As someone who started life as a lowly postdoctoral fellow and junior lecturer on the RDS councillors. It used to be when it was chaired by Sir David Jack and I'll mention David again later in my lecture because he's had profound influence on my own research activities and I think he's been outstanding as a person contributing to this area. Now, as Jeremy said, my whole career has really been looking at understanding lung disease and particularly aspirin CPD. I wanted to concentrate on that this evening and talk about how animals have helped us develop the drugs that we use and how they continue to help us understand both the pathogenesis of disease but also in finding new treatments. Now, lest you think that we don't need to work on lung disease anymore, this is the European Lung White Book from 2013, showing you that one in eight deaths in the EU are caused by respiratory disease and a considerable number of people die every year from respiratory diseases and indeed they occupy obviously a lot of our hospital beds and take a great part of the healthcare budget, particularly this time of year with people getting chest infections. This is an area that costs society a lot of money and whilst you've made significant progress, as I'll hopefully show you, I think there is still more to do. Now, I realise you've got a very mixed audience and just really to say that if you look at someone undergoing an asthma attack and this is a picture of somebody undergoing a bronchoscopy, you can see without being an expert that there is profound inflammation, edema fluid occurring in the airway lumen that brings about this wheezing and coughing that's seen in asthmatics and for many years we've used drugs to relieve this by relaxing the airway's smooth muscle but over the last 20 years particularly we've recognised that this is a complex inflammatory condition and sadly people particularly under the age of 30 still die from asthma. Several thousand people died in the UK last year from asthma mainly under the age of 30 and this is because as you can see here if they do not treat that underlying inflammatory response properly we end up with a very thick mucus plug obstructing the airway lumen and preventing gas exchange and no one in 2017 should be dying of asthma but unfortunately we still have this situation going on. If we look at this histologically it's very clear that this is indeed something that is due to inflammation we can see inflammation into the airway wall and you can see here the airway lumen which is absolutely covered or is filled with mucus and this mucus I can tell you from experience of working with airways like this is actually like cement to get this out is really difficult because the inflammatory cells coming into the lung release enzymes and mediators that change the composition of the mucus and again we now recognise that this inflammation contributes to this mucus plugging. If we turn to COPD and I started going to respiratory meetings in the 1980s and COPD was almost never talked about because it was a disease associated with smoking and everyone said let's give up smoking and clearly that's very sound advice. However I've put up their air pollution because we now recognise and I think in the next 20 years we're going to see more and more younger patients developing COPD having never seen a cigarette in their life because they have exposure to air pollution and the air pollution in turn is producing inflammatory changes in the lung that are different to asthma but nonetheless are causing profound changes in disease and in particular it leads to bronchitis early on and then in a longer period of time we get alveolar wall destruction and emphysema and if we look histologically we can see on the left a healthy normal lung parenchyma and you can see your airways are there for gas exchange that the size of a tennis court in most of us in the middle we have an early inflammatory response in the form of bronchitis and on the other side we have the extreme form when we get alveolar destruction and of course this is not something we can reverse we cannot rebuild airways but we can I think in the longer term hope to prevent this and if we look at this at a different level you can see compared to a lung from someone who does not have emphysema from somebody that has you can see the profound pathological changes that we're up against and trying to prevent. Now actually the pharmacology of asthma and COPD is relatively simple we use bronchodilated drugs now and anti-inflammatory drugs in both conditions we have the short acting beta-ragonis and I'll come back to this shortly such as salbutamol or for those of you who have asthma or know people who have asthma the blue inhaler and more recently we have longer acting beta-ragonis but most importantly in the last 15 years there's been the introduction of fixed combinations of taking bronchodilators and anti-inflammatory drugs together because physicians want the patient to have the anti-inflammatory drug primarily glucocorticoesteroids whereas the patients have what I call the McDonald effect they likely secute bronchodilation and symptom relief and we have some very very successful drug combinations both in terms of medical care and also commercial success so the formalteral buidesonide and salmetrol fruticazone between them generate about $11 billion a year from sales to people who are treating asthma. Now if we look at the beta-ragonis there's actually a very long history going back to 3000 BC and the discovery of ephedra and ephedra and epinephrine as we know now as adrenaline of course they're all very successful at causing the airways to open and people to feel better but they have the problem of also increasing heart rate and blood pressure and over the years we've made this progressive improvement in these drugs and particularly the ability to deliver these drugs directly into the lung through aerosols or powders right up to day where we have drugs that actually one puff can last for three days and that is a profound improvement in terms of both selectivity of the drug but also the duration of action to make it easier for patients to comply with. Now everybody in this room is familiar with this particular blue inhaler which contains salbutamol, it's used by approximately 90% of the world's asthmatics but no one gives a second thought really as to how it got there and I think it's only fitting this evening that I pay tribute to David because David chaired the