Good afternoon everybody and thank you very much for coming along to this lecture. And what I hope we would achieve in the next 30 minutes or so is that I try and convince you that instead of just using the eye to look outside your bodies at the world, we can actually use the eye to look within at the brain. So just starting off with a few fundamental things, what do we know about vision? And what do we know about the eye and the brain? Well, when you see something, it actually is a very very complicated route to how we actually perceive an image in the end. So over here you can see what has happened is a signal from the eye travels along to in fact part of the brain called the thalamus and from there it goes to the cortex at the back of the brain called the occipital cortex, which is where you actually see your image. In fact, there have been people who’ve used art to try to depict this and this is just one of the many paintings around showing that actually if you didn’t have the brain or even that particular part of the brain, you wouldn’t be able to see anything at all, you wouldn’t be able to perceive an image.
So the brain is obviously terribly important for vision as you know for a lot of other things as well. And these are all pathways that basically require the same intrinsic structures. What do I mean by that? Well, you may or not have seen this sort of assimilation before but each of these round bodies that you can see on the screen is a single nerve cell and what’s happening is they’re sending signals to each other. So in that long pathway, I showed you, between the eye and the brain, there is a series of events that have to occur and go in a very ordered fashion so that the signals are received in time to actually present to us something that our brain understands, and we perceive as an image. And within this process, you see synapses where you have chemicals releasing to allow the signals to occur. So this is a very complex part of our beings and obviously it would be great if we could actually see these processes before our very eyes. Well, we can in the retina. It is the only part of the body that you can see individual cells, individual nerve cells functioning in their normal environment.
So let’s go back a bit to the eye because I’ve talked about the brain, I’ve talked about the eye sending messages to the brain. But how actually does it occur? Well if you imagine this as a camera, as I’m sure you’ve heard the analogy many times before, what happens is a light has to pass to the back of the eye, which is the retina, which forms the film of the eye and it stimulates a particular cell called the photoreceptor cell and that cell, in turn, fires off a whole series of cells till eventually, you get a nerve conducted back to the brain. So this is a section of the eye seen histologically, just to bring this notion a little bit clearer. And it consists of 5 different types of nerve cells, all very similar to the nerve cells that you see in the brain. But again I will emphasize that the eye is the only place in the body because it’s transparent, you see, just as you’re using it to create an image to the brain because of its transparency, you can actually use that same transparent properties to image. And that basically is the fundamentals of the lecture today.
Well, it’s unique because you can’t do that in the brain. This is an x-ray of the brain and what gets in the way? Well it’s obvious isn’t it? It’s the skull, the bone. And if you could see the individual cells it’d be terribly helpful but you know there are other techniques and you may have all been aware of these. I hope you all haven’t had one of these but it’s a very complex piece of machinery. Anyone who’s been in one, I don’t know if anyone has been in one here, will tell you that an MRI scanner is very claustrophobic, as is a PET scanner. And yet to date, if you want to see signals in the brain, that’s the way you have to do it. So just to show you historically, this is a CT head scan, this is the first time we were able to image the brain. This is an MRI scanner, this is a PET and this is a functional MRI where you’re seeing brain activities. But notice, it’s clumps of activities, so you cannot individually see the cells working.
So can we use the eye as a window into the brain? Well, I’ve explained to you that we can take advantage of the fact that you have the transparent media to help you. And if you are readers of the Daily Mail and if I can ask you to avert your eyes from Beyonce, if I can possibly do that at this time of the day, this is the headline that we managed to get earlier this year. This is from the research from our group which showed for the first time that it may indeed be possible to try and use the eye to pick up early Alzheimer’s disease. And I’ll discuss that in a little more detail as we go along.
But let’s just start off with another premise which is what I often say to medical students and to ophthalmologists and try to convince my neurology colleagues that the eye is an extension of the brain. Is there any evidence of that? Well, the best evidence would come from what we know of the development of the brain, the embryology. From the time you have the first cells in the womb, the very elemental stages. The brain subsequently gets formed through the whole cycle of being in the uterus for 40 weeks so that it’s already specialised by the time the baby is born. But did you know that from the very early development of the brain, you have an out pouching of specialised tissue which is the retina. So the eye is actually formed from the brain even at those stages and that is why the same nerve cells that you find in the brain are found in the eye. So let me put this a different way.
