The Diseased Brain

The most sophisticated eyes in the animal kingdom belong to mantis shrimps a group of extraordinary species that live on coral reefs around the world. In a brand new paper just out, a team of scientists examine just what lies behind these complex eyes and they've uncovered some tricks of nature that could find applications in the cutting edge of modern technology, perhaps spawning a new generation of DVDs and CDs.

Last year, a paper in the journal Current Biology announced the discovery that mantis shrimp can see both linear polarized and circular polarized light. Now a team led by Nicholas Roberts from the University of Bristol have discovered that mantis shrimp eyes do this using special light-sensitive cells that act as a device known as a quarter-wave plate. Essentially these plates convert circular polarized light into linear polarised light. Manmade quarter wave plates are vital components of DVD players and some camera filters, but they don't work nearly as well as the ones that have evolved in the eyes of mantis shrimps.

Normal light behaves like a wave that can vibrate in any direction. In contrast, linear polarized light only vibrates in only one plane. We usually don't see polarized light, although we are aware of it, for example the light that reflects off glass or the surface of a pool of water (putting on polarizing sunglasses cuts out those polarising rays and lets you see through the water).

Circular polarized light behaves like a spiral or a helix. The remarkable mantis shrimps can even tell the difference between circular polarized light spins to the left or to the right.

Not only that, but unlike manmade quarter wave plates that only work well in one colour, mantis shrimp eyes work almost perfectly across the whole visual spectrum from near ultra violet to infra-red.

Leading on from their earlier work, the research team discovered that the receptors that detect circular polarized light are located in a central band across the mantis shrimp eye - their eyes are divided into 3 distinct regions, giving them trinocular vision in each eye and are packed with light-detecting units called omatidia, similar to other invertebrates including insects. They did this essentially by shining polarized light of different types through thin sections of parts of the eye and measuring how well those cells absorbed the light.

Part of the reason why these biological structures work so much better than manmade structures is because they are so tiny - on the nano scale - with components that are smaller than the wavelength of even ultra violet light (10-400nm). That is very challenging to create in manmade structures.

The big question is why on earth do mantis shrimps need such incredibly complex eyes?

There is lots of polarized light bouncing around the clear shallow waters of coral reefs where most mantis shrimps live. Their favourite prey includes small slivery fish whose scales polarize light.

Scientists also think that mantis shrimps might use circular polarized light as a way of secretly communicating with each other. Parts of their bodies reflect circular polarized light, and we so far don't know that any other animal can detect this type of light. So perhaps they send out signals - flashing mating colours maybe - without any fear of being detected by anyone else except another mantis shrimp.

So when it comes to solving technical problems like how to see well in a bright watery world, natural selection has come up with an elegant and simple solution. And perhaps the mantis shrimp will teach us a thing or two about how to build the optical devices of the future.

Ben -   I'm sorry to say that this week, Dave Ansell is actually in bed with a flu, leaving me to handle Kitchen Science all on my own. But luckily, I'll be joined later on by Meera Senthilingam who will help me demonstrate an old experiment that I've known about since I was very little where you can fool your brain into making your body do something very strange. It's a really simple one to try out at home, so do please give it a go. All you need is a doorway and your arms. So, find the doorway, stand in the middle of the doorway, facing in to the room and drop your arms down by your side. Then press the backs of your hand doorframe and push and push and push and push. You need to push for about a minute. It'll start to hurt, it'll feel very uncomfortable, but you need to keep going. And after a minute, all you need to do is step forward and relax your arms.

....

Ben -   Welcome back to Kitchen Science.  Today, I'm having to cope without Dave but I do have a very willing victim.  Sorry, volunteer, Meera Senthilingam.  Hello, Meera.

Meera -   Hello.

Ben -   Now, you've seen this experiment done before, haven't you?

Meera -   Yeah, but a while ago.

Ben -   So then you might have an idea to what's happening, but hopefully will still be a bit of a surprise.  So if you could come with me over to this doorway then we can get you set up.

Meera -   Okay.

Ben -   So, you need to stand in the doorway, facing into the room.  Now this door is actually quite narrow which is kind of perfect for us because you don't want to have to lift your arms too much.  If your door is a lot wider then it might work better to get somebody to put their foot behind the door and just make the right size space between the door frame and the door itself.  But here, there's maybe 6 inches maybe either side of your hand, so that's pretty much perfect.  You feel comfortable standing in the doorway?

