Ears, hearts, and halting Huntington's
This month on the eLife Podcast we hear about why whale-watching boats are just too noisy, how oily fish combats heart failure, breakthroughs in halting Huntington's disease, and how your wiggling ears can betray your intentions...
In this episode
00:32 - Antihistamines halt Huntington's Disease
Antihistamines halt Huntington's Disease
Peter Mccormick, Queen Mary University of London
Huntington’s is a horrible, inherited neurodegenerative disease. The symptoms normally begin to appear in a person’s 30s and include abnormal movements and cognitive changes. They’re caused by the progressive loss from the brain region known as the striatum of a population of neurones that respond to the nerve transmitter chemical dopamine. Blocking dopamine to reduce the activity in the cells can produce some symptomatic relief, but the side effects of doing this are unpleasant. Recently QMUL’s Peter McCormick has found that, alongside the dopamine receptors on the affected cells, there are also histamine receptors. And blocking those secondarily quietens the response to dopamine and in experimental mice seems to halt the progression of symptoms, as he told Chris Smith…
Peter - We discovered several years ago that the histamine receptor can modify the dopamine receptor's ability to function. So we thought, could we take advantage of that characteristic and dampen the out of control dopamine via histamine?
Chris - How does that work then - is the histamine signalling to the same cells, and it's just having an effect on the way those cells respond to the presence of dopamine?
Peter - What we think is happening is we've got a histamine radio tower right next to the dopamine one. And by targeting the histamine with a drug, we can dampen the output signal of that dopamine radio tower, which doesn't allow it to signal as well. So it's running interference basically.
Chris - And why does this ultimately translate into a benefit for the disease process?
Peter - We think it slows down the ability of dopamine to signal and those neurons don't fire as much. So they're more likely to stay alive and not die.
Chris - So the disease process is still grumbling along underneath, you haven't affected that. But what you have done is to control some of the ways in which it impacts on the vulnerability of the cells that would otherwise die.
Peter - That's correct. So we're not specifically targeting the Huntington's protein, and we're not fixing the disease, but we are able to slow progression. And the hope is because there are quite a number of histamine compounds in the clinic, they might be repurposed for Huntington's.
Chris - How did you do this though? Presumably this is not a clinical trial yet. This is preclinical animal data.
Peter - That's correct. That's correct. So we have to initially show that our idea would work and sell. So we first worked in a cellular model of Huntington's and then we later took that to a mouse model of Huntington's. And then we later showed from a brain bank, human brain bank, that the same target of these two receptors together existed early on in Huntington's patients.
Chris - So that suggests that were you to translate this to humans, because the same target's there as in your experimental animals, it should work. But what sort of difference do you get in these animals with the rodent equivalent of Huntington's disease? What sort of a difference to the outcome and clinical course does your intervention make in these mice?
Peter - Yeah. So typically in this disease, especially in the preclinical model, you start to see neuronal death very early on. You start to see cognitive problems. So they have trouble remembering, short term memory, long term memory, spatial memory, and motor problems. All of those, we were able to reverse by treating with a drug targeting the histamine receptor.
Chris - And when you say reverse, does that mean as long as the animals keep taking the drug, they just don't manifest any of the usual signs of Huntington's disease?
Peter - That's correct. We saw no development of any of the symptoms of the disease, and we didn't see any neuronal death. And what was interesting is we did a very short treatment with these animals, and yet we could still see benefits a month after we removed treatment, suggesting that an early intervention with such an approach might really provide some exciting benefits.
Chris - The problem is that people who are prescribed some of these dopamine blocking drugs, describe horrendous side effects.
Peter - Yes.
Chris - Is there a possibility though, because the histamine receptors are there for a reason in these brain cells, is there a possibility that we're just trading one set of side effects for another and your animals are still going to manifest cognitive problems or at least emotional problems, perhaps problems even staying awake because you block these receptors?
Peter - Now we didn't go in depth in terms of the side effects. And that's certainly I think one of the questions that will have to come up. We didn't see also in the control animals any cognitive changes that were unusual. There certainly will be a risk. But I think that if you speak with a lot of patients suffering from this disease, it is quite debilitating. My prediction is these side effects would be much less than targeting the dopamine receptor itself.
Chris - And is that the next step to now formally evaluate this in a clinical trial with a cohort of Huntington's patients and put them on some of these antihistamines and see if you can change the progression of their syndrome?
Peter - First what we would like to do is select the right molecule. I think the molecule we used in our preclinical experiments was very effective, but there are other candidates out there that I would like to test in a preclinical model to just really make sure that we've got the right one before we go into humans.