This is yet another video to show you how we can take advantage of this. This is using what’s called an optical coherence tomogram, allowing you to look at the finer details of the retina in a living person. This actually is a caricature here showing you the photoreceptor cells that I’ve already discussed and how maybe in the future it’ll be possible to even show how those photoreceptors work and how they’re eaten away when they’ve done their job. And this is very recent work which has actually only just been published showing you those individual photoreceptors; those cells that I said to you were at the bottom of the retina that picks up the light signals when the light enters the eye. And every small spot that you see here is an individual photoreceptor. There’s nowhere else in the body that you can see this and this is in a human, a living person.
So what else can we do using the eye? Well as Bob Swan told you, I’m actually an ophthalmologist and my specialty is in glaucoma and a lot of the research previously of our group has been based on glaucoma. And in glaucoma, what happens and why patients eventually lose their vision if they’re not well treated is they lose their nerve cells. And this is showing you a model of the disease, where the white spots are the healthy intact retinal nerve cells and over a period of time – and this is a model where pressure is raised in the eye – you see the cells dying off.
Another thing that we have done - and this is our most clinically relevant at work – this started back a few years ago now. What we were trying to do is see if we could identify those cells that were not healthy. Because actually when you’re trying to look at disease, you’re trying to look at pathology, it’s the unhealthy cells, it’s the sick cells that you want to identify because they will tell you whether that patient really has an early disease and whether they are responding to treatment. So this process is really quite simple, it’s based on the fact that cells that undergo a particular form of cell death which is called apoptosis or program cell death, have a specific characteristic where their cell membrane changes and you can label a marker to pick up those cells that are undergoing that disease process.
So over here this is again a model of the disease where you see the white spots indicating cells that are dying through the process of apoptosis. So these are single nerve cells in a living eye. And currently, this work is being funded by the Worldcom Trust. We’re hoping to start our first patient with this very same test. Initially, it’ll be a glaucoma but obviously we are hoping that it’ll be soon used even for Alzheimer’s - to try to use this as a way of picking up early disease and looking to see if we can look at responsive treatments.
Well, what sort of machine do you use to see it? Well, I showed you why the brain is too complex to image very easily. If you compared the machine I showed you, the CT scanner, the MRI scanner, the PET scanner, you have to admit this is much simpler. You can have this in any opticians or optometrists office and its non-evasive and the patient feels particularly comfortable. In fact, quite a few of you may have had a photograph taken on one of these machines because they are in such common usage. I’m using guys from my group – this is Eduardo and this is Joanna. I have to say that I don’t think Joanna has Alzheimer’s disease, she’s still a PhD student but it serves the purpose to show you how easy this is to use.
I’m just going to show you a video over here now because I think to explain Alzheimer’s disease is terribly complex and I think this has a very good message on the mechanisms of the disease:
The human brain is a remarkable organ. Complex chemical and electrical processes take place within our brains that let us speak, move, see, remember, feel emotions and make decisions. Inside a normal healthy brain billions of cells called neurons constantly communicate with one another. They receive messages from each other as electrical charges travel down the axon to the end of the neuron. The electrical charges release chemical messengers called neurotransmitters. The transmitters move across microscopic gaps or synapses between neurons. They bind to receptor sites on the dendrites of the next neuron. This cellular circuitry enables communication within the brain. Healthy neurotransmission is important for the brain to function well. Alzheimer’s disease disrupts this intricate interplay by compromising the ability of neurons to communicate with one another. The disease over time destroys memory and thinking skills. Scientific research has revealed some of the brain changes that take place during Alzheimer’s disease.
Abnormal structures called beta-amyloid plaques and neurofibrillary tangles are classic biological hallmarks of the disease. Plaques form when specific proteins in the neurons of cell membranes are processed differently. Normally, an enzyme called alpha-secretase snips amyloid precursor protein or APP, releasing a fragment. A second enzyme gamma-secretase, also snips APP in another place. These released fragments are thought to benefit neurons. In Alzheimer’s disease, the first cut is made most often by another enzyme beta-secretase. That combined with the cut made by gamma-secretase results in the release of short fragments of APP called beta-amyloid. When these fragments come together, they become toxic and interfere with the function of neurons.