Meera -   Yeah.  As comfortable as you can be in a doorway.

Ben -   And now the next thing to do is put your arms down by your sides and then just  and place the backs of your hands against the doorway.  So they're level with your hips and pushing out on the door.

Meera -   Okay.

Ben -   Now, here's the tricky bit.  What I need you to do now is to push outwards on the door frame, as hard as you're comfortable with and you're going to have to do this for about a minute.  So, when you're ready, start pushing.

Meera -   Okay.

Ben -   Well I can see from your face that you are genuinely putting some effort in here.  Now the thing with this is initially doesn't feel too bad.  You're just pushing out against the doorway and nothing really feels like its happening.  But then after, probably about this much time, it actually starts to get quite uncomfortable.  But don't stop.  Do keep pushing.  How are you feeling?

Meera -   Uncomfortable, but I'm trying.  I'm trying.  I'm concentrating.

Ben -   Well we still have to go for a little bit longer yet so I may as well distract you by explaining what's going on in your brain.  Now your brain sends messages to different groups of muscles, telling some to relax and some to contract in order to create the movement that you need.  Right now, certain muscle groups will be contracting as hard as they can to try and push out against the door.  But obviously, they're not doing very well unless you have a very flimsy house.  In which case, you may have broken your own doorway.  How are you feeling now?

Meera -   It's quite painful actually and is it okay that my arms are actually shaking a little bit?

Ben -   The shaking I think is just evidence that you're really putting in the effort to it.  I think you've probably had long enough now.  So what I need you to do, when I say go, I need you to step forward and just relax your arms completely.  So, are you ready?

Meera -   Okay.

Ben -   Go.

[Meera's arms mysteriously rise up from her sides - without her trying to do so]

Meera -   My arms!  Okay.  That was quite cool.

Ben -   And you do look a bit like you're sleep walking now as your arms appear to be stuck out in front of you.  But how does it feel?

Meera -   It feels completely normal.  Like it doesn't feel that my arms have raised at all.  It just feels that they're just dangling and I can actually just happen to see them in front of my face.

Ben -   And normally, if were to hold your arms out in front of you, it would actually take some effort.  But does this position feel like you're totally relaxed and this is where your arms are supposed to be?

Meera -   Yeah.  Basically, as if I was in a swimming pool or something and my hands were just sitting on top of the water.  That's what it feels like.

Ben -   Well, what's actually happening to your arms has, until very recently, been a bit of a mystery.  Back in the 1920s, people knew about this experiment but they assumed that it was all to do with the spinal cord.  Because there are nerve clusters that control the length of muscle and so they assume that the spine was involved.  But now, in a very new paper that came out in September in the journal Brain Research, Amy Parkinson and her colleagues have actually done this very experiment inside a brain scanner to have a look at what's going on.  Now they compared scans of people making this movement on purpose, to people doing it exactly how we've just done, pressing against something for a while and then this involuntary movement happening afterwards.

If people had been right in the '20s and it was a spinal cord only issue, then you'd see very little brain activity or certainly nothing significant compared to normal.  But what they found was significant brain activity in the areas that were concerned with making and planning movements.  And they found this activity just before the movement happened.  So this wasn't a response to the fact that your arm was moving of its own accord.  This really was the effect that made it happen.  They also did find some activity in the brain that happened after the movement and this suggested that that was a response to the fact that your arm was involuntarily moving. 

One of the bits they did find quite a lot of activity in is called the cerebellum.  Now this is what's responsible for motor learning and error corrections.  So it must have learned while you were pushing out.  That your arm was apparently supposed to be shorter than it really is and that's why the muscles contracted and your arms rose up at their own accord.

This is very similar to an experiment that we did a little while ago on The Naked Scientists where we put special prismatic glasses on.  These shift your vision 10 degrees to one side and then when you try and throw and catch a ball, initially, you're totally useless until your cerebellum kicks in and corrects for the fact that when you thought you'd thrown it in one direction, your eyes tell you you're throwing it in a different direction.  After a little while, you can throw and catch because the cerebellum has done its job.

Meera -   I actually remember having a go on that around the office and it did adapt really quickly.  I was really surprised.

Ben -   It's strange and frustrating when you take the glasses off again and you find that you can't throw and catch for a little while.

