How Do I Smell?

20 July 2019
Presented by Katie Haylor.




This month, we're talking smelly neuroscience! Can how we smell, and what we smell like, say anything about our health? Plus, we pick apart some of the latest neuroscience papers with the help of local experts...

In this episode

Brain schematic

Can green spaces curb your cravings?
with Helen Keyes, ARU; Duncan Astle, Cambridge University

Can green spaces curb your cravings? What's the genetics behind cannabis addiction? Katie Haylor dips into some of the latest neuroscience research with local experts - perceptual psychologist Helen Keyes from Anglia Ruskin University, and cognitive neuroscientist Duncan Astle from Cambridge University.

First up, Duncan looked at a paper about the genetics of cannabis use disorder...

Duncan - In essence it's a high dependency on the use of the substance. We already know that about 50 to 70 percent of the variance in whether you have cannabis use disorder is explained by your genes, but little is known really about the underlying biology of why it is that some people seem so prone to this highly habitual use of cannabis, and that's what the authors in this study have been looking at. And they've used a Danish sample of around two and a half thousand individuals who have cannabis use disorder and about 50,000 controls; and they have conducted what's called a GWAS or a genome-wide association study, which is where you put essentially all the genetic variants through an analysis and you're looking to see whether there are any specific genes which seem to really reliably predict who has cannabis use disorder and who doesn't.

Katie - How easy are these to do?

Duncan - They're really hard to do because you need a lot of people. So in fact two and a half thousand versus 50,000 - those sound like big numbers, but in the world of GWAS studies that's still pretty tiny. So in their analysis they found a specific gene which is the CHRNA2 gene, which is a catchy title, and that really reliably distinguishes people who have the cannabis use disorder from control subjects. But the really exciting thing is that what they then did was find some collaborators in Iceland. So in Iceland everybody who has a substance abuse problem mostly is treated within the same single clinic, which means they have a really big sample of about 5000 people who have cannabis use disorder. So they could then repeat their analysis with the Icelandic sample, and they found the same gene replicated. So that's really compelling data to suggest that this CHRNA2 gene is a really good predictor of why some people have cannabis use disorder and others don't.

Katie - And we know this is a causal link?

Duncan - So generally it's considered that if you find a single gene that it is causally related. But then it's interesting to start wondering, why is it causally related? So actually this gene has also been implicated in nicotine dependence, and so the authors suggest that it might have a more general role in addictive behaviours rather than in something specific to do with cannabis.

Katie - Oh I see. So you might be at increased risk of getting addicted to stuff; in this case we're talking about cannabis.

Duncan - Yes. And in many cases actually substance abuse problems seem to co-occur with other sorts of psychiatric difficulties: things like anxiety disorder, or psychosis, or depression. And there's an emerging view within the field that there's what we call a hierarchy of genetic risk, and that there might be some genetic factors which put you in an at-risk category of developing some kind of psychiatric difficulty, but not specific. And then presumably there are other environmental or further genetic factors that, further down the line, will further specify the kind of psychiatric risk that you have. Because these individuals with cannabis use disorder, they were able to then test whether they have a higher genetic susceptibility for all sorts of other psychiatric conditions, so things like risk of schizophrenia, depression, ADHD; and it turns out that they do. So there's this emerging view that there's sort of a general risk that might be genetic, but that becomes further specified by different kinds of environmental influences.

Katie - How would knowing that you have an increased risk help you if you were at increased risk of addictive behaviours, or getting addicted to cannabis?

Duncan  - Gosh that's a very good question. So the current model that we have for identifying and supporting people who have psychiatric difficulties is under massive strain. And in fact some people would say that it's failed altogether. And one of the reasons that it's under massive strain is because it's what we call a reactive system. So we wait until someone develops some symptoms and then we think, right, how can we help that person. And what lots of health care systems worldwide are trying to move towards is a proactive system, where we identify people who are at high risk - in advance of them developing their symptoms - and try and put in place preventative measures or strategies that might reduce the overall symptom burden in the population. And that's why these kinds of studies are really important: because we don't really know what are the main kind of risk factors for these different kinds of disorders. And that's why establishing what the genetic susceptibility might be is really, really useful. Because it means that in the future we're able to move to more of a preventative model rather than this kind of overwhelmed reactive model that we've been sticking with.

