This week, Alzheimer’s Disease goes under the microscope: What is it? Why do people get it, and can we cure it? Plus in the news, why the planet needs more trees, a breakthrough in storing computer data, and the science of a good excuse!
In this episode
00:46 - Planting forests for climate change
Planting forests for climate change
with Robin Chazdon, University of Connecticut
As well as cutting carbon emissions to limit climate change, scientists in Switzerland have reported that increasing the amount of forest on the planet should also be a major priority. According to calculations, 1 billion hectares of new forest would lock away over 200 billion tonnes of carbon: that’s enough to keep temperature rises by 2050 to within 1.5 degrees Celsius. But have we got the space for all these trees? And can this really work? The new study suggests that we do and it can, but we need to act fast. University of Connecticut ecologist Robin Chazdon, who wasn't involved in the work, took a look at the figures for us...
Robin - Bringing back about one billion hectares of forest cover would help to limit the effects of global warming to only 1.5 degrees by 2050. This would be additional forest cover because we have lost a tremendous amount of forest cover already.
Chris - What's the proposed mechanism? Because a forest is only a temporary stopgap, isn't it, in the sense that a tree pulls some carbon out of the atmosphere, granted. But, as soon as that tree gets burned or it rots down, the carbon goes straight back into the atmosphere so it's not a permanent way of sequestering carbon like the coal and the oil that we burned and then released the carbon from in the first place...
Robin - That's true. But when you restore a forest you have more than one tree and you have trees that are continually growing over time. So even if individual trees may die you have new trees coming up, and after that forest reaches an equilibrium point then you have more long-term or almost permanent storage unless some disaster happens.
Chris - So how does this sit with what we anticipate human population is doing? Because the reason at the end of the day that we have declining forest cover, is chiefly because humans have gone in there with chainsaws.
Robin - Exactly. I think we need to consider this from a very holistic perspective. In addition to protecting what forests currently remain on our planet we need to find ways to continue to source our products without further deforestation, and we need to replenish forests on land that has been cleared and is currently being used for crops or for grazing land.
Chris - But the human population's going up not down and we can't even feed the ones we have got at the moment. And so you're advocating, or this paper is advocating that we pull even more land back and turn it back into forest, as well as, in some way, feeding an increasingly hungry population?
Robin - I think the key is that, first of all, not all of the cleared land in our planet is being used effectively to produce food and not all that food is getting to the people who need it. It's not just a matter of creating more forests and protecting them, it's also a matter of improving the delivery of agriculture, the sustainability of agriculture, and the distribution of food to needy people.
Chris - So this group are advocating that we need about a billion hectares more forest than we currently have, and that includes recouping some of what's been lost, but does that prediction also take into account land loss owing to climate change? Because if one looks at the models of what we think climate change is going to do to the planet we think that the available land area that we can depend on is going to shrink.
Robin - Yes. And if we don't act quickly to begin to restore the tree cover it's going to become virtually impossible in the future because climate change is already affecting the ability of trees to grow and the ability of forests to remain. And the simulations done in this paper highlight the urgency of beginning restoration and reforestation now. But I would caution that we don't need quick fixes, we need quality fixes. We need intelligent planning and we need to think about the social and economic issues as well, because the new forest cover that we need, needs to endure and it needs to be beneficial. It's not just a question of throwing trees on the ground and planting trees and wishing for the best. I think there's a huge array of social issues and economic issues that also need to be confronted as part of this activity.
Chris - And are people, do you think, politically, internationally on board with this?
Robin - Well, we do have many obstacles and certainly our political leadership in many countries is putting obstacles in place. But there are many grassroots efforts and there are many international organisations and programmes that are getting countries on board. For example, the Bonn challenge which has over 47 countries that have made commitments for restoration within their countries. Over 170 million hectares have been committed and I think as scientists we need to point out what we need to do and how we can do it.
05:56 - Storing data in molecules
Storing data in molecules
with Brenda Rubenstein, Brown University
My first computer hard drive held 10 megabytes of data and it was the size of a shoebox; these days we routinely fit systems with discs that hold a million times that amount but are a fraction of the size. Even so, at the rate we're going, we'll soon be churning out so much data each day that the physical space we need to store it - and the electricity needed to power it - will become a huge problem. At the moment, we convert the data we want to store into a series of 0s and 1s, a bit like computer Morse code, and this sequence is written onto a hard disc. To store more noughts and ones, you need bigger - or more - discs. But Brenda Rubenstein, at Brown University in the US, has come up with a much better way of doing it: using molecules. In this system, the presence of a specific type of molecule in a droplet of liquid equals a 1; the absence of that molecule signals a zero. And because she can mix many different types of molecules together in the same droplet, she can store much more information and in a fraction of the space. To read the information back, she feeds the droplets into an analyser called a mass spectrometer that detects whether a molecule is there or not. She’s using it at the moment to store small images. Ankita Anirban heard how it works...