Meera -   Yeah, but I'm not amazing at that any way, so it's alright.

Ben -   Hopefully, Dave will be back in action for another Kitchen Science next week.

We'd like to say huge thank you to Dr. Ellie Dommet at the Open University and Professor Patrick Haggard at UCL for helping out with this week's experiment.

One of the most important neurological diseases is one called Huntington's disease.  It affects about 8 in every 100,000 people here in the UK.  It's a genetic disorder and people tend to get the disease symptoms by the time they're aged about 40 or 50.  It affects a person's ability to move and also impairs cognition and behavioural processes, especially in the later stages of the illness. Research is on-going currently to try work out why Huntington's disease occurs, why people get the symptoms they do and whether we can reverse, or at least arrest the process.  One of the scientists studying Huntington's disease is Ed Wild; he's based at University College London's Institute of Neurology. He's interested in how the disease affects the functioning of the immune system, and what role that might play in the disease. He spoke to Chris Smith about this work, beginning with the genetics of Huntington's disease...

Ed -   We're quite lucky in Huntington's disease research because the genetics is quite well worked out and we've known what the gene is that causes Huntington's disease since 1993, after a massive international research collaboration to look for it.  And that in many ways, puts us at a bit of an advantage over other brain disease like Alzheimer's which we'll be hearing about later on, motor neuron disease, Parkinson's disease where there are genes that are known to influence the disease.  But in Huntington's disease, we know exactly what gene causes it.  It has two names.  One is the Huntington gene and the other is IT15 which stood for Interesting Transcript-15 which is perhaps the genetic understatement of the '90s.  And this is a gene that encodes for a protein called Huntingtin.  So the gene is the recipe for this Huntingtin protein.  We've known about this now for 16 years.  We know a lot of things that a Huntingtin protein does but it's still a very mysterious protein.  It's a very big protein and it's one that's very difficult to work with.

Chris -   Do we understand at all about why it is that it causes the very discreet symptoms it does?  I mentioned some of them.  People with Huntington's first of all tend to notice that their movements go a bit array and then they start to get other symptoms as well and this takes up to 40 years before it manifests itself.  So why is that and why are there these very discreet changes to people's movements and behaviour?

Ed -   Well, what we do know about HD is that the bit of the brain that's affected earliest, at least as far as we can tell, looking at it under microscopes or with brain scans, is the basal ganglia.  And those are the sort of deep grey matter structures down in the brain that have very important stop-go and coordinating functions for movements.  And so, one of the characteristic features of Huntington's is a phenomenon called Chorea which is from the Greek word for dancing.  That's where we get the word choreography from.  And that's because patients with HD almost invariably get these unusual dancing like movements, involuntary movements of the arms and legs, and face.  On top of that though, they get problems with voluntary movements.  They lose their voluntary movements, a bit like what you see in Parkinson's disease.

Chris -   Is this because they're actually physically losing brain cells?  And if so, what's going on in the cells that are dying?  Why are they dying?

Ed -   Well, that's the million dollar question for HD families.  We know lots of things are going on, but at the moment, there's no clear consensus on what the most important function of the Huntington protein is, that makes the cells die.  What we're certain about though is that the cells are unhappy or dysfunctional for many years before they die.  And that's good news because it means if we can reverse that dysfunction, we could potentially prevent patients who we know have the mutation from going on to develop the disease.  But exactly, you know, what the processes are that are going on in the cells, we know that there are lots of them.  But, exactly what the balance of problems is, is unclear at the moment.

Chris -   Interestingly, not all brain cells seem to be vulnerable to the same extent though, do they?  So do we know why some cells seem to perish and others are less affected?

Ed -   No.  that's a really important question and as I say, we know that the cells of the basal ganglia, the striatum are selectively involved early on.  What's weird though is that those aren't necessarily the cells where, under the microscope, you see the most accumulation of the abnormal Huntingtin protein that's seen throughout the brain, but the striatum doesn't seem to display a lot of that.  And there are various theories as to why this might be.  Probably, the most popular theory is that those cells receive a lot of inputs from other areas of brain.  So those are incredibly busy cells, very metabolically active cells and they're connected to a lot of other cells, and it may well be that there's a phenomenon called excitotoxicity going on where the cells get too many inputs.  And that tips them over into the balance of not being able to cope because they were unhappy already because of having the abnormal protein floating around. But there's another theory which is that - and this goes to the heart of the mutation that causes HD - It's unlike other mutations where it's a single spelling mistake.  You know, changing one DNA letter to another.  This is a genetic mutation in which one word, one three-letter word, CAG is repeated again, and again, and again, too many times, and that causes the protein to take on an abnormal shape.  And the striatum does seem to contain cells with even more abnormal repeats than the rest of the brain and that may be one reason why it has this selective vulnerability early on in the disease.

