Meera Senthilingam: Welcome to the Diamond Light Source Podcast with me, Meera Senthilingam. This month we are moving away from academia and into the world of industry to see how Diamond can benefit the fields of Engineering and Pharmaceuticals. We’ll be finding out how x-rays can be used to visualise a drug’s active ingredient, and how being able to distinguish between right and left-handed forms of this ingredient is crucial to ensure a drugs safety.
Chris Frampton: So it’s important to know which one is the active and which one is not and a classic case of this was thalidomide where only one hand of the molecule was active but the second hand actually did some very, very bad things.
Meera: Chris Frampton will be explaining how his team is able to distinguish between the two and how they go about using the synchrotron to develop more potent drugs. We also investigate how Chemical Industries, such as those creating catalysts, set about producing better, more efficient catalysts to clean up our environment.
Peter Ash: So we relate the structures that we see using the synchrotron radiation techniques to the activities of the material that we’ve generated and then understand which of the structures that are present within the materials are giving us the best activity.
Meera: Peter Ash will be explaining how they go about looking into this, as well as how other technology such as fuel cells are benefitting from the use of Synchrotrons. All that insight into the world of industry, plus the latest news and events from Diamond, coming up in the March edition of the Diamond Light Source Podcast.
Meera: This month we’re looking into how Diamond can be used to further research in Industry and coming up we’ll be hearing how the fields of Pharmaceuticals and Catalysis can be enhanced using Synchrotron Science. But first, we set the scene with Trevor Raymont, Director of Physical Sciences at Diamond Light Source. He explained to me who classes as an Industrial user at Diamond and how they go about using the synchrotron in their research.
Trevor: The simplest way to explain what we mean by an Industrial User, is to ask what they do with the information afterwards. If they want to use Diamond and to publish the results, then they are no different from any other academic user, in that they would compete for beam-time and go through peer review. However, if they want their data, the results, to be proprietary, they keep them for themselves, then we would ask them to pay. So the real difference, the distinction is whether it is proprietary or non-proprietary.
Meera: And what types of Industrial Users do you have coming in to use the Synchrotron?
Trevor: There’s no doubt that the largest single group of users of Diamond, and indeed of any synchrotron in the world are those that come from the Pharmaceutical Industry. They solve the structures of proteins and proteins with pharmaceutical agents bound to them, and they do that because it is the quickest and most direct way of developing new drugs.
Meera: and other than Pharma, what other types of industry are you hoping to attract in the future?
Trevor: We are hoping to attract, and in fact are attracting in fewer numbers, a very wide variety that span industry as in engineering. We are building a beamline at the moment that will be excellent for looking at engineering materials and we are hoping that we will get a wide variety of people from the Aerospace industry, from the Motor industry, from the Manufacturing industry. But we are also building beamlines that are of enormous interest to people in the Chemical Industry, people who make Catalysts for example.
Meera: Now you mention that pharmaceuticals are your biggest client at the moment but obviously that industry itself is very large so what other things can be looked into as well as drug development?
Trevor: One of the things that is quite challenging is when you have made a drug, you then have to crystallise it, you have to make it into a tablet and that’s where problems can arise. It may be that the tablet you make is not stable, or it may be that when you take the drug and you put it into a tablet form, it changes its form. And that’s the sort of thing that a Technical Powder Diffraction is really good at telling the answers to that sort of question. We can use some facilities at Diamond to look at the form of compounds that are made into drugs and to check that they are the ones for which a patent, for example, has been granted.
Meera: So it seems that quite a wide variety of industries can be used here, so drug development of pharmaceuticals, but also engineering components, and also the chemical industry, but what are the benefits to these industries of using a synchrotron and so x-rays and beam-lines over laboratory techniques?
Trevor: I should say that unless there is an advantage, they shouldn’t come to a synchrotron. The reason why people come to the synchrotron is that the quality of data is better than they can get in a laboratory or perhaps it’s simply they can’t do the experiment in a laboratory. Alternatively, it may be that it is actually cheaper to do it at a synchrotron. Now that might seem a strange thing to say, because if any of your listeners have looked at pictures of Diamond, it is obvious that this is a large facility and clearly very expensive and that is true – but what we’ve also invested in immensely is in automation and so experiments that would have taken perhaps a day, or two days, or a weekend in the laboratory, we can do in minutes. And if you can do it in minutes you can make the experiments more reliable and very cost-effective.
