How animals have helped with the discovery of drugs for asthma: Prof Clive Page, Paget Lecture 2017

How animals have helped with the discovery of drugs for asthma: Prof Clive Page, Paget Lecture 2017


thank you very much Jeremy for that kind introduction and I have so that it is an absolute honour to be standing here this evening as someone who started life as a lowly post-doctoral fellow junior lecturer on the RDS council as it used to be when it was chaired by Sir David Jack, I will mention David again again later in my lecture because he has had profound influence on my own research activities and I think he has been outstanding as a person contributing to this area, as Jeremy said my whole career has really been looking at understanding lung disease and
particularly asthma and COPD and 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 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 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, so this is an area that cost society a lot of money and whilst
we have made significant progress as I will hopefully show you, I think there is
still more to do, now I realise we have 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, oedema fluid occurring in
the the airway lumen that brings about this wheezing and coughing that is seen
in asthmatics and for many years we have used drugs to relieve this by relaxing
the airways smooth muscle but over the last 20 years particularly we have recognised that this is a complex inflammatory condition and sadly people
particularly under the age of 30 still still die from asthma, everal thousand people died in the UK last year from asthma mainly under the age of 30 and this is
because as you can see 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 is 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 plug-in, 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 us give up smoking and clearly that is very sound advice, however, I have
put up there air pollution because we now recognise and I think in the next 20
years we are 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, if we look
histologically we can see on the left a healthy normal lung parenchyma and you
can see your your airways are there for gas exchange, they are the size of a tennis
court in most of us, in the middle we have an early inflammatory response to the former bronchitis and on the other side we have the extreme form when we
get alveolar destruction, of course this is not something we can reverse we
cannot rebuild airways but we can I think in the longer term hopefully
prevent this, if we look at this at a different level you can see compared to
the lungs from someone who does not have emphysema from somebody that has, you can
see the profound pathological changes that we are up against and trying to
prevent, now actually the pharmacology of asthma and COPD is relatively simple we
use bronchodilator drugs now and anti-inflammatory drugs in both conditions ,we
have the short acting beta-agonists and I will 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-agonists but most
importantly in the last 15 years there has been the introduction of fixed
combinations of taking bronchodilators and anti-inflammatory drugs together,
because physicians want the patient have the anti-inflammatory drug primarily
glucocorticosteroids whereas the patients have what I call the MacDonald
effect, they like this acute bronchodilation and symptom relief,
we have some very very successful drug combinations both in terms of medical
care and also commercial success, so the formoterol, budesonide and salmeterol, fluticasone, between them generate about 11 billion dollars a year from from
sales to people who for treating asthma now if we look at the beta-agonists
there is 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
are all very successful at causing the airways to open and people to feel
better but they had the problem with also increasing heart rate and blood
pressure, over the years we have made this progressive improvement in these
drugs and particularly the ability to deliver these
directly into the lung through aerosols or powders right up today 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 everyone in this room is
familiar with this particular blue inhaler which contains salbutamol it’s
used by approximately 90% of the worlds’ asthmatics but no one gives a second
thought really as to how it got there I think it is only fitting this
evening that I pay tribute to David because David chaired the Research
Defense Society Council when I joined David is the man if we go back, who
really discovered beta agonists and particularly salbutamol but also his
team went on to discover salmeterol, the long-acting beta agonist, and very
importantly as I will come on to topical corticosteroids and I think the world
owes this man a lot and I think he really should have deserved to have a
Nobel Prize, and sadly David passed away a few years ago but he has certainly been a
fantastic mentor to me, and I will come back to a project that I worked on
previous prior to him passing 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 beta-adrenoceptive stimulant but unlike adrenaline that
also stimulates heart rate and blood pressure, this drug at the right doses
did not, 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 piece of blocker the response disappeared, you could also see that when
you aerosolise this to guinea pigs, and the important thing here is that he did
all of 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, isoprenaline which was a beta but non-selective beta
agonist to salbutamol shown there, at the bottom is salmeterol, and salmeterol is a drug that instead of taking it four to six times a day, he put this long
lipid tail on it to produce a drug that is actually active by bronchodilation
twice a day, now how did he do that was very simple and I think unfortunately
we have forgotten how we have discovered many of the drugs that actually worked
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 we put isoprenaline on there is a very transient
