Episode 14 Transcript

 

Meera Senthilingam: Hello and welcome to the July edition of the Diamond Light Source podcast. This month we’re on location at the Light Source to bring you inside access as we attend one of the facility’s Inside Diamond Open Days. We’ll be meeting some of Diamond’s top Engineers and technicians who design the components of the synchrotron and keep it running smoothly; hear from Diamond’s CEO Gerd Materlik about the main highlights of open days such as these; and talk to a scientist working on one of Diamond’s latest beamlines, I24, that is enabling research that wasn’t possible before.

 

Danny Axford: Typically other beamlines would have an x-ray beam of maybe 50 – 100 microns, whereas on I24, we’re working towards 2 or 3 microns. If we can reduce the beam, a very weak signal becomes visible when otherwise it wouldn’t have been.

Meera: Beamline scientist Danny Axford, explaining what insight can be given by such small beams of light later in the show, when we also hear how Danny’s beamline has been used in the battle to develop more effective anti-histamines. As well as hear what the visitors at the Inside Diamond Open day had to say about science at the synchrotron. So all that coming up in this month’s Diamond Light Source Podcast with me, Meera Senthilingam.

 

 

Meera: So this month we’re on site at Diamond bringing you an insight into the Inside Diamond Open Days held at the facility. A day where members of the public get to come along and tour the Lightsource to learn the workings of a synchrotron. There are many talks and tours throughout the day, but before they all began, I spoke to Diamond’s CEO Gerd Materlik about the aims of getting the public inside Diamond.

 

Gerd Materlik: We are living within a community so we need to, from my point of view, show the community, invite the community to see what we are doing really. To give them the feeling of one side of how interesting science is. And the other side is the more, the aspect that we are for 80% financed by the government. I think it is always good for the people to see what happens with the taxpayers money, where does it go, what is it about. We really do something, or we can help people, for example in terms of we think about a spectrum of things, to look at viruses, virus structure, to look at histamine structure. On the other side, look at the conservation of the Mary Rose, or hip replacements, and so on. It’s a broad spectrum, basic science to understand function of life and to understand magnetism on the other side.

 

Meera: And what does a day involve?

 

Gerd: Well a group comes here in the morning or in the afternoon and they will first have a talk, an introduction/overview of Diamond – the managerial structure, but also the broad science structure. And then for an hour we take them around and show them the accelerators, we show them the instrumentation, the beamlines, and we tell them about a few science examples and hopefully they have an understanding of how broad it is.

 

Meera: Diamond’s Chief Executive, Gerd Materlik. Now the open day to go inside Diamond starts with a talk explaining the workings of an electron accelerator like Diamond and how different beams of light can be produced by basically getting electrons to move close to the speed of light around a ring. Following this talk is access into the ring itself to see where it all takes place and this is guided by the many engineers and technicians working at Diamond, providing their insight into running such a large scale, but precise, experiment.

 

David Hawkins: Hello, my name is David Hawkins. I’m a mechanical design engineer at Diamond Light Source and today I’m a tour guide showing people around the facility.

 

Meera: David, so what are the key points that you want to get across to visitors as you take them around the facility?

 

David: A general appreciation of how the machine works and then looking at individual pieces of the machine and then taking them to a talk by a scientist so they can understand what the scientists are trying to get out of the machine. What I do try to do is to make it understandable. For instance, the radio frequency cavities, I try and make analogies to the kitchen and the microwave unit

 

Meera: And what’s the general reception of the crowds you get of the group you take around?

 

David: I find they are usually aghast, and also the sorts of work that is done. Things like working on the hip joints, the Mary Rose Trust, being able to read the deep sea scrolls without unrolling them, it just carries on and on and on. They really are amazed.

 

Meera: And what about your role here at Diamond then. You’re a design engineer, what do you design and what does it involve?

 

David: I design bits of the beamline. I’ve designed things like Diamond windows; diamond fluoresces when it is hit by light and we use that to work out where the beam is. So, as the beam comes into the hutch, we want to know where it is, but designing a piece of diamond 0.9 of a millimetre thick that’s got to take a lot of heat without breaking, that takes a bit of effort.

 

Meera: What’s the role of this diamond window with regards to the synchrotron as a whole and how important is it?