Research and Defence Society Council when I joined David is the man if we go back who really discovered betragonus and particularly salbutamol but also his team went on to discover salmetrol, the long-acting betragonist and very important as they've come on to topical corticosteroids and I think the world owes this man a lot and I think he should really should have deserved to have a noble prize and sadly David passed away a few years ago but he's certainly been a fantastic mentor to me and I'll come back to a project that I worked on previous to or prior to him passing. Now I want to take you back to 1969 because this is actually the first demonstration that salbutamol was a new class of drug it was a betragonus septus stimulant but unlike adrenaline it also stimulates heart rates and blood pressure this drug at the right doses did not and this experiment was initially done in guinea pigs as you see here so this is actually showing you the overflow of air and giving salbutamol to show that you can suppress the effect of 5HT in causing bronchoconstriction he then went on to show this is through a beta receptor because if he blocked with a beta blocker the response disappeared. You can also see that when you aerosolise this to guinea pigs and the important thing here is that he did all of his work early on in guinea pigs you can see that there is this very clear dose-related effect when we inhale salbutamol in guinea pigs to reduce bronchoconstriction and the number of people this very minute taking salbutamol somewhere on the planet have no idea that this all started with dosing guinea pigs and in fact David really was I think important in going from what was adrenaline that affected both alpha and beta receptors isopreniline which was a beta but non-selective beta agonist to salbutamol shown there and at the bottom is salmetrol and salmetrol is a drug that instead of taking it 4 to 6 times a day he put this long lipid tail on it to produce a drug that is actually active by bronchodilating twice a day now how did he do that was very simple and I think unfortunately we've forgotten how we've discovered many of the drugs that actually work and this is actually a series of experiments that have been done by taking an isolated guinea pig trachea electrically stimulating it and the little spikes you see there are actually the contraction of the tissue and if you look at what happens if you put isopreniline on there's a very transient reduction in the contraction of the air we smooth muscle the same is true with salbutamol you can see it reverses it's got a very short half life but then look at what happens when he puts this new drug salmetrol on the guinea pig trachea you can see it's suppressed and 7 hours later it stays suppressed and that is translated into the clinic as a drug that we now have twice a day and this very same assay has been used to now as I say discover drugs that are active for once a day or in some cases even longer so the guinea pig has been profoundly useful in helping us discover a very very effective clinical bronchodilator for treating asthma and COPD the other thing and this is again taken from one of David's early studies he actually at the same time as doing these experiments in guinea pig trachea also took pieces of tissue from the heart for example to actually show that you've also got very selective effects in the airway but you do not have the same effect on receptors in the heart now the other major class of drugs that are used today not just for asthma and COPD but a range of inflammatory conditions of course of glucocorticoesteroids and animals have helped us really profoundly in getting to the drugs that we've got today and again we take for granted so we have to go back to the 1940s when cortisone was extracted from adrenal glands and used as an anti-inflammatory drug but of course cortisone, whilst effective, also suppresses your hypothermic pituitary axis and it leads to all sorts of changes in the endocrine system that are unwanted in people with inflammatory conditions it was David's work that led to the discovery of the Beclemethosone Diopropionate and please, if you ever write Beclemethosone down in any article make sure you put the Diopropionate on it because David once said to me when I left it off it wouldn't do the same thing without the Diopropionate it's there to give it the activity locally in the tissue because this is the first steroid that was developed for the treatment of asthma in 1972 where we could inhale the Beclemethosone and have a very pronounced anti-inflammatory effect in the lung but it was poorly bioavailable and therefore you did not have the same degree of suppression of the hypothermic pituitary axis and this drug and subsequently the discovery of other topical steroids such as Bidesonide have really revolutionised the treatment of asthma and COPD because we can now give large doses locally to get a very clear anti-inflammatory effect without the systemic problems associated with oral or systemic steroids and I just wanted you to go back to this is a patent actually for the ticker zone and other steroids but the same was true of Beclemethosone of how this drug was actually shown to be anti-inflammatory it was nothing to do with molecular biology it was nothing to do with cellular biology it was a very simple test called the Croton Oil Test and you rub Croton Oil on the ear of an animal and you can compare the activity to suppress inflammation locally in the ear whilst measuring levels in the blood and changes in the hypothermic pituitary axis as simple as that and this test has been used widely to discover nearly all the steroids that we currently have in clinical practice and this can be done in rats it can be done in mice and you can see here by rubbing the Croton Oil onto the ear we end up with a local inflammatory response and we can then add a topically active anti-inflammatory drug to see if we get suppression now the reason that I show you this and people forget this is that the activity of all the currently topically active steroids actually weren't developed for the lung they were developed in the skin and they used something called the Mackenzie Skin Blanching Test and that is that light is probably not conducive to seeing it properly here but if you put steroids topically on the skin you get blanching and the blanching is a feature of the vasoconstriction caused by the steroid reducing blood flow and why steroids actually have an acute