reduction in the contraction of the air way smooth muscle, the same is true with
salbutamol, you can see it reverses, it has got a very short half-life but then look
at what happens when he puts this new drug called salmeterol on the guinea trachea
you can see it is suppressed and seven hours later it stays suppressed
and that has 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 was doing
these experiments in guinea pig trachea also took pieces of tissue from the
heart for example to actually show that you have 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 are glucocorticosteroids,
and animals have helped us really profoundly in getting to the
drugs that we have got today and again we take for granted, so we have to go back
to the 1940s when cortisone is extracted from the adrenal glands and used as an
anti-inflammatory drugd but of course cortisone whilst effective
also suppresses your hypothalamic 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 beclomethasone diproprionate, and please if you ever write beclomethasone down in any article make sure you put the diproprionate on it, David once said to me when I left it off would not do the same thing without the
diproprionate, it is there to give it the activity locally in the tissue, this is the first steroid that was developed for the treatment of asthma in
1972 where we can inhale the beclomethasone have a very pronounced
anti-inflammatory effect in the lung but it was poorly bio-available and therefore
you did not have the same degree of suppression of the hypothalamic
pituitary axis, and this drug and subsequently the discovery of other
topical steroids such as budesonide 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, I just wanted you to go back to, this is a
patent actually fluticasone, another steroid but the same is true of beclomethasone, 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 air whilst
measuring levels in the blood and changes in the hypothalamic pituitary
axis, it is as simple as that, this test has been used widely to discover nearly all
the steriods that we currently have in clinical practice, this could 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, the reason that I show you this is and people forget this, is
that the activity of all the currently topically active steroids actually
were not developed for the lung they were developed in the skin, they used
something called the McKenzie skin blanching test, that is, the
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, one of the reasons in my
opinion we have not managed to find a so-called soft or safer steroids beyond
the ones we have is because this is a non genomic effect and we have 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, the reason I show
you this is if you go back to the potency of these corticosteroids in these
rodent test in the air 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, 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 have started my PhD on which was the so-called
leukotrienes receptor antagonists they were proved in 1998, Montelukast
is the first tablet that actually acts as an antagonist for leukotrienes.
I am 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, you can see on the left from the original paper in the 1940s, getting
contraction of the tissue that was not you to histamine, we are thinking now,
in the mindset of the 1940s, that was a very novel observation that contraction
was long lasting and it was actually the day that I got my BSE degree the paper
appeared in Nature from Priscila Piper and Howard Morris 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 2pm in the afternoon but to identify SRS-A as
leukotrienes C4 and D4 that being these very powerful lipids produce
arachidonic acid that would distinct from the prostaglandin blocked by
aspirin and then receptors appeared, we could find drugs that targeted this and
montelukast being the first, now I say this because this is a tablet, it is
very widely used in certain parts of the world particularly the US because it is
not a steroid and it is actually something that is generated commercially
a lot of money, four billion dollars a year for MERCK since it was actually
approved, you might think it Is all good we have got some very effective drugs
but actually respiratory this is a recent study from Tufts University with
the FDA and actually respiratories have 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 have become too reliant on the mouse and
it is 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 bronchodilators 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, 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 have shown you it is an
inflammatory condition there is a need for novel anti-inflammatory drugs in
this disease, and so with 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 are effective does also
have significant shortcomings, and for that we turn to a group of enzymes
called phosphodiesterase, a very complex set of enzymes are in fact 11
families of phosphodiesterase enzymes that actually involved in modulating second
messengers in cells, the cyclic nucleotides, cyclic GMP and cyclic AMP,
now I don’t need to tell most of you in this room that if we inhibit PD5, it is the
basis for why we have the effect of sildenafil or viagra and many others that
followed that actually bring about vasodilation and an erectile dysfunction, we have used inhibitors of PD3
such as milrinone for heart failure, for claudication, the question is, given we
now know that PD4 is found in inflammatory cells and PD3 is found in
airway smooth muscle, could we actually target this to produce new drugs for
asthma and COPD, I am pleased to say that one of these, roflumilast, has
recently been approved for the treatment of COPD as a PD4 inhibitor and also
another one called apremilast has recently been found for the treatment of
psoriatic arthritis, what David and I set out to do and I am pleased to say I think
