C-Reactive Protein and Heart Disease – true and false facts on CRP’s role (II) 9

C-Reactive Protein and Heart Disease – true and false facts on CRP’s role (II) 9


That’s the good news. The bad news is because it’s so easy to do,
people have done it in all sorts of other investigations and produced wildly misleading
results. You mentioned “It’s a risk marker” It is indeed
a very modestly significant risk marker for cardiovascular disease. But that story was greatly overhyped and people
started talking about CRP as a “risk factor”. A “risk factor” is something which actually
contributes to the disease. Cholesterol is a risk factor, we know that
cholesterol causes atherosclerosis. You’ve got too much – you get atherosclerosis. You lower it – you protect against atherosclerosis. – [AT] Again, playing loose with the the words! – [MP] It’s not only playing with the words,
it’s also a serious scientific error, the conflation of association with causality. So people did epidemiological studies that
seem to be large, because there were thousands of people involved, but the number of events,
number of heart attacks in them, for example, was very small. Now, it doesn’t matter if you’ve got 10,000
people in a study if you’ve only got a hundred heart attacks – and then if you divide them
into quintiles of what their CRP was a year before or 10 years before, you can get all
sorts of funny results, so the original epidemiological results suggested a fantastically, incredibly
literally, unbelievably high association between having a raised baseline CRP and whether you
have a risk of having a heart attack later on. But when the epidemiology went up to proper
epidemiological scale and hundreds of thousands of people were tested, either in meta-analyses
or in very big studies – it turned out that the association was much much weaker and it’s
still there, but it’s pretty modest and all it really means, and you find the same association
with many other inflammatory markers, it’s nothing specific to CRP, you find it with
low albumin, when the CRP goes up, albumin goes down, sedimentation rate [ESR], or the
cytokines, all sorts of things like that, so this was a complete conflation, wrong conflation
of association and causality, and it got exacerbated because people did experiments in vitro with
commercial sourced CRP, which was impure, contaminated with bacterial lipopolysaccharide,
which is very pro-inflammatory, and they put that onto cells and the cells went “whoa!” And they said “this is the CRP causes atherosclerosis!”
– they even did in vivo experiments, where they infused this dirty stuff into people
and they got lots of inflammation going on – [AT] the body has strong response to bacterial
polysaccharides… – [MP] Yes… So CRP was claimed to be pro-inflammatory,
and it turned out that it isn’t. Eventually we were so concerned by these reports
and not being able to reproduce them in vitro, or in an animal models and so on, we made
pharmaceutical-grade human CRP from human donor blood, very laborious, very expensive,
and we infused it into volunteers, healthy volunteers and guess what happened to them? Absolutely nothing! So we showed that CRP is not pro-inflammatory
if you’re healthy, so the whole story of CRP as a risk marker for atherosclerosis, and
for cardiovascular risk – that has evaporated, and the final nail in the coffin was what’s
called “genetic epidemiology”, Mendelian randomization. If you find the genes which encode different
levels of C-reactive protein [CRP] at baseline, at different acute-phase responses, and there
are such genes, there are various polymorphisms in the human population. Some people have genes which give them a low
baseline CRP, 0.1 mg per liter, and other people go around with a CRP baseline 5 mg
per liter. When they have an acute phase response, correspondingly
the one goes up more than the other. Now if CRP was causative of cardiovascular
disease, the people who have the genes encoding more CRP would have more cardiovascular disease,
and other ones would have lower cardiovascular disease. It turns out that there is no relationship
between any of these genes that control CRP production and whether you get heart attacks
or strokes. Completely “no”. So it doesn’t matter what people found in
in vitro experiments that they can argue about or experiments, infusions and so on… It’s unequivocal that CRP does not cause heart
attacks and strokes. That’s one side of the story. The other side of the story is that CRP is
a binding protein. CRP is actually very closely related to SAP
that we talked about in regard to amyloidosis, which binds to amyloid fibrils. What does CRP bind to? CRP binds to dead or damaged cells. It recognizes phosphocholine residues, which
are ubiquitous in plasma membranes, phospholipids, and these are exposed when cells are sick
or dying or dead. So CRP binds to dead and dying cells, and
human CRP also activates a protein system in the blood that’s called the Complement
System, which is a pro-inflammatory and host defense system. It is used by the body for getting rid of
bacteria and for clearing up debris. We use it in our amyloid treatment to get
rid of the amyloid deposits, the antibody activates complement – that’s what gets rid
of amyloid deposits. The body uses CRP to bind to dead cells to
activate complement and that helps to get rid of dead cells. But, as we showed first of all in 1999, and
many people had been “hinting” about this, making “observations”, “suggesting it” – we
did the first definitive experiments, where we show CRP actually makes the damage in a
heart attack worse than it would otherwise be. Get a heart attack, when your coronary artery
is blocked, no arterial blood going to part of the myocardium – the cells die from anoxia. And a chunk of your heart muscle dies. If you put human CRP into such an experiment
in rats, where human CRP activates rat complement, you greatly increase the size of the infarct,
and that is complement-dependent. So we know the mechanism, we showed all the
molecules there, so we showed that in 1999. That’s the validation of CRP as a therapeutic
target, because if you look at anybody who has died of a heart attack, you always find
CRP and complement in and around the infarct, where the dead muscle is. It’s always there. These are the actors which make things worse. And so we set out to make a drug, which would
prevent CRP binding there. We showed the same thing in a rat model of
stroke. We can make rat strokes bigger by adding human
CRP. So we set out to make molecules that would
block CRP binding to dead and damaged cells and reduce the damage in a heart attack, and
we made a successful candidate compound and family of compounds, which actually in the
animal model worked very very well, but they turned out not to be developable as drugs,
at least so far. So we’ve talked before about the nightmare
journey of drug development, and it really is a nightmare journey. There is nothing that the human race does
which is so difficult, so slow and so expensive, as trying to develop a new medicine. It can take decades and cost billions of pounds,
so it is an indescribable nightmare journey and these particular molecules, which looked
very favorable at least for use as infusional drugs, they couldn’t be taken by mouth but
could be infused into a vein, which is fine, if you’ve got a patient in a hospital with
a heart attack, or a stroke, or burn, for example, where I think CRP also contributes
to the damage, or trauma, and other things, but they were very difficult to purify on
a scale that would be necessary for drug development. So those molecules have stopped development. We are currently trying with considerable
difficulty to invent other molecules that will do the same thing, which will be nice
solids that can be made in large amounts at a cost that’s acceptable, and so on, and you
know we’re deep in the bowels of developing these drugs. And if anybody wants to come and give us a
few million pounds to help that journey along – it will be very gratefully received!