As more fragments are added these oligomers increase in size and become insoluble, eventually forming beta-amyloid plaques. Neurofibrillary tangles are made when a protein called tau is modified. In normal brain cells, tau stabilizes structures critical to the cell’s internal transport system. Nutrients and other cellular cargo are carried up and down the structures called microtubules to all parts of the neuron. In Alzheimer’s disease, abnormal tau separates from the microtubules, causing them to fall apart. Strands of this tau combine to form tangles inside the neuron, disabling the transport system and destroying the cell.
Well, I hope you did find that interesting. There are a few principles in there that I will repeat later on. One is not only the fact that the nerve cells are dying, but that there are two lots of proteins that are implicated – those that are refined in the brain are deposited in Alzheimer patients, plaques which are beta-amyloid and tangles which are made from the protein called tau. So how is Alzheimer’s disease currently diagnosed? It’s a very difficult one and for those of you who have friends or relatives with the disease, you will know that unfortunately despite all the advances that have been made in this area for a long time, it’s the fact that we have a very few objective ways of picking out Alzheimer’s disease until there are very symptomatic patients. And actually, as you know, you don’t want to really identify your patient far down and away, you want to identify them early.
The current way of thinking is in addition to checking a mental state examination to see how cognitively intact your patient is, in other words, what their memory is like, you can do a whole lot of screening tests to omit other causes of the disease. But then you end up relying on scanning and it’s only serial scans – scans that you do over a period of time that really will tell you if the disease is progressing. And sometimes that’s what’s used to help in the diagnosis, and certainly in clinical trials of potential drugs that have these terribly expensive clinical trials for Alzheimer’s disease because you’re relying on these rather soft signs.
But why is it important? Well, you know that our population – our aging population is increasing. These are the expected rates of Alzheimer’s disease over the next few years. And something that I think makes us all well hope that we don’t live too long will be this statistic, that by the time you’re 90, your risk of getting Alzheimer’s disease goes up to 1 in 2. So 50% of the people over the age of 95 are going to develop Alzheimer’s disease. So it’s a significant cause of disability and one of the reasons why that is the case and I have said this already but I will repeat it, is because that by the time we pick up this disease, it’s actually very late and why is that? Well, this is still what we’re searching for. The unmet need in Alzheimer’s disease is a screening test that is sensitive enough to pick up the disease early so that you can actually begin treatments. And there are treatments out there.
If you were to look at the website for clinicaltrials.gov and you actually looked for the keyword Alzheimer’s disease, there is a whole load of neuroprotective treatments that are currently being trialed. But one of the big problems is how do you show that they work very easily. Can the retina be used? I’m not going to review all the literature on this but these two papers perhaps show what I’m trying to say. So we’ve talked about an Alzheimer’s disease that the nerve cells die. And actually there is very good evidence that because the retina is an extension of the brain, that the nerve cells in the retina also die in Alzheimer’s. So this work was back in 1995 by Blanks et al and it shows that if you count the number of nerve cells in post-mortimized patients with Alzheimer’s disease, there is a significantly lower number of nerve cells than in an aged match control.
Now one step beyond that is instead of just looking at the individual nerves, you could also look at the nerve fibers. And so far our imaging technology using the techniques that interestingly is what I apply every day to my glaucoma patients where we measure the thickness of the nerve fibers in the retina of the eye. If you use those same machines to look at Alzheimer patients again there is a significant reduction in the thickness of the nerve fiber layer showing that the retina is involved. What other evidence is there? Well in this day and age there are transgenic models of every disease, the very good models of Alzheimer’s disease show that in the retina itself, the protein beta-amyloid – if you remember back to the video that I showed you earlier that is implicated in the plaque deposition in brains in Alzheimer patients is also deposited in the retina among the nerve cells in the transgenic models.