we have succeeded in doing this, is to really find a class a drug that is both
bronchodilator and anti-inflammatory in a single molecule that is not a β-agonists is not a steroid, and I want to acknowledge particularly Alec Oxford
who is a Royal Society medalist in chemistry for his discovery and
synthesis of sumatriptan but also David who I have mentioned and my own group,
particularly Victoria Boswell-Smith who did the initial experiments and my late
friend Dom Spinner who died almost exactly a year ago today and I want to
pay tribute to Dom because without him most of the work that I am going to talk
about now would not have happened so we set about trying to find
something 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 phosphodiesterase-3 in airway smooth muscle
and it inhibited phosphodiesterase-4 in inflammatory cells, and at the same dose
when we give this we can have both acute bronchodilation
as you’ have seeen with a β-agonist 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, what do we
start? How do we start going about finding a drug from a man who has done it multiple
times?And there are very few people on the planet who have done that and he said
it is 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 thus
stimulating the parasympathetic nerves releasing acetylcholine, contracting the
tissue, 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 bronchoconstriction just as we have seen with salmeterol all 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 bronchodilates you will pick
it up, and I want to just show you one of the first experiments we did where in
the upper panel we are measuring increasing doses of histamine given to
an anesthetised guinea pig to measure airways resistance and you can see
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 have 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, 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 effect so we knew we could get a local effect in the airway, 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 eosinophils, the main
inflammatory cell present in allergic disease, the allergen causes the
eosinophils to come in the lung, that is suppressed at the same dose of the
drug that we get at inhibition of the bronchoconstriction, and you see other
markers of inflammation that are reduced and if he compared that to now two
existing anti-inflammatory drugs that are in the clinic, fluticasone propionate
which is a very very effective steroid roflumilast 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 that bronchodilate also caused equivalent
anti-inflammatory effect to the steroid or the PD 4 inhibitor, so then I said
about a long journey around the planet finding some money and because to go
from there through toxicology to put this into
people when you are not black so you are not Astra [AstraZeneca] takes a lot of effort and I
have to say it has been a real journey that I have enjoyed doing but it 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 that any drug has to go through and 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 allow us to pick the dose that
we then put into human beings for the first time. 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 bronchodilation is profound,
it is 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 MHRA allowed us to go
immediately to 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 patients
with COPD, we got actually very good bronchodilation that lasted over many
hours and more recently the company that has taking this forward have
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 cause
the the bronchodilation in people, working with Professor Dave Singh’s group in the
University of Manchester we actually did something fairly heroic that other
people have done taking lipopolysaccharide, getting animals to inhale it,
we knew that it was blocking neutrophil infiltration in the animal, we then did
exactly the same experiment in people so in this study in Manchester they inhaled
lipopolysaccharide, you then ask the patient to cough up sputum and you can
see at different time points afterwards the students full of neutrophils and if
we give this drug that the same dose as bronchodilation 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 prednisone and steroids, and so if we’re
thinking about a disease like COPD where steroids for many people are not
effective, clearly a model that is intensive to steroids but works we know
two drugs that block phosphodiesterase we thought was a useful way of checking
whether this was truly anti-inflammatory in people, now one of the exciting things
and we first of all done this in guinea pig trachea, we then were very fortunate
to get access to human bronchial smooth muscle, I want you just to look at the left
here is what happens if we take a submaximal dose of this drug, we cause it
to relax airway smooth muscle, we take a muscarinic receptor antagonist like a glycopyrrolate against again submaximal, the third column is what you would expect to get if you
put the two drugs together and actually what happens, you get profound, really
pronounced synergy in terms of greater
bronchodilation, 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 byPprofessor Singh’s
group in Manchester that if we take a low dose of this drug and we take a low
dose of a muscarinic receptor antagonist that is widely used in the
treatment of COPD mainly tiotropium, you can see here that if you add the drug
you get a much faster onset of bronchodilation so instead of having to
wait 40 minutes before you see a change in lung function, you are seeing it in
four to five, so this is a really clear indication that there is increase
benefit of having this drug to an anticholinergic, it’s not just on
smooth muscle, people with these disease have hyperinflation and gas
trapping, you can see here again combining this drug with 554 in
people also reduces gas trapping, so everything that we have 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,
has ended up with a drug as you can see here that has clinical benefit.