Meera: Now are there any other benefits say, I know that particular environments are much easier say to create at a synchrotron than in a laboratory
Trevor: There are certain areas where, for example in engineering materials, where the quality of our x-ray beams, their intensity and their brightness means that you can look at samples under their real operating conditions. Whereas in a laboratory, that would be much harder. So there are certain types of experiment which are simply much, much better and only feasible at synchrotrons.
Meera: You’re now opening up to Industrial Users, so what kinds of users have you had come in so far, if you’re allowed to mention them!
Trevor: Well, part of our confidentiality is that unless a company tells us, we can’t say who has been – but Pfizer and EvoTech for example are very happy to tell the World that they use Diamond.
Meera: Do you have many Industrial Users at the moment or are you looking to recruit more in the future?
Trevor: We are looking to recruit more as we are building more beam-lines. We are limited at the moment by our board to a cap of 10% of the beam-time and we haven’t yet reached that. But we are very definitely keen to take new users, Industrial Users.
Meera: Diamond's Director of Physical Sciences, Trevor Raymont, explaining how scientists in Industry, such as Pharmaceuticals and Engineering, can go about using Diamond’s beam-lines in their research. Now, as Trevor mentioned, Pharmaceutical Companies often use the techniques available at synchrotrons to study structures which are important in their drug and one such structure is the Active Pharmaceutical Ingredient, or API. Which, as you can probably guess, is a biologically active component in a drug. To find out more about how this ingredient can differ in various drugs and how its activity can be monitored, controlled and enhanced, I spoke to Chris Frampton, Chief Scientific Officer at Pharmorphics to see how his company go about studying the structure of their drugs.
Chris Frampton: We basically look at the solid state arena which involves salt selection, polymorphism, co-crystallisation, any area where the solid state of the drug impacts on its behaviour.
Meera: At what stage of the grander picture of drug development does this particular area fit in?
Chris: this usually fits in somewhere around the pre-clinical area, so for the pre-clinical stage you need to demonstrate to the FDA that you have control over the process of manufacturing this drug and since different solid forms can give different pharmacokinetic behaviour, these two solid forms are called polymorphs, and its they way the material packs into a crystalline lattice what you’re trying to do is find the most thermodynamically stable form to go forward.
Meera: When you are actually studying how stable and strong these drugs are, you are actually looking at the active ingredients within these drugs. What is an Active Ingredient?
Chris: The API is the active chemical within the drug itself. It’s the molecule that’s actually fit for purpose to do the job it’s supposed to do. The drug is often composed of many things and the API obviously is the molecule that is going to do the job but there’s lots of other materials in the drug itself which are called excipients which are there to do different roles to support the API and these can include things like glidents, binders and even materials whichwhen in contact with the acid stomach will disintegrate the tablet itself.
Meera: So I can imagine focussing in on the active ingredient itself is crucial to how a drug will work. So how do set about studying this ingredient?
Chris: These ingredients are sent to us usually as white powders and we perform crystallisation screens and screens through controlled environments such as temperature, pressure, humidity to see how the solid state behaviour, or the crystalline behaviour, is modified by these screens and what we’re hoping to do is determine a whole range of crystal structures of these materials and various other properties that go along with the crystal structure, such as solubility, to make sure that we have the most thermodynamically stable, non-hydroscopic form which is stable to go forward into drug development.
Meera: Could you give an example of a drug you have worked on in the past and what the active ingredient was and what you looked into with it or found out about it?
Chris: One example that I can give is that we do a lot of work on a drug called Sodium Diclofenac, this drug has been around for about 30 years, it goes under the name Voltarin. In the literature, there was a crystal structure presented which was a pentahydrate, which means that the drug molecule itself has 5 molecules of water associated with this drug molecule. And through crystallography, we found the stoichiometrry, or the relevant amounts of water present relative to the API, turned out to be not 5 molecules, but 4.75. So there were 4 molecules of Diclofenac and 19 molecules of water in a stable lattice. One structure that had never been determined before was the anhydrous version of this, which means that you have the drug molecule sodium diclofenac on its own without any water present and we were able to determine this structure at Diamond with a very, very, very small crystal.
Meera: And how did understanding the combinations of the water molecules and the sodium allow you to develop the drug further or what did you do with this information.
Chris: Well once we have this information, we’re able to say whether or not this phase we’ve produced is stable, we then actually take this phase and go off and do various other experiments on this phase to say whether or not it’s stable for drug development.
