designed, built, and currently work at synchrotron beamlines.