I am pleased to say that this is now currently in phase2B in the United
States and has been in more than 600 people now, there is no nausea we have got
no major cardiovascular effects but is clearly a novel class of
bronchodilator that also has anti-inflammatory
properties, and my good friend Wisia Wedzicha who works at Imperial in London
and I knew nothing about this when it came out, we talked about media but The Lancet Respiratory Medicine wanted to make a lot of noise about this study
because it was so new and I think what Wisia 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 is very
little coming along that is 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 action strategy drugs? Now that a very good
understanding of how cells recruit into tissues and
we clearly know that we have 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 in people we would wash the lungs out, we can
collect sputum, we can quantify inflammatory cells but w ha’ve all been
taught from school about keeping chemotraction and a single mediator causing
particular cell to migrate into a tissue and I think our concepts of how
inflammatory cells come into tissue is very simple, with my colleagues at
Kings, particularly Simon Pitchford who is now back at Kings as a lecturer but when he was a PhD student with me actually made some interesting observations that
many of the leukocytes that migrate out into the tissues such as the lung often
have inflammatory cells attached to them and the platelet which is a cell that we
are considering as something that plugs up holes and Jeremy Pearson knows very well,
spent his career looking at platelets this is something that has nothing to do
with haemostasis, these are platelet leukocyte interactions rolling on the
endothelium prior to these cells coming out into and the tissue such as the lung,
why is this important, well we did a very simple experiment one day we took
neutrophils up there, PMNs, we incubate them with endothelium and you can
see if nothing happens a few of them stick to the the surface of the blood
vessel, if you put platelets back in as you find them in the circulation you get lots
of leukocytes attaching but more importantly if we then took animals,
we have done this now in rabbits and we have done it in guinea pigs, we have 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 have already shown you, causes neutrophils to come into the lung, in the
animals without platelets they do not show up, so our concept of a chemical
causing
one cell to my cell type to migrate in-vivo far more complex and it is 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 very different cell types,
that 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 are actually migrating 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 would love to have been the author of because this shows you using
intravital microscopy by looking at the cremaster muscle, and you can see hear in green the leukocytes and the platelets are actually sitting at either
end of them, that polarised and you can see them there prior to them sticking to
the blood vessel and getting into the tissue and that is partly why when we take
these plateless away, the leukocytes don’t show up, they need platelets to
cooperate in terms of moving into the lung now, another very very interesting
and Jeremy knows from my time in early on in my career that I have been
interested in platelets in the context of lung disease and this is a beautiful
study and my PhD student Simon Cleary who generated this data at UCSF in
San Francisco with Mark Luny’s group this is based on a previous work from
Luny’s study recently that shows that actually megakaryocytes that go
into the lung, they are breaking up and you are getting platelet formulation and
you can actually watch this happen, we have 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 have got any volunteers we want to have some kind of thoracic window put in
to allow us to do microscopy 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 leukocytes behave in the lung and platelets are
necessary for that the other area and again another one of my PhD students
Blaze O’Shaughnessy has very recently done similar experiments with something
that we have often neglected in this area is that there are key pathogens in
respiratory diseases, they lead to exacerbations, they can lead to pneumonia
and again we have very litle understanding, we have all heard about
leukocytes phagocytosis bacteria but less is understood about how those
leukocytes appear and from our work showing the platelets are necessary for
leukocytes to come in to tissue and inflammatory diseases the obvious thing
was, were plateless necessary for host defense and just really wanted to show
you a few slides here to say 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 saw is that we could find
platelets coming in at the same time as leukocytes
in response to this infection and very important when we took the platets 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 we’ve got lots of bugs
going into the blood and you get death from septicaemia,
now we have spent 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 have just had accepted in an American
journal, I think it’s a really profound observation that says the platelets are
absolutely necessary for host offence in 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? I had the pleasure of giving Rachel a
prize earlier on for her work with primates and Fergus Walsh but one of
the interesting projects that she knows I’ve been involved with over the years
starting life here working with 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 biofouling and they asked 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 science stor; it is me slightly younger with Rebecca Leaver some of you will know Rebecca, she is at
UCL in London and we took the NERC sea vessel out into the Minch and started
dredging for these guys and these guys are echinoderms, 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 or in a marine environment
and to cut a very very very long story short and published actually last year