Meera: When you’re actually setting about creating these crystal structures and looking into various active ingredients, what are you trying to do essentially, what’s the type of information you are trying to clarify?
Chris: Two pieces of information – one is the straightforward connectivity of the molecule, where we’re just trying to make sure the medicinal chemist has produced what they’ve said they’ve produced, but probably the most important aspect of determining the drugs structure is that many of these drug molecules or APIs are chiral which means they have left-handed and right-handed forms and you may have 2 identical molecules, but they could be one left-handed and one right-handed form and it is a FDA requirement, a regulatory requirement, that you determine the absolute stereo-chemistry of your API and you can do this through small molecule crystallography.
Meera: Why is it so important to understand the chirality of these ingredients and therefore which ones that are particularly active?
Chris: It could be that both are equally as active against the target enzyme or protein that you are intending to hit, or it could be that one is more specific than the other. So it is important to know which one is the active and which is not and a classic case of this was Thalidomide where only one hand of the molecule was active but the second hand actually did some very, very bad things
Meera: So what’s the next stage on from this in drug development, how crucial is this part in drug development?
Chris: It’s a very crucial role. The polymorphism and cystallisation aspect is a regulatory requirement, you are required by the FDA to have studied the material, to understand if there are any issues with polymorphism, i.e. are there different crystalline forms of the drug out there which may demonstrate different biological behaviours, and so answering these regulatory questions is very important in the drug discovery, drug development process and if using the synchrotron can answer one of these questions or any number of these questions, then it’s a good way to go.
Meera: Chris Frampton, Chief Scientific Officer at Pharmorphics, part of SAFC Pharma.
Voice-over: Did you know that Diamond’s floor level monitoring system, shows Diamond tilting twice a day due to the moon passing overhead?
Meera: Welcome to the Diamond Light Source Podcast with me Meera Senthilingam. This month we are peering into the world of Industry and coming up we’ll be finding out how emission control catalysts work to convert the unburnt fuel and harmful gases in our car exhausts into more environmentally forms but before that, let’s join Sarah Bucknall from Diamond’s Communication Team for a round up of the news and events that took place at Diamond towards the start of this year.
Sarah: So recently we’ve had 3 of our scientists accepted to take part in Set For Britain, this is an event that’s held at the House of Commons and its for early career scientists to basically present their research to Members of Parliament.
Meera: So what scientists have been chosen and what areas will they be talking about?
Sarah: So there’s Jen Hiller who we’ve featured on the Podcasts before and she’s working with the Central Laser Facility to produce an optical trap which is basically like Laser tweezers to hold tiny particles in place, rotate them and apply small amounts of force, so basically creating lots of tiny little laboratories to carry out experiments at the microscale. This could have an application in bionanoscience, for example the ability to study inter eye lenses which could be deformed and the structural changes observed in real time. Then there’s Julia Parker who’s presenting I11s research into the strength of muscle in clam shells for potential use in engineering and domestic applications. Since the complex material that shell is made out of is so strong and robust it rivals the most advanced engineering materials made by man. And finally there’s Claire Pizzey, who’s presenting her teams work towards efficient photovoltaic device performance which they hope will help inform the design of large scale manufacturing processes to produce the next generation of efficient, environmentally friendly solar cell technology.
Meera: Now moving on to what’s actually taking place at Diamond at the moment, this month’s podcast is about Industrial users coming in to use the synchrotron and one of your recent beam-lines has just had its first Industrial User.
Sarah: Yes, that’s IO4-1, that’s our 5th macromolecular crystallography beamline which was opened to users at the end of last year and they’ve recently welcomed Pfizer to the beam-line.
Meera: What kind of things are Pfizer hoping to look at with this new beam-line?
Sarah: Well Pfizer use Synchrotrons to solve the structure of potential drugs bound to their targets and IO4-1 helps them with faster data collection on routine samples. The groups current drug development research areas are allergy and respiratory conditions and pain and anti-virals and hopefully Diamonds latest MX Beam-line will help them to increase the efficiency of their drug-development programme.
Meera: Now focussing on some of the more recent actual discoveries that have taken place at Diamond, a recent paper published in Nature by users of Diamond solved a puzzle to do with HIV.
Sarah: That’s right, researchers from Imperial College London and Harvard University used Diamond to figure out how HIV establishes itself in the human body. They used the synchrotron to determine the structure of an enzyme called integrase. Integrase is used by HIV and similar viruses to copy their genetic information into the DNA of the host
Meera: So why were they looking into this particular enzyme and what have they found that will hopefully help with future treatments for HIV?