anti-inflammatory effect and one of the reasons in my opinion we've not managed to find so-called soft or safer steroids beyond the ones we have is because this is a non-genomic effect and we've spent our entire life trying to find effects of drugs that affect the genome around steroids and that has not proved very successful to date now the reason I show you this is if you go back to the potency of these corticosteroids in this rodent test in the ear against the ability to be anti-inflammatory compared to their ability to suppress the hypothalamic pituitary actus you can get a therapeutic index and as reviewed by Phillips and colleagues some years ago that therapeutic index the potency of these steroids absolutely predicts their potency in the nose and also in the lung so they were never ever developed just for the lung they were developed topically for a whole range of things which of course is why we can use corticosteroids topically in other tissues and what happened in the rat and the mouse absolutely bore out what happened when we did this blanching test in human skin it predicted so a very simple assay in vivo predicted the potency of these steroids in man now a third class of drug that has been introduced for the treatment of asthma was really something that I started my PhD on which was the so-called leukotriene receptor antagonist and they were approved in 1998 multi-leukast as the first tablet that actually act as an antagonist for leukotrienes and I'm often asked how we got there and you have to go back to the 1940s from experiments taking venom from snake venom adding it to guinea pig lung and as you can see on the left of the original paper in the 1940s getting contraction of the tissue that was not due to histamine and we're thinking now in the mindset of the 1940s that was a very novel observation the contraction was long lasting and it was actually the day that I got my BSE degree the paper appeared in nature from Priscilla Piper and Howard Morris and I got asked about this at my viva which I thought was really unfriendly given it came out in the morning my viva was at 2 o'clock in the afternoon but to identify SRSA as leukotriene C4 and D4 that being these very powerful lipids produced from arachidonic acid that were distinct from the prostaglandins brought by aspirin and then receptors appeared we could find drugs that targeted this and Montelucas being the first now I say this because this is a tablet it's very widely used in certain parts of the world particularly the US because it's not a steroid and it's actually something that has generated commercially a lot of money $4 billion a year for Merck since it was actually approved now you might think it's all good we've got some very effective drugs but actually respiratory this is a recent study from Tufts University with the FDA and actually respiratory has had a lot of failures and the question is why have we had lots of failures and I might come back to that later if we have time but partly I think is that we've become too reliant on the mass and it's a discussion we might have later on but clearly we still have quite a lot of failures in the respiratory area compared to other therapeutic areas what is absolutely clear particularly for COPD is we still need new drugs and particularly new anti-inflammatory drugs we have very good bronchodiliters and I say that because this is one of three very large studies in the literature showing if you give inhaled steroids every day over many many years it has no impact in the majority of people in the decline of lung function now that means that whilst they're being used for the majority of people it may not be the best thing to do we also now know that many of these patients have a bigger risk of pneumonia and in fact there's a very recent study in the New England Journal of Medicine that if you withdraw steroids the majority of patients with COPD nothing happens now that means given I've shown you it's an inflammatory condition there is a need for novel anti-inflammatory drugs David, I set about trying to say can we find new drugs that were alternative to steroids that actually could improve on some of the therapies we have because each of them whilst they're effective does also have significant shortcomings and for that we turn to a group of enzymes called phosphodiesterases a very complex set of enzymes are in fact 11 families of phosphodiesterase enzymes that actually involved in modulating second messages in cells the cyclic nucleotide, cyclic GMP and cyclic AMP now I don't need to tell most of you in this room that if we inhibit PD5 it's the basis for why we have the effect of sedenaphil or Viagra and many others that have followed that actually bring about vasodolation and in erectile dysfunction we've used inhibitors of PD3 such as mylrenone for heart failure for claudication the question is given we now know that PD4 is found in inflammatory cells and PD3 is found in airways smooth muscle could we actually target this to produce new drugs for asthma and COPD now I'm pleased to say that one of these, Rheflumolast has recently been approved for the treatment of COPD as a PD4 inhibitor and also another one called a Premolast has recently been found for the treatment of psoriatic arthritis now what David and I set out to do and I'm pleased to say I think we have succeeded in doing this is to really find a class of drug that is both bronchodilator and anti-inflammatory in a single molecule that is not a beta-ragonist and is not a steroid and I want to acknowledge particularly Alec Oxford who is a royal society medallist in chemistry for his discovery and synthesis of summa triptan but also David who I've mentioned and my own group particularly Victoria Boswell-Smith who did the initial experiments and my late friend Don Spina who died almost exactly a year ago today and I want to pay tribute to Don because without him most of the work that I'm going to talk about now would not have happened so we set about trying to find that something had never been done before was to find a drug that was a bronchodilator and an anti-inflammatory in a single molecule and to do this we found a drug that actually inhibited Fosidae Stray 3 in airways smooth muscle and it inhibited Fosidae Stray 4 in inflammatory cells and at the same dose when we give this we can have both acute bronchodilation as you'd seen with a beta-ragonist and a clear anti-inflammatory effect with the 4 inhibitor and I want to take you back to