The UK built the first synchrotron in the 1980's 1, 2, 3, in which it was dedicated to producing synchrotron light that would be used for experiments. Synchrotron light is a source of electromagnetic radiation, and it was this that could be considered a massive contribution to the world for new scientific research. For the past 30 years, the UK have been on the forefront of Synchrotron science, and have again shown how advanced they are compared with the rest of the world. 4, 5
A Synchrotron is a huge accelerator in which charged particles are accelerated around a fixed circular path by an electric field and held to the path by an increasing magnetic field.4 Worldwide there are more than 50 synchrotrons, all ranging in size and function. Each synchrotron has a varied number of beam lines and with each also producing a different brightness of synchrotron light. 6 The beam lines all produce very intense beams of x-rays, IR and ultraviolet light, which will help scientists study samples at a molecular and atomic level and to a level of detail that would be otherwise be unavailable to them.4, 7
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Each synchrotron falls into two main categories; high energy physics machines and sources of synchrotron light. A well known example of a high energy physics machine is the Large Hadron Collider, whereas the UK's newly built synchrotron is an example of a source of synchrotron light.8
Known as a medium energy synchrotron, it has been named The Diamond Light Source. Construction began in 2003, with the first phase being completed in 2007, taking two million man hours. Costing a total of £263 million pounds so far, with a further £120 million to come by 2012, it covers an area of 45 thousand square metres, and is located in south Oxfordshire. 9, 10, 11
The 'super microscope'7 was funded by the UK Government and by the Welcome Trust. It is the world's largest, medium energy, Third generation synchrotron. There are only a few third generation machines worldwide, which are able to produce the most intense beams of light as of today. This is achieved by the advanced magnets that are used, which means the potential for new scientific breakthrough is at a greater likelihood.12
Scientists from all backgrounds; universities, students, researchers, museums and even large companies want to and are able to use the facilities Diamond produce. At this current moment, the Diamond have all 7 beam lines operational, and are now in construction of a further 15 beam lines by 2012, meaning that at any time, 15 separate experiments may take place, using the three main techniques Diamond provides: diffraction, imaging and spectroscopy. The hope one day is for Diamond to achieve its full potential by reaching the number of 40 beam lines.13, 14
The machine will be able to produce X-rays that will be 1,000,000,000,000 times brighter than an x-ray from a hospital, 15 and as said earlier; this is achieved by the 22 specially designed insertion magnets, which will cause the electrons to wiggle, causing a higher intensity and the much greater brightness.11
The machine is made up of three key components: a linear accelerator, a booster ring and a storage ring, with the storage ring being a 561 m ring. Electrons are shot from the linear accelerator into the 158 m booster ring.11 Made up of stainless steel tube, surrounded by strong magnets, the electrons are accelerated to near light speed and is then injected into the storage ring. This is where the electrons pass through the specially designed insertion devices and so producing the very intense x-rays, along with ultra-violet and infra-red light. These beams are then injected into the experimental stations, which is itself is made up of 3 components: optics hutch, experimental hutch and control cabin. As the X-ray beam is passed through the optics hutch, it is focused and filtered where it then enters the experimental hutch and hits the sample. The control cabin is where the experiment can be remotely controlled and also where the collected data can start to be analysed.16, 17
With the Synchrotron now operating at a high level, many scientists come to conduct their own research, ranging from Palaeontologists and architects to forensics and oceanography. With Diamond able to study such a huge variety of samples, techniques which have been based and used at the synchrotron have had a major effect in all walks of life. The Diamond Light Source can help benefit many health issues. The synchrotron is used to see 'invisible' matter by looking at things to the atomic and molecular level. 7 The synchrotron has already been used to help develop Tami flu, the anti-flu drug, and also helped show the structure of the Foot & Mouth virus. 8 Recently brain tissue has been examined, in order to further the current understanding of Parkinson's disease.18, 19, and 20
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At the American Association for the Advancement of Science (AAAS) conference in Chicago, a Diamond scientist spoke in the group project, casting a New Light on Ancient Secrets, and she discussed the reasons and uses for the new beam line opening up at Diamond, which can be used for cultural heritage scientist. The new beam line will have a large experiment hutch, so larger artefacts can be brought in to be X-rayed by the synchrotrons immense lights.21
