 Thank you Veronica and Anurad for the invitation. Yes, today I will tell you a bit about ESS. Sorry, there we go. I will give first a brief introduction to the neutron landscape as it is today in Europe to give you a bit of context. I will explain a bit about the very basics about reactor versus spallation sources. And then I will go to a few slides on an ESS update. I will tell you a bit about how the ESS will work, what kind of instruments will offer and what scientific communities we aim to serve with these instruments. And then Anurad asked that I spent a bit of time to explain to you guys how to actually get access to large facilities, in this case neutron facilities. And I will cover a bit about proposals, peer review, how access works and the kinds of things you should think about when preparing a beam time proposal. I will move to the life sciences or biological materials, and I will tell you a little bit about the importance of isotope labeling of your organic or biological samples. And then finally, I will show you a kind of specific research example from my own work and how I got into neutrons in the search for cancer treatments against a metastatic cancer marker. This is a map of Europe showing you all the different neutron scattering centers that are existing. And you can see the list here on the left. The list is, I would say from 2017 from an ENSA report that was prepared to give an overview of all the facilities and it looks like quite a lot, but I will point out that LLB down here in Germany, I'm sorry, HZB in Germany and EFEN Norway are three examples of reactor based neutron scattering facilities that have been closed in recent years. So we've lost actually quite a number of instruments and beam lines. At the moment, the only new one that is being constructed in all of Europe is in fact, the ESS. As you can see here in the bottom tip of Sweden. Almost all of these facilities shown here are in fact reactor based neutron sources, and today there is only one operating spallation neutron source and that's ISIS in the UK. And ESS under construction will be the second spallation source in Europe. And of course, this has a lot to do with the politics of reactors. They're not popular things to build new at the moment. And in fact, much of Europe is trying to phase out and get rid of not only power nuclear reactors but also research nuclear reactors. And this is a trend we could probably reasonably expect to continue. This is a timeline of neutron sources or facilities, and it shows the effective thermal neutron flux, and then the year along the bottom. And what you can see here is of course that neutrons have been around for a long time, but the early days really were dominated and to today actually by reactor driven sources of neutrons and orange. And, and but what you can see is like since the 60s or so the the maximum flux that we are able to extract from these facilities has really plateaued. And there have not been any major advances in squeezing more neutrons out of a reactor for 5060 years now in blue towards the right of the curve, or the graph you can see the advent of spallation sources, and the kinds of improvements in flux that we can get out of these facilities. And there are quite some modern sources available to researchers today the SNS in the US J Park in Japan. The Chinese are constructing a spallation source that will soon be commissioned any day now. And of course the ESS in a couple of years. And you can see that the ESS at the far end here is expected and built to be the brightest neutron source in the world. As I said in the slide before, many of the reactors shown here in orange have been shut down or will not be renewed at the end of their lifespan. So we can really expect this domination of spallation sources to continue. However, places like the SNS J Park and ESS are really large and cost a lot of money to build and operate. And there is a bit of talk in the physics community about finding alternative options to maybe not to be built only these huge spallation sources but maybe fewer, more compact, less politically dividing reactor type sources to have more opportunities for users in different parts of the world to do research. That of course is just a discussion at the moment. I'm not sure what will happen in the future for the moment Europe is putting its eggs in the ESS basket you could say This slide in the next is like a really, really basic explanation of the differences between research reactors and spallation sources. And at the heart of a reactor as shown here in this diagram is a core of enriched uranium 235 typically eight to 10 kilos of fissionable material kept in ponds filled with light or heavy water to keep them cool. Of course, naturally uranium 235 undergoes fission where it decomposes to smaller lighter atoms and with each fission event there is a release of neutrons. These neutrons come out at a fairly high energy and they have to be slowed down or moderated and in fact we use moderators to cool or slow them down so we can actually use them in neutron scattering experiments. So besides sewing them down. We also introduce monochromators and they essentially chop up the beam in some way so that we only extract the relevant wavelength or energy for the particular material we would like to study. So beam lands are often equipped with moderators and monochromators around this core. Then there are beam guides that then transport the the neutrons to the relevant instruments shown here