Gene therapy for epilepsy, and beastly botany
In the news this week, the novel gene therapy for epilepsy which reduces side effects, how birdsong can provide listeners with a mental health boost, we take a terrifying tour of Cambridge University's Botanic Garden, and hear about how Aluminium formate could bring carbon capture to the masses...
In this episode
00:57 - New epilepsy gene therapy
New epilepsy gene therapy
Dmitri Kullmann, UCL
A new way to tackle epilepsy using gene therapy has been announced this week by scientists at UCL. Epileptic seizures or fits occur when a group of neurones in one region of the brain begin to fire inappropriate salvoes of nerve impulses. These spill over into other regions of the brain disrupting normal activity - and often causing unconsciousness - until the abnormal activity subsides. The condition can be controlled by drugs that damp down the activity to prevent fits occurring, but they can make users feel sleepy and struggle with concentration. The new approach, from Dmitri Kullmann, is, having identified where in the brain seizures are originating, to add to those nerve cells a small piece of DNA. This contains instructions that detect when a nerve cell is showing the electrical features of a fit, and switches on a gene that then damps down nerve activity in just those nerve cells. This means the treatment is only active when it’s needed and where it’s needed, minimising any side effects...
Dmitri - There are a lot of neurological diseases which are characterised by overactivity of populations of brain cells. The most obvious of these is epilepsy. So when people have seizures, it's a manifestation of a population of nerve cells firing excessively. And so we've have recently been trying to use gene therapy - using viruses to manipulate the genetic makeup of brain cells. Now you can target to some extent some of those viruses to the specific area of the brain where the seizures arise. But when you do that, you're still treating brain cells permanently and also both brain cells that are participating in the seizures as well as bystander brain cells that don't need to be treated. So that's the problem that we try to address using this on demand gene therapy, as we called it.
Chris - So tell us how that actually works then. What's going on that triggers it and how does it rein in the epilepsy,
Dmitri - There are ways of reducing the excitability of brain cells. So we know quite a lot about what makes cells fire and it's to do with the movement of electrically charged ions, these little atoms that go across the membrane and carry a charge. So we know what sorts of proteins underlie that. So we can simply increase the expression of some of these proteins that underlie normal inhibition of neurons. But what we wanted to do was to do it in a more refined way so that only those neurons that need to be treated are treated and only for as long as they need to be treated. So the treatment could switch itself off if it doesn't need to continue.
Chris - It's a bit like a sprinkler system in a supermarket. When the fire alarm goes off, you only turn the sprinklers on when you need to damp down a fire.
Dmitri - Absolutely. If we permanently express a protein that reduces the excitability of neurons, that's like having the hose on continuously. Now we could use another strategy which is to put in a receptor. So it's a protein that responds to a drug. In that way we could switch on this receptor by giving the drug and thereby reduce the excitability of those brain cells. So that's more like the equivalent of a hose with a tap on it. But what we wanted to do is to remove the need to give that additional drug to activate that protein. So the protein would only be produced in response to seizures. In the DNA you have something called a promoter, and the promoter is what tells a cell to produce that protein or not. So what we've decided to do was to use a promoter which has a special property that it can detect whether the cell is overactive. So when a seizure happens, this promoter switches itself on and that then leads to the production of the protein and the protein then reduces the firing of those brain cells.
Chris - And you know, this works. How did you demonstrate that you could actually get the promoter to register the overactivity of a nerve cell with activity akin to an epileptic discharge so that it would turn on your therapeutic gene?
Dmitri - So we started in brain cells grown in a dish. And so we verified that these promoters could indeed switch on the expression of a protein in response to conditions where the cells are firing too much. And then we moved on to a way of recording the activity of a whole population of brain cells in a dish where they can be made to fire in such a way that you're starting to mimic something a little bit more like a seizure. And then we tested this in mice, which were spontaneously epileptic. And then we verified that the treatment would indeed suppress the seizures. And then we found that indeed this treatment was highly effective and we could completely suppress all the seizures in some of the mice and in other mice the seizures were reduced in frequency without any deleterious side effects.