Brenda - Typically, when we are thinking about data which can be images, it could be text, we usually store that data in a series of zeros and ones. And when we want to store those in different media, basically what we need are two states to represent the zero and the one. We are trying to think about how we can actually store those states, those zeros and ones in the smallest possible volume that we can think of. What we do is we store information in the presence and absence of molecules. If we have a solution, we can either put a very specific identifiable molecule in the solution or we can leave it out. And so by choosing which molecules we put in or out we can encode a string of bits.
Ankita - So how big are your molecules?
Brenda - Our molecules are roughly several angstroms by several nanometres across, so we're talking about areas of nanometres squared or so. However, we can use all different types of molecules so those specifications are for some of the smallest molecules that we're thinking about.
Ankita - So in terms of size, how does that compare to your typical hard drive?
Brenda - The comparison that I love to make is a little 'back of the envelope' calculation that I did a while ago. If we're able to store bytes in absolutely every molecule in a glass of water, for example, that glass of water would be able to store about 10 to the 28 different bits. Now if we scaled that up to what that would mean in terms of hard drives, that same amount of information would require about 200 Empire State Building's worth of hard drives in order to store it.
Ankita - And so how are you actually picking up these molecules which are absolutely tiny and mixing them up?
Brenda - So this is the part that makes me super excited. We've gotten to the point where engineers can essentially create very automated, very fast liquid handling robotics, so our robot can very quickly mix all the molecules that we need to make our information.
Ankita - Once you've mixed up the solution, you've got your image in a liquid form, how do you then get that image back from that?
Brenda - Yeah. So here is where we use some excellent modern technology that's really come along over the past decades, which is mass spectrometry. And the whole idea of mass spectrometry is that this very nice machine can read out the individual masses of all of the molecules in a solution. We know which molecules that we're using to store the information. We run our solution through the mass spectrometer, and then we see if the masses that match up with those molecules actually appear in the spectra that we take, and that allows us to read out exactly what was in our solution to begin with.
Ankita - How long does it take?
Brenda - We've stored images of the scale of tens of bits, all the way to hundreds of thousands of bits, and in order to make these images, it takes on the order for the liquid handling tens of minutes to hours. Some of the limitations there are the speeds it takes to actually mix that many molecules, and the other limitation is really how much can we resolve using mass spectrometry? As we advance those techniques we’ll be able to not only mix more molecules, we also will be able to read out more molecules accurately.
Ankita - This sounds like quite a sophisticated setup you've got in your lab, do you think realistically it's something that everyday people could use in the way that we use say, USB sticks?
Brenda - Yes. Eventually, I foresee that. Now obviously, the technology is young and we are doing this for the purpose of doing basic science to figure out what it is that we need, what are the engineering barriers and so forth. And so once we work these things out like we have, it's actually not that difficult to do and I certainly see these things being miniaturised in the future. Exactly what direction that will take, we'll see as the science proceeds...
11:25 - Non-destructive imaging: helium microscope
Non-destructive imaging: helium microscope
with Paul Dastoor
They say seeing is believing, and the revolution in our understanding of the world and universe around us that came with the invention of the telescope and microscope is hard to over-state. Devices like the electron microscope now mean it’s possible to see what even atoms and molecules look like. But one of the problems with these existing techniques is that you can end up destroying a sample in the course of looking at it. Which is why a new technology being developed at the University of Newcastle in Australia and the University of Cambridge, which uses helium atoms to image things non-destructively looks set to be a game-changer. Naked Scientist Matthew Hall went to see it in action with help from Dr. Paul Dastoor.
Matthew - Imagine you're looking through a microscope, you see something magnificent and decide to zoom in on it, but as you twist the knob you realise you're already at max magnification. This unfortunate circumstance is one of many that plague microscopy, the science of looking at super tiny. In a mission to spread awareness on the varying solutions for these issues, Paul Dastoor from the University of Newcastle in Australia is visiting the UK. Paul is working on a microscope that takes images with helium atoms instead of with light...
Paul - Light can actually damage materials. If we think about what happens to our clothes when we leave them in sunlight for long periods of time, what happens to them? They fade. They fade because the light has enough energy to actually damage the dye molecules in the clothing itself.
