How to Save a Life

Scientists in Ireland may have found a new way to stop an individual developing Alzheimer's Disease. Alzheimer's occurs owing to a build up in the brain of a toxic material called amyloid beta, which kills nerve cells. Reducing the levels of amyloid beta in the brain should therefore cut the risk of Alzheimer's occurring. Researcher Matthew Campbell has found a way to do this by deactivating two molecules - called claudin-5 and occludin - which control the "blood brain barrier". Temporarily disarming the barrier allows the beta amyloid to be carried away harmlessly in the bloodstream. He explained his findings to Chris Smith.

Matthew - In our brains at the moment, we are producing amyloid beta and it's able to get out of the brain via the blood-brain barrier. Something is happening in Alzheimer's disease that is preventing this material from getting out of the brain. In patients who have Alzheimer's disease, this material builds up to such an extent that it eventually begins to kill brain cells. If they're the cells that allow you to make memories, that allow you store memories, well then those memories would be gone forever and they won't come back.

Chris - What do you think is governing that process then and why does it go wrong?

Matthew - In all our blood vessels in our body, there are cells that we term 'endothelial cells'. There are specific - what we term 'receptors' on the endothelial cells and what these receptors do is they allow for material to remove from brain to blood and blood back into the brain. Now, in ageing, we lose the potential to be able to transfer this material from brain into blood and blood into brain. And some people for whatever reason, we still aren't fully certain, are more susceptible to these processes slowing down.

Chris - So, what have you found now that might influence that process?

Matthew - What we've discovered for the first time is that this molecule - amyloid beta - itself can open up these junctions between endothelial cells and facilitate its own movement from brain back into blood.

Chris - How does the amyloid beta open up the blood-brain barrier?

Matthew - In effect, what we've discovered is that amyloid beta can itself decrease the levels of these two components. One of them is called claudin-5, the other one is called occludin. These components hold endothelial cells together very, very tightly. If we can now go ahead and design drugs that specifically target these molecules, it could lead to a therapy that could allow for the clearance of amyloid beta from brain to blood in the context of Alzheimer's disease.

Chris - Summarising that then, the brain makes amyloid beta. Normally, this would exit harmlessly into the bloodstream. It probably is doing that, you're saying because it stimulates the blood-brain barrier to open up a little bit for some reason this process goes wrong in people who are destined to develop Alzheimer's disease. But if we could crowbar-open the blood-brain barrier again, we might be able to encourage this stuff to come back out of the brain. It wouldn't accumulate and that should stop someone developing Alzheimer's disease at such a high rate as they would've done.

Matthew - Exactly. So, what we need to do when we're thinking of therapies is to get in pre-emptively before the damage has gone to such an extent that the cells that we're trying to preserve have actually died.

Chris - How do you know this is going to work?

Matthew - We have mice that have genes that cause Alzheimer's disease. So, we have shown in these animals that we control claudin-5 and occludin levels. Over time, we can decrease the levels of amyloid beta in their brains and lead to better cognitive performance in these mice as well. We also recently have data from a non-human primate study whereby we've shown that the molecule that we use that targets these molecules, claudin-5 and occludin, is very, very safe when it's administered into a vein of a larger animal such as a non-human primate. So, it gives us a lot of hope that we're on to something here that this could be a new form of therapy for Alzheimer's.

Chris - Is there not though a potential risk of there being a problem because the blood-brain barrier is being rendered deficient or defective by what you're doing?

Matthew - It's a really, really good point and it's something we have to be very, very acutely aware of as we move towards clinical deployment of this. But we've dosed some animals for up to a year with the material that modulates the blood-brain barrier. There's very, very limited effects in the animals. The safety profile of this approach is very, very strong. So, we have a lot of hope that it's actually quite safe.

Chris - It's very encouraging, isn't it? That was Matthew Campbell from Trinity College Dublin, describing the study that he's published this week in Science Advances.

A coating that can make an object appear "disappear" has been developed by scientists in the US. Science writer Mark Peplow has been taking a look at how it works. He revealed all to Chris Smith. 

Mark - It's Harry Potter time again, Chris! Researchers in California have created a tiny invisibility cloak which seems to be more effective at concealing objects than previous attempts to make these sorts of things. Because scientists have been working on invisibility cloaks since the mid-2000s. Many of them depend on meta materials. As light passes through them, it actually bends back on itself almost as if it was being reflected by mirror. So in theory, you cover an object with these materials and light from behind the object is bent around to the front so it looks as though the object isn't there anymore.

Chris - So, what was the problem with those particular formulations?