Also at the AAAS conference, Dr Joanna Collingwood, from Keele University, was speaking about all the research she has already conducted into Parkinson's disease. Parkinson's disease affects a small region in the mid brain region, but in particular a region which creates dopamine,20 a neurotransmitter, which is needed for control to movement, with an estimated 6.3 million people worldwide22, and over 120,000 people in the UK suffering from the degenerative nerve disease.23
She looked into the concentration levels of metal ions in healthy brain cells and also into cells of people who have the disease. Looking at a cellular lever, she used autopsy tissue from brain banks and she prepared thin slices to bring to the Diamond. Here she used microfocus spectroscopy, in which high intense x-rays were focused onto the samples of the tissue. By being able to control the beam, the brain tissue as a whole could be mapped, and what was found was the iron concentration is significantly higher than compared to healthy brains. Also using this technique, the distribution of the iron can be seen in and around the surrounding cells and tissues, and also what the iron is bound to in its chemical state, and so a contrast map can be built up.24 The hope behind the research is that magnetic resonance imaging scans can track the contrast change, with the hope of an early diagnosis, as early diagnoses could lead to a therapy in which the metals are removed, before the damage done is too much.
Pharmaceutical companies and independent researchers are all allowed to use the Diamond to conduct work and such as, they are increasing the use of macromolecular crytallography25, which has been found to be the most powerful method to observe a three dimensional structure of biological molecules. It is also used to investigate function of a molecule, such as protein folding and unfolding, and so Macromolecular Crystallography can be used as a tool to help with rational drug design.26
At Diamond, they have three different beam lines to focus on determining the structure of a protein or virus. For pharmaceutical companies especially, knowing membrane proteins is important. This is down to when they are looking to design a new drug; they need to know how the drug will not only react with membrane protein, but also which membrane protein will be targeted.
Even though the macromolecular crystallography has been found to be the most powerful, it is by no means the only research method being used by pharmaceutical companies. Non-crystalline diffraction, Circular dichroism and also Infrared micro spectroscopy are all methods that look at separate aspects of the sample, with each method giving a different benefit, and with all the knowledge together, scientists can grasp a greater understanding of a molecule, thus a much more effective drug may be prepared.27
Non-crystalline is a method can be used to gain a greater understanding about how a disease affects a certain protein, as an example. Also a change in a protein, for example if it denatures, can cause it to become a virus. This change can be mapped, and so a better understanding as to why such protein would denature will be recorded.28
Circular dichroism is a form of spectroscopy that uses UV and Visible light. It is used to determine isomerism and the secondary structure. Again it is a good technique to use to investigate binding interactions in healthy and also cancerous cells. The synchrotron helps by having a much higher signal to noise ratio and so the measurement time for the circular dichroism is reduced and the amount of material needed is a lot less.29
IR Micro spectroscopy identifies molecules and also spatial resolution and so physical-chemical properties can be understood at the micro structural level. Again the synchrotron provides a high brightness for experiments to be undertaken, and so a wide spectral range can be observed.30
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All these methods together give researchers a very detailed image into the atomic world, and so with all the new knowledge being provided by the synchrotron, brand new effective drugs can be thought of and previous unanswered health issues may be resolved.31
In 2006, the guardian posted an article, about how the Diamond Light Source could be used to examine cancer cells, in much more detail to the synchrotrons previous to the Diamond Light Source. Scientists were using Diamonds predecessor, in tandem with the newly built light source in France, with the scientists planning on studying the way lung cancer cells react to drugs32.They did this by bombarding the cells of the cancer with IR light, measuring how absorption changed depending on which chemical change is taking place. This was used to examine the tissue after different rounds of chemotherapy, and the synchrotron will be able to show if the cancer has been destroyed or not, by testing the absorbency again.32