at these end stations. The situation at spallation sources looks very different. We don't have fissionable uranium material on site. Instead we produce neutrons in a pulsed on demand way. This cartoon at the top shows the components that the ESS has all the way from the source to the target where the neutrons are produced. At the front end we have an ion source where we boil the electrons of hydrogen plasma to produce protons. This proton beam is then injected into the accelerator that is composed of many many very technical components that ultimately all together serve to accelerate the proton beam to roughly 96% the speed of light when it reaches the end here. At this stage they are directed into a tungsten target that is helium cooled and it is this interaction between the incoming proton beam and the tungsten target that actually produces the neutrons. This shown in the bottom right here where you have a primary incoming proton and you knock out a secondary neutron in very basic terms. This is this process is called spalling hence spallation neutrons. These are produced in this interaction at roughly 10% the speed of light so they have been massively slowed down but they're still extremely fast and high energy for what we would like to use them for. So the same situation that we have at reactors we also build moderators to slow them down. Beyond moderators we then direct them into beam ports you can see in the bottom kind of here. And then often at most beam lines at spallation sources we introduce a series of chopping discs or choppers that spin and chop up the neutron beam into the appropriate wavelengths. So you can literally slice and dice quite a range of neutron energies into the appropriate ones that your instrument is optimized for. Finally the same as at reactors at the very end of beam lines of course you have all your various sophisticated instrumentation where you will put your sample and measure your scattered neutrons. The ESS is a next generation neutron source in that it will be incredibly bright. First a little bit of history or overview the total construction budget that the member countries have committed to building ESS is 1.843 billion euros. The host countries of course are Sweden and Denmark. The actual accelerator complex where I'm sitting today is being built just outside of Lund Sweden next to the synchrotron Mach 4. And our scientific computing and data center actually sits in Copenhagen. So Sweden and both Denmark host the ESS. Then there are a number of additional member countries that will put in money and contributions to make it happen. As of about a week ago the project construction-wise is about 72% complete. So we've made a lot of progress despite the pandemic in 2020. In the picture to the left you see an arial view of a layout, a diagram of the ESS facility. In red you can see the actual proton accelerator and to the far right is where this ion source is where we will produce the initial cloud of protons that will be injected into the red part. These will then be accelerated until it hits what isn't shown in green, which is this tungsten target. And then in yellow we have a number of experimental holes are quite large and they will house the first 15 instruments that today are already under construction. We expect to make the first proton beam to hit the target late 2022 maybe early 23 and sitting over here I can tell you that date is coming very very soon and there's a lot of work that still has to be done. And shortly after that we will immediately start commissioning our instruments and be ready for first science and users in 2023. At the moment we are constructing 15 instruments but the ultimate goal is to put in 22 and have those completed by 2030. Here is an actual photograph taken with a drone last month to show you how it looks from the sky. If you can see my cursor this is the linear accelerator over here and under the P for progress is roughly where the ion source sits. I am sitting in these container box office boxes over here. And this out here is our campus building where we will move to in February over here and here and the long haul you see the three experimental halls. And this gives you a really good idea of the scale if you look at the construction vehicles down here. These buildings are massive. And back here you can see scornotrafic and the tram depots so it comes right in front of our facility but the ESS stop is actually back here. So that's how it looks today. Again it looks really impressive and a lot of progress. Here is a cartoon version of the experimental halls and I show you a list of the 15 instruments that are currently under construction. And you can see on the cartoon roughly where they are distributed in the different halls. Several of these already have quite some infrastructure installed. I often go into these e-buildings over here and NMX and BFrost have already completed or started their cave construction. So these things that looked like cartoons are actually now huge blocks of concrete. So things are really becoming real and the instruments are coming together. All of these instruments are designed and where they are located to receive a huge range of neutron energies. And each of them really have a specialist neutron science community that they are designed to cater for. The ESS will really support researchers coming from a wide background of disciplines. We have many instruments that support life sciences, soft contents matter chemistry. There is quite