Matthew - The reason I made my way into the Cavendish lab was for a new microscopy method - it is called the scanning helium microscope, or SHEM for short, and it operates in a completely different manner to previous microscopes...
Paul - So rather than a charged particle like an electron we are, for the first time, using neutral species - helium atoms.
Matthew - The microscope itself is huge, about the width of a sofa with the main chamber looking like a futuristic barrel to a canon. Lots of little boxes comprise the front of the device as well, allowing for the entire system to be under vacuum. Why is operating in a vacuum so important though?
Paul - In order to create a helium beam, what we have to do is to take helium gas and pump it up to high pressure and allow it to expand through a tiny hole into a vacuum, and that hole is around about 10 microns in size. And when you do that, psst, and you get a beam.
Matthew - That beam then travels to a sample holder where it strikes whatever sample is in its way...
Paul - Its energy is many, many orders of magnitude lower than electrons, even than light, and so there's no chance of the helium atoms damaging the surface at all.
Matthew - The beam then flows through the canon-shaped barrel to a very sensitive helium detector that uses the flux or flow of force from the atoms paired with position data to form an image...
Paul - We pump the helium gas out and then that helium gas can be collected through actually just a large balloon and then recompressed and recycled.
Matthew - Thanks to wave particle duality, a theory in quantum mechanics that says all particles can be represented by wavelengths, helium atoms have their own wavelength. Helium's is absolutely minuscule compared to light's wavelength. This allows for a theoretical maximum resolution of an image taken with helium to be 12,000 times better than the maximum of a light image because the wavelength is 12,000 times smaller than light's.
Paul - We're limited at the moment to a resolution of around about a micron. The next stage of development is to get that now to around about 50 nanometres, and that new instrument is actually being built next door right now.
Matthew - Even with future plans underway to make the resolution much better than it is now, the microscope is still a busy bee in the microscopy community. Up on the screen during my visit were images of a fossilised dinosaur tooth, microscopic glass spheres, and even a live stem cell changing into a different cell type.
Paul - If you want to image them in an electron microscope they are very difficult to image because, of course, electrons are charged, you put them on an insulator, they can't go anywhere. It's like rubbing and balloon on your head, you build up static. So in an electron microscope to image these things you would first have to coat them with gold. You don't actually see what's really there then, you see a coated sample, and for many of these samples they don't want them coated in gold because that means never be able to use them again. And so that's the key point here, we've got a technique that doesn't need to do that and because the helium atoms are electrically neutral, they're not charged.
Matthew - Having the power to image on the nanoscale without damaging a sample has tremendous potential for material and life science research.
Paul - All of science is based on observation. If, when you're actually observing something you change what you look at, how can you be sure of your measurement? The process of measurement should not change what you measure. What we see now here for the first time, I think, is an imaging technique that is guaranteed not to damage what we look at.
Can plants think?
with Howard Griffiths
This week an opinion article published in the journal Trends in Plant Science, argues that plants are not conscious, in other words they are not aware of their surroundings in an intelligent way. Well so what? Surely everybody knows that plants are not conscious already? In fact the question of whether plants can think, learn, and intentionally choose their actions has been under debate in the plant science community. To try to get to the root of this, Heather Jameson went for a garden stroll with plant scientist Howard Griffiths...
Heather - We’re sitting amongst all these flowers. Are they aware of our presence; are they conscious?
Howard - Well they would be when we shaded them, or when we pulled them up.
Heather - Right, okay. But they're not conscious in the way that we think we're conscious.
Howard - Well that is debatable, but my take on it is that no they are not conscious in the way that we understand intelligent beings to be conscious and capable of making independent decisions.
Heather - And the authors of this paper they would agree with you on that.
Howard - They would, yes. They are arguing that where another paper has suggested that plants can have innate consciousness and intelligence, they argue that this is incorrect.
Heather - One of the studies referenced in the paper apparently demonstrated that plants were capable of learning the association between the occurrence of one event and the anticipation of another event, known as Pavlovian learning. This has been widely demonstrated with dogs. If you always ring a bell when you give a dog food, eventually the dog begins to associate the ringing of the bell with getting food such that the dog salivate when it hears the ringing of a bell without actually getting any food. The scientists replicated this study in pea plants by exposing them to two different stimuli during the training phase: light, and wind. The results seemed to suggest that the plants could be trained to associate the presence or absence of wind with the anticipation of light. However, the authors of this new paper argue that this study needs to be repeated with more stringent controls in place before a clear conclusion can be drawn. So, what do we know?