Helen looked at a paper asking whether access to green spaces can curb cravings...

Helen - Based on the past research that being in green spaces or seeing green spaces can reduce your negative affect, they wanted to say, well if there's a strong connection between negative affecting cravings, will exposure to green space help to reduce the frequency and strength of any cravings you're feeling? They surveyed 149 people across southern England. They measured their levels of depression, anxiety, and stress - so their negative affect. You would have to identify something that you found as an object of desire, so something you crave; and not surprisingly it was things like chocolate, and alcohol, and cigarettes, and coffee. And then they also measured people's local exposure to nature. So we could look at your postcode and see how much green space you have access to, how much green space you could see out your window, and they also looked at whether you had access to a garden or allotment on a daily basis. And they found having access to greener views from your residence and also having access to a garden or an allotment did significantly reduce the frequency and strength of any cravings you were having. So they found statistically that this was very much driven by a reduction in your negative affect. Any sort of access - even passive access to just viewing green spaces - reduced your negative affect, which in turn had the knock-on effect of reducing your cravings, which is what they expected to find. I mean I really would say that if you are struggling to get on top of your cravings, being outside or frequently viewing nature can have a nice effect for you.

Katie - So do we know what it is about looking at trees or green that has this effect?

Helen - I look at access to green space from a cognitive restoration perspective. So we know that if you're exposed to nature you will actually perform better on mental arithmetic, on vocabulary tests, a range of cognitive tasks. We think this may be something to do with the mental load associated with being in a built environment. So for example, how many things your eyes land on in a built environment is a lot higher than in a green environment for most people. Or it could be a more associative thing, so being in green spaces for a lot of us means we're not actually in work, we're away from perhaps the things that would be bothering us most and taking up a lot of emotional and cognitive space. We're not entirely sure what drives the effect but there's a lot of different hypotheses being tested. I would have liked them to also look at this cognitive restoration. It's tied into so many things around cravings like self-control, impulsivity... it would have been really neat to see whether the exposure to nature was driving the reduction in cravings through just the reduction in negative effect, or also through that increase in cognitive control, that restorative effect. I would also say about this study: it's very difficult, if you're going to talk about access to a green view from your home for example, or access to a garden or allotment, it's very difficult to disentangle that from socio-economic status. In general addictive behaviours, a higher proportion of addictive behaviours are associated with lower economic socio-economic status. And the authors didn't really address this. They did measure people's educational attainment level and they said that wasn't really connected with any of the findings, but they didn't delve any further into that. And I think it will be very difficult for us on the basis of this study to say there's a causal relationship between passively viewing green spaces and a reduction in cravings. However when we take this study in conjunction with all the other literature that has more carefully controlled for socio-economic status, we can fairly safely say that there is something happening when you're exposed to a natural environment, even possibly whether it's emotional or cognitive.

Kid smelling something bad and holding his nose

12:10 - Smelly Naked Scientists

What scents do The Naked Scientists love or loathe?

Smelly Naked Scientists
with The Naked Scientists' office

What scents do The Naked Scientists love or loathe? Katie Haylor sniffed out the answer!

Heather - I really like the smell of cut grass. I always feel really bad for people who have hayfever because they can't appreciate that spring smell.

Ankita - Definitely the smell of baking something with tons of butter and sugar and cinnamon. Just all of those smells.

Matthew - I actually really enjoy the smell of fish, like out in the ocean. I grew up on the ocean, though. I really like the sea breeze.

Phil - My favorite smell is peanut butter in some sort of baked thing. So like a peanut butter cookie. I'm getting a lot of angry glares... OK, least favorite smell: I really hate the smell of aniseed.

Emma - The smell when petrol spills. Just makes my nose tickle.

Matthew - Yeah, I'm not a fan of lavender at all. I can't... nope! Get it out.

Heather - I think it brings back memories of: we had a lavender plant in my garden and it was always covered in bees, as a child, and so I think I have this fear of the smell of lavender.


How does smell work in the brain?
with Elisa Galliano, Cambridge University

What actually is a smell? And how does it get into the brain? Katie Haylor sniffed out the science with neurobiologist Elisa Galliano from Cambridge University...