a use of neutrons in battery research that of course has a huge impact on our future. Magnetism, engineering, geosciences and then of course people like to use neutron imaging to also study archaeologically relevant or important samples. And finally of course the particle physics community is very keen to build something out here as well. Due to this extreme high flux that we are building the ESS to deliver but also all these support labs we are building on site. We are in a good position to enable high impact science. There are a few reasons for this. Due to the flux we can really expect to look at much smaller samples than is possible in other facilities. The measurement times will be significantly shorter, which will really not only increase the tone turn over the number of samples we can do but also allow us to probably take the time to do better measurements. And then all the support labs. We are building to help users not only synthesize but also characterize their samples when they're coming for a beam time. So the next few slides I will tell you about how to access these facilities. First of all it is important to know that all operate on a peer review proposal based system. They all have different access rules and some may have restrictions on the national balance. That is the nationality of the people applying for beam time or they may even exclude certain countries based on them not being members or paying for the operations of these facilities. The proposal and nationality of the team requirements then can really vary. So it's really good to check with each facility because the rules can be quite complicated. Usually the facilities issue calls one to once to twice a year. And despite or in addition to these calls that are announced and then have a strict deadline and closing date. Many also offer rapid access if you can write a proposal and argue why you urgently or rapidly need access to beam time and this rapid access mode is open all year. And you're not bound by these deadlines but you have to have a real urgent reason. The next two slides I'm showing you an example of how it looks if you go hunting for information for users and beam time. The ILL in Grenoble. This is their website and you can always go to any of these Isis and LZ and so on and find similar types of information specific to that facility. So here you can see what you want to apply for beam time. It gives you all the many different complicated options and like I said it varies from facility to facility so it's really good to educate yourself on what each facility offers. There's quite some fine print. And so in this case you can see if you want to go for the standard beam time that is free to users you have to subject yourself to external peer review. They list the different kinds of calls they have what the deadlines are and should you be a member from an ILL member country or what kind of team nationality rules apply. They also give you an estimated response time and you can see that it varies if it has to go for peer review. It can be four to eight months before you get a yes or no. The peer review process is incredibly important. These panels are made up of external scientists experts in their field, not affiliated at all with the facility. And they give their expert scientific opinion if the work is important or transformative and does it necessarily earn beam time. There are other options of course, not everybody wants to write a peer review proposal and you can think of industry for example, where they are often quite willing to pay for beam time to not have their proposal peer reviewed or be forced to publish their results if they get anything out of it. So here you can see on the bottom you actually can bypass peer review if you want proprietary beam time. For urgent experiments, like I said, this rapid access mode, these are often reviewed internally. Again, this varies from facility to facility. And these are open all year and you can expect feedback very quickly, but you have to demonstrate the urgency of course. So if you're interested in this, I invite you to go to ILL or ISIS or MLZ website and click around and see how it works for the different facilities. Also at the ILL up here you can see they have a special tab where you can actually get guidelines for it and many also give you guidelines for how to how to write a proposal or what the specific facility may want to see. Typically, however, this is quite a generalization your proposal is typically limited to two to three pages of content and this includes figures and references so it's good to be brief. You should explain the current state of knowledge around the scientific question you're looking to address and also what the expected impact is of neutron measurements or studies of your particular scientific problem. You should also clearly state or motivate why you absolutely must have neutrons and why you can't use other complementary techniques to get at the question. And for example, I'm a protein crystallographer, and often in the kinds of proposals we write or review, we would say that we really want to know where hydrogen atoms are in a protein crystal, so that we can understand how a drug binds or how the enzyme works. And these are things you cannot do with any other method. So that is usually strongly emphasized in the proposal. And then you should also spend a little bit of space in your proposal to clearly explain what is the measurement you would like to do. So this will