Howard - We know plants can remember - in inverted commas “remember” - because we have plants that track the sun. They're called heliotropic plants, and we know, for instance, that they will start the day ready to face the sun and then they will follow the sun round just like sunflowers are set to do to maximize the amount of sunlight that they get to develop their pollination and so on.
Heather - Speaking of memory, what about Venus fly traps? You might have heard that they can count up to five when an insect lands on it, the plant counts the footsteps to check that it is actually food, and not just a drop of water say. Surely this must require some sort of memory because for me to count to five I need to remember that I just counted 4 and 3 etc. Scientists believe that the planet can count by releasing a chemical for each count. Imagine you have a bottle with a small hole in the bottom if you half filled the bottle water will start to drain out and eventually empty, if you don't put any more in. But if you quickly add some more water, the water level will go up. If you do this a few times in quick succession the water bottle will overflow. The Venus flytrap uses a similar method on when the threshold is reached, the trap snaps shut. But what about pain. If I was to pluck off a leaf of one of these plants here, would the plant feel pain?
Howard - Pain is a difficult stress to define even in animal terms and we have to be very careful with the terms we use. But nonetheless I think if you went across and plucked a leaf or if you had a caterpillar walking across the surface of the leaf you can certainly see that a plant can detect that. You can see the footprints marked across the leaf surface where chemicals have been produced within the leaf, defense chemicals. And also we know that if you pull that leaf off of bite a piece out of the leaf, chemicals will be produced that will move to an adjacent plant and warn it that the plants are under attack from potential pests or pathogens. So there is a warning system, they can respond. They can send signals but I don't think they can feel pain.
Heather - So is it just a problem of metaphors? The plants seem to be able to show some sort of ability to adapt their behaviour in response to their environment in the way that we think of as learning. But actually it's very different process and it's not really appropriate to call it learning in plants.
Howard - Yeah I think so. I think that's exactly it. I mean we have a number of different definitions now of intelligence. When we talk about whether animals can show intelligent responses such as maybe shrimps or octopus or indeed humans and so on. Equally so we have artificial intelligence. You know we've all now been hearing about self-driving cars and so on. So in some respects do we define that motor vehicle as having intelligence and at what level. And I think that one could equally rationalize that plants have a form of intelligence, if you move along the spectrum of definitions. But it's not cognate intelligence as we understand it from a human perspective.
The making of a good excuse
with Paulina Sliwa, University of Cambridge
We’re all guilty of making up excuses; “Sorry, there was traffic”, “I couldn't come to work because I accidentally got on a plane…”, Or, as one person told the UK Tax Office, “My ex-wife left my tax return upstairs, but I suffer from vertigo and can’t go to retrieve it.” Clearly, some excuses more plausible than others. But do they really work? And what makes some excuses better than others. Paulina Sliwa is researching excuses at the University of Cambridge and she joined Chris Smith in the studio...
Paulina - I got interested in excuses because they're absolutely everywhere. It's something that we come across in our daily life all the time. But then they also come up in the courtroom, for example, where lawyers evaluate excuses and there are valid excuses that you can make in the course of a criminal inquiry.
Chris - And what's the best one you've come across? As in, the best...perhaps the lamest excuse?
Paulina - Oh, the lamest one, particularly when teaching undergraduates, is, “sorry, I forgot to attach my essay.”
Chris - That's classic, yeah. “The email must have gone missing.” Everyone blames the technology, and yeah, that's pretty that's pretty common, I must admit. So how are you actually going about studying this, then? What's the actual methodology?
Paulina - Right. So I am a philosopher, and of course philosophers’ laboratories tend to be armchairs in general, but we draw on a whole range of methods. Ordinary speech, you know, how we speak about a particular phenomenon, how we make excuses, how we respond to excuses. A little bit of linguistics as well. And then also psychology is important.
Chris - And what are you...are you just gathering examples of people making excuses, and then looking at the context to try to understand, why do people make excuses in what sorts of settings?
Paulina - What originally started interesting me is just: what the various different kinds of considerations that we appeal to - from a headache, to provocation - what they have in common.
Chris - What do you think people resort to excuses? Why are we not just honest and say, “look I'm really sorry, I'm just lazy”? Or, “I'm really sorry, but I had a better offer. I went to the pub, I didn't do my homework.”
Paulina - Well I think it's important to distinguish two things, right: having excuses, and making excuses. So very often we do genuinely have an excuse; we failed to do something, but there is a consideration that mitigates our blame for it.
Chris - Is this almost like the, sort of, the verbal equivalent of haggling, then? You know, I want to buy something for X, and you want me to pay Y, and we kind of meet in the middle where I make an excuse for what I have done or haven't done, and that's kind of middle ground?