Chris - In summary, you put into the region of the brain where we know the epilepsy stems from this construct. It sits there doing nothing until the cell starts to describe the sort of electrical activity that we know is associated with an overactive nerve cell in epilepsy that then recruits this promoter and says, "Make this therapeutic gene", which then turns on temporarily, damps down the seizure and then the cell goes back to normal?
Dmitri - Yes. Now of course people always ask the question, "Well surely the seizure happens so quickly that this treatment won't have time to stop that seizure." And indeed this treatment typically switches on we think within about half an hour and then will gradually switch itself off over a few days unless it's reactivated. So we won't be able to stop the first seizure, but we can certainly reduce the likelihood of a second seizure occurring. Now a lot of people with drug resistant epilepsy have clusters of seizures, so they may have several seizures in the space of a day or so. So the time scale of the expression of this protein that we're making to reduce the excitability of neurons is entirely consistent with a sort of clustering of seizures that people have. So we hope that this, if and when we get it into the clinic, would have a very powerful effect in stopping those clusters.
07:36 - Listening to birdsong reduces anxiety
Listening to birdsong reduces anxiety
Emil Stobbe, Max Planck Institute for Human Development
Now we all love a walk out in the countryside, and a pivotal part of the experience is birdsong. Whether it be the soft song of a warbler, or the laughing cry of a woodpecker, birdsong is an essential part of our wildlife soundscape. But does bird song have a real tangible effect on our state of mind? Well, a new study pitted varying intensities of birdsong against varying intensities of traffic noise, to see how these sounds affected people’s level of anxiety and paranoia whilst doing practical tasks. Emil Stobbe, from the Max Planck Institute for Human Development, spoke to Will Tingle about the findings…
Emil - Our experiment revealed that states of anxiety and paranoia were significantly reduced after listening to the birdsong audio, while depressive states and subjects became stronger when those subjects listened to the traffic noise audio. The effect was actually stronger when the city audio or the traffic noise audio contained various sources of traffic noises. And with respect to the anxious and paranoid states, the bird songs demonstrate to alleviate those states, but irrespective of the diversity of the birds contained there.
Will - Why do you think these noises have such an effect on our mental state?
Emil - In order to explain these effects that we found, there are several theories in debate. There's stress reduction theory, and it claims that the presence of birds signals an intact and vital environment, which is, evolutionarily speaking, a signal for very good chances of survival due to shelter or resources. And at the same time, traffic noises signal the acute presence of threats like cars running by, something that you have to pay attention to so you don't get run over. And therefore they're conveying these negative effects. Another theory, which is called Attention Restoration Theory, claims that natural stimuli such as bird songs are so-called 'softly fascinating'. And that means that they are something that we direct our attention towards voluntarily, while traffic noises are dragging our attention towards them, making them deplete our capacity much faster. And that's then resulting in the beneficial or negative effects of the city. Then we have conditioned restoration theory, which is a relatively new approach. And this is basically claiming that when we visit natural environments, we feel joy and pleasure and we often do this in our free time. And once we then encounter related stimuli such as bird songs in a different situation, such as in this experiment, then these feelings of joy and pleasure gets triggered again, like a conditioned response. And in turn they can convey these non-benefits.
Will - And now that we have this knowledge of bird song being able to reduce these negative emotions, is there a potential scope then to be using bird song, for example, in clinical settings for people who experience a lot of anxiety or paranoia?
Emil - Yeah, I definitely think so. That is the case. So bird audio can be used in a clinical setting, for example, as a background noise in order to help reduce the mental distress of patients. This can be for a clinical population, but at the same time also for a healthy population. It could be a really easy accessible way to prevent the emergence of negative mental states. And this can be by just being at home and listening to an audio recording of bird songs, but also of course at the same time visiting nature and trying to seek those audio stimuli in real life. And both would have the effect that we found in our study and could be beneficial for preventing those mental states, but also helping patients who already suffer from those to help them relieve under distress.