of course be aimed at a specific instrument, how you want to configure the beam line, what kind of sample environment you may need, are you doing ambient measurements, do you need a cryostat, do you need a high pressure device, and so on. And then how many hours or days you need and why, and also how many different kinds and types of samples you would like to bring on site. This part is very important, not necessarily for the scientific review of the importance of the proposed work, but for the internal feasibility review that the facilities do. This is a crucial bit of information so that we can do some initial assessment of safety and what is involved and if the proposed experiment is even at all possible on the instrumentation the facilities offer. So that is an important bit of information. And often for the researcher by themselves, this is not easy to figure out. So almost every facility on their website encourage you to talk to the beam line scientist, or to the local contacts to reach out to them to discuss your experiment if it's feasible if it's possible. And it is really important to do that before you sit down to write a proposal so that you know what to put in these important sections. Then you are submitting these proposals on a deadline or not depending on the mechanism you're applying through. Then there is some time usually while proposals are assessed internally and externally, and then upon review and acceptance of your proposal of course you will be notified of your beam time. And I will warn that there are quite some logistics involved from you getting being told your proposal is accepted to you arriving with a sample. So it's really good to plan in advance and not wait till the last second. The user office and your local contact could be the instrument scientists are playing a very important supportive role in getting users on site to do sensible experiments. There are many things you have to keep in mind travel accommodation you need lab access you need to ship your sample. We may need to prepare special equipment before you arrive and you need to complete safety training and so on. So it's really important to plan in advance and build in enough time in your being time plans so that you can do everything you would like to do. So now for the last half of my talk I will tell you very specifically about life sciences and biology using neutrons and it is quite focused on my work and journey and how I got to to use neutrons and actually work for a large scale facility. Actually for my entire career since I left graduate school. So really the secret why I got interested in neutrons lies with the scattering links and the isotope sensitivity that the probe offers. Sean on the bottom here is my biologist view of the periodic table you can ignore all the other elements and only focus on these because of course they're fine in protein and DNA to the most extent. And what you can see here is a comparison of x-ray and neutron scattering links with the same element types. And it is important to note that in pink or red with x-rays you see an increase in the scattering magnitude as you increase the number of electrons. So the amplitude is related to the atomic Z number. Neutrons however interact with the atomic nucleus so this means they can discriminate between different isotopes of the same element and they are blind to the number of electrons. And if we go to the very left end here of this reductionist view of the periodic table we see hydrogen and its isotope deterioration. And I will remind you that roughly 50% of the atoms by number in biological samples are in fact hydrogen and you can see with x-rays they are in practice invisible. Which means we're missing a lot of information. Naturally abundant isotope of hydrogen has a negative scattering length however this is very hard to see but there's a little great dot in the middle of this sphere. But its isotope deuterium which is chemically extremely similar has totally opposite scattering. It's actually positive and quite a bit bigger. So it gives a huge advantage if you can replace hydrogen in your sample with deuterium and this is of course called deuteration or delabeling. And this is really important so that you can maximize the benefit from using neutrons and these unique scattering properties of deuterium. What you would like to see and the technique you want to use really determines then the kind of deuterium labeling you should do. On the right hand side we show here that for small angle neutron scattering and reflectometry deuteration isn't really used not so much to see the hydrogens but really to use the labeling as a tool. So we can employ something called contrast variation. And in very simple terms you can label one component in a complex. So the red green bit on the bottom here is a complex. If we do to write the red and then put the whole sample in a solvent where we can match the amount of deuterium in the solution. We can actually make that red part completely invisible and only study the green bits. This strategy is called contrast variation and it is a very important and often indispensable part of doing sands and reflectometry. For crystallography on the left, which is where I live, we are actually interested in finding the atomic 3d positions of the actual hydrogen atom. So here we're not deuterating as a tool to do contrast variation here we are actually deuterating to maximize from this positive scattering from the deuterium atoms. And what you can