Chris -   And looking outside the brain, you're interested in the immune system because of course, this gene isn't just turned on the brain.  It's turned on in other cells in the body too.  So how does it affect immune function?

Ed -   Well, that's right.  The gene and the protein have been found to be expressed basically everywhere that they've been looked for.  And what we did was to look in the blood of HD patients.  We're looking for biomarkers, things that can be used to measure from the outside, what's happening to a patient's brain on the inside.  And we need, basically, accessible tissues.  You can't go diving into someone's brain so we look in blood to see if we can find changes due to the gene.  And what we found quite surprisingly, we weren't really looking for it, but what we stumbled on almost was a signature of immune activation that the cells, that the blood of HD patients contains a signature of cytokine proteins that suggests that the patient is in a sort of chronic inflammatory state.  The immune system is overactive and we did a bit of detective work to try and figure out what the relationship was between the gene that causes the disease and the cytokine production.  And we think that we've identified that it's actually the white blood cells which are expressing the gene and that in some way makes them over active.  They become hyperactive and we've detected that in the blood.  Meanwhile, our collaborators in Washington and the US have been looking at expression of these cytokine proteins in brain and found that they're over-expressed in HD brain as well.  So there seems to be a sort of commonality between the brain and the blood there.

Chris -   And just to finish Ed, does that mean then potentially that some of the pathology could be because the immune system is attacking cells and making the situation worse or it could be triggering the cells to become diseased or is this just literally a red herring?  The immune system has these useful predictive markers that tell you what the state of the brain is, but they're not in themselves bound up with what's going on with the brain.

Ed -   I think at the very least, it suggests that these might be useful as markers, but I think - to be honest, I think there is more to it than that because a number of people have looked at trying to adjust the immune system in HD in the brain.  And have produced some very promising results showing that if you can damp down certain pathways involving the microglial cells, the immune cells of the brain, you can produce quite a dramatic survival effect on HD mice.  So it seems that the microglial, immune cells of the brain are acting as policemen which are having a useful effect early on in the disease but later on as sort of becoming a rather unruly bunch of riot policemen, hitting innocent civilians in the face and doing more harm than good.

Helen -   Now, Alzheimer's disease is the most common form of dementia, mostly in the elderly, and a great deal of research is underway to understand, treat, and try and prevent Alzheimer's.  But there are currently no effective treatments for it.  Now Professor Julie Williams and her team at Cardiff University recently discovered a pair of genes that seem to be link to Alzheimer's.  And she joins us now.  Hello, Julie.

Julie -   Hello, Helen.

Helen -   Thanks for coming along on the show.  First of all, just what causes Alzheimer's?

Julie -   Well, Alzheimer's is caused by genetic and non-genetic factors.  We know that there are three genes already that contribute to and cause rare forms of Alzheimer's disease and one gene that increases risk of developing the common form of Alzheimer's disease.  And that's the position we were at before we publish our research. 

Helen - And do we know what's going on inside the brain when people have Alzheimer's?  What's the problem there?

Julie - Well, we know there are certain markers of the disease.  So, you see in the brains of Alzheimer's cases, plaques that are made up of what we call beta-amyloid mainly and these occur outside the dying brain cells.  Within these brain cells that are dying, you see tangles made up of microtubules.  So those are the two markers there.  But what exactly is going on is still a basic mystery for us.

Helen -   So we have these plaques of beta-amyloid and that's a type of protein, isn't it?

Julie -   Yes.

Helen -   Yes and do we have any idea now, how these genes now might be involved in those markers, those plaques that we're finding in the brains of people with Alzheimer's?

Julie -   Okay.  The rare forms, the forms that are contributed to by single gene defects, these occur in genes known as APP and the pre-sinilins, these we know affect the amount of beta-amyloid that occurs in the brain.  But what we don't know is, is that the same process for those with the more common form of Alzheimer's disease?  And our results will actually tend to support a different, slightly different, process involved in common Alzheimer's disease compared to the rare forms that we've known about for some years.