Mark - They tend to be relatively bulky compared to the objects that they're concealing. They were really difficult to make and they're very hard to scale up to work for everyday objects. Crucially, they change the phase of the light coming through. So, if you think of a light wave, the sort of peaks and troughs going up and down, in that exiting light wave, peaks have become troughs and vice versa. Now, it's pretty easy for instruments to see that phase change. So, if you really wanted to detect something that was being cloaked, it will be very easy to spot it because you can see this characteristic phase change. But these scientists at Berkeley say they have a solution to actually many of these problems. They made a small 3D object which is actually only the width of like a fine blonde hair. It's about 36 microns across and then they covered it in thin layers of gold and magnesium fluoride and topped it off with tiny pillars of gold that sit pround of the surface just about 30 nanometres high. Now, these act as antennae that reroute light around the object. Crucially, they also ensure that a phase of the light is unchanged. So the result, abra cadabra! The object disappears.

Chris - Does it really disappear? I mean, it sounds like it could be ideal if you have a head of hair with one hair on it and you've got your root showing or something. But no, could you scale this? Could you crucially make a big version of this to do something practical?

Mark - Well, that's one of the things that they're suggesting is different about their technique. They made them using electron beam lithography which is widely used in the semiconductor industry to make computer chips. They point out that you can do this sort of nanofabrication on meta long sheets now and their calculations, although they haven't done it yet suggests that you don't have to directly coat the object with this cloak. You could make a free-standing cloak that could be draped over it. For the moment, one of the main drawbacks is that this only works well with red lights. So again, that's a key thing that they are going to be working on in the future to try and make this work across the visible spectrum.

Chris - Why does it work at all and why does it get around that problem of not flipping the light waves back to front like the previous tries that people have had at making these things?

Mark - It's because it's bending the light in a slightly different way. The thing with the nano antennae is that the light is interacting with them and it's causing, if you like, ripples in the electrical charge around the surface of these nano antennae. Those ripples are what are then producing a beam of light which sort of shoots out. So, it's a slightly different process of channelling the light. If you like, it's translating the light from being light to being an electrical wave on the surface and then back out again as light.

Chris - Do you think they will be able to surmount the colour issue? I presume this comes down to how big those antennae are on the surface because a red light wave is much bigger than a smaller blue light wave. So, can they get around that?

Mark - That's exactly right, Chris. What they might have to do for example is tailor different sizes of nano antennae so that you're having some with one shape, some are a little bigger, some are a little smaller so that they can cope with different wavelengths of light to have this same effect overall. It's not impossible to do. It makes it more complex to make this. So, it remains to be seeing whether they can do that or not.

From the moment an emergency call is made, doctors and paramedics are in a race against the clock. Every second counts, meaning medical pioneers are continuously trying to pushing the boundaries of what's possible, from open chest surgery on the roadside to using a balloon to stop internal bleeding. Graihagh Jackson went to see some of these pioneering treatments in action with Dr Gareth Davies, Medical Director at London's Air Ambulance...

Gareth - In London area, there are literally several thousand 999 calls every day. In amongst those thousands of 999 calls, there's probably 5, maybe 6 that require the specific interventions and skills of the Air Ambulance team. One of our big tasks is sieving all of those calls to find the needle in a haystack where the patients are so critically injured. They are literally in the dying process.

Graihagh - Is that what distinguishes you from a normal ambulance to - I noticed you've got advanced trauma team on your vehicle. Is that what distinguishes you too?

Gareth - I think that we have additional skills, additional equipment that we bring to the patient's side. So, we effectively try and bring what's inside a hospital right out into the pre-hospital arena where we can start those treatments as early as possible.

Graihagh - I suppose, once you receive that dispatch, the clock is ticking to get to them as fast as possible.

Gareth - For trauma patients, time is of the essence. Seconds and minutes really count. So part of the car checks, is taking all our equipment out of the boot and checking it, make sure it's all absolutely there. There's no point in turning up, waiting for one piece of kit which we don't have.

Graihagh - There's a lot of it.

Gareth - There is a lot of it.

Male - Yeah, it's a bit of a tardis actually.

Gareth - I left Gareth and Richard, our paramedic and driver for this evening to it whilst they checked over what seemed like hundreds of bits of kits. They really did have everything except the kitchen sink. And they wouldn't have needed it anyway because they had sterilisation wipes.

Within an hour, the first 999 dispatch came through. A message popped up on Gareth's tablet, alerting him to the possible injuries that the patient may have.