see in the maps here is that it really allows us then to nail down where all the hydrogens are in a protein crystal structure. None of this information you would get normally with x-rays alone even at extreme or ultra high resolution. So here is a very basic summary then or overview of the different types of things you can do. On the left, like I already said we can do 3d atomic structure determination with crystallography and neutrons. There's more about that when I get to my science. And then in the middle and on the right here we have solution structures and also surfaces. Small angle neutron scattering is really well suited to complexes of things. This could be DNA and protein complexes. It could be lipids and protein complexes and typically systems like this are quite large and dynamic. So they're not the kinds of things you can pack into a crystal. So you need to study them in solution and maybe you're interested in the dynamics as well. Then here you would use contrast variation and this selective deuteration to be able to study them together. For surfaces we can actually do reflectivity measurements where we're looking at surfaces, membranes. These can be mono layers, bilayers, even natural lipids extracted from living things. And here you may want to study a membrane protein embedded in a membrane itself and study the changes and things that happen to the membrane when you introduce external factors. So for structural biology what I call structural biology which typically in my very biased view is crystallography. Neutrons are very useful and complementary to almost every other method that biochemists may use. It allows us in the case of crystallography to really visualize directly hydrogen or deuterium atoms. If we can see hydrogen atoms we can also figure out what they're doing. And many hydrogen atoms are of course involved in hydrogen bonds. It can be within the protein between water molecules and other waters. It could be between waters and the protein. If we can see or not see a hydrogen that also tells us something about the protonation state of amino acids in the case of histidine or lysine where it can be neutral or positively charged. And this gives us an overview of the electrostatics of the active site. We may be studying. Furthermore, if we extend from there we can also study the details of ligand or inhibitor or substrate binding to an enzyme or a protein. Because again we can see the electrostatics and we can also see the hydrogen bonds. And finally water is an extremely important thing enzymes use as the catalytic agent. And sometimes it is really important to know what kind of water your enzyme may have to understand the mechanism. And here you can really have quite a few waters. You can have H2O, hydronium, hydroxide and of course just a proton. And the proton of course has been stripped of all electrons so it is in practice and in theory totally invisible with X-ray crystallography. For the other three, all three of those would actually just appear as an oxygen in standard X-ray derived electron density maps. But neutrons because they were super sensitive to these hydrogens will actually reveal and clearly show the difference between a hydroxide and a hydronium for example. And this has been again and again demonstrated in neutron protein crystallography. And I will say there's exactly all these features that were dangled in front of me as a grad student that actually got me into this field. I was studying at the time an enzyme called carbonic anhydrase that actually catalyzes the conversion of carbon dioxide to make bicarbonate proton. And at the core of this enzyme catalysis is a nucleophilic attack on carbon dioxide followed by a series of proton transfer steps through a water network. And my graduate studies were focused on high resolution X-ray studies of this active site to try and figure out is the water bound to the zinc, a water or a hydroxide and what is the charge state of this tyrosine and histidines around the active site. And I was presenting a result at a conference. I was midway through graduate school when a beamline scientist came up and chatted about my poster and suggested that I try neutrons to to get at this problem that neutrons may be a tool that can actually help give me the information I was desperately looking for during my graduate studies. So, and that's what happened. And 15 years later I'm still working for large scale neutron facility. So back to see a in humans are 15 expressed as isoforms of carbonic anhydrase, and they are involved in many physiological processes. The ions bicarbonate and protons of course are extremely important to use for pH homeostasis in the body. They're used to synthesize cerebrospinal fluid, gluconeogenesis and a whole bunch of other stuff. But really one of the most important job CA does it is to make carbon dioxide soluble so you can transport it where it is produced in your tissues, all the way back to the lungs. So you can exhale it. So without CA's we wouldn't exist they make respiration and the exhalation of carbon dioxide possible. So one of these isoforms, which has been studied to death you can say is one of the fastest enzymes known its carbonic anhydrase two, and it does this CO2 hydration and proton transfer roughly a million times per second. So it is one of these ultra uber fast enzymes. And what is also known about CA is that it has been clinical target for many decades. The first CA inhibitors were developed in the 1950s and have been