Sarah: Anti- retroviral drugs have already been developed which work by blocking integrase, but the mechanism behind this wasn’t fully understood until now. These scientists have found that retro-viral integrase has quite a different structure to that which had been predicted based on earlier research. So this exciting breakthrough means that researchers can begin to try to improve existing drugs and stop HIV developing resistance to them.
Meera: And obviously with things like HIV, resistance is very important so that’s obviously quite a crucial discovery. Now moving away from Viruses and onto bacteria where team from Oxford University have been using Diamond to engineer bacteria cells. Is that right?
Sarah: Yes, it’s two teams of Oxford University Researchers and one of the teams is actually led by our Life Sciences Director Professor Dave Stewart. They’ve made the first step’s towards being able to engineer a bacterial cell that can sense and respond to environmental cues and they demonstrated that it should be possible to design synthetic signalling circuits within a cell, ultimately enabling the development of new biosenses
Meera: How does the group look into this? How does understanding the signalling pathways and circuits of a bacterial cell then enable them to adapt this and create biosenses.
Sarah: If you understand how something works, then it helps pave the way to recreating it, basically synthesising it. The researchers use Diamond to solve the structure of a particular complex that is crucial for a process that controls the movement of a bacterium when it senses a chemical or nutrient change in its environment. They found out what happens during the protein interaction that causes a particular response, so by understanding this process, they can look to create it elsewhere with other proteins. So this re-engineering paved the way for producing custom-designed circuits. The ultimate goal would be to produce a synthetic cell which does exactly what you want.
Meera: I can’t imagine anything better for a scientist than to create things that do exactly what they want! Thank you very much Sarah. Now looking forward to what’s coming up at Diamond in the next couple of months, you’re hosting a few conferences?
Sarah: In July we’re actually bringing together 2 International conferences. It’s the 7th International Conference for Synchrotron Radiation and Materials Science – that’s SRMS and the 6th International conference on Mechanical Engineering Design of Synchrotron Radiation Equipment and Instrumentation – that’s MEDSI. Because they’ve got similar core topics, they’re going to run alongside each other and this will basically increase networking opportunities for the delegates.
Meera: Thanks Sarah. That was Sarah Bucknall from Diamond’s Communication Team who’ll be back in the next edition with more news from Diamond. If you would like to take a look at the Diamond synchrotron for yourself and see how the science is actually done, you can do so at the Inside Diamond Public Open Days. Now these events are pretty popular and the event in March is now full, the next available Diamond open day is Saturday 5th June and you can register for this online at www.diamond.ac.uk.
Meera: Now moving back to the science taking place at Diamond, this month we are investigating how industries, such as the pharmaceutical industry, are using synchrotron light to develop better drugs, but now we move over to the chemical industry to find out how the field of catalysis can benefit from visualising the components of catalysts such as emission control catalysts, down at the nanoscale. I spoke to Peter Ash, Research Analytical Manager at Johnson Mathey to find out more.
Peter Ash: Johnson Mathey is probably the largest chemical company British registered in the UK and our specialities are really in Catalysis and in fine chemicals
Meera: What aspects of the catalytic industry do you work on? What kind of research takes place at Johnson Mathey and what kinds of developments take place there?
Peter: Most of the general public will recognise Johnson Mathey from their car exhaust catalyst. We are the world leader in emission control technology for car exhausts from petrol engines through to the light duty diesel that’s becoming more popular, and now especially for the heavy duty diesel for cleaning up the large buses and heavy transport vehicles around the world.
Meera: When it comes to these particular catalysts, is this an area that needs constant improvement and development to just make them as efficient as possible.
Peter: Absolutely yes, what we have noticed through the years is that the emission controls attributed to vehicles have been steadily being reduced by all the legislative bodies around the world that are targeting cleaner air from vehicles that are driving through their streets and towns. Catalyst companies have responded to that magnificently over the years by developing new technologies to make emission control catalysts more efficient, cheaper and more reliable.
Meera: Would you be able to give us an overview of how an emission control catalyst works, how it actually helps control emissions.