06:24 - Boat noises disturb whales
Boat noises disturb whales
Kate Sprogis, Aarhus University
When Chris Smith was little, his Dad used to laugh at the young Chris trying to wrap his tongue around the line “a noisy noise annoys a noisy oyster”. But a new paper out this month argues that noisy noises annoy humpback whales. Do the boats that take tourists out to watch whales - despite respectfully keeping a safe and sensible distance - nevertheless disturb the animals and potentially jeopardise their health, and the long-term health of the industry itself…? Chris heard the story from lead researcher Kate Sprogis...
Kate - So my name is Kate Sprogis and I'm a Marine mammal researcher and I'm an Australian, but I've been based in Denmark. When we did this study, we were trying to find out if the noise from vessels or boats impacted the behaviour of the whales.
Chris - Which sorts of whales?
Kate - We studied humpback whales because around the world, they are one of the whale species that are most common. They're also the target for whale watching, because they're so interesting to look at because they do a lot of breaching and pectoral slapping. And so we wanted to see if the noise from the whale watching boats impacted their behaviour or not.
Chris - When you say noise, is that people being rumbustious and sort of revelling on deck, or are we talking about the underwater noise made by moving bits of boat propellers and so on?
Kate - We looked at the noise from the boat engines because the whales stay underwater for most of the time, and that's the noise that they're hearing, and how they perceive their environment is through sound. Whereas ours is primarily through vision. So we use our eyes to interpret our environment, whereas whales and dolphins that live under the water primarily use sound.
Chris - And how did you actually monitor the change in the whale's behaviour and do it in a way that meant that by doing that monitoring you weren't changing the outcome of the experiment?
Kate - So how we set up our experiment was that we approached the whale with the vessel and we played back different noise levels. And to determine if the way or change their behaviour or not, we actually flew an unmanned aerial vehicle, or drone, above the whale at all times at an altitude of about 30 meters and we recorded video. So then we could see if the whale had changed its behaviour or not.
Chris - What sorts of changes in behaviour were you looking for? How did the whales respond?
Kate - Through the drone video what we were recording are the number of breaths the whale would take, and we would also record if the whale began moving. They would normally rest on the surface, and then if there was a change in behaviour, they would increase the number of breaths that they took, but they would also start swimming away. And this was reflected in the drone video.
Chris - And putting all this together then, how does the different levels of sound map onto what the whale's response is?
Kate - When we drove past the whale and we played back a quiet noise, the whale would continue sleeping on the surface. Whereas when we drove past the whale and we played back a loud noise from the boat, then the whale would actually change its behaviour. It would start swimming away from the vessel. And if you put that into a whale watching scenario, what you actually want is the whale to stay there so that the tourists on board can see the whale in an undisturbed way and not in a way that you know that they're being disturbed from your presence.
Chris - How does this compare the amount of noise that you produced with the amount of noise that a whale watching tourist boat would make? Was this a relevant level of sound intensity that you're exposing these whales to, and then seeing them change behaviour in this way?
Kate - Yes. So the noise that we played back was a vessel noise and it was within the range of other whale watching vessel noise that we have also recorded the noise levels from.
Chris - In other words then the boats that are going out there to take tourists to go and look at these wonderful creatures are nevertheless causing them disturbance. Is that the interpretation, and we should therefore give them some guidance about how not to do that?
Kate - Yeah. So right now on the whale watching guidelines globally, there are no noise emission standards. So a loud boat can be whale watching a whale at a hundred metre distance and then a quiet boat can also be at that same distance. However, the loud boat is going to have an impact on that whale, whereas the quiet boat won't. So if we can encourage that whale watching boats are quiet boats, then this is going to have less impact on the whales than a loud boat would.
Chris - And can you actually offer them some guidance as to what constitutes loud and quiet?
Kate - What we recommend is that vessels be quiet enough that the vessel is around the ambient noise level within the area. So vessels should be able to be recorded within the area so that they know what their source level, or the noise level of their boat, is.
Chris - You looked at humpback whales. Do you think this is true of other whales that people go and observe as well?
Kate - Yes, it can be used for other whale and dolphin species because they also use hearing as the primary sensory modality as they're underwater. So if there is a loud vessel, then they're going to be able to hear that loud vessel instead of seeing that loud vessel. So if they're a whale that is resting on the surface, then they're most likely going to be disturbed by a loud vessel compared to a quiet vessel.