clinically used pretty much since then CA inhibitors are used as I drops to treat glaucoma. And they can also be taken systemically to be used for hypertension because they diuretics. And in recent decades, they've also been used to control epilepsy and also to treat acute altitude sickness. And beyond this very traditional hypertension and glaucoma treatment CA nine in the last 15 years has been identified as actually almost exclusively over expressed in 30 tumor types. Only in small parts of the digestive system where we see CA nine constantly or constitutively expressed, but an over 30 tumor types to date. It has been found that it is massively over expressed when the tumors reach a certain size, and they become starved for oxygen. They start to express a number of metastatic markers in fact glucose transporters and geogenesis growth factors and so on they're basically saying help I'm starving I need sugar and oxygen. And part of this cascade is CA nine that starts to be over expressed when tumors become hypoxic. The presence of CA is really a very negative clinical indicator, it often indicates that metastasis may already be happening or has happened, and its presence is associated with very low survival rates in patients. When this link was found about 10 years ago, CA nine has really emerged now as a very popular cancer targets. And there's a lot of efforts globally happening and trying to find compounds that can inhibit CA nine. As I told you in the previous slide, CA two and other CAs are doing a really bunch of really important life sustaining actions in our bodies. So taking CA inhibitors to knock down CA nine systemically is an extremely bad idea. And of course to complicate things further, the CA isoforms in the human body are highly conserved. So it is very difficult to design compounds that target one over the other and not just inhibit them all. So there is quite some push to find isoform specific inhibitors and I would argue to do that we really need to know where the the hydrogen atoms are. So CA has literally was described in 1933, and up to now there's over 15,000 publications in this field, and almost 1000 deposited structures. And I will say in the last 10 or more years when we started to get more neutron data on the active site of this enzyme we have really been able to start to understand some of the catalytic features in the active site and what they may mean. And now this work has sort of progressed more into looking at CA nine and ligand binding using neutrons so we can discriminate between the different isoforms and see if there's anything we can maximize or profit from to make inhibitors that bind one and not the other. So this is a funny little story on the on the left is a cytosolamide it's one of these classic glaucoma inhibitors that were developed in the 50s. Clearly unsuitable to take systemically it has a lot of side effects and the amounts you need to reach chemotherapy levels would be extremely deleterious to the patient. So in the literature popped up some decades ago that saccharin was thought to be a sort of low level inhibitor of carbonic and hydrase find in our mouths. And it was given as a reason why diet sodas that are saccharin sweetened taste funny to some people. Well the PhD student in my former lab had this idea to go to Starbucks and get a coffee and grab some sweetened low and he actually went back to the lab dissolved it and soaked it into crystals of CA nine and observed with x-rays that it bound directly to the active site zinc. This caused a lot of excitement and they since then collaborated with people looking at cancer cell lines. And just dissolving sweetened though they've since corrected for this and repeated the result with pure saccharin from Sigma. But in this case they just use sweetened low sweetener and showed a dose a dose response curve for cell killing in this breast cancer line. Collaborators of ours in Australia took this idea of using saccharin as a base molecule and synthesize the whole library of inhibitors where they conjugated through a linker different sugars. And one of the best candidates from this screening work was then this SGC saccharin glucose conjugated molecule. And you can see from the K eyes that it has slightly better inhibition profile against CA nine, but really it doesn't at all bind to CA two, which is the CA and red blood cells that help us get rid of CO two. So this was a really important discovery and it was also shown to kill cells at a much lower concentration than sweetened low. I think that's mostly because sweetened low is a bunch of filler the actual amount of saccharin in those is quite low. So we set out to use neutrons then to understand what are the differences between how saccharin and this conjugated to glucose saccharin molecule operates. And we collected a number of neutron data sets of the enzyme was nothing bound of the enzyme with only saccharin and the enzyme with only this SGC compound. And then we very carefully and specifically compare the different structures to try and understand why one binds better than the other and why CA nine is better inhibited by these but not at all CA two. So there's a lot of technical crystallography results here and they're really not important for you to understand. We can just look at the pink and blue bits at the bottom and I will just say, if we compare saccharin bound complex to the April. We see that in blue, the water molecules that overlay with the saccharin molecule are completely