Will - And on a more ecological note, this study therefore surely means that we need to conserve bird populations, particularly in urban environments. Do you think bird song and traffic noise have the potential to cancel each other out?
Emil - So we think that bird songs are really special natural stimuli as they have the power to bring nature everywhere. So, the soundscape of an environment is something which is really impactful for how this environment is perceived. And due to the fact that we spend most of our time in urban environments nowadays, this opens up a really great possibility to incorporate the healing aspect of nature into our daily life. The more connected you feel to nature also enhances its beneficial effects. And sometimes there's just not the time to visit pure nature so often. So you have the option to experience birds inside the city, and this is something we should be really aiming for and trying to take this knowledge up in the design of a part of the city where parks or recreational spaces are designed.
12:50 - Bone-chilling botany
Sally Petitt, Cambridge University Botanic Garden
For a belated Halloween treat, the Naked Scientists were invited to take a tour of Cambridge University’s Botanic Garden, but with a terrifying twist. An opportunity Will Tingle and James Tytko thought too good to miss…
James - Will, another day, another expedition you've led us on. Where are we and what are we doing this time?
Will - Well, James, I've come to scare you senseless. We've been very kindly invited to Cambridge's Botanic Garden to sample some of their spookiest, most Halloween appropriate plant life.
James - Is the anticipation here that, the plants themselves, they look scary, or they do something scary?
Will - Maybe even a bit of both.
James - Well, yeah, Good luck scaring me with plants.
Sally - Hello, I'm Sally Pettit. I'm head of horticulture here at Cambridge University Botanic Garden.
James - And we're here on our whistle stop tour of all things spooky and horrible here at the Botanic garden - not that anything's that horrible here - what have we got in front of us ? It's like a purplely coloured plant. It's covered in little hairs they look like, and it's got a sign next to it which says, "Smell me."
Sally - Well, this is a very rare orchid. It's called Bulbophyllum phalaenopsis. So it's quite a mouthful. And it's flowered on cue for Halloween. It sort of has a sinister coloring, that deep purple-y, red-y colouring with those little yellow hairs on each of those little flower hoods. But it's most intriguing aspect or facet is really the smell that makes it very Halloween-y
James - Shall I get stuck in?
Sally - Oh yeah, get stuck in.
James - Oh, it's pretty nasty <laugh>. It's mouldy.
Sally - It's the plant giving off a scent, which some people think is a bit like drainage. Some people think it's rotting flesh, but it's actually there to attract pollinators. So it'll be pollinated by something obscure - beetle or a fly - that really is drawn to that rotting flesh smell.
Will - Well, we are stood here in front of what you've dubbed the eyeball plant.
Sally - We are looking at the seed cluster of this extraordinary climber that scrambles up through host plants in Africa. And it's basically the seeds in a head. So this would've been the flower head and it's developed the seeds and you've got this kind of white outer, the fleshy part of the fruit. And popping out from the center of those are these black beady seeds, and together it looks like somebody's bursting eyeball.
Sally - So this is a small houseleek. Latin name is Sempervivum - which means always living - and arachnoideum from spider. And it's something that grows through the Alps, a European species. So they make these fantastic rosettes and you can see neighbouring plants have these very succulent large leaves, but no cobwebbing. This one's particularly adapted to grow this cobweb, which will help protect it.
Will - Very apt. What is it protecting it from?
Sally - It would just be protecting it from predation by something that may otherwise go along and just gnaw at those leaves. I can't imagine that there's a lot high up in the Alps that's going to go along and graze on that. Story goes that they were grown on the roofs of houses to ward off evil spirits.
Will - Well, do you see any old spirits around here?
Sally - Get a few passing through.
Will - Fair enough.
James - Well, no exploration of Halloween themed vegetation would be complete without referencing pumpkins. Now these are a bit different from the pumpkins you might pick up in the supermarket. I don't think they're pumpkins at all actually. They just look like them. They're about the size of an eyeball as it happens.
Sally - So this is a member of the potato family, but it more closely resembles tomatoes, which are in the same family. And it's called commonly 'cannibals tomato.'