this very familiar picture I showed you earlier because when we sat down I said to David well what do we start how do we start going about finding a drug from a man who's done it multiple times and there are very few people on the planet we've done that and he said it's obvious you take a piece of guinea pig trachea you electrically stimulate it and I just show you here the same piece of guinea pig trachea in an organ bath that is electrically stimulated every single second over a period of six hours and you can see it's a beautifully robust preparation you're stimulating the parasympathetic nerves releasing acetylcholine contracting the tissue and if we add the vehicle for the drug on this you can see nothing happens and we made 180 molecules with Alec Oxford and David and one of them just shown here as 554 forget anything else about it you can see almost immediately suppresses the bronchod constriction just as you'd seen with cell metrol and over the next three to six hours you can see this suppression continued I said to David what should we do next he said put it into a dry powder blow it into the lungs of guinea pigs challenge them with something that constricts their airways and if it bronchod delates you'll pick it up and I want to just show you one of the first experiments we did where in the upper panel we're measuring increasing doses of histamine given to anesthetised guinea pig to measure Ewi's resistance and you can see a beautiful increase in resistance if we give them lactose powder which is the carrier for the drug there is no suppression whatsoever over in this case three and a half hours whereas in the lower panel we've added the 554 drug and you can see by powder inhaled by guinea pig we got complete suppression and that lasted as it did in vitro over many hours so we knew we had a drug and we were looking for something that we could give that had a very long duration of action you can see very good suppression and what was interesting is that we achieved that without changing blood pressure to any dramatic effects so we knew we could get a local effect in the airway but then the second bit is was this drug that causes bronchodilation capable of anti-inflammatory activity and again just some summary of work that we did over a number of years we can show that it suppresses the sinophils, the main inflammatory cell present in allergic disease the allergen causes the sinophils to come in the lung that is suppressed at the same dose of the drug that we get at inhibition of the bronchod constriction and you can see other markers of inflammation that are reduced and if you compare that to now to existing anti-inflammatory drugs that are in the clinic fluticazone propionate which is a very effective steroid, reflumolast I've already mentioned to you is very recently been approved for COPD you can see that compared to this this drug when inhaled at doses of bronchodilate also caused equivalent anti-inflammatory effect to the steroid or the PD-4 inhibitor so then I said about my long journey around the planet finding some money because to go from there through toxicology to put this into people when you're not Black Sur, you're not Astra takes a lot of effort and I have to say it's been a real journey that I've enjoyed doing but has taken a lot of time and effort but the bottom line is we got through toxicology we used dogs, we used rats for 28 days all of the things that any drug has to go through and I think is why I was happy to talk to the sun journalists not so long ago about the use of dogs because we just finished the study with dogs that allowed us to pick the dose that we then put into human beings for the first time and I show you this because the very first patient that inhaled this drug just absolutely told us they felt better and you can see here that the extent of bronchodillation is profound it's a very marked change in FEV1 compared to placebo we did that in a group of patients with asthma and we were very good the NHRA allowed us to go immediately into asthmatics because they said no healthy person is going to help tell us whether or not this drug is effective so when we then went on we published some of this work in the end of 2013 a single inhalation in patients with COPD we got actually very good bronchodillation that lasted over many hours and more recently the company that's taking this forward has got a new formulation that this is now I think very clearly a twice a day drug which is exactly what we wanted to try and do but at the same dose that calls the bronchodillation people working with Professor Dave Sing's group in the University of Manchester we actually did something fairly heroic that other people have done of taking lycopolisaccharide getting animals to inhale it we knew that it was blocking mutual infiltration in the animal we then did exactly the same experiment in people so in this study in Manchester they inhaled lycopolisaccharide you then asked the patient to cough up sputum and you can see different time points afterwards the sputum is full of neutrophils and if we give this drug the same dose as bronchodillation you can see that the very clear statistically significant inhibition of the infiltration of cells into the airway of people now the interesting thing of why people use this model is it's not sensitive to pregnancy and steroids and so if we're thinking about a disease that's not effective clearly a model that is insensitive to steroids but works, we know to drugs that block phosphidasterase we thought was a useful way of checking whether this was truly anti-inflammatory in people now one of the exciting things and we've first of all done this in Guinea-Petrakeer we then were very fortunate to get access to human bronchial smooth muscle I want you just to look on the left here is what happens if we take a sub-maximal dose of this drug so we cause it to relax airway smooth muscle we take a muscranic receptor antagonist like a pyrrolate again sub-maximal the third column is what you'd expect to get if you put the two drugs together and actually what happens you get profound, really pronounced synergy in terms of greater bronchodillation now this is important because it means we can lower the doses of existing drugs whilst not compromising on efficacy and we now know from recent work again done by Professor Syng's group in Manchester that if we take a low dose of this drug and we take a low dose of a muscranic receptor antagonist that's widely used in the