displaced. And of course there's an energetic cost that comes with that that affects the inhibition constant. And we see in the bottom part here, we see an amino acid side chain and a water molecule that has flipped and rearranged to accommodate or create a slightly bigger pocket for the saccharin to bind. And in fact, this residue that changes is not present in CA two, it is unique to CA nine. And we think it is the presence of this specific amino acid at this position that allows this rearrangement to occur that allows saccharin to bind. Now what happens if we add this massive linker and glucose molecule to this compound is quite dramatic. This molecule, of course, this view is far more complicated than the saccharin, it's quite a long molecule. And what we observed in the neutron and x-ray crystal structures is that this molecule extends far to another side of the active site and actually interacts again with a set of residues present in CA nine that are completely different in CA two. And in fact, in CA two, where this glucose sits, we see that they are these huge bulky hydrophobic amino acids that are not present in CA nine. In other words, the active site side shape in this area actually allows this glucose to sit or be accommodated in the pocket, giving this far better binding to CA nine. In CA two, this part of the molecule have the inhibitor, there is basically no place for it to go. And we think that is why we can't detect any binding at all. And then in addition to this bulky clash, we also see a number of hydrogen bonds broken, rearranged and water molecules being pushed out of the way. So in summary, then neutron studies here really allowed us to look in atomic detail on the changes in the target protein when the inhibitors go to bind. What I didn't say is we could also see here that both saccharin and this SGGC compound bind in the minus one anionic state. And this is really important for drug design to know the charge of the thing that preferentially binds. We could also then carefully map an inventory, the numbers of waters displaced for each compound and the number of hydrogen bonds that were made broken or remodeled to accommodate compound. And we were of course able to observe the hydrogen bonds between the ligand protein. And all of these together allowed us for the first time to really rationally explain why we observe this preferential binding to CA nine versus CA two and how that is reflected in the inhibition constants. So all of these details we never could do with only high resolution or even ultra high resolution x-rays neutrons really delivered a complimentary view to completes to complete all the levels of information we need to see to do these kinds of studies. And finally, I will just point out with the ESS coming online very soon, we will be able to do all of this on far smaller crystals in a fraction of the time. So it took for the APOL, Suckerin and SGC complex it took roughly two years at different facilities to collect all the data. These would be three days at the ESS, even in the beginning when we're still commissioning. So I very much look forward to that and I think we can expect big steps forward for drug design and pharmaceutical type research at the ESS in the future. On my last slide, I will just there's so many people involved with these projects over the years. But what I want to point out for for you guys is really these data were collected at ILL at the MLZ at ESRF and the old and new max lab. And without these facilities, we would not have been able to collect the six data sets we needed for that one paper. And the instruments scientists and support staff are really, really excellent during and after the measurements to help us make sense of it all. So I am finished and I'll hand back to Veronica and Ani Ragh. Thank you very much as I was so we clap to this great presentation in the name of all the audience. As you can see from the coffee hands presentation. So we asked to the audience, if someone would like to address that question to Zoe, because the number of participants is manageable this time. Please feel free to write on the chat. You can write on the chat. And if you're not if you're shy, you can also email me if you have any specific questions or want to know more. I mean, I have like one, it's a question. It's also kind of a, yeah, a kind of a suggestion for the audience, because as you've shown before, in the process of applying for a for a being time from the ILL webpage, you can see that you can apply you also for the D lab sample preparation. So which means that you don't have your own facility in your home. So this is a working place. ESS will allow users to apply so to write a proposal for the sample preparation to have them those rated that if you don't have the expertise because the ESS will have the expertise on site right. Exactly. So, yeah, I should have pointed that out. Not all these facilities have support labs open like the D lab, the deuteration laboratory at the ILL. And in essence, you would apply for access or support from the lab in the same way you would apply for a being time. But in that case, you're specifically asking for help to prepare your deuterated sample. The D lab does this. ISIS in the UK do chemical deuteration. So they make small organic molecules synthetically. And us here at ESS, my group provide both chemical deuteration, biological deuteration, and we also support users for protein crystallization. And we do have one proposal call a year