Using Diamond, with the extra intensity and brightness it provides, the shape and structure of the molecules can be studied by being bombarded by X-rays, as these will diffract off the molecule to produce a pattern. By doing this, researches can discover the shape of the protein membrane, the gateway for viruses, and so therefore can create vaccines to help fight off viruses. Diamond can be used to effectively light up a specific cell and then using this as a marker, to see if the round of chemotherapy has actually worked. So unlike using IR light, using Diamonds new techniques, treatment for therapy of the cancers can be made on a person to person basis and so improving treatment for everyone.20, 32
In 2001 there was a serious outbreak of foot and mouth disease in Britain. A highly contagious virus that affected, and is still affecting: cows, sheep, pigs and many other cloven-hooved animals. This disease has torn through livestock throughout the world, with no cure for the disease, but only a vaccine to control the spread. This was done by injecting the animals with the dead virus particles, which takes weeks for the animal to build up its own antibodies. As foot and mouth affects so many people worldwide, scientists from Imperial College are trying to create a drug that will be effective immediately and will stop the virus from replicating in its tracks.33
The disease is an RNA virus, an information encoded strand of nucleotides34, a small sphere made up of protein composed up of singular molecules of RNA. It is these RNA molecules that make up new proteins. So once this virus gets into a healthy cell, it will begin to reproduce its virus, and so the healthy cells will become infected.20
So with the synchrotron, the researchers are trying to design the drug that can help stem foot and mouth, and this is done by focusing on the protein, 3c protease from the virus. This is the protein that reproduces itself inside the infected cells, by tricking the cell to make more infected proteins. As such the virus gene only carries a single gene in its RNA which is translated along a long poly-protein. The virus however can't work on the long poly-protein and so needs to cut it up into individual pieces before the virus can start reproducing. So to prevent this from happening, researches are trying to design a drug that will prevent the poly-protein from being cut up, and so therefore preventing the virus from spreading, and limiting the diseases impact.20
By using X-ray crystallography, a detailed three dimensional structure of the 3C protease can be determined, and so a specific drug can be designed to precisely interact with the virus protein, and to stop it from affecting healthy cells. Shining the X-rays onto the protein diffracts the pattern giving the structured shape of the protein, and so with this information, a ration drug can be designed. This drug will then be able to mimic the healthy cells, so the virus attaches to the drug, instead of the healthy cells. To make a well designed drug, the drug, or inhibitor, needs to bind strongly to the virus protein, and so only a low concentration of the drug is needed.
Finding a drug that will be effective against a given target and the fact of the matter is that thousands of combinations will be tested before the right match is found. That is why rational drug design is a focussed approach in which pharmaceutical companies have used methods such as X-ray crystallography and nuclear magnetic resonance spectroscopy, and so the use of trial and error and thousands of possible incorrect choices is not needed, and that a drug can be made quickly and effectively. These methods both give a three dimensional picture of a protein, which is then used to find a chemical compound which will interact with its receptors. A drug works by interacting with receptors to benefit our health, by either stimulating or blocking activity to avoid a negative and unwanted outcome.
An American based company, Vertex Pharmaceuticals Incorporated, was the first industrial customer to use Diamonds advanced technology. With Diamond able to focus synchrotron light into very intense X-ray beams, Vertex Pharmaceuticals have attempted to further their understanding and research into the treatment of serious diseases.
Vertex in the past have been a part of developing drugs to help with cystic fibrosis, rheumatoid arthritis and also an oral protease inhibitor for the treatment of hepatitis and now using Diamonds X-ray Crystallographic techniques, Vertex have furthered their rational drug design, to try and find ways to stop varies human cancers and bacterial infections. By being able to see such a clear three dimensional structure, a better inhibitor compound could be found, which will increase the effectively of the given drug and so interactions between them and with the relevant proteins will have a greater success rate. 35, 36, 37
These were only a few things the synchrotron has been able to help with over the last few years. Currently scientists are looking into how to inhibit tuberculosis bacteria38 and also looking into the tumour suppressor gene, p53, so that its protein can be duplicated and a new anticancer drug could be developed39. This is all possible due to the immense synchrotron light that the Diamond Light Source can create. They can place any size sample in a beam line and the information they can achieve will be much more advanced than ever, and so creating drugs that will help cures or even just treat diseases that are life threatening and harming to all life.