(Sirens)

Interestingly though, Gareth didn't tell Richard the nature of the dispatch. This is to avoid any possible biases that paramedics may or may not have. For instance, Richard might be inclined to drive faster if he knew a child's life was at stake.

(Gareth directing Richard)

25 minutes later, we arrived at the scene. To protect the confidentiality of the patient, I turned my recorder off and under the same line of thought, I equally can't really describe what I saw. Not that I saw an awful lot because I rather embarrassingly fainted and found myself in an ambulance on the way to a hospital which rather scuppered my plans for this report. But fortunately, I managed to dial-up Gareth later, after I had recovered.

Gareth - Will she just appear in my ear?

Female - Yes, it's ISDN.

Graihagh - I'm here.

Gareth - Hello.

Graihagh - Hello Gareth. How are you?

Gareth - I'm alright. More to the point are you okay? Have you recovered from your trauma?

Graihagh - Yes, thank you. I was rather embarrassed about that.

Gareth - No, you shouldn't be.

Graihagh - So thank you so much for taking such good care of me.

Gareth - Well, I'm glad you're okay.

Graihagh - Back at the scene, I was amazed at not only how calm and collected everyone was but also, how everyone's attitude was extremely soothing. There was a general sense of, "Everything is going to be okay. Don't worry." Despite the fact that doctors like Gareth are sent to scenes just like these because the patient is already dying.

Gareth - Our patients are entering the dying process and they may do that through several ways. It may be as simple as they don't have an airway. Without oxygen, all of the cells in the body will eventually die. Sometimes patients may have problems with their circulation that might be the heart or there may be damage to blood vessels where the blood is simply leaking out. There is a part of the dying process that we haven't touched upon and that is when patients are injured, they release chemicals and those chemicals affect how cells utilise oxygen. They affect how the blood clots. So, there is this sort of hidden part of the disease which no one can physically see but we know is going on. So, we can do it at a macroscopic level with operations and what have you, but what's going on at a chemical level, we're beginning to understand and we're beginning to treat in some ways, but there's still a long way to go.

Graihagh - I'm conscious about keeping this patient anonymous but what can you tell us about the situation?

Gareth - In patients that have fallen from a height, they may be unconscious. They may damage their limbs, they may damage their pelvis. Inside the pelvis, there is a myriad of blood vessels and the minute those blood vessels get damaged they can ooze into the spaces within the pelvis with what is basically uncontrollable haemorrhage because you can't press it like you can press a cut on the skin. They can bleed to death from that. But we can initiate procedures such as REBOA which a new innovation where we can put a balloon in the top of the leg, float it up into the aorta - the main artery and close off that blood vessel temporarily to try and control some of this haemorrhage.

Graihagh - I assume this is something that a paramedic wouldn't be able to do. This is something you, as a doctor can do.

Gareth - Yeah. Some of the procedures are literally operations that would normally take place in the emergency department or in a theatre, so it's pretty high end stuff.

Graihagh - I was going to say, it sounds pretty ground-breaking because what you're describing is surgery on the street.

Gareth - Yes. There are circumstances for example, a patient that may have been stabbed and they have injuries to the heart, we can literally open the chest and then try and re-animate the heart by doing internal cardiac massage.

Graihagh - Once you have stabilised your patient, what happens next?

Gareth - As soon as we have established that position, we will always make our way to a hospital. We put in what's called a code red call which identifies to the hospital that they are quite literally bleeding to death.

Sometimes life-saving procedures aren't enough, and there comes a time when a decision has to be made to withdraw treatment and allow a person to die peacefully. Dr Ari Ercole is doctor in the intensive care unit at Addenbrooke's hospital, and he explained to Kat Arney how this decision is made.

Ari - So, these are incredibly difficult and very emotive thoughts and concepts. Intensive care is all about keeping the body alive while treatment succeeds hopefully to sort out the underlying disease, not just trauma but other life threatening infections and various other diseases. Sometimes those diseases are too severe and things become futile. Under those circumstances, that's relatively straightforward if it's clearly futile and the patient isn't going to survive then we shouldn't proceed. There can also be quite difficult situations when in fact, actually, what we may be doing is going against the wishes of the patient if we're not careful. So for example, some patients may arrive at a state of acute or life threatening illness after a long period of chronic illness. Generally speaking in medicine, what the key priority for us as doctors is to think about the autonomy of the patient, what it is the patient would want. Generally speaking, we would never offer or enforce a treatment on someone that they didn't want. The difficulty in intensive care of course is that many of our patients, in fact, most of our patients are unconscious because the disease whereas the necessary treatment induced in coma. And so, what we then have to do is think a little bit about try and understand what patients would find acceptable in terms of their treatment. It's pretty tough being critically ill and it's not necessarily for everybody. Now, the only way we can really find that out is to speak to family, try and understand that particular patient and formulate an opinion of what they were like, what they would want or they would not want.