where we ask, we invite users to ask us to make them things. And these range from deuterated proteins to small molecule deuterated materials, detergents, lipids, surfactants, and so on. And yeah, it's working and we are going to be a key part of operations here when we also have instruments. Yeah, we have the rather specialized deuteration labs and then we're also building sort of more general purpose chemistry labs on sites that will be fully accessible to users as well during their beam time, or even before if they need to come and prepare something in the labs. And that's a really important aspect. I think I think neutron facilities operating with no support labs will not be as successful at those that really reach out to help the users prepare the proper sample. Precisely, because users can come from both the like academia also private sectors and might not be that familiar with the process of deuterated samples or so. The deuteration is complicated. It takes long, not always straightforward. And we, many of the facilities at least in Europe have these support labs to really take that burden off the user. So they focus on their science and we focus on the sample. Which is really great service that ESS will provide the future users. So, yes. I have one question. What we do is we have a solid state electrode and we somehow immobilize the enzymes by our enzymes onto those electrodes and try to study these the reaction at different timescales. So what is the resolution or is it possible to take the snapshots of this different processes which happens between from picosecond to nanosecond time regime. Absolutely, you would of course have to choose an instrument that have the right time resolution. It sounds like spectroscopy or some beam line like that maybe perfect for those motions and time scales. Yes, and we're building one of those. And for this rapid access that you suggested before like during the proposal. So is it more for the private sector, the private sector we have like a highway to apply it for proposal or it will go together with the I don't really, I don't know, we don't have, I have never had industrial users, so I don't know if they use rapid access more. But I myself have applied for rapid access beam time and in those cases it's usually I unexpectedly got a sample and the sample is unstable. And I believe I have a short window of time to take a measurement before the crystal falls apart. So in those cases we have written that we know these things are not going to survive until the actual next run cycle. And maybe we don't have the ability to prepare more than we would beg for rapid access beam time so my experience that's how I would use it it may also be that there's competition. Maybe you know a competing group is doing something and you have an edge maybe you want to ask for rapid access. Yeah, that's considered scientifically important or not it may be a consideration. Yeah, yeah. That's why it's really good to know that actually if you do if you're studying a very unstable system or material then it's really good that you can actually use this future. Yeah, I have certainly done that. And of course now what we're seeing is almost all these facilities are offering rapid access for any scientific issue question related to SARS Coronavirus 2 or COVID-19. So it may also be that facilities choose to do topical or very urgent health topics to society and essentially prioritize to give access very quickly and easily to researchers that have a need. Yeah, that's a really good. Yes. Yeah, that's a great question and it really depends on what the material is composed of. So all the sort of standard atoms that that I study protein crystals in other words, they do not activate at all. There's no radio activity at the end of a measurement. However, if you're studying biological materials in buffers containing things like sodium. So a PBS buffer or something like that sodium will actually activate not to a high level it'll cool down after some days or a week. But you can just walk out with your lab waste at the end other materials like I think cobalt copper a few of these metals really really really activate. So there you can really end up with a problem and your sample may need to be locked away for quite some time to cool down or it may have to be disposed of as radioactive waste. So for the average materials, carbon, hydrogen, oxygen, nitrogen, these kinds of things not a problem. But some elements really really do activate. Yeah, we are interested in this transition metal oxides. Yeah, for sure. Those will probably be a problem. But they're not a problem. All the facilities are actually designed and equipped to deal with these things we will have and shielded cabinets to lock activated things up in we have radiation protection support around the clock to monitor and measure these things and to ensure that we dispose of them properly, of course, many for many types of samples it is sufficient to just wait for some cool down period. We can release them and we survey everything before we release it. So that should be okay. Okay. If the audience doesn't have any question, because they are shy probably or because they find they can they can email if they have something burning. Yeah, that's no problem. And they also know that this video has been recorded so they can go back. They were so entertained they can watch it again. Yes. Information. Yeah, I would say that it's the time to then thanks Zoe for a great talk. Thank you guys.