Elisa Smell is what we perceive in our brain. It's not so much a chemical molecule, a chemical substance; it's the way in which our brain makes sense of all the chemical substances there are in the environment around us. We need to first detect them - there is a part of our nervous system that will recognise them - but then we need to make sense of them. There is specific molecule that makes the smell of banana, for instance; from there to the concept of banana there is quite a lot of processing that needs to happen in the brain, and that's what we call a smell.

Katie - So say a bit of banana gets into the air, it floats across, it wafts around your nose... how does that actually get to your brain?

Elisa - In the nose there are specialised neurons called olfactory sensory neurons. These are very, very long neurons. They have some sort of tentacles called cilia, and this is where the bit of banana gets stuck and activates this neuron. They become overexcited and they send this information like, "look, there's banana," down into the brain. This information about banana gets processed by different brain areas. The first one is called the olfactory bulb which sits at the bottom of your brain ready to receive information from the nose, and then there are other areas in the cortex, specifically the piriform cortex. And where all these neurons in this area do their processing and their work, there in the piriform cortex is probably where the concept of banana, the idea of 'banana' starts taking place.

Katie - So in order to get these electrical impulses rocketing up into the brain, does that mean there are specific receptors for specific smells? Because there's a lot of smells...

Elisa - That's exactly right. And if you can think of smells like keys and the receptors as locks, there are lots of keys and so we're gonna need lots of locks. And those are the ones that are expressed in the epithelium in the nose. And each single person expresses a completely different set of them. So not every single nose is the same. Genetic variation and mutations, events that happen in your life, can really change the composition of your nose. So that's why the same chemical, the same substance, does not necessarily smell the same to different people.

Katie - So could that explain why for instance I love banana, but I know one of my friends detests it and will actively leave a room if someone is eating a banana?

Elisa - Absolutely. So your friend could have a different set of receptors, but also - and this is very important - the smell, being a perception, is very tightly linked to our emotion and experience of the first time that we were introduced to banana. Probably you were given banana by a teacher, or one or your parents, and they told you that it was yummy and it was quite sweet, and it was a good day. But if your friend for instance who had the same receptors as you, or similar, ate the banana and then immediately after had terrible stomach flu; and then this idea of banana becomes tightly linked to a very unpleasant feeling and the smell will bring back this unpleasant feeling.

Katie - So there's the detection of the chemical or the chemicals, and then there's how the brain interprets that information. And what you're saying is those are two different things, right?

Elisa - Very different. The detection happens in the nose by these olfactory sensory neurons, and the perception happens higher up in the brain. And because those areas in the brain are very closely related to the areas of the brain that encode for emotions, and associations, and memory... that is why odours have such powerful emotional attributes to them.

Katie - Now I believe I have a better sense of smell than anyone else in the Naked Scientists office. I've been referred to as a bloodhound, and I want you to put me to the test. So what exactly have you got, this contraption that's sitting in front of us?

Elisa - This was a task that was developed by my colleague Dan Rokni when we were both in Venki Murthy's lab at Harvard University. We do this with mice. I'm gonna ask you to smell a small bottle which contains a pure chemical, one single odour, and you're going to have to learn it and remember it. And then you're going to have to go through the rack of smaller bottles. Some of them could contain the odour I asked you to remember and some may not contain it. But to make it even more difficult, some bottles that I'm going to ask you to smell will contain only one odour. Other bottles will contain up to five. And I want to see... if you think you're a bloodhound you should be able to spot your remembered odour even in this more messy situation.

Katie - Feeling a bit intimidated now. But this is a bit like an olfactory cocktail party, right? My task is to differentiate a combination of smells - rather than voices in a loud room - and I need to pick out one particular smell from many. Is that the idea?

Elisa - Yes, that's the idea.

Katie - Okay, well I'd better smell the target smell then.

Elisa - There we go.

Katie - It's really nice! It's quite sweet. Okay, I think I've got it. It's kind of fruity and melony maybe. So this is the first test.

Elisa - It's the first small bottle. And again you don't know - because I'm not telling you - if this bottle contains the target odour or no target odour, only one, or up to five.

Katie - So this is bottle A?

Elisa - Is the target odour - the one that I just asked you to remember - in here or not?

Katie - Here goes. No, I think I know what that is. Am I allowed to say?

Elisa - You can.

Katie - I think it's DEET. I think it's an insect repellenty-type thing. I'm feeling quite confident so far.

Elisa - Let's continue with the second bottle, which is gonna be bottle C.