Kat - In terms of the clinical signs and symptoms that you're looking for, are there particular things where you can say, "I think we should stop now."

Ari - There are some situations. They're probably in the minority where it becomes very obvious. So for example, brain stem death, we know there is no recovery from brain stem death and therefore, we really have to stop. This person has died, their heart may be beating. We're getting oxygen into them because of the life support system, but they cannot recover. But those are probably the minority. One of the difficulties in medicine, it is very often difficult to know exactly what the final outcome is going to be. So, this can pose us with real clinical and ethical decisions. The main thing we have to consider is what that patient would have wanted if we can possibly ask them.

Kat - Once that decision has been reached, that we've come to the end of the road. It's time for this person's treatment to be stopped, what actually would happen then? What sort of processes? I assume that it is not just like you pull the plug out of the wall. What actually happens?

Ari - No, not at all. I think that's the really important point. So, the way I like to look at it is really, we're changing our attention from - we've been trying to prolong life. We've come to a point at which we've realised that actually, what we're doing is we're prolonging death instead of prolonging dying process. And then what we really want to do is change our attention from that physiological support, that life support to thinking very hard about how we can keep people comfortable in the last minutes or hours, or sometimes days of their life. So, it's very much about changing from technology and keeping the patient alive to palliative care and controlling symptoms and keeping them as comfortable as possible.

Kat - And  to end on a slightly more positive note, obviously, we do hear a lot about stories of organ donation when people have ended up in this situation, and have become organ donors, tell me a little bit about that process. How does that decision get made and what happens? Why is it so important?

Ari - Yeah. I mean, for a lot of people, the decision to donate their organs is one that may give some meaning to a death and actually, can improve the quality of lives and survival of a great number of people. So, the organ donation originally arose from sort of brain stem dead patients as donors. These are patients in whom whilst their brain has irreversibly destroyed or damaged, the heart is still beating and with life support, oxygen can get into the lungs and the organs are still well perfused, and survive very well and may be very healthy. In recent times, there've been huge advances in so-called donation after cardiac death. The problem with the heart stopping is of course at the same time that it stops blood getting to the various organs and the organs then also subsequently die. But in situations such as in intensive care where life support is being switched off, and we have some idea about the timing of the heart stopping, it may be possible to organise things in such a way that organ donation may still be possible.

Kat - And sort of very briefly, to encourage people to become organ donors or to think about it and look into the process, what should people do if they think, "Yeah, if the worst should happen, I want to help"?

Ari - There are lots of resources out there and particularly, we've had some huge numbers of different resources. I think more than anything, the most important thing is to make your wishes known, discuss it with your friends and families. If you do feel that you would like to donate your organs then ensure that you're in the donation register.

Kat - We've had a tweet in from listener (Ed Wilson) and he raises a really interesting question. Are organs ever unacceptable for donation if for example if people have been given certain drugs or treatments?

Ari - I would say, that's almost never a consideration whilst it is true that some drugs can cause organ damage, that's almost never severe enough to preclude organ donation.

Kat - Are there any circumstances that do save certain diseases or illnesses that would?

Ari - Some diseases such as cancer can prevent people donating some of their organs. But again, everything is dealt with on an individual basis so it's a matter of looking at each person as individual...

Recovering from a brain injury can be a slow process, taking months or years, but what does it involve, and what outcome can a patient expect? A number of years ago, science communicator James Piercy suffered a severe head injury and has had to rehabilitate himself. He's since made it his mission to use his experience to help others to better understand the process. He started by telling Chris Smith how his life changed forever...

James - I was just out for a normal drive like everybody does every day. A nail punctured the tire of the car that I was in. it spun off the road and hit a tree. So, in a minute, my life kind of changed. I was treated by the East Anglian Air Ambulance at the scene as we kind of heard described earlier on and flown to Addenbrooke's Hospital. When I get to hospital, I'm put in a CT scanner and they find that there's really quite a severe injury actually to my brain.

Chris - What does the scan look like? Which bit of your brain is affected?