treatment of COPD namely Teotropium you can see here that if you add the drug you get a much faster onset of bronchodillation so instead of having to wait 40 minutes before you see a change in lung function you'll see it in 4-5 so this is a really clear indication that there's increased benefit of having this drug to an antico-energia but it's not just on smooth muscle people with these diseases also have hyperinflation and gas trapping and you can see here again combining this drug with 554 in people also reduces gas trapping so everything that we've done in the guinea pig and I say here and now we never did an experiment in the mouse it was all done in the guinea pig because it was David that was mentoring me to do this as it ended up with a drug as you can see here that has clinical benefit and I'm pleased to say this is now currently in phase 2B in the United States and there's been in more than 600 people now there's no nausea we've got no major cardiovascular effects but it's clearly a novel class of bronchodillator that also has anti-inflammatory properties and my good friend Visa Vajika who works at Imperial in London and I knew nothing about this when it came out and we talked about the media but the lance it was working medicine wanted to make a lot of noise about this study because it was so new and I think what Visha has said in this editorial is that this actually could turn out to be one of the most substantial advances in the management of patients with chronic airway obstruction because there's very little coming along this novel but again none of this would have happened without guinea pigs none of it would have happened without the dog so the question is do we need further anti-inflammatory drugs we've now got a very good understanding of how cells recruit into tissues and we clearly know that we've got lots of drugs that have been through this kind of cascade and not done very well and one of the things that has been done for many years is to try and measure inflammatory cells into the airway as I've shown you both in animals and people we can wash the lungs out, we can collect sputum we can quantify inflammatory cells but we've all been taught from school about chemoattraction and a single mediator causing a particular cell to migrate into a tissue and I think our concepts of how inflammatory cells come into tissue are very simple and with my colleagues at King's particularly Simon Pitchford he's now back at King's as a lecturer the one who's a PhD student with me actually made some interesting observations that many of the leukocytes that migrate out into the tissue such as the lung often have inflammatory cells attached to them and the platelet which is a cell that we are consider as something that plugs up holes and Jeremy Pearson knows very well spent his career looking at platelets this is something there's nothing to do with hemostasis these are platelet leukocyte interactions rolling on the endothelium prior to these cells coming out into the tissue such as the lung now why is this important well we did a very simple experimental one day we took neutrophils up there PMMs we incubated with endothelium and you can see if nothing happens a few of them stick to the surface of the blood vessel if you put platelets back in on the circulation you get lots of leukocytes attaching but more importantly if we then took animals and we've done this now in rabbits we've done it in guinea pigs we've done it in mice if you actually remove all their circulating platelets by destroying them so these are animals without most of their circulating platelets and we then look at the ability of lipopolysaccharide on the left which I've already shown you there are animals without platelets they don't show up so our concept of a chemical causing one cell type to migrate in vivo is far more complex and it's very clear both in the lungs and other anatomical areas that the platelets are necessary to optimally recruit leukocytes into the tissue this is not something I can do in people furthermore others have come up with some really interesting examples of microscopy where you can label these different cell types so the endothelium here is labeled green you can see the neutrophils are in blue the platelets are in red and that these are actually cooperating and we can look at that over time and see how these cells actually migrate into tissues and if the video works which it did earlier I just wanted to show you an example which is not my work but is a paper that I'd love to have been the author of because this shows you using intravital microscopy by looking at the cromastomuscle and you can see here in green these leukocytes and the platelets are actually sitting at either end of them they're polarised and you can see them there prior to them sticking to the blood vessel and getting into the tissue and that's partly why when we take these platelets away the leukocytes don't show up they need platelets to cooperate in terms of moving them into the lung now another very very interesting and Jeremy knows from my time early on in my career that I've been interested in platelets in the context of lung disease and this is a beautiful study and my PHC's Simon Cleary who generated this data at UCSF in San Francisco with Mark Looney's group this is based on a previous work from Looney's study recently that shows that actually megacarocytes are going into the lung they're breaking up and you're getting platelet formulation and you can actually watch this happen we've got adhesive platelets in blue non-adhesive platelets in green and then we can actually study those that are activated or not in real time in the lungs of an animal again if we've got any volunteers you want to have some kind of thoracic window put in and I'll cross with you on their lung I'm happy to talk to you but this is a good example of why we have to continue to do in vivo work to understand more about how megacarocytes behave in the lung and platelets are necessary for that the other area and again another one of my PHD students plays a short of sea has very recently done similar experiments with something that we've often neglected in this area is that there are key pathogens in respiratory diseases that can lead to exacerbations they can lead to pneumonia and again we have very little understanding we've all heard about leukocytes phagocytosing bacteria but less is understood about how those leukocytes appear and from our work showing that platelets