Katie - Oh that's nice. Smells a bit like sweets. I reckon it is in there.

Elisa - Okay halfway, two more bottles to try. Bottle E...

Katie - Hmm, bottle E I'm not sure about. I'm gonna suspend my my answer on that one.

Elisa - Okay. And then the last bottle is bottle H.

Katie - That's absolutely got it in it.

Elisa - Do you want to have a smell again of E?

Katie - Yes. On second smell, no I don't think that has got it in it.

Elisa - Alright. Here are the results. The first two bottles, as you already picked out, they were simpler and they only had one odour each. And the first bottle didn't have it, and you were correct; and the second bottle C had it. So again, the first two: both right! The following two bottles E and H had five odours each in them. So that's why it was more complicated. Again you got them both right. Maybe your colleagues have a point calling you the bloodhound of the office.

Katie - You're a smell expert so I'm going to take your word for that. Is the sense of smell capable of changing throughout our life course?

Elisa - Yes it is. Actually for women it changes every month if you're cycling. It's known that smell sensitivity is tightly controlled by hormonal fluctuations. This is work that has mostly been done in mice and not in humans. But you need to be a better smeller during the fertile period of your cycle because you need to select appropriate partners and etc, avoid predators, eat properly, especially when you're pregnant, and so on. Very, very interesting area of research that is now being investigated a little bit more, we need to look into this a little bit further. Your sense of smell can change for the worse if you have a viral infection, if you have a traumatic injury to your head; but it can also change for the better. There is this thing called smell training. It's a thing, as every sommelier or perfumer will tell you. So you can become a better smeller if you train for it. Like London cab drivers get better at navigating through London while they acquire the knowledge, which is the knowledge of all the streets in London without using a GPS, we can become better at smelling by daily training and exposing ourselves to a specific set of odours and getting better at discriminating, like similar to what we've done before, "is this odour A or odour B." But also what sommeliers especially do, it's quite difficult, you found it yourself very difficult when I made you smell the target odour: to describe it. Putting words to smell is quite challenging and it's very dependent on your culture, background etc. But you can train yourself by being able to label with words the odours more easily, and then perceive them better later on.

Katie - Okay. So I could train myself to be a better smeller. But is there any chance that I have got some sort of genetic advantage? Are some people just better at smelling than others?

Elisa - I don't know if you can define it as better or worse because it depends for which specific smell. But yes, as I was mentioning before, everybody has a unique set of olfactory receptors in the nose. It's very common for some people to lack one specific receptor genetically because they just don't have the gene. So they will not smell that odour. You could also just have more functional neurons or... we couldn't know until after a post-mortem. We shouldn't. You don't want to.

Katie - What does this mean for people for whom smells are their business? So say people who make perfumes. There's such a wide variety of smells and different people like different things, so I guess there must be lots of potential right, of different combinations?

Elisa - I think there is a terrible lot of potential. One of the main problems that they have is that when they're creating a perfume, they can't create a perfume that everybody will like. Because again as we were saying before, smell is a perception very much dependent on the cultural environment in which you were raised and you were exposed to. I read somewhere that the US military was trying to create a stink bomb that was universally repulsive, and they failed. Because there is no one smell that everybody finds repulsive. So yeah, it comes with great possibilities but also quite great challenges.


24:59 - Sniffing out disease

Incredibly, some people can smell Parkinson's disease...

Sniffing out disease
with Joy Milne; Perdita Barran, University of Manchester

Someone with a truly amazing sense of smell is retired nurse Joy Milne. Incredibly, Joy can sniff out Parkinson's disease. Katie Haylor spoke to Joy, and mass spetrometry expert Perdita Barran from the University of Manchester, to find out more...

Joy - My husband was 31, 32 and I began to smell a change in his basic male musk smell became quite different, it changed. I put it down to the fact he was a consultant anaesthetist in an enclosed environment, sweating and that and really he wasn't pleased about me going on about it so I was quiet and we just put up with it.

Katie - But now, University of Manchester scientist Perdita Barran and her colleagues have, using Joy's impressive nose, been able to identify a handful of biomarkers for Parkinson's disease which currently has no conclusive diagnostic test. First off, Perdita told me how her and Joy met.