James - The most obvious thing you can see when you look at the picture and I have looked at the picture a lot, it's quite a large area of bruising and bleeding. Now often in brain injuries, you might have a haemorrhage, kind of on the surface of the brain or just outside the membranes around the brain. And in most cases, you'd have a surgery to remove that blood. My injury actually was intercerebral, actually, inside the brain so it wasn't treated. But it's very important to make sure that it's not going to get worse. So, I have got a little whole drilled in the top of my head and they use that to monitor the pressure and the blood flow inside the brain. The real problem after a serious brain injury is that things can get worse. There's nothing you can do really about the initial injury, but you can give treatment to stop things getting worse inside the brain.

Chris - I suppose we should emphasise here that because your skull is a sealed space, if the brain swells, there's nowhere for it to swell into because it presses on the skull and that can obviously compound the injury that's already been done.

James - Well, that's right and also, that increased pressure then will restrict blood flow to other areas of the brain. So, we get this hypoxia, this lack of oxygen to certain parts of the brain and then that's what causes these secondary injuries.

Chris - When did you first become aware that you'd ended up out of the car accident and you were in a hospital?

James - Yeah, I don't know. It's not like in the movies where you suddenly wake up and realise what's going on. I had a prolonged period of post traumatic amnesia, so I just couldn't store memories. So, I don't remember waking up. I don't remember being told what had happened to me. I had the kind of more gradual realisation that I was in a hospital and really, not very well.

Chris - How has it affected you?

James - I've had to learn over the last 4 years or so that I need to slow down. I can't do things at the pace that I used to do. I can do everything that I used to do but it takes longer, and it's much harder work. So the biggest change I've had to make in my life really is to plan things. I need to know in advance what I'm doing and when I'm doing it.

Chris - How long did it take you to realise the constraints that you were facing in terms of what you used to be able to do and what you now could do?

James - Probably, 6, 8 months, but yeah, my family would say, "He hasn't learned yet" because I still push myself too hard sometimes because I expect to be able to do things that I've done for 40 years.

Chris - What did you do to recover or rehabilitate yourself from your injury?

James - Mostly, I just had to try and do things. I had quite a bit of support from professionals when I was in the hospital and a little bit as an outpatient afterwards, just really trying to do everyday things - so making cups of tea and beans on toast and normal things. What I had to really push myself to do is the things that were normal for me - so trying to get back to work, so using the computer, cooking the kid's dinner at the end of the day.

Chris - A person who is pushing themselves to do things like you did, what is that doing to the brain in order to promote recovery?

James - What we need to do really is relearn and when we're learning things as young children, we're reinforcing these neural pathways in the brain, making connections that the neurotransmitters will pass along from cells in the brain and we're just reinforcing new pathways. So, repeating actions continuously and pushing is hopefully cementing and reinforcing these new pathways in the brain and helping us to learn stuff.

Chris - Some people characteristically get much better outcomes than others, don't they? Have you any instinct for what makes that difference?

James - It's kind of a big unknown around brain injury really. There's some fascinating research which came out in 2014 building on an idea of something called cognitive reserve. The idea of cognitive reserve is that some people have this kind of backup if you like, enhanced ability to relearn things. So, this study used number of years of education as a kind of proxy measure for this cognitive reserve. The thinking being that the longer you've spent learning stuff, the better you ought to be at learning new stuff or relearning things. What they found was a really dramatic result. People who had done further in higher education, been through a university, had a huge increased chance of having made a good recovery after 6 months, something like 6 times the chance of a better recovery. So, using your brain seems to help it recover after injury.

Chris - In your case, have you been able to recover pretty much all your function or a bit with some limitation, you can hold down a job and go about your life in a happy go lucky way?

James - I can do everything that I used to be able to do, but everything takes me a bit longer and I still suffer enormously from cognitive fatigue. So, things that are very taxing on the brain will get me literally really very tired. So, going to supermarket, sort of very busy, noisy environment, 6 million different kinds of baked beans to choose from and banging trolleys into, that will leave me really exhausted. There was an interesting study. They put some people in fMRI scanners and got them to carry out simple tasks and compared the brain activation of people with brain injury to those without. And they found that the brains of people who have had an injury were actually more active. They're literally working harder to do the same tasks. So, that may explain this kind of problem of fatigue.

Chris - What would be your advice to somebody who may find themselves in the same position as you and what would you urge them to do?

James - It's easy to say, "Just have a go and try and do stuff" but you need to give that caveat of, "Don't try and do too much too soon". A common story is pushing too hard, trying to go back to work too soon and not being able to cope, and then having a huge kind of psychological effect of failure really. So, try things, do things, but accept that you will have limitations and you're never going to be back to the same person that you were before. It's really very unusual for people to make 100 per cent recovery and be the same as they were before their injury. But you can get close to it and you can embrace the new you and run with that.