 

David: When you’re commissioning that beam, you need to know where that beam is because it can get deflected all over the place. So we have 4 diamond windows down the length of that particular beamline I15, it’s the high pressure and extreme conditions beamline, so we have 4 diamond windows down there so as we were getting the light into the hutch, we could find out where it had gone wrong and they were invaluable in setting up otherwise you were working in the dark. You know you had a big dark room and you didn’t know where the beam was.

 

Meera: So they help you guide where to get the beam to I guess and then do they stay in place or are they then removed?

 

David: They stay in place all the time. The second role is that they provide a barrier so if you have a loss of vacuum you don’t contaminate the next section up.

 

Alan Morgan: I’m Alan Morgan and I’m one of the Beam Diagnostic Physicists here at Diamond.

 

Meera: What do you diagnose here, what’s your day to day role at Diamond?

 

Alan: Well I’m part of the diagnostic team on the machine side so we’re looking mainly at the electrons. So we have systems to find out what the position of the electron beam is in the machine, because we need to keep that very stable so that the beamlines have a stable thing to look at and use, and also the amount of charge in the beam, basically how well behaved it is. Also if something is going wrong, to find out what is going wrong with it.

 

Meera: So is this in every beamline?

 

Alan: Mainly it’s on the machine side. We do have position monitors in the beamlines and the beamlines do have some diagnostics but it varies from beamline to beamline. Some have lots, some have very few.

 

Meera: And how do you maintain stability, what do you have to look into and what do you have maintain?

 

Alan: Generally you have feedback systems that keep the stability that we need. So we look at where, for position, we look at where it is and we look at where we think it should be and we try and move it to where it should be. For us, feedback systems are a vital part of keeping it stable enough.

 

Meera: What are the actual requirements, how stable does the beam have to be and how important is it that it stays stable at this particular level?

 

Alan: Generally with our feedback systems we can keep it stable to within about 200 nanometres of movement. Some beamlines are more sensitive to motion than others, it really depends on what experiment they want. So there are certain beamlines that we will be more aware of that they are more sensitive and we will check with them that they can see things. They are almost a bit like the canary, if they see something, then we need to check it, if they can’t see anything then probably nobody can.

 

Linda Pratt: My name is Linda Pratt and I’m a software systems engineer and I work in the Controls Department

 

Meera: so what do you have to control as part of the synchrotron and what do you look in to?

 

Linda: We have different technical areas of control. Two of the major ones are Motors and the Vacuum systems. We also have diagnostics systems and other instrumentation to monitor the state of the machine, the beamline or indeed part of running the end stations for the experiments.

 

Meera: So that’s quite a few things there. Could you perhaps pick one or two and explain to me how you control them or how they are controlled, and how important it is for them to be controlled.

 

Linda: The vacuum systems, for instance, a typical vacuum component like a pump will have specialist control piece of instrumentation and we interface that into one of our computers, either a standard PC or a specialist rack-mounted computer and that ties into the monitoring alarm system and the screens that the operators use so the operators can tell, and the experimenters can tell, from their computer screens whether a particular pump is on or off, and if you add all that up together for controlling the vacuum system, it maintains the quality of the vacuum that allows the beam to travel round the storage ring or down the beamlines.

 

Joe Williams: So I’m Joe Williams, I’m a mechanical design engineer at Diamond.

 

Meera: What aspects do you design and engineer?

 

Joe: It’s to do with the beamlines. So, outside of the storage ring wall is when you get into the beamlines and we designed the equipment that goes on the beamlines to make sure it’s tailored specifically for the sort of science the scientist wants to do on that beamline. Most of the work is on the end stations, most of the end stations are specific to each beamline so we’re tailoring the design.

 

Meera: So, to adjust the beamline accordingly to what’s going to be looked at, or....

 

Joe: It’s more handling different samples, on I24, looking at microscopic things, and looking at some of the other beamlines like JEEP, they’re looking at much bigger things such as Aircraft turbine blades, so you’ve got a completely different mechanism you’re going to need to handle that to holding a tiny little crystal.

 

Meera: So you deal with actual components, all the pieces of equipment that handle the samples, or hold the samples for testing?