Peter: Yes, car companies have done fantastic work in making their engines much cleaner, but the engines still actually produce un-burnt fuel and they produce some oxides of nitrogen etc, and it’s the job of the catalysts to take out that remaining reside of the noxious materials. The main job of a catalyst is to take the un-burnt fuel in the exhaust system and convert that into harmless CO2 and water but also to convert those oxides of nitrogen back into nice clean nitrogen gas. The catalyst itself consists of active metal particles - these are real nano-particles. So we have nano-particulate supported metal that’s then reacting with its oxides-type support based on oxide type material such as cordierite, and increasingly with a new range of materials called violites, all which work together in harmony to improve the performance of those catalysts.
Meera: Before the days of beamlines like Diamond, how would you have set about researching these, to study them further and therefore try and enhance their performance?
Peter: Traditionally what we’ve been able to do is to look at the constituent parts of a catalyst and analyse them in isolation, if you like. What we’re able to do now with the increasing complexity that’s available through things like synchrotron radiation sources is look at the catalyst in its entirety and to understand how it’s working in the environment in which it’s trying to work. So we’re very interested in doing things like in-situ measurements of catalysts responding to gases at pressures and at temperatures.
Meera: So which beam-lines are beneficial to your areas of research and how do you set about using them?
Peter: Well if I take you back and look at the entire length scale of a catalyst. At the micron scale, we are using imaging, we’d like to know where the active parts of the material, i.e. the metal parts, are placed in relation to the supporting materials. That gives us an idea that we have effectively put our catalyst in the right place. We then sort of move onto the nano-scale of particles and we’re wanting to understand the size and the shape and the dispersion of those particles and we can do that by using things like small-angle-scattering. And then really down at the atomic scale because the active site of a catalyst is really an atomic scale feature. We’re looking at things like high resolution powder diffraction, we’re looking at x-ray absorption spectroscopy and we’re looking at the atomic scale chemical environment. And then finally on a very interesting area, we’re looking at something called Total Scattering for understanding the atomic scale of a bulk material.
Meera: You’re obviously looking into a variety of aspects of catalytic reactions and one thing you’ve mentioned is you can look into the particular active sites to see how active a particular catalyst is. So what have you managed to fine out to perhaps enhance this further?
Peter: One of the things we try to do always, is to understand the difference between different catalysts that have been tested through our activity testing programmes. So we relate the structures we see using the synchrotron radiation to the activities of the materials that we have generated and then understand which of the structures that are present within the materials are giving us the best activity. Synchrotron radiation is just another technique, if you like, in our arsenal of catalysts characterisation. It goes with advanced microscopy, it goes with advanced molecular spectroscopy. All of those together will produce a coherent picture of a catalyst to improve our performance.
Meera: So you can really just understand the process that’s taking place as much as possible?
Peter: That’s right, but the really exciting thing about synchrotron radiation will be coming in the future. It’s going to allow us to do much better time result analysis, much higher temperatures, much higher pressures and understanding how process catalysts and as well as emission control catalysts really do work under real conditions
Meera: What are other applications of the catalysts you work on and what are the future applications and challenges in the catalytic industry?
Peter: Aside from the emission control areas, I can talk about some work in fuel cells where we are taking the polymer electrolyte membrane fuel cell and taking it from a very useful and interesting demonstration of technology and making it mainstream. You’ll be aware of some of the Government backing for that in both the US and the UK now. We are also working in the useful green area of taking things like biomass and converting that through a process to useful chemicals for the future that are based on a sustainable source and we’re also looking at the other side of the coin where the low carbon technologies are being investigated for their applicability in the carbon capture and sequestration type area. So all of those are the long term, future challenges and opportunities for catalysis.
Meera: That was Peter Ash from Johnson Mathey explaining how many areas of the chemical industry, more specifically the field of catalysts, can benefit from using synchrotron radiation sources, to look at and probe catalysts to understand their functionality and improve them to make them more efficient.
Now that’s it for this edition of the Diamond Podcast but do join us again in May when we’ll be looking at the role Diamond can play in environmental research. In the meantime if you have any questions about Diamond, or the research taking place there, you can email us at firstname.lastname@example.org. You can also listen to previous editions of this programme online at www.diamond.ac.uk/podcast or www.nakedscientists.com/diamond. Plus you can subscribe to the Diamond podcast on iTunes.
Thank you this month to Trevor Raymond, Chris Frampton, Sarah Bucknall and Peter Ash. I’m Meera Senthilingam, thank you for listening and I’ll see you next time.
Voiceover: The Diamond Podcast is brought to you by Diamond Light Source and produced by the nakedscientists.com. There’s more information on our website at www.diamond.ac.uk/podcast