are necessary for leukocytes to come into tissue and inflammatory diseases the obvious thing is were platelets necessary for host defense and just really wanted to show you a few slides here that we think they are so on the left here is a strain of pseudomonas put into the lung attached to beads into the lungs of animals you can see a profound inflammatory response associated with neutrophils coming into the lung compared to sham animals or the negatively untreated controls what we then also show is that we can find platelets coming in at the same time as leukocytes in response to this infection and very important when we took the platelets away not only did the bacterial load go up but the bacterial load this is a mild form of infection that is restricted to the lung suddenly you've got lots of bugs going into the blood and you get death from septicemia now we've spent many many many years trying to stop leukocytes coming to the lung to treat acute lung injury what this tells you is if you get rid of the leukocytes by removing the platelets we have a self-contained infection in the lung that actually goes systemic and increases your risk of death and I think that this is a paper we've just had accepted in an American journal I think is a really profound observation that says that platelets are absolutely necessary for host, defence and the lung and that is not something that has been generally accepted up until now so finally we need new drugs where are we going to find them from now we've already had the pleasure of giving Rachel a prize earlier on for her work with primates with Fergus Walsch but one of the interesting projects that she knows I've been involved with over the years started life here working with some marine biologists up in Oban in Scotland this is their lab view and they are marine biologists who are interested in why these guys and things smaller than this and oil rigs things stick to them we call it by a fouling and they ask a very simple question what is it that allows things to stick to these artificial structures we put in marine environments whereas the things that live there nothing sticks to them and this has been a very interesting story it's me slightly younger with Rebecca Lever some of you will know Rebecca she's at UCL in London and we took the NERC vessel out into the Minch and started dredging for these guys and these guys are echinoderms we've got all sorts of different echinoderms and one of the things about these echinoderms is nothing sticks to their surface and the question is why because they are reasonably sedentary compared to fish or other things that are in a marine environment and to cut a very very very long story short we published actually last year the identification of holy saccharides from the surface of these marine organisms that are anti-inflammatory in vivo in experimental animals and the thing is they look a bit like heparin but they're not anti-coagulant because they're far enough back in evolution where we don't have a pressurised cardiovascular system so we don't probably need anti-coagulants and so these molecules are very interesting because they're completely novel structures that are found on the surface and it looks very similar to heparin sulfate that we find on the surface of our own vascular endothelium which I like to think is a bit like Teflon and anything we do to disturb that Teflon surface a bit like me trying to poach an egg on a source of them that's damaged surface you get it sticking the same is true here if you think about metastasis of tumours thrombosis inflammatory responses all happening at the level of the endothelium so if we can find things in nature that are actually able to restore the negativity of the endothelium we may have a whole new class of drug and to that end working with my good friend Charlie Bavington in Scotland John Hobward and Barbara Malloy who are the National Institute of Biological Standards and Control which is now part of the MHRA and others working in Edinburgh David you're pleased to know that you've identified a whole series of new chemicals from these sugar-like structures on the body wall in this case of a cucumber that actually have very selective binding for some of the adhesion molecules that are involved in leukocytes recruited into tissue so there's a whole family of new anti-inflammatory drugs unconvinced out there because we already know that Heprin has a very good anti-inflammatory effect it's just it suffers from being an anti-collagulant this is just an example from our recent journal of biological chemistry paper of the ability of some of these materials that we've identified for being anti-inflammatory so you might sit here and think well we haven't really made any progress I just wanted to take you back to 1684 if you had asthma a physician from Oxford defined asthma as a difficult, frequent breathing with a great shape of the breast without any fever the organs of breathing which are the pillars of life are shaken by this disease as if by an earthquake the treatment then before David and others came along was sleeping on a chair powered on millipedes and volatile salts and I think we have made some progress even as I said to you not always I recently had the great privilege of going to Honihara in the Solomon Islands and I took this because this is actually in the last three or four years their approach to respiratory diseases is putting a big sign up in the market I said stop spitting about places always cover your mouth and nose when sneezing and keep children safe at home which is another approach and then if we go back not very far we had this potas asthma smoking mixture which this is an early form of what David Jack I think has improved on greatly is inhalation of drugs that actually lead to improvement of symptoms so there's no question that we've made a lot of progress but as I've said I think there's still more to do but I wanted to leave you ladies and gentlemen with a book that one of my postdocs found some years ago in Bath and some of you have heard me speak before I've probably seen this but it's such a beautiful I think example of how we've moved forward this was AJD Cameron for those of you don't know there's a general practitioner in tumbridge wells and this was a book about the treatment of asthma and this is an absolute quote from the book I was amazed to find cutaneous reactions could change or disappear entirely by desoxification from that I was bound to include that