Perdita - Well, Joy found us as she approached colleague of mine, Tila Kunar, at the University of Edinburgh, who's a basic scientists like me working on Parkinson's disease, and she told him that he should find out why people have Parkinson's disease smell differently. I have to say, we didn't really believe her at first. We thought that perhaps it was just an associated sense with the disorder movement of people with Parkinson's but we thought we better prove it, and we thought we'd better divorce the smell from the person and the motor symptoms. So we devised a test which got people who had Parkinson's and people who didn't to wear T-shirts and then the T-shirts were cut up and put into bags for Joy to smell way away from any patient. And, well Joy, you can say, she was right!

Joy - And yes, as a parting gesture I said you've cut them in half and I don't know which witch is which, will I put them back together again to the person? And I did.

Katie - Joy smelled 12 T-shirts: six were worn by people with Parkinson's and six were controls. And she got them all correct. What's more, she identified one control subject as having Parkinson's. This was labelled as a false positive but they actually got in touch later to say they'd received a diagnosis. So I asked Joy, what exactly does Parkinson's smell like?

Joy - It is a quite deep animal musk and it has quite a rancid smell in it when it's a little bit stronger.

Katie - Lovely. So having controlled for variables like sex or diet that could be separating the T-shirt wearers, and confirming that Joy really could smell Parkinson's, Perdita and the team took a closer look at where on the T-shirts these odours were actually coming from.

Perdita - So you might think it will be under the armpits; that's where we think people smell, but it wasn't. It was in the middle of the back underneath the hairline, and that's a region of our bodies where we excrete a lot of the oily substance called sebum. That's the place where when you're a teenager you get spots - face as well. So we then had to develop a test that could be applied to patients that would extract sebum from them and we would then waive volatile molecules from the sebum - that means the ones that go through the air - and so that's what we did.

Katie - Once Joy's sense of smell told them which molecules to look for the team were then able to put the sebum in a machine that essentially weighs different molecules, called a mass spectrometer, in order to define what molecules are there and in what abundance.

Perdita - We've been able to pinpoint four compounds, which are three of them upregulated and one of them is actually down regulated in people who have Parkinson's, and those molecules have been given back to Joy and she smells them and she smells the smell. So we now have four biomarkers that tell us whether someone has Parkinson's or not just from swabbing their skin.

Katie - The four markers in question are eicosine, hippuric acid, octadecanal and perillic aldehyde - quite a mouthful. These compounds are normally found in sebum but it's the quantities that could, the team hopes, mean these could form a diagnostic tool for Parkinson's disease. But could looking for the quantities of these compounds in sebum reveal anything about the severity of someone's condition?

Perdita - That's a really good question and I can't answer that now. There are definitely some patients who have a much stronger smell and much stronger signal than others. Definitely people at late stage Parkinson's the smell is stronger and the signal is stronger and we've really focused on people who are called "drug naïve". That means that they haven't yet been put onto medication for Parkinson's disease because we want to see how early we can diagnose it and actually those cohort have a very strong smell as well. So we think we will be able to go even earlier and that's where our research is taken us now, to see if we can diagnose people before the motor symptoms.

Katie - We don't currently have a cure for Parkinson's disease, but if we can pick up on it earlier the hope is that we might be able to make interventions to prevent the condition from spreading. But why should Parkinson's disease smell at all?

Perdita - We really don't know the answer to that. What we do know is that people who have Parkinson's do produce more sebum, and sebum is a nice oily environment which bacteria would certainly like to eat and colonise on. So it may well be that this is a signature based on the change in the microflora on the skin of people with Parkinson's, but why that smells I don't know.

Katie - And now to Joy. What's it actually like to have this ability?

Joy - It can be a curse but it in this instance it's a superb gift I’ve been given. And I feel that I really do have to use it because having lived with Parkinson's for so long I think now is the time. We have the science, we have the research, and with those together we could diagnose Parkinson's earlier and then look at the inflammatory process far before the motor symptoms come in. And I think that's so important.

Close up of a doctor's coat, with a stethoscope and a pocket full of pens

31:42 - Diagnosing a changing sense of smell

Can changes in our sense of smell say anything about our health?

Diagnosing a changing sense of smell
with Isabelle Cochrane, trainee doctor

Can changes in our sense of smell say anything about our health? Trainee doctor Isabelle Cochrane investigates...