the identification of polysaccharides 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 anticoagulant because they are far enough back in evolution where we
don’t have a pressurised cardiovascular system so we don’t put need
anticoagulants and so these molecules are very interesting because they are
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 vascular
endothelium which I like to think is a bit like Teflon and anything we do to
disturb that Teflon surface; it is a bit like me trying to poach an egg on a saucepan
that has damaged surface you get it sticking, the same is true here, if you think
about metastasis of tumors, thrombosis inflammatory responses, is 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
Babbington in Scotland, John Hawkwood and Barbara Malloy who the National
Institute of Biological Standards and Control which is now part of the MHRA,
and others working in Edinburgh David you will be pleased to know, we have
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 is a whole family of new anti-inflammatory drugs I am convinced are out there because we already know that
heparin has a very good anti-inflammatory effect it is just that it
suffers from being an anticoagulant and this is just an example from our recent
biological chemistry paper of the ability of some of these materials
that we have identified for being anti-inflammatory, so you might sit here and think
well we have not 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 shaking of the breast without any fever, the organs are
breathing which are the pillars of life are shaken by this disease as if by an
earthquake, now the treatment then before David and others came along was sleeping
on a chair powdered 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 Honiara in the Solomon Islands, 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 and it said stop spitting about places,
always cover your mouth when sneezing and keep children safe at home,
which is another approach and then if we go back not very far we had this
Potter’s 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 is no question that we have made a lot of
progress but as I have said I think there is 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 who have heard me speak before have probably seen
this but it is such a beautiful example of how we have moved
forward, this was A.J.D Cameron, for some of you don’t know him, he was a general
practitioner in Tunbridge Wells and this was a book about the treatment of asthma
this is an absolute quote from the book “I was amazed to find a cutaneous
reactions to change or disappear entirely by detoxification, from that I
was bound to conclude that whatever part allergy played it was certainly not a
fundamental one”, that is very interesting because we beginning to
allergy and asthma often coexist but one does not necessarily lead to the other, “a
secondary condition of affairs in the syndrome, a the condition which departed
with adequate detoxification”, so what is detoxification if you are a patient in
Tunbridge Wells in 1933 it included colon irrigation and the
method of irrigation which I will go with you because you are experimentalist most
of you and you will appreciate this, it 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 Y-shaped glass, to the stem of which an ordinary
soft esophageal tube in which an extra aperture is cut is passed into the
rectum” so far so good “the water at body temperature is run into the bowels
stopped before discomfort and then allowed to drain off, this procedure
is repeated again and again until the prescribed quantity, anything from two to
eight gallons” I have never worked out whether its Imperial or the US “has been passed through
the pressure employed is determined by the fact 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 learned 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 said
absolute, this is a real quote from what was done in Tunbridge Wells in 1933,
now I presented this at the Edinburgh Science Festival some years ago and a
lady came running up to me and said I hope you are not really laughing
at colon irrigation, I get it every week and my asthma improves, I believe
actually IBD is basically asthma with a different tube in a different smooth
muscle, maybe there is something in here but again I think you would find that most
people would the treatment we have got now, however it could be improved, much improved over this or inhaling millipedes, this is the
final bit I will leave you that before you go to
your canapes, so finally ladies and gentlemen thank you for your attention,
I would like to thank my current group many of which have contributed to the work, I
certainly want to thank my colleague Michael Walker and Lui Franciosi in
Vancouver who did a lot of the work the early work on RPL554, David
without whom I think we would not have most of the drugs we have currently got I
think as I said previously, previous chairman of RDS, this man has had a profound influence on this area and he certainly had a profound influence on me,
Charlie Bavington in Scotland, Rebecca Lever in UCL who is a former PhD student of mine
and also I would like to acknowledge Mario Cazzola and Luigi Calzetta
who have done all of the human airway work and human studies in Tor Vergata
University in Rome and very much I would like to stand here and acknowledge Dom at the back there with glasses because Dom has been an absolutely profound
influence of my career, helping as I I say tomorrow is the anniversary of him
dying prematurely and h is sorely missed by all of us who knew it, and I leave you
with this because I think without the dog, without the guinea pig we would not
have any of the drugs that certainly I’ve talked about this evening and I
think they will continue to lead our experimentation to help us understand
some of the complex things such as beta leucocyte interactions as I have 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 that this to Caroline Flint when she told me that I
should start working in sub-culture, I said, you find me the cell that coughs
and I will use it and with that thank you very much for your attention

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