 

Joe: Yes, but it’s all the equipment before that to tailor the x-rays to be specific to what that sample needs. First of all you need to block out all the radiation that you don’t want from the storage ring. So the first component is something called a collimator which is a big block of lead which blocks out all the radiation you don’t want, so you just get your x-ray beam coming down the centre of the tube. After that you get things called monochromators which then select the energy of the beamline and you’ll get focusing mirrors – slits which are just blades which come in from the sides and bottom and top which define your wide beam into a nice little narrow beam.

 

Meera: So all of this variety of equipment basically homing it in, so from this large beam just narrowing it and focusing it and narrowing it and focusing it.

 

Joe: That’s it exactly and because that’s essentially what your scientist is interested in is getting the right energy of x-rays at this sample.

 

Meera: So it’s clearly not about building a synchrotron and then leaving it to run itself. Every step and every material along the way needs to be monitored closely by the wide range of highly skilled scientists and engineers at the light source.

 

Meera: This is the July edition of the Diamond Light Source Podcast and this month we’re taking you inside Diamond and down into the storage ring to see what the public have access to when the facility holds its Inside Diamond Open Days. Now we’ve heard that they involve the tour around the synchrotron, so seeing where the electrons are generated, how they’re boosted to reach speeds close to the speed of light, and how various beams of light can then be generated by the use of magnets. But along the route, it then makes sense to see one of the many beamlines and hear from the beamline scientists about the scientific research made possible by that beam of light.

 

 

Danny Axford: My name is Danny Axford and I’m a support scientist on beamline I24 which is a microfocus macromolecular crystallography.

 

Meera: What kind of research is done here? What can be looked into here?

 

Danny: Primarily we’re looking at the atomic structure of biological molecules. So these are molecules that are fundamental to how life processes work and I24 in particular has been designed to look at the most challenging samples that have so far proved difficult to analyse. So we use an especially highly-focused x-ray beam which allows us to probe smaller samples, typically we’re analysing crystals and the more complicated the molecule the harder it is to produce a crystal and when you do get a crystal it is typically small. So we’ve designed our x-ray beam to be focused as small as possible which helps with this analysis. The idea with macromolecular crystallography is in order to get a strong enough signal from the diffraction experiment, you grow a crystal and the crystal is an ordered lattice of the molecule and the bigger the crystal is, the stronger the signal you’ll get. Now complicated molecules really don’t like to grow into crystals. Typical examples are membrane proteins - these are typically embedded in the surroundings of cells so they’re involved in transporting molecules in and out of cells and because they sit in the membrane they are not water soluble. So to grow a crystal from solution is very tricky.

 

Meera: Why does this feature make them harder to get into crystal format then?

 

Danny: Because typically they would be surrounded by the lipid that forms the membrane and we’re not interested in the lipid, we just want to look at the protein, the protein itself. But, if you remove too much of the lipid, then these molecules then just fall apart. What you have to do is replace the lipid with detergent which allows you to solubilise these molecules and then grow them into crystals.

 

Meera: And they form quite small crystals?

 

Danny: Typically they will be very small, often very thin so you often get plates. So they are sort of 2 dimensional and this lack of volume means that the signal that you can detect from these crystals is very, very weak.

 

Meera: So why has seeing such small crystals been difficult with other beamlines and how has this beamline overcome those problems?

 

Danny: Typically other beamlines would have an x-ray beam of maybe 50 to 100 microns whereas on I24 we’ve managed to get our beam below 10 microns, we’re now working towards 2 or 3 microns and if your sample is only 2 or 3 microns and you hit it with a beam that is maybe 100 microns then most of the x-ray beam will be missing the sample and that is essentially just adding ‘noise’ into the signal that you detect. So the signal that you are looking for is just washed away by the noise. Whereas if we can reduce the beam to the size of the crystal itself, then the signal to noise ratio is increased massively and so the very weak signal becomes visible when otherwise it wouldn’t have been. So we can actually have a look at the beamline and see the components in action

 

Meera: So we’ve come through to the beamline now and there’s a large metal box basically in front of which there’s another attachment out of which the beam, the x-ray comes out and then in front of that there’s a very small, miniscule looking pin which the sample is placed. So how small is this sample again?

 

Danny: Ok, so some of our samples are just a few microns in size so we’re talking less than a tenth of the size of a human hair. So even under the optimal microscope that we’re got integrated into the beamline, these samples are very difficult to make out.