Paulina - Yeah that's right. So, you know, when we when we fail to live up to our obligation, in general it means that we incur some other obligation. So now I owe an apology, or I owe an explanation, or I might owe you a drink or some other kinds of compensation...
Chris - So reciprocity.
Paulina - Reciprocity, yeah. So part of what happens when you're making an excuse, I think, is you're trying to negotiate just what the fallout is from your norm violation, or your failed obligation. You're trying to negotiate just how much of an apology you owe, and what kind of apology it really is.
Chris - And some people are obviously better at that than others. But have you come across a formula, then, almost, for what constitutes a good excuse? So if I want to make an excuse for something, and I want it to actually sound pretty plausible and actually have the consequence I intend, which is people will forgive me or let me off for whatever I’ve failed to deliver on; is there a recipe for success in this?
Paulina - There is. The devil lies in the detail. So a good excuse acknowledges that things went wrong. You didn't act as you should have done.
Chris - So I’ve got to hold my hands up first of all, “I'm sorry”. So a bit of an apology, and then a, “I'm sorry, I should have done X,” so I acknowledge the issue…
Paulina - You acknowledge the issue...
Chris - What comes next?
Paulina - And then you say, “but, the intention on which I acted,” where intention is something like your plan for action, “that one was morally adequate.” And the reason why it failed to work was because of some unforeseen circumstances, something beyond your control
29:05 - Alzheimer's in the clinic
Alzheimer's in the clinic
with Tim Rittman, University of Cambridge
What happens when a person begins to notice that there might be something wrong with their memory? To understand the clinical side of things, Katie Haylor was joined in studio by Tim Rittman, a clinician from Cambridge University...
Tim - That's a really difficult question to answer, when people think about Alzheimer’s typically you think about the memory problems that people have. So certainly memory loss is a part of Alzheimer's disease but there are other things which can come along with it as well. So difficulty with coordination, difficulty with vision what we call visual spatial difficulties. So that might be judging distances or driving for example people might find it difficult to reverse their car. People often have anxiety as well particularly for social situations. So someone who is previously very outgoing might become a lot more nervous in those situations. I think it's very hard to say what a typical person with Alzheimer's looks like because you know, in my clinic I see people who can't read and write, and English is their Second Language and Alzheimer's disease is very different for someone else who's a professor from the University of Cambridge. So there's certainly a loss of function and problems with memory and other cognitive processes but it's very individual as to how that affects people's lives.
Katie - Can we generalise about the progression? Is there a pattern that you tend to see?
Tim - There is to some extent in most people the first thing that will be noticed will be the memory problems. And it's a particular type of memory problem where you'll forget things about events that have happened in the past or you might get lost. And usually these will be more noticeable to other people than to the person who's suffering memory problems or experiencing those memory problems. Over time they become more problematic and more noticeable and people begin to lose function so they begin to fine day to day things more and more difficult. So for example if you cook a roast dinner it might be that you've never had to think about doing that. But then those processes become more difficult. It takes you more time and then eventually that will be impossible to do because you just can't remember or put together all of the different parts of that particular process.
Katie - Now Alzheimer's isn't the only kind of dementia. So what other kinds are there and how is Alzheimer's different?
Tim - Yeah there's quite a few different types of dementia and the commonest that we see certainly is Alzheimer's disease. Close behind that is something called vascular dementia so that affects the blood vessels in the brain. From a clinical point of view that often comes with difficulty walking people's gait becomes very short they make sort of small strides and often comes with a sort of grumpiness as well and the slight change in behavior. There are other forms of dementia so frontotemporal dementia which is completely different from Alzheimer's disease and that often the memory is quite good but there's a lot behavioral change. So people might become very inappropriate make rude comments or completely inappropriate comments but that can also affect language as well. So there is certainly a whole group of dementias where problems with grammar, or with syntax, or with remembering what words mean are that the first presentation.
Katie - Is Alzheimer’s a terminal illness? Can you die of having Alzheimer's disease or is it a bit more complicated than that?
Tim - It is a bit more complicated than that. I think there's no getting around the fact that Alzheimer’s is a progressive disease and if nothing else happens in your life then you'd expect that your life expectancy is shortened if you have Alzheimer's disease. Having said that if you look at the death certificates of people who've had Alzheimer's disease mostly it will say something like pneumonia because of the gradual loss of brain function eventually leads to a loss of those basic functions. So breathing, monitoring different bodily functions, and that can lead to a shutdown of the body. So yes Alzheimer's is certainly progressive and it does lead to a shortening of lifespan. I think increasingly as clinicians we're recognizing that and taking on board the more palliative aspects of Alzheimer's disease which is is really important along with all the other things that we have to address in the illness coming to the end of life and addressing those specific issues is increasingly important.