Isabelle - From sniffing out food, to telling fresh from rotten, to catching a whiff of a sneaky predator hiding behind a bush, smelling is key to survival. In many animals, the olfactory system - which processes smell - is intimately connected with some of the most primitive areas of the brain. These areas are known as the limbic system, and are responsible for driving behaviours that we would often consider to be instinctive, such as feeding and mating. One component of this system is the hippocampus, which deals with associative memory: forging links between disparate pieces of information such as a specific location and a particularly tasty crop of berries. Another important part of the limbic system is the amygdala, which has a key role in the regulation of pleasure and emotion - another powerful motivator for behaviours of evolutionary importance. In humans, these links between olfaction and the limbic system are no longer as significant, as much of our behaviour is driven through conscious decision-making rather than instinct. But we all know that smell can be strongly evocative, with a particular scent bringing back a flood of memories, often with a strong emotional component.

For something of such importance in our evolutionary past, our sense of smell is perhaps a little overlooked in modern clinical practice. We don’t know much about what can cause a disorder of the sense of smell, and should this occur, we aren’t quite clear on how best to treat it. Nevertheless, anosmia (the inability to smell) and hyposmia (a weak sense of smell) are relatively common, with studies putting the prevalence in the general population at somewhere between 3 and 20 percent.

Usually people are born with a normal sense of smell and problems occur later in life, with the incidence of olfactory problems increasing with age. Most commonly people lose their sense of smell after an infection of the nose or sinuses, or due to allergic inflammation of the lining of the nose as might occur in hay fever. This loss is normally temporary, and resolves without intervention. However, in a small proportion of people the loss of smell can persist, particularly following a viral infection of the nose. Another cause of smell loss is head trauma. The olfactory nerve, which transmits signals from the cells lining the nose to the brain, passes through narrow gaps in the base of the skull, and is therefore very vulnerable to injury if the head is violently shaken or there is a fracture to the skull. Very, very occasionally, a loss of smell can indicate the impending onset of a degenerative neurological disease. Both Parkinson’s disease and Alzheimer’s disease are known to be preceded by a loss of sense of smell in some patients, sometimes by as much as five years - meaning that this can be the very first indication that something is amiss. Much more commonly, in up to a quarter of people who lose their sense of smell, no cause is ever found. This is known as idiopathic anosmia.

In some rare cases, some people are born with no sense of smell at all. This can be an isolated problem, or may represent part of a broader issue. Some people have the unusual experience of smelling much too much: in phantosmia, patients experience ‘phantom smells’, also known as olfactory hallucinations. This can occur in ‘organic’ brain disease such as epilepsy, and is thought to be due to abnormal nerve cell activity in an area of the brain called the temporal lobe. This phenomenon can also occur in the context of psychiatric disease such as schizophrenia, which is characterised by hallucinations - although these are much more commonly either auditory or visual.

Though it may not seem obvious, losing one’s sense of smell can have a real impact. Smell is almost as important as taste in stimulating appetite and enjoyment of food. People with a disordered sense of smell often struggle with eating too little, or indeed too much to compensate for the lack of enjoyment. Personal hygiene becomes a concern due to the inability to detect unpleasant smells, and this can affect personal relationships and confidence. Perhaps it’s no surprise that people with problems in their sense of smell are more prone to depression. Additionally, an inability to smell food that has gone bad, or to detect dangerous substances such as natural gas, leads to sufferers of anosmia to report greater levels of anxiety and feeling less safe than those whose sense of smell is normal.

So how do we treat someone who has a problem with their sense of smell? In inflammatory conditions such as allergies and sinusitis, or following infections, nasal steroid drops are often given - with some success. Surgery to the nose and sinuses is also commonly attempted, but the results of this approach are not always good. Patients who have lost their sense of smell following infection or trauma in particular can undertake a course of ‘smell training’, in which they are instructed to smell a number of different substances at regular intervals in an attempt to ‘re-sensitise’ their nose. There is some evidence that this can be effective if used regularly over a long period of time, although it is unclear if it works as well in other patient groups. For the unfortunate significant minority with idiopathic anosmia, as well as for sufferers of phantosmia, treatment relies much more on guesswork than solid scientific evidence, and is relatively ineffective.

However, olfaction is a field that is attracting more and more medical research, and with rapid advances in areas including gene therapy and olfactory stem cells, it may not be long before we sniff out a cure.


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