James - What's the story behind that name?
Sally - It comes from the South Pacific and story goes that cannibals of that region did use this as accompaniment when they were eating human flesh. What a great story.
James - A nice pairing, I'm sure.
Will - I wonder what it would taste like. Probably better than human flesh.
Will - You've got me in front of this maggot riddled eyeball here. What are you playing out?
Sally - This is a member of the Mulberry family. It's a plant called Broussonetia kazinoki. It's the Kozo paper Mulberry, so you can make paper from it. But I think the most interesting thing about this are the amazing fruits.
Will - They almost look like fingers coming out of the centre fruit in a way.
Sally - Oh, they do, don't they? They look as if they're like little fingers with tiny nails on them. But this is how this plant distributes its seeds. So these little orange, like almost pustules are actually the seeds.
Will - It's getting worse.
Sally - Birds come along and eat these. They're quite sweet. They're quite juicy and succulent, but they are just bonkers to look at.
Will - This is intense closure for me here. I've seen this fruit plant, whatever it is, around in the wild for about 10 years. I'd never known how to identify it. Could you please put me out of my misery?
Sally - This is a tree from North America called the Osage Orange or Maclura pomifera. So it is named after a William McClure who is a geologist. Pomifera describes the fruit because it in theory looks a bit like an apple, but it doesn't altogether look like an apple really. We refer to these as gardeners' brains, sort of a limey green, nearly yellowy green, and they have all these fantastic fissures across the surface. So it's quite rough and it does resemble a brain.
James - We've entered the spooky forest. This tree here, the colour palette especially reminds me of a zombie. The green flesh and then the haggard bark and then that tree over there is looking pretty ghosty. What part of the botanic garden are we in here?
Sally - We're in the Gilbert Carter Woodland. It's quite a naturalistic area of the garden. In spring we let all the cow parsley grow up, so it's all soft and lovely and quite daydreamy and yeah, this time of year, you lose all the grass. It highlights the trees, particularly when they lose their leaves as well. And you get these fantastic bark colorings and things.
James - A very distinct look to the trunk.
Sally - It's a slightly peeling bark. It is a dogwood. This is Wilson's Dogwood Cornus wilsoniana. And many of the dogwoods are renowned for their coloured stem. So they have brilliant reds and oranges as in our winter garden. But here, this is much more subtle. Yeah, just quite an unusual tree, but it just has that moodiness about it. .
Will - So James, are you suitably spooked after that chilling experience?
James - Well, yeah, just a big thanks to you actually, Will. I've very much enjoyed my time looking at all things scary and smelly in the plant world. I don't think Sally will mind me saying too much that she's got quite the imagination, doesn't she?
20:55 - Carbon capture made cheap
Carbon capture made cheap
Hayden Evans & Craig Brown, NIST Centre for Neutron Research
When it comes to heating and lighting our homes, many find their desire to see and keep warm at odds with our best intentions to cut carbon emissions and reduce the rate of climate change. One obvious way to preserve our standard of living and salve our consciences, at least until science can endow us with better sustainable energy sources, is to come up with ways to reduce the impact of fossil fuels, such as systems to capture the CO2 that would normally go up the chimney. The problem hitherto is that materials and chemicals capable of doing this have been either very expensive, hazardous, and hard to make at a meaningful scale, or the cost of using them is prohibitive. But now scientists in the US think they might have hit on a substance that won’t break the bank. Aluminium formate naturally forms a molecular sieve with holes just the right size to grab and loosely hold on selectively to molecules of CO2. It’s cheap, easy to make, and can soak up a lot of the gas before it needs flushing to regenerate it. It’s the brainchild of Hayden Evans and, kicking us off, Craig Brown…
Craig - Some materials, it's very energy intensive to release the CO2 once you've captured it and that's the energy penalty. So we've been working on materials that are naturally selective for CO2 over the other major components of gases in the air, like nitrogen for instance. And so if you selectively capture the CO2, you are reducing that energy penalty. Another concept in the cost of all of this is the capital cost, how much it costs for the system. And so we found a material that's both selective and extremely cheap that could be a candidate for this type of selective capture.