whatever part allergy played it was certainly not a fundamental one and that's very interesting because we're beginning to realise that allergy and asthma often coexist but one doesn't necessarily lead to the other a secondary condition of affairs in the syndrome a condition which is associated with adequate detoxification so what is active detoxification if you're a patient in tumbridge wells in 1933 it included colon irrigation and the method of irrigation which I'll go with you because you're experimentalist most of you and you'll appreciate this is a stand with a two gallon container which can be raised or lowered is used the container is connected by a rubber tube to one of the arms of a Y shaped glass to the stem of which an ordinary soft esophageal tube in which an extra aperturist cup is passed into the rectum so far so good the water that body temperature is run into the bowels stop before discomfort is caused and then allow to drain off this procedure is repeated again and again until the prescribed quantity anything from two to eight gallons I've never worked out of this Imperial US has been passed through the pressure employed is determined by the height of the container above the couch and I find as a rule a height of 12 inches is most satisfactory listen to this bit carefully it is dangerous to use too much pressure the optimum for each patient is learnt by experience now ladies and gentlemen we may sometimes think are we doing the right thing with our experiments I think that I would not want to be a volunteer in this particular experiment but he is an absolute this is a real quote from what was done in Tunbridge Wales in 1933 now I presented this at the Edinburgh Science Festival some years ago and a lady came running up to me at the end and she said I hope you're not really laughing at colon irrigation I get it every week and my asthma improves I believe actually IBD is basically asthma of a different tube and a different smooth muscle going in here but again I think you'd find most people would consider the treatment we've got now however it could be improved much improved over this or inhaling millipedes this is the final bit I'll leave you with that before you go to your canapase so finally ladies and gentlemen thank you for your attention I'd like to thank my current group many of which have contributed to the work I certainly want to thank my colleague Michael Walker and Louis Franciosi in Vancouver who did a lot of the early work on RPL554 David without whom I think we would not have most of the drugs we've currently got and I think as I said previously previous chairman of RDS this man has had a profound influence on this area and he's certainly had a profound influence on me Charlie Bavington in Scotland Rebecca Lever at UCL is a former PhD student of mine and also I'd like to acknowledge Mario Catsola and Luigi Calzetta who have done a lot of the human air we've worked and human studies in in Torfa Garter University in Rome and very much I'd like to standard acknowledge Don the back there with the glasses because Don has been an absolutely profound influence on my career in helping and as I say tomorrow is the anniversary of him dying prematurely and he's sorting this by all those who knew him and I'll leave you with this because I think without the doc without the guinea pig we would not have any of the drugs that certainly I've talked about this evening and I think we will continue to need our experimentation to help us understand some of the complex things such as platelet-leucosial interactions I've shown you this evening and to help us find new classes of drug going forward because we still need them and I think anybody who tells you otherwise as I once famously said on a platform like this to Caroline Fleet when she told me I should start working in cell culture I said you find me the cell that costs and I'll use it and with that thank you very much for your attention


Hi everybody Sean with Jaspys case breaks calm here doing 2020 Panini NT baseball pick your team 16 random number block randomizer For the Yankees white Tox cardinals Phillies Brewers and Marlins these six teams All 10 spots in the format just like all random number blocks Every spot gets a random number zero through nine if you get the number three you get all team all cards with the number For the teams in the random number block with three being the first the last letter to the Number to the left of the slash so for example the card is two forty three out of two ninety nine thirteen and ninety nine thirty out of Twenty-five forty three out of forty nine ninety three out of ninety nine and so on the number three will get the card all Redemption cards go to the zero spot Even if it is a known one-of-one redemption It will still go to the zero spot any and all in person one of ones will obviously go to the one spot So let's do the break Here are the Customers from Patrick down to Tyler and the numbers from zero down to nine We're gonna do random dice roll One of three to randomize both lists three times and match them up one Tyler down to Adam and three times on the numbers From one down to seven So Tyler with spots one and two Tyler Schoenfelder Adam Harper with spot five Matt Arnold the spot four Adam Harper with spot six Nick Stover with zero and eight Patrick Katzik with three Joseph falsetti with nine and Adam Harper with seven so Nick Stover with spot zero gets any and all redemptions even known one-of-one redemptions while Tyler Schoenfelder would get any and all in-person one-of-ones So does anybody trades? Very uncommon, but give everybody's chance By the time it takes me to print this No, no trades So that is the random number block randomizer for The Yankees white socks Cardinals Phillies Brewers and Marlins NT baseball full case break coming up next I'm Sean Jaspies case breaks calm. Thanks for hanging out and I'll see you next time


Oh, boys. It looks like we got an antler ahead of us. Let's get up there. Yeah, baby. Yeah, boys, we got an antler. Never gets old. This one's super weird. I haven't touched it yet, but it looks like there's no moose track in sight, but there's coyote tracks all around here. So I don't know. Before I grab it, I want you guys to see it. If the coyote actually dragged it over here, chewed all the heck, and it's missing a big tine. I don't know if the moose broke that off or coyote chewed it off. There it is. Yeah, that looks like it's chewed off. Chewed on the tine there.


