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Transplantation – Professor Dave’s Amazing Molecules 8

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A personal story of the chemistry behind organ transplantation. Without chemistry, transplants would not be possible – it is only chemical drugs which prevent organ rejection. This video explains some of the major pharmaceutical molecules in the field. I hope this video inspires you to join the organ donor register. Music by Marillion (Happiness is the Road).

Hi so i haven’t made a video in a little while so i thought i’d tell you a story today about some personal chemistry which has had a really massive and dramatic influence on my life so i’m going to show you a photograph first of all of me and my partner sam and you’ll learn quite a few things about me by looking at this photo the first thing you can obviously tell

Is that i’m gay the main reason you can tell that is who else would seriously wear purple shoes to their own partnership ceremony the second reason you can workout this was taken on our civil partnership here in the uk is that the closest we could get to york minster we’re sitting on the steps outside and then we went off and got our partnership ceremony somewhere

Else but there’s a few things that you can’t see in this photograph a couple of things about sam in particular that aren’t so obvious here’s an x-ray of some lungs and this is the kind of lungs that sam has because he has cystic fibrosis cystic fibrosis is a genetic disorder that causes progressive lung damage what happens is you’re unable to balance the chloride

Ions in your lungs and that causes to a buildup of mucus around the cells of the lungs the mucus effectively catches bacteria you get bacterial growth bacterial infection fungal infection and repeated infections caused damage to the lungs and eventually the damage to the lungs leads to early death of cystic fibrosis patients and the life expectancy of a patient

With cystic fibrosis is in the uk currently about 37 years so it was exactly a year ago today that sam got to the point where he was really too ill to carry on with cystic fibrosis this is a picture of sam taken around the time he was on oxygen 24 hours a day at this stage and his lung function had declined to about 16 percent of its normal function and at that

Point they recommended that he very seriously consider a transplant a double lung transplant to replace the damaged and unhealthy lungs with cystic fibrosis so in november of 2010 son was listed for transplant up in newcastle at the freeman hospital and we had only a short wait until the pair of lungs became available in fact in january 2011 sam was transplanted

That was a third visit to the hospital the first two transplants didn’t go ahead and the third pair of lungs was good enough to transplant and the transplant went ahead i’ll tell you a little bit later more about how that went and the story that i want to tell you about today is transplantation and in particular the chemistry of transplantation it’s very tempting

To think of a transplant as being a medical model the surgeons there is no doubt the surgeons are geniuses the way they manage to make a transplant work however without some incredibly smart chemistry which underpins the process of transplant it simply wouldn’t be possible early attempts at transplantation failed and the primary reason that transplants are rejected

Is because the body rejects the organs we have an immune system which is designed to recognize what is ours and what is foreign and if you transplant somebody else’s organs into your body the body views them as foreign and it’s unable to cope with them it sends out an immune response against those organs and they’ll be rejected in the absence of any other treatment

Simply transplanting the organs in they are rejected within a period of hours and this was a problem that plagued early transplantation and the early transplant doctors were really in all sorts of doubt that the process of transplant was ever going to be possible at all so the secret to successful transplantation lies in chemistry what you need are effective drugs

Which can suppress the immune system of the patient so what are the key drugs in transplantation what are their molecular structures and where do they come from so the earliest strokes which were found to help return plantation was steroid based drugs it was known since about the 30s or 40s that steroids could suppress immune response if you think about it cortisone

Cream which you would put onto a sting or a rash to reduce the inflammation and swelling which is caused by your body’s immune system responding to what you’ve been in contact with well you can use steroid drugs in very high dose to try and suppress the entire immune system and prednisolone is the drug of choice for this and you’re looking here at the structure of

Prednisolone you’ll see it’s a fairly standard steroid based structure those three six membered rings fused to one another and a five membered ring on the right hand side in this case prednisolone has a conjugated ketone down in the bottom left hand corner and an alcohol up in the top right hand corner it’s a very effective drug at high dose for suppressing the

Immune system and so the first transplant surgeons tried to use this to suppress the immune response and they found that post transplantation the organs would last a little bit longer before rejection took place but this drug on its own was not enough to allow transplantation the next drug that came along was a more designed drug and it was a sapphire print and

You’re looking here again at the structure of a sapphire print it’s a very interesting drug the part of the structure that’s now circled in pink is from a dna base type structure it’s the kind of base that you would find in dna and you can look for comparison at the structure of one of the dna bases and you can see the similarities that are there in the top

Left-hand corner of a sapphire print is the nitro aromatic and it’s connected to the dna base through thio ether linkage that part of the molecule is designed to fall off in the body releases a free file and that interferes with the processes of dna in the body and what it actually does is it kills rapidly reproducing cells rapidly reproducing cell a generating

Dna very quickly and if this molecule is around it gets involved in the process and the cells die because they can’t use this building block for the synthesis of normal dna the cells in the immune system are some of your most rapidly reproducing cells in the body because once your immune system is kicked into action lots of immune cells are synthesized and so if