Likewise, our group has very recently shown that in a different type of transgenic model you see not only an increase in the level of this beta-amyloid but also in the levels of tau. And remember tau was the other protein that is strongly highlighted as a hallmark in Alzheimer brains where it forms the tangles. A very recent paper has been this one which has shown in human-eyes – so this is post-mortem again – that you can actually visualise and pick up the individual beta-amyloid plaques. So the retina is becoming more and more one of the most exciting parts of the human body that can be accessed but also be used to look and hopefully try and identify early disease.
Going back to our own work from the group regarding glaucoma and there are very close parallels with lots of diseases that involve nerve cell loss in the brain as also in the retina, glaucoma is one of them. We’re one of the first groups who showed conclusively that in the retina, where you have this protein beta-amyloid – the plaque protein in Alzheimer’s disease – present in the retina, in the nerve cells you also have apoptosis or cell death. So in other words, in a glaucoma model beta-amyloid is very important and you can identify that where the beta-amyloid is present you have nerve cells dying. Well is that important enough for us to actually pay attention to? Well, this is further evidence from our group. So this is a normal eye and I did describe to you the technique that we’ve given the acronym DAR, which is the detection of apoptosing retinal cells.
This is the technique that is currently going forward to a Phase 1 clinical trial. This is the same technique we’ve applied here to a normal eye, where we were given an injection of beta-amyloid. And you can see in this video here that over a period of time, the beta-amyloid is initiating and causing cell death. Those are the white spots that you can see on the retina. Now I want you to cast your mind back again, to that rather long video that I showed you regarding Alzheimer’s disease and the mechanisms of disease. And there were some key enzymes that you heard in the pathway of making the beta-amyloid.
I don’t know if you can remember, there was one, one was the secretase enzymes that clipped the longer protein. Well in our models what we did was we tried to assess whether treatments that are already currently in use in clinical trials for Alzheimers disease could prevent the cell death in the retina caused by glaucoma. And in this paper what we showed that an antibody to beta-amyloid reduced the number of dead cells quite significantly after just one treatment. So that's an extremely encouraging result because that antibody actually is already on trial in patients. It's a phase 3 trial in Alzheimer's patients, but also we looked at other ways of doing that one is the beta-secretase enzyme that was less effective, but still reduce the number of cells that were dying in the retina. And also congo red which stops the beta-amyloid actually forming the plaques basically when it aggregates. So again, this is encouraging because it's the only place in the body that you can realistically look to see whether the response of treatment is actually changing the course of cell death.
This is another video. This is again, very recent work from our group. It's a living eye once more and instead of just black and white here, we've used different markers of different types or different phases of cell death. So what you're seeing is some cells are dying through a process called necrosis, which is different from what I described earlier, which is apoptosis. Those are the two main forms of cell death and also very importantly, you can judge at what phase of this death process your cell is in and the implications of that is in the very early stages of apoptosis and it's been recently shared by us and other people as well, you can reverse the cell. So the cell doesn't go down that committed pathway of cell death. It can actually go back to its healthy state and that is what we would like. Our treatments to work on are to actually stop the cell from getting unhealthy and reversing to being healthy again.
So I'm just going to gallop through this more than I had intended to but it gives us more time for me to answer questions. I'll end with this the last slide and I'm sure one thing you remember would be the Daily Mail headlines that I showed you probably more for Beyonce rather than our headlines, but the actual data that accompanied that headline was this picture. So this is a transgenic model of Alzheimer's disease wherein green in the retina you are actually seeing cells dying through apoptosis. And that would suggest that we were eyeing the very early stages of disease because in this particular model at the time we were looking at there is very little evidence yet of the symptoms being developed so that they have very few behavioral defects. This is very early on in the natural history. And in this very same model, the other thing that we did show was when we stressed the retina and there are various ways of doing this when we added some sort of stress, we could visualize actually the stress response immediately. We could pick up the fact that the retina under stress had very many more cells undergoing early apoptosis.
Well I’ll end here and I need to thank this all of this work and I've just briefly gone through it rather superficially I'm afraid, is due to some very hard-working people within the group and I've named some of them here. This is us looking fairly happy at our Christmas dinner last year, but I'm particularly indebted to the Welcome Trust. They've actually supported me since 1996 now and the work in the group is very much part of that.
I'll be very happy to take questions if you'd like. Thank you.