2 thoughts on “C-Reactive Protein and Heart Disease – true and false facts on CRP’s role (II) 9

  1. Now if CRP was causative of cardiovascular disease, the people who have the genes encoding more CRP would have more cardiovascular disease, and other ones would have lower cardiovascular disease. It turns out that there is no relationship between any of these genes that control CRP production and whether you get heart attacks or strokes. Completely "no". So it doesn't matter what people found in in vitro experiments that they can argue about or experiments, infusions and so on… It's unequivocal that CRP does not cause heart attacks and strokes. That's one side of the story. The other side of the story is that CRP is a binding protein. CRP is actually very closely related to SAP that we talked about in regard to amyloidosis, which binds to amyloid fibrils. What does CRP bind to? CRP binds to dead or damaged cells. It recognizes phosphocholine residues, which are ubiquitous in plasma membranes, phospholipids, and these are exposed when cells are sick or dying or dead. So CRP binds to dead and dying cells, and human CRP also activates a protein system in the blood that's called the Complement System, which is a pro-inflammatory and host defense system. It is used by the body for getting rid of bacteria and for clearing up debris. We use it in our amyloid treatment to get rid of the amyloid deposits, the antibody activates complement – that's what gets rid of amyloid deposits. The body uses CRP to bind to dead cells to activate complement and that helps to get rid of dead cells. But, as we showed first of all in 1999, and many people had been "hinting" about this, making "observations", "suggesting it" – we did the first definitive experiments, where we show CRP actually makes the damage in a heart attack worse than it would otherwise be. Get a heart attack, when your coronary artery is blocked, no arterial blood going to part of the myocardium – the cells die from anoxia. And a chunk of your heart muscle dies. If you put human CRP into such an experiment in rats, where human CRP activates rat complement, you greatly increase the size of the infarct, and that is complement-dependent. So we know the mechanism, we showed all the molecules there, so we showed that in 1999. That's the validation of CRP as a therapeutic target, because if you look at anybody who has died of a heart attack, you always find CRP and complement in and around the infarct, where the dead muscle is. It's always there. These are the actors which make things worse. And so we set out to make a drug, which would prevent CRP binding there. We showed the same thing in a rat model of stroke. We can make rat strokes bigger by adding human CRP. So we set out to make molecules that would block CRP binding to dead and damaged cells and reduce the damage in a heart attack, and we made a successful candidate compound and family of compounds, which actually in the animal model worked very very well, but they turned out not to be developable as drugs, at least so far. So we've talked before about the nightmare journey of drug development, and it really is a nightmare journey. There is nothing that the human race does which is so difficult, so slow and so expensive, as trying to develop a new medicine. It can take decades and cost billions of pounds, so it is an indescribable nightmare journey and these particular molecules, which looked very favorable at least for use as infusional drugs, they couldn't be taken by mouth but could be infused into a vein, which is fine, if you've got a patient in a hospital with a heart attack, or a stroke, or burn, for example, where I think CRP also contributes to the damage, or trauma, and other things, but they were very difficult to purify on a scale that would be necessary for drug development. So those molecules have stopped development. We are currently trying with considerable difficulty to invent other molecules that will do the same thing, which will be nice solids that can be made in large amounts at a cost that's acceptable, and so on, and you know we're deep in the bowels of developing these drugs. And if anybody wants to come and give us a few million pounds to help that journey along – it will be very gratefully received!

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