Katie - So Tim if somebody comes in to see you in your clinic what kinds of assessments would you get them to do to potentially diagnose Alzheimer’s? How does it work?
Tim - So first thing, the most important thing, is to take a history and talk through what's been going on. But we do get people to do some cognitive tests so this tests a range of things. So memory, visual spatial function, language function, what we call executive function so that’s planning an organisation of the brain and we look at patterns within those tests. So there is no one specific answer that you know if you fail on that you'll definitely have a diagnosis of Alzheimer's disease or dementia, it doesn’t quite work like that, it’s more fitting into a pattern along with the history and other bits and pieces.
Katie - And do you allow for the fact then that this is quite a nerve racking thing to do potentially? So people might not necessarily perform great on particularly one day or one time?
Tim - Absolutely yeah. There are a lot of things you have to take into account. Certainly nerves come into it and we recognize that the nurses who administer the testing clinic are really used to assessing people and when we discuss the cases afterwards we'll say, you know, how did the person perform on the test? Were they really making an effort for example or were they really struggling and nervous? And we take into account the levels of education as well we know, someone who’s got a very high level of education is naturally going to do a bit better on the cognitive tests and someone who isn't so educated and we take all of those things into account.
Katie - So these tests where someone is doing a particular task and giving you some information they play one part, but do you actually look at what's going on inside someone's brain?
Tim - We certainly do brain scans. Yeah. One of the reasons and probably the main reason for doing a brain scan is to make sure we're not missing something like you know brain tumour or a stroke or some other cause for memory problems. But we do look for certain patterns of change in the brain and shrinkage in the brain.
Katie - So is it fair to say then that people shouldn't panic perhaps if they forget something a couple of times, but it's a pattern that they should look out for. What would you suggest people are wary of?
Tim - Yeah I think we've all had the experience you know this morning I got up and went upstairs and couldn't remember what on earth I gone there for and that's entirely normal. Or that what we call a cocktail party anomia, you go to a party you can't remember someone's name five minutes later. These are all entirely normal and part of everyday life. Usually, it's when other people are worried about your memory other people start noticing it or you find that those memory problems are really stopping you doing things. That's when we start thinking about you know, could this be the early signs of dementia?
Katie - And briefly after you’ve diagnosed someone, what happens next to them?
Tim - We start thinking about some treatments sometimes. Particularly in Alzheimer's disease, we don't have any treatments which can stop the disease process or turn the clock back. But we do have some medications which can boost some of the chemicals in the brain to help with memory and attention.
36:37 - Alzheimer's in the brain
Alzheimer's in the brain
with Claire Durrant, University of Cambridge
What’s actually going on in the brains of people with Alzheimer’s, and why does it cause the symptoms that it does? Claire Durrant is from the Department of Clinical Neurosciences at the University of Cambridge, and she joined Chris Smith in the studio to fill us in...
44:23 - Finding drugs to treat dementia
Finding drugs to treat dementia
with John Skidmore, ALBORADA Drug Discovery Institute
Treating Alzheimer’s is a difficult thing. Often by the time you know the diagnosis, a lot of the damage has been done. So the emphasis is currently very much on preventing or slowing down the progression of the disorder. And drug developers are looking for drug molecules that can do that. Adam Murphy spoke to John Skidmore, from the ALBORADA Drug Discovery Institute in Cambridge, to learn about the work they do...
Adam - At the moment we can't cure Alzheimer's but that isn't going to stop people trying. John Skidmore at the Alborada Drug Discovery Institute in Cambridge is working to find ways of treating, and perhaps even curing the disease. But how do you go about doing what's eluded so many...
John - These days drugs are either small molecules which typically have perhaps about 70 atoms, or large biomolecules that might be 2 or 300 times bigger than that, we're finding small molecules. The reality of drug discovery is that we're still not good enough to sit down and use computers to design the drug from scratch. So we have to go about it in an interactive way where we make a series of potential molecules, look at their properties, and then try to improve them with the next round of molecules, and over a period of weeks and months we get better and better.
These small molecules are interacting with a particular protein in the body that we've identified as having a role in the disease. So the first thing we do is to take a big library of molecules, perhaps a couple of hundred thousand, and look to see whether we can find some that interact at any level with that protein.
Adam - With so many proteins and so many potential molecules to choose from, how do you even begin?