Recently here on the YouTube channel. We showed you a really cool trick on how you could use the adjustment brush to make some light rays But I had said during that video that that trick was not necessarily Only to make light rays that there were other ways to use that same trick and to go ahead and have some fun with it Well, we received a comment asking us to show you maybe another way that you could use that same trick in a different photograph So today we're going to do exactly that I'm going to pull up another photo and show you how to use the adjustment brush in the same way But on a different Photo all together. So let's jump into Lightroom and show you exactly what it is. I'm talking about So here we have a picture of some mountains and this is a completely different image than the one in the light rays video The light rays video had a bunch of trees There was sunburst and that kind of stuff and in this video We just have this vast landscape with some mountains in the background and when you look at this particular image It almost at least in my mind looks like Stack of pancakes and what I mean by that is it's really got some distinct layers If you look at it here We've got the bottom section of this photograph, which is the foreground element the bottom part That's one layer then we've got the mountains Which are another layer here where the mountains are in the center and then you have the third layer Which is the sky layer and so when I'm looking at something like this It's quite possible that I would probably decide to edit this picture in three separate parts and so for the for the first part I might use a graduated filter to edit the bottom half of this picture something like this and then I might make a new adjustment for the sky and You know makes some adjustments that might look something like you know something like this where I add a little bit of clarity and maybe Saturation or whatever and so the top part of the picture has been edited with one tool The bottom picture has been edited with that same tool But the middle part the mountain section in the middle of this photograph is kind of being left alone and the only way to really tackle that Middle section of the photograph that goes all the way across from edge to edge is to use something like the adjustment brush in particular To use it in a similar fashion than we used with the light rays tool Let me show you what I mean by that We're gonna set up one brush just like we did before and what I want is this brush to be slightly a little bit larger Than the mountains in this photograph so something that looks a little bit like this You can see where the radio the the adjustment brush the radius of the adjustment brush actually covers the mountains Into the sky and into the foreground Then what I'm gonna do is go to the edge just pick a side whether it's the left side or the right side It really doesn't matter, but I'm gonna pick the left side and I'm gonna click one time and Then I'm gonna hold my Shift key down. I'm gonna go to the other end of the photograph on the opposite side and What I'm gonna do here is I'm gonna hold my shift key down and click Just like that You can see how I've got this strip of Adjustment that's going to be applied to the middle of the photograph. That's exactly what I wanted to happen Now this adjustment as it stands right now is god-awful because my exposure is set to four So let's just hold our option key down Which will change the word effect up here to reset just by holding option I can click the word reset one time and that'll set all of my numbers back to zero so now that my Selection has been made I can go in and now make the necessary adjustments to make this mountain range Look exactly the way I want so for this photograph I'm gonna maybe pull some clarity up. Maybe add a little bit of de-haze. Maybe pull up My whites. I don't know. I'm going kind of fast here. Maybe my highlights Maybe maybe a little bit of contrast and maybe even some sharpening or something like that And then I can even play with saturation To get the color just right But all of these adjustments that I've just made if I toggle this adjustment on and off you can see are only affecting the mountain range in the center because it's a completely separate independent adjustment the trick though was The shift key to hold the shift key down and click on one end and the other end and boom you get this adjustment That's straight across all the way across the photograph and if I want to take that one step further When I turn this overlay on I could always go to the eraser and get rid of any Part of the of this adjustment that got applied I could just go in here and erase it and take it out and So you can you know spend hours getting getting this perfect not hours But you know spend a couple minutes getting getting that perfect You know I just talked for about 30 seconds and boom, you know, that's out and then you can refine it however you want to but There you have it There's another example of The way we used it for the light rays and this particular example instead of using One that was you know at this at this weird Triangular angle we used an adjustment that was actually an even keel across the middle of the photograph just by holding the shift key down So hopefully you found this useful go ahead and give it a try like I said Experiment with it experiments gonna be your best friend for learning and practice You're never gonna get good at these things without practice So practice experiment have fun with it. Hopefully you enjoyed this video if you did give it a thumbs up Subscribe to our channel where we'll have lots more episodes coming to you soon and until then My name is Adam. This is photo nerds