 

Meera: This large metal box, this very thick metal box, behind it is where this beamline comes into its own I think, it is quite unique

 

Danny: That’s right, inside this vessel here we’ve got an extra set of focusing mirrors. That allows beamline I24 to get the really small microfocus beam required to hit these samples.

 

Meera: So that hits on to the sample. The pin that the sample is on is just a couple of centre metres in front of where the beam comes out, but then that’s diffracted onto a big, about half a metre squared, board about a metre and a half away?

 

Danny: That’s right, this is a detector. We can actually move it closer in, it’s extremely sensitive and it can read out very quickly.

 

Meera: You mentioned that an example of a complicated molecule is a membrane protein but what other examples can you give, what has been looked at so far on this beamline?

 

Danny: Ok, so another good case are virus particles in samples. These typically are very large molecules, in the order of millions of atoms. Typically they won’t freeze very well at all so often instead of freezing the samples, we have to collect the data at room temperature and that means that the samples do not last for very long at all. They are destroyed by the x-rays inside of a second which is why we need the sensitive detector which is very fast and typically we’ll have to get through lots of samples and then try and combine the information we get from them into one complete picture.

 

Meera: So viruses, membrane proteins, so largely biological molecules?

 

Danny: I mean in some cases we will shoot small molecules, which could be in the form of drugs for example, but these would be attached to the biological molecules, so we can see where the drugs attach, that allows us to maybe ‘tweak’ the design of the drugs to have a better interaction with the target molecule.

 

Meera: Danny Axford, Beamline Scientist at Diamond’s I24 microfocus macromolecular crystallography beamline and as Danny concluded there, this beamline enables scientists to visualise how drugs are binding to certain proteins found in our bodies, such as membrane proteins and this is what Dr Simone Weyand from Imperial College London has been doing. More specifically she’s been watching the binding of antihistamines in our bodies.

 

Simone Weyand: Yes so I work on different proteins which are all membrane proteins and the latest result is the histamine receptor and the histamine H1 receptor is a protein which is specifically recognising histamine and histamine is a compound that is involved in our local immune response. So as part of our immune response to foreign objects such as pollen or pet hair or whatever, food for instance, histamine is produced in our bodies. Now binding to the H1 receptor histamine is able to trigger the inflammation response associated with allergic reactions such as hayfever, food and pet allergies.

 

Meera: So you were looking at the histamine H1 receptor, whereabouts is this particular receptor found, what cells is it on and what role does it play?

 

Simone: The receptor is found in all sorts of tissues, human tissue, well mammalian tissue essentially. Histamine is a substance that is produced by our bodies and we also have this receptor recognising this histamine in our bodies. So in principle, allergy is basically a hypersensitivity of our immune system

 

Meera: So hayfever and allergies to things in the environment cause histamine production which then comes and binds to this receptor, is that right?

 

Simone: Exactly!

 

Meera: You’ve been looking at the structure of the actual receptor, why is it important to know this structure and what was known about it before and what have you now been able to see that was new?

 

Simone: There was not a lot known before about this receptor. In biochemical terms, yes, but not how it looks like exactly and for us it was really very important to have a high resolution picture of how this protein looks like and especially what we show is this receptor binding antihistamine drug to it. What we actually could show is a high resolutions picture of this complex and what it means essentially is now the Pharma(ceutical) companies can produce a highly specific drug which is treating or getting rid of the allergies. These drugs are not really specific against this receptor. For instance, heart receptors, receptors for proteins in the heart, like the potassium channel and we can therefore have problems with the heart like arrhythmia, dry mouth or drowsiness, sickness, all these kind of things.

 

Meera: So how do current antihistamines work then? Do they bind to this histamine receptor and therefore stop histamine binding to it?

 

Simone: Exactly, that is what happens. So the antihistaminic drugs, they bind to the receptor and block it from histamine binding to it.

 

Meera: Knowing then the structure of the receptor, how could you make then, or potentially think about designing a drug that would attach to the receptor better? What could you now do knowing this structure and knowing what happens when the antihistamine binds?

 

Simone: Because we have really the atomic detail of how this structure, the binding site, the active site of this protein reacts with histamine or drug molecules, how it looks like in the smallest detail, atomic detail, the Pharma industry can really specifically design a drug which is only binding to this receptor. We could really see the interaction, the specific interactions of the drug molecule doxypene which is an antihistamine drug available on the market and by comparing this protein, this receptor, with other receptors of known structure we then can also see what other differences, what is important in this environment for the selectivity of the drug molecules etc.