John - Well, that's the difficult thing actually. Sometimes if you have a crystal structure of that protein, you might be able to what we would say rationally design something. So perhaps you know a little bit about how the protein works and you can build it from first principles, in the way that you might design a car. But in lots of other cases, we simply don't know what the molecules are going to like at all and so you have to go back to screening. The library we have is as diverse as we can make it. It has as many different types of chemical structures as we can find and so it represents lots of potential start points.
Adam - What are these molecules going to do though? When you've found something, how is it going to help?
John - In terms of the drugs we're developing, we have to go back to the observations that the basic scientists are making. And really the science points to the fact that in Alzheimer's and, indeed, lots of other diseases that cause dementia there are mis-folded proteins in the brain. In Alzheimer's in particular, we have beta-amyloid and we've got a protein called tau.
Now, in fact, amyloid has been the focus over the last 15 or so years and it hasn't been all that successful. We know that the protein tau, which also mis-folds and aggregates, is sort of further down the disease progression. And so if we could find ways of changing the behaviour of tau, then that might be a way in which we could change the course of Alzheimer's disease.
What we'd really like to do is to reduce the mis-folded form of tau and we have a number of ideas about how we can remove that mis-folded protein. The body and cells have got mechanisms in place for clearing mis-folded proteins, and we've got ideas about how we can increase those processes in order to try to clear proteins such as tau, but also other proteins that cause other neurodegenerative diseases.
Adam - And what stage are you at with things here?
John - We've got a couple of really exciting projects that are looking at different ways of clearing these proteins. One of them is designed to increase a process called autophagy, and what autophagy does is it surrounds the clumps of mis-folded proteins with a membrane and then is able to destroy the materials that's within that membrane. Working with our collaborator, Professor David Rubenstein here at the University of Cambridge, we've identified a signalling molecule that can turn on autophagy and also a process by which an enzyme can remove that signalling molecule. And so the idea is if we can block the enzyme that removes the signalling molecule then we’ll see an increase in the signalling molecule, an increase in autophagy, and we'll start to clear the mis-folded proteins. And we've now got molecules that are able to interact with that enzyme at very low concentrations, which is what you need to be able to give something as a drug, and we are in the process of testing them. We've done lots of experiments in cells, we've got some very exciting data, and I think we going to be moving those molecules into animal models in the coming months.
The latest Alzheimer's research
with Katy Stubbs, Alzheimer's Research UK
Even in the scientific world, Alzheimer’s can be a complex issue. Just in the last couple of months, there have been papers saying the route cause of Alzheimer’s is as diverse as high cholesterol, to gut microbes and even herpes virus. But can all, or any, of these things be true? And what’s worth picking out from things like this? Chris Smith was joined in studio by Katy Stubbs from Alzheimer’s Research UK...
Katy: It is yeah. And unfortunately we can't turn back the clock on that and because we're living longer we experience so much across our lifetimes and this combined with our genes is really what is going to be driving the risk of Alzheimer's disease.
Chris: Is it fair to say then that it's a multifactorial thing, it's not just one trigger for the majority of people. The minute number of people who have a defined genetic cause aside, for most of us it's going to be the excesses of life including living too long which ends up causing this.
Katy: Indeed you're exactly right. So that's what's really hard for us is trying to pinpoint what are the most important things that we could maybe change. So in terms of lifestyle factors trying to understand where we can give people advice to reduce their risk.
Chris: Is that where the claim about high cholesterol comes in?
Katy: Yes. So that the message really is what's good for your heart is good for your head. Your brain is only about 2 percent your body weight but needs about 20 percent of your blood supply. It’s a hungry organ. And so if the blood vessels in the brain aren't kind of in tiptop condition if they're not providing those nutrients and the oxygen to your brain cells then those cells aren't able to do their job as well. And so the thing with cholesterol is it's essential for all the cellular processes that we have but too much of it is damaging. So it clogs up our arteries and if this happens in the brain, then this is going to cause damage within the brain.
Chris: And the link to gut microbes because the microbiome is on everything these days not a week goes by without some new paper alleging that the microbes that live on us and in us are changing our lives and all kinds of manifold ways we haven't previously anticipated.
Katy: Yes, our guts are full of bacteria and they do important things in helping us digest our food and get all the nutrients out of our food. But actually what’s emerging from the science is that it's the variety of your microbiome and the levels of that variety as well so the kind of the profile that you have and we're not at the stage where we know what a healthy one looks like and what one from someone with Alzheimer’s looks like. So we are just at that early stage of trying to see the key differences. And so we don't know whether the changes in the variety of your bacteria are they driving the disease process or are they happening at the same time and are just kind of a consequence of what's happening? We need to understand that. So we don't yet know what is shifting those changes. Is it things in people's diet. Is it their genes that can affect the bacteria you have in your stomach so there's so many other things which I understand and we're still at those very early stages with understanding it.