They can’t create the dna effectively then the ability of the immune system respond is knocked down knotch and this drug which came on stream in the 1960s significantly enhanced the outcomes of the early transplant experiments but still it wasn’t enough to allow transplantation to safely take place in humans without rejection occurring the drug that led to the

Breakthrough and transplantation was isolated from spores from fungus it’s a chemical natural product isolated from a fungus and the structure of that compound is shown here as you can see it’s a cyclic peptide with relatively large molecular weight and a number of distinctive side chains on the ring this compound cyclosporine so named because it’s cyclic and cyclic

And sporran because it comes from the spores of the fungus this compound inhibits a very important enzyme within your immune system essentially shutting down the immune system so how the cyclosporine actually work well the immune chemistry is incredibly complex here’s an image of it i don’t want you to get too worried about it think of it as being like a massive

Transport network if even the uk think of it as being like british railways if you from the states think of it as being like the airway system in the states and in this box in the bottom left-hand corner are a whole load of key processors it’s the hub of the network it’s like birmingham new street on british rail it’s like chicago in the american airport system if

You can take out that box you can shut down the trance you can shut down the immune system it’s like the signals failing at birmingham new street or the air traffic controllers going on strike in chicago and that’s what cyclosporine does it binds to calcineurin which is one of the key enzymes in that box and it stops that part of the immune system from working

Properly now that sounds incredibly complicated but it happens to a very understandable process fissures lock and key hypothesis in 1892 emerald fisher said a chemical molecule interacts with a biological molecule like a key going into a lock and cyclosporine interacting with calcineurin is no different to that here is a crystal structure which shows calcineurin

Interacting with cyclosporine you can see cyclosporine is the small chemical molecule depicted in purple in this diagram you can see it’s ring like structure and it’s interacting within the complex biological pocket the active site of the calcineurin enzyme switching it off and inhibiting the immune system of the patient it’s the combination of these three drugs

That effectively depresses the immune system of the patient prednisolone a sapphire print and cyclosporine those three drugs taken together allows transplantation to take place safely and it led to christian barnard’s breakthrough of the first really successful human transplant now i’m not saying that surgeons don’t have an incredible input without a surgeon a

Transplant can’t take place but to some extent what the surgeon does is like what a plumber does they have to take the relevant parts out from the patient they have to put the new parts in and they have to connect them all very precisely but none of that would work without the chemistry to make sure that the connections don’t go back and it’s these three drugs

That allow transplants to take place so let’s get back to sam how did his transplant go well his transplant was very successful the lungs went in and here’s a picture of sam soon after his transplant had taken place you’ll see that he has a neck line in which is taking lots of the drugs that he requires against rejection also pain-killing drugs and a number of

Other drugs taking them intravenously because at this stage that’s the easiest way to deliver the drugs to the patient well what they do it’s sound after the transplant in terms of their anti-rejection medications is they titrate the patient with the drugs they measure key markers in the immune system they add a certain amount of drug to the patient and they see

What effect it has on the immune system and then they adjust the medication over a long period of time until you’ve got the perfect amount of anti-rejection medication if you use too much of course the patient will get sick all the time from every bug that’s going around if you use too little they’ll reject the organs and ultimately die so now sam’s back home he’s

Been back home for nine months or so this is a picture of his typical daily medication some of which vitamins and supplements some of which are there because they keep him alive on a daily basis to leave you with a happy image so here’s a recent picture of sam taken just a couple of weeks ago and at this point he has a lung function of a hundred and eleven percent

So that’s all the function and more than would be expected of a normal healthy individual of his age there’s never any promises for the future because the chemistry of transplantation is always in a fine balance between rejection and infection but fundamentally you only get a transplant when you have less than two years to live often much less than that and the

Ability of this operation and the chemistry behind it to extend people’s lifespan is really a remarkable story of medicine and chemistry working together so there’s one final thing to say and that’s about organ donation if you’ve not previously thoughts about being an organ donor do here in the uk it’s on an opt-in basis you have to choose to be an organ donor and

It really does save lives more important than just signing the register or carrying the card is make sure your family know your wishes what often happens when somebody unfortunately dies is the next of kin gets asked and even if the person who’s dying wanted to be an organ donor the next of kin often says no and the doctors will usually listen to the next of kin

Even though you have a legal right as the organ donor having expressed your wishes so do have an organ donor card do sign the online register and do make sure your next of kin know if you want your organs to be used to save lives because i can tell you it makes a massive difference so now some thought 111 percent lungs how’s my life change well i can’t keep up

With him anymore and he has an extra 11 percent to nag me with to do things around the house so it’s not all great but overall is absolutely fantastic and i’m so grateful to the surgeons who did the work and to the chemists who developed those drugs in the first place

Transcribed from video
Transplantation – Professor Dave's Amazing Molecules 8 By ProfessorDaveatYork