Helen -   So what do we think is going on in that common form of Alzheimer's?

Julie -   Okay.  What our research has shown is that we identified two new genes that increased risk of developing common Alzheimer's disease.  The genes are clusterin and PICALM.  And when we put our data are studied together with a French study.  We now have definitely three new genes and an additional fourth new gene.  And this is opening up new ideas about what actually causes the more common form of Alzheimer's disease.

Helen -   And how did you find that association?  Did you go out and look at people who got Alzheimer's and look at the genes they have and compar that amongst the population and discover these, sort of, unique genes that might lead to the condition?

Julie -   That was exactly right.  But it was quite a large experiment and we looked at the genes of 4,000 individuals with Alzheimer's disease and compared over half a million individual variations in each of those individuals, and compared those to 8,000 individuals without Alzheimer's disease.  So this is the biggest study of its type, currently published.

Helen -   And do we have any idea what these genes normally do and what might be going wrong in the people who got Alzheimer's?

Julie -   Okay, some of these genes are involved in a theme that's developing in this program of inflammation which surprised us to some extent.  So, the compliment receptor gene, clusterin, is involved in protecting the brain through the inflammatory response, the classical compliment system.  And what this is telling us is that inflammation is a primary event in the disease production.  We had known for a number of years that you see markers of inflammation within the brains of Alzheimer's individuals.  We thought this was secondary to the amyloid plaques for example.  But this appears now to be a primary element in disease production.  The other element is cholesterol.  We see a lot more genes involved in cholesterol and sterol, and we really don't what they are doing but we do know that they are playing a crucial role in disease development.

We posed this question to Julie Williams from the University of Cardiff...Julie - Alright. I think it probably is a general problem. Learning, you probably need to have well activated nerve cells to create the synapses to learn new information. So I think this probably could be affected by stress. So I would say it's a general problem. Chris - Because one other thing that people have realized is that the hormones that make our stress cortisol, there are receptors for those chemicals in the brain, and they do seem to cause damage if they're present chronically to those parts of the brain, particularly the hippocampus which is concerned with making memories. So maybe that's part of the manifestation, Julie. Julie - We also know that people who have had major depression throughout their lifetime or bipolar disorder tend to have a highly - a slightly higher risk of developing Alzheimer's disease at later life. This could be due to the medication they take or it could be due to the actual process of depression. So there are some areas of support for that.

Absolutely. People talk about this blood-brain barrier. This notional structure which in some way keeps the brain isolated, cocooned inside you biochemically and physically-away from what's happenign in you blood stream and it;s absolutely true. The history of the blood brain barrier goes back a hundred and something years to a guy called Paul Ehrlich, who was a German scientist, he was interested in dyes initially. He used to inject dyes inot animals and then see which bits of the body got stained. andhe was intrigued to see that when he put dyes into the blood stream, much of the time the dye did not get into the brain. And so he realised there must be some kind of barrier separating what goes round in the blood stream from the delicate issue inside the brain. We not understand more about what this blood-brain barrier is. It's a bit contrived, what what's going on is that you basically have special junctions between ceels that line the surfaces of the brain, that separate the brain tissue from blood vessels and these cells make very tight junctions, that's what they're called, and this effecttively means that there's a barrier which is the membranes of those cells separating what's in the blood stream from what's in the blood tissue. And what this means is that certain substances can move very easily into the brain, especially if they're substances that can dissolve well in fat, because of course the membranes of cells are made of fat. So lipid-solube drugs like heroin, cigarettes-nictone, cocaine, they're very oily molecules. they go into the brain beautifully and that's why they tend to be addictive. Because they move preferentially into fatty tissue like the brain. Other substances which don't dissolve in fat very well, don't get into the brain very well. But there are some exceptions. Those exceptions are things that the brain needs. So sometimes if it needs a certain chemical that wouldn't be able to diffuse in very easily, it has special transporters which can scrutinise what is going past in the blood, grab goodies that it wants and move those into the brain. This is what people found when they were giving the drug L-Dopa for Parkinson's Disease. -Dop is an amino acid, dissolves in water, doesn't dissolve in brain tissue very well but it gets into the brain much betetr than it should do and the reaon is theer are these special transporters that get hold of it and shove it into the brain.