Malcolm_Skingle_220_330The Diamond Light Source synchrotron has a wide number of applications to the pharma and biotech industries. GlaxoSmithKline’s Malcolm Skingle, Chair of Diamond Industrial Science Committee (DISCo), explains more.

Since November 2004 I have had the pleasure of being Chair of the Diamond Industrial Science Committee (DISCo). During that time Diamond has grown from being a construction site to a thriving science facility, helping hundreds of researchers a year deliver world-leading science.

Diamond Light Source is the UK national synchrotron facility, one of the biggest public science investments in the UK in the last 40 years. A synchrotron accelerator produces infrared, ultraviolet and X-ray beams of exceptional quality and brightness to scientific end-stations, referred to as beamlines. These beams are of high intensity, extremely well collimated and tuneable. This allows researchers to collect data substantially faster, on smaller samples and using different wavelengths than they can in their home laboratories.

Diamond Light Source synchrotron

Diamond Light Source synchrotron

The applications of synchrotrons to the pharma and biotech industries are widespread and we here at GSK are making extensive use of Diamond.

Structural characterisation using X-rays forms a major proportion of the research done by GSK at synchrotrons, with applications ranging from protein crystallography, through small molecule crystallography to high resolution powder diffraction.

Macromolecular crystallography is used to study complex macromolecules and their binding to ligands with potential inhibitor effects. This is one of the most important steps in the rational drug design process. Diamond has invested heavily in automation and detector technology to make it possible to go from crystal to electron density map in a matter of minutes.

For colleagues in drug development, the synchrotron is ideal for supplementing home laboratory equipment. Small molecule crystallography is the gold standard technique for determining crystal structure of drug candidates but unfortunately, not all samples co-operate during crystallisation and chemists are left with crystals that are too small to be studied using standard X-ray diffractometers. In addition, with samples that do diffract well, the benefits of the synchrotron are significantly higher resolution and very fast data collection. Because of the higher intensity of the X-rays generated, smaller crystals can be used for structural studies, with samples of a few cubic microns routinely measured. Additional facilities allow samples to be studied at high temperature, low temperature, high pressure and under controlled humidity conditions.

The solution of more complex structures from powder diffraction data is a newer technique. While it is possible to solve structures using standard laboratory based diffractometers, the low symmetry of most organic materials can make analysis of the patterns troublesome due to severe peak overlap. The high resolution data obtainable using the synchrotron light can usually overcome this problem. With the incorporation of robotic sample changers on beamlines, along with state-of-the-art detector systems, high quality diffraction patterns can be collected in a fraction of the time that it would take using a standard laboratory diffractometer; this also makes the technique ideal for polymorph screening.

GSK uses many of the techniques available at Diamond and also accesses the facilities in a variety of ways including:

  • Full Service – GSK scientists send samples, Diamond staff collect the data, perform the appropriate analysis and report back;
  • Mail-in Service – GSK scientists send samples, Diamond staff collect the data and then return it for data analysis;
  • Remote access – this route allows our scientists to ship their samples to Diamond and then collect the data from home. This minimises our travel costs and also allows the whole team to be involved in the experiments;
  • Beamtime only – used by our experienced users when they prefer to collect their own data.

The industrial use of Diamond has, to date, been dominated by the life sciences sector, with around 80% of proprietary use by pharmaceutical and biotech users. The crystallography techniques mentioned above make up the majority of this use. However, for industry to get the maximum benefit from investment in synchrotron facilities then we need to broaden our usage to other synchrotron techniques. Structural biologists are starting to explore the use of complementary techniques such as Small Angle X-ray Scattering (SAXS) and Circular Dichroism (CD) alongside their traditional use of macromolecular crystallography. Other new developments at Diamond include the introduction of facilities for X-ray pair distribution function measurements. This technique, while in its infancy relating to use by the pharmaceutical sector, allows characterisation of amorphous drug candidates. Powerful imaging techniques are also now available. The figure shown illustrates how synchrotrons can support the entire scope of the drug development process.

Technique areas where synchrotrons can support the drug discovery process.

Technique areas where synchrotrons can support the drug discovery process.

While Diamond engaged with industry early on in the construction phase, in order to facilitate the use of Diamond by industrial scientists and engineers, a dedicated team of industrial liaison scientists was later established in 2007.

The Industrial Liaison team (L-R): Anna Kroner, Leigh Connor, Alex Dias, Elizabeth Shotton, Jitka Waterman and Claire Pizzey

The Industrial Liaison team (L-R): Anna Kroner, Leigh Connor, Alex Dias, Elizabeth Shotton, Jitka Waterman and Claire Pizzey

These Industrial Liaison scientists assist our in-house scientists, helping with experiment design, collecting data and, in some cases, analysing the data and reporting back. The establishment of this dedicated support group recognises the fact that the customer profile has altered dramatically since the early industrial usage of synchrotrons more than 25 years ago. At that stage, only large, multinational companies such as GSK had the resources to either partly fund beamlines or have the in-house staff capability to run beamtime. Now, with flexible access and support from synchrotron staff, large science facilities are accessible to all researchers from industry from the traditional large users through to start-up companies of only a few staff. I would encourage you to contact the Diamond team if you believe that synchrotron science may help you drive your research projects forward. They are professional, helpful and like me, they want UK Industry to benefit from this world-leading facility.