 

Meera: So you’ve been able to see how antihistamines bind to the receptor, what will the next steps be to make a better drug, think about designing a better, more targeted drug?

 

Simone: For designing a highly selective drug really it now over to the Pharma companies but what they will probably do is design a whole library of drugs which is only interacting with the residues of the active site of this receptor, then screen it probably in animal models to see if it’s highly specific, does in interact with other receptors, other proteins, do side effects occur or not and make it really specific enough and reduce it. For me, or for us, one of the next steps will probably be to see how different antihistaminic drugs available on the market bind to this receptor to see what are the interactions there, what is the difference for the drug that is bound currently and are there some interactions that we didn’t see so far, are there more interactions or less interactions. All these differences they have a big influence on designing a highly selective drug against allergies.

 

Meera: Simone Weyand from Imperial College London. Now this month we’ve been hearing from tour guides, engineers and the Chief Executive of Diamond about the importance of letting members of the public inside the facility to give them a good insight into how a synchrotron works. A wide range of visitors across all ages and professions do come along. But what do these visiting members of the public actually think of the facility?

 

Visitor: My name is Thiella Buddy and I’m in Market Research, so nothing to do with sciences at all and the reason I came along is because my flatmate is quite interested in sciences and everything else that goes round and she said would you mind coming along, there’s something happening around work and I said no, that’s fine and I’m very, very glad I did.

 

Meera: What were you expecting before you came along?          

 

Thiella: I was expecting something a bit more physics orientated and so a lot of mathematical formulas and explaining what’s happening, but in more of a scientific way, whereas what you’ve done today is explain what is happening but in everyday language which is very, very helpful.

 

Meera: And did it help I guess because you go on a tour and actually see the whole facility, so that must have been quite different?

 

Thiella: Yep, that definitely helped as well because you saw what was happening in the presentation, but to actually see it in real life was very different to what I imagined, even though I saw the picture in the presentation, to actually see how it was built and all the different magnets that are around it was fantastic.

 

Adam: I’m Adam, and I’m hoping to study at Leicester University to do Physics. You just can’t comprehend how massive the whole place is and the amount of equipment and how technical it all is and just hoe technical experiments on this sort of scale are and how much equipment is actually required and how precisely it has to be monitored. Everything has to be at the right temperature for it to work and it’s just mind-blowing how technical the whole thing is.

 

Liz: Hi, I’m Liz, I’m a student Nurse and I’m in my 3^rd year at Oxford Brookes University.

 

Meera: What did you think of the open day? What were you expecting before you came along, did you know much about Diamond before?

 

Liz: I didn’t know anything really, apart from it was an accelerator, so I didn’t really know anything at all about what they did and the talk was really good because it was scientific based but it was really easy to understand. Obviously, the medical side of it I was more interested in and I think it is amazing what you do here.

 

Meera: Was there anything in particular you found interesting, was there anything in particular that you’ve retained in your mind?

 

Liz: Yes, obviously for me the important things are the cancer research that you are doing and the very topical thing about hip replacements, so for me, I’m going to go back to my placement that I’m in at the moment and tell them all the stuff I’ve learned all about that.

 

Meera: So it seems the sheer scale of the synchrotron, combined with the wide variety of scientific disciplines that are studied there are what impressed the public the most. This is something that impressed me as each of our podcasts focuses on a different area of research ranging from microbiology and environmental pollution, to reading the Dead Sea Scrolls and preserving ancient pieces of art.

 

Now unfortunately we’ve come to the end of this month’s podcast, but we will be back in September with more research, news and events from Diamond. In the meantime, if you have any questions about Diamond, or the research you’ve heard about in this podcast, you can email [email protected] and as you’ve heard so much about the Inside Diamond Open Days held at the synchrotron, you can also get details of the next open day online at www.diamond.ac.uk. Thank you very much to Gerd Materlik, David Hawkins, Alan Morgan, Linda Pratt, Joe Williams, Danny Axford and Simone Weyand for taking part in this month’s podcast. I’m Meera Senthilingam and thank you for listening.