Chris - And Hayden, would the notion be then that you put this between the source of the CO2 and the atmosphere, so it's basically selectively sieving out the CO2 instead of just dumping it into the air?
Hayden - Yeah, so that's generally the gist of these kinds of materials, right? Is that you're trying to find something that you can engineer a process where you have a point source burning the fossil fuels, you're generating the CO2 and then along the way before it's released into the atmosphere, the CO2 is quickly sucked up in some meaningful amount into our material. And then what we launch into the atmosphere is just predominantly nitrogen.
Chris - What's the magic chemical?
Hayden - The chemical itself is aluminum formate. The beautiful thing about this material is that it is very simple in its composition. It's made from chemicals that are very non laborious, really to combine and create the material. And then to get it to a state where it can capture carbon is very straightforward because the material is porous, it is ready to capture CO2, when it's exposed to it in the right conditions.
Chris - And is that process reversible? So once it gets saturated, those pores in the material are full of carbon dioxide, can you just heat it up, drive the CO2 off it's back to ready to capture more?
Hayden - Yeah. And the beauty of this material is that you're trying to find a material that grabs the carbon just tightly enough, but not so much so that it's very difficult to release it after the fact. Right? And so our material does this that's able to sort of grab the CO2, load it inside of it, and then if you heat it up ever so gently, it will release or burp the CO2 at our discretion, right when we decided that's a time for it to release.
Chris - And how good is the material, Craig? When you actually look at how much carbon dioxide it can lock away, what's the performance like?
Craig - If you have a kilogram of this material, it'll absorb about 20% of its own mass in CO2.
Chris - Is that good if, if one compares with other materials and chemicals that people have tried to use? Is that good?
Craig - There's more than one factor that you're looking at in this process, but it is good. So you're looking at the selectivity, how easy it is to regenerate, you know, optimizing the heat you have to put in to get the CO2 out, but that 20% value is very good. Yes.
Chris - I'm just thinking though, if one takes a big power station, some of our coal fired stations that we've been busy closing down here in the UK would easily eat through tens of thousands of tons worth of coal on an afternoon. That means presumably then you would need hundreds of thousands of tons of this material to get all the CO2 from one power plant, wouldn't you?
Craig - Chris, I think you've hit the nail on the head there. This is really a big scale up problem. So we have some interesting materials that could potentially capture CO2 selectively in a process here. The problem is getting those tens of thousands of tons and that becomes a resource problem and a cost problem. The great thing about this material is made of cheap commodities like Hayden was saying. So we can easily scale up the process to make this and just on the back of the envelope calculations that we've been doing is, you know, as basic fundamental scientists we're talking about two, $2 per kilogram, something like that. So you can imagine that the scale up is quite possible with these materials. There's also an interesting twist in this. When we capture the CO2, there's a possibility that we can take that CO2 and convert it into one of the building block chemicals that make up the material in the first place. So it's almost like a closed cycle that we can reduce the final cost of the product by using the CO2 as a commodity to make it even more of the material in the first place.
Chris - That was going to be my next question actually to you Hayden, which is, okay, you say you can make tens of thousands of tons of this material to soak up the waste stream from the power plant. What do you do with all the CO2? So is there the potential to, to get it out easily and then put it somewhere into processes like this or, or even into fuels for example? Cause there are now people working actively on turning CO2 back into fuels.
Hayden - Yes. This is sort of almost the keystone sort of problem in this. Okay, great, you've captured all the CO2, you've done it now, Hooray. But obviously you got to do something with the CO2, right? Otherwise you're just sort of going to be generating an infinite amount of CO2. And so there's a lot of research where they're trying to turn CO2 into usable fuels or just commodity chemicals. And so our vision for how aluminum formate or you know, we call it Alf, but how this material is sort of the cornerstone of this CO2 economy is because if you can start to turn CO2 into the compound that we use to make reagents, then you've now got this, you know, recyclable loop where, where you have a viable place to put the CO2 at least to a certain point.