Chris: What about genetics though, because we've alluded to this a bit and we know that there are rare examples of almost every disease on Earth where genes plays a huge role but on average does genetics play a role in Alzheimer's?
Katy: So there is some role for it and it's really important to understand the different types, the different ways in which genes can affect our disease risk. So Claire's already mentioned genes that can cause disease and for Alzheimer’s that’s incredibly rare.
What we're mainly talking about is risk genes. So genes that if you have a change in them they might increase your risk maybe 5 percent but for most genes it's more like 1 or 2 percent they might be shifting your risk so it's across the whole of your genetic code. All those different changes could put you in a high risk category compared to somebody else. And we've discovered about 30 genes that can affect your risk of Alzheimer’s at this point but the likelihood is it could be in the hundreds and the thousands. So we need to again understand that profile of change and see what makes somebody high risk versus low risk.
Chris: Have you found genes, because it's easy to obsess about problems that we do get. Have you found anybody who has certain genes that seem to protect them from Alzheimer's disease. Because arguably they'd be the ones to look at to find out why.
Katy: There is a lot of interest in a group of people that are often called super agers so people who reach their 90s or over 100 and they don't seem to have any kind of ill effects of it with their health. And if we're trying to understand why are those people are doing so well, that could offer up some clues as to what's going on with their genes and is it protecting them because it's more likely that than their lifestyle.
Chris: What's the take home message with Alzheimer's then what should a person listening to this take away as the best way to run their life course to reduce their risk to the minimum it can be?
Katy: So it’s that message of what's good for your heart is good for your head so healthy balanced diet.The Mediterranean diet has the best amount of evidence behind it so lots of lean meat so fish and poultry and nuts and oils and lots of fresh fruit and vegetables for the diet really.
Chris: Is exercise protective?
Katy: Exercise, it's not protective, it's more that if you're not active your risk is increased. If you're active you're your risk is more normal so keeping physically active, your weight, your cholesterol, your blood pressure... all those things. Keeping socially integrated as well is really important.
54:03 - QotW: Can transfusions change your blood type?
QotW: Can transfusions change your blood type?
It’s time for Question of the Week, and Emma Hildyard has been searching for an answer to this vital question from Mark...
Emma - Hmmm… interesting question. We put it to our forum. Polly didn’t think it was possible, Chris and Evan said you need a bone marrow transplant to change your blood type. So we asked Dr Cedric Ghevaert from the University of Cambridge.
Cedric - Our blood cells are divided into red cells, white cells and platelets. All our blood cells carry an identity card on their surface made out of different proteins or sugars: we call these blood groups.
The most important and well known blood group is the one carried by the red cells and it can be O, A, B or AB combined.
Emma - When doctors need to give someone a blood transfusion, they try to match the blood group of the red cells in the new blood with the red cells in the patients’ blood - so, you’d give type A blood to someone who has type A blood in their body. This is important because otherwise the new blood cells would be destroyed very quickly by the patient’s immune system and cause a really serious reaction. But in an emergency, you might not have bags of the exact blood group to hand…
Cedric - In hospital, emergency departments and surgical theatres will have access to “emergency” blood packs that can be accessed very quickly for people who are bleeding and need blood urgently. And this is O blood.
The O blood group is the most common. O cells can be given to all patients.
I had a patient who was group A and had a very big bleed after delivering her baby. She had to have 76 packs of blood over a period of 8 hours, most of those were group O. Each pack replenishes about half a litre of blood and an adult has on average 5 litres of blood. This patient basically bled her whole blood volume 7 times over! By the time the bleed was under control, she had bled all her own A cells and she only had the O transfused cells. So we basically changed her blood group!
But, that change was only temporary: over the following three to four weeks the transfused O red cells gradually disappeared and were replaced by her own newly produced A cells. That situation is very different from people who have regular small transfusions for example when they have leukaemia: two or three packs of red cells every two to three weeks. In those cases we match the blood and do not replace the whole blood volume several times over.
So to answer your question, can we change a blood group with transfusion. Yes, we can, but only in very rare emergency situations.
Emma - Thanks for that Cedric. There’s always chance to be-positive about these things. Next time we’ll be answering a question from Alex:
Alex - I have several friends with huskies, who claim that the thick fur of the dog protects them not only from the cold but from a hot summers days as well. Could this possibly be true?