12:51 - Ears wriggling in response to sound
Ears wriggling in response to sound
Daniel Strauss, Saarland University
We’re all familiar with the way our dogs and cats move their ears about to tune in to the source of a sound. They do it using muscles attached to the external ear tissue. Modern humans don’t visibly do this of course, but we do still have scraps of the same muscles, and if you record the activity of these muscles, you can work out what they are paying attention to, as Eva Higginbotham heard from Daniel Strauss…
Daniel - Our far away ancestors moved a lot their ears to orient their attention. And in the course of primate evolution, we moved from a more nocturnal lifestyle to a more diurnal lifestyle, we became more eye-oriented, evolution just decided that we don't need to swivel around our ears a lot. But still, you know, there are these muscles, maybe they don't serve the original purpose, but they are still there. And so we measured the electrical activity of the muscles and we use the signals to decode attention.
Eva - So you saw that electrical activity in the muscles around the ears could indicate where the person was paying attention?
Daniel - Exactly. And we decoded two types of attention: one type is the exogenous attention, so this is what is driven by the physical world outside. And the endogenous attention, this is the voluntary attention - you know, when you say 'Oh, I want to pay attention to this, or I want to pay attention to that'.
Eva - Did you have to do different experiments then for the exogenous and the endogenous? Or could you do it altogether?
Daniel - Exactly. We did two types of experiments. One the person was sitting there in a chair, there was a chin rest. They had to read texts in front of them and they were surrounded by loudspeakers and while they were reading the text suddenly there was a sound coming front-left, front-right, or from behind. And this was the exogenous experiment because we wanted to see how this new surprising sound captured their attention. And in the endogenous experiment, we played two stories either from the two front speakers or from the two speakers from behind. And the participants had to focus on one of these stories.
Eva - What did you find in those experiments?
Daniel - We found out that the activity of the muscles that we just mentioned before, really pretty nicely indicates the direction in which a person is paying attention to. And it was really all the time there, this effect of the ears trying to move in a way to this particular direction. So there was this sustained activity over a longer period of time, basically for the entire listening period. And this was a way surprising result for us.
Eva - And does the electrical activity in the muscle mean that the ears were actually moving? Like were the ears twitching trying to get closer to the source of the sound, is that what you saw?
Daniel - Exactly. We had a stereo-vision camera set up - stereo vision means we had two high definition cameras on both sides. So each ear was monitored by two cameras. And the stereo vision allows us really to see, you know, the movement in the three dimensional space. And indeed we observed these movements in some subjects. We used also a technique called video magnification that allows you to see the movements a little bit better than the original video. In some subjects, we really saw pretty large movements and they are really correlated and consistent to the muscle activity. So you really see the nice correlation between the muscles being active and the ear moving this direction.
Eva - That's really amazing! So now we know that our ears are moving in response to where we're paying attention, what can we do with that information?
Daniel - There is an application if you talk about hearing aids. You know, modern hearing aids have these directional microphones. So they should amplify the sounds in a particular direction. If you are in a conversation you look at somebody, but then you listen to something here, maybe you focus your attention over there, and this can be realised by this technology. So this directional microphones really follow the listening intentions of the user. So there's a way friendly human-machine concept. You know, you really have your intentions and the machine does what you want. It's really, I think a big promise for our findings here.
17:39 - Trimethylamine oxide cuts heart failure death
Trimethylamine oxide cuts heart failure death
Marcin Ufnal, Medical University of Warsaw
Oily fish is claimed to cut the risk of cardiovascular disease. Indeed, populations with a high fish diet do have a lower heart disease risk. Why though, remained a mystery. Now researchers think that one molecule - trimethylamine oxide -TMAO - might be the key. But it has a chequered history, because previous work had labelled it a metabolic bad boy. Turns out though that that was incorrect: the finger had been pointed at the wrong molecule. And, as Chris Smith heard, Marcin Ufnal has instead discovered that TMAO is powerfully protective against heart failure, an effect it achieves by acting as a diuretic to reduce the workload on the heart and prevent fibrous tissue from stiffening the muscle…
Marcin - So our interest in trimethylamine oxide started a few years ago, when a paper was published in the New England Journal of Medicine that people who suffer from cardiovascular diseases have a high level of trimethylamine oxide. And we were wondering, how is it possible? Seafood has a lot of trimethylamine oxide, and at the same time, if you eat seafood it's good for your health. So in the next series of experiments, we found out that trimethylamine oxide actually is beneficial. Whereas what is harmful is its precursor trimethylamine, and trimethylamine is changed into trimethylamine oxide by our liver.
Chris - What is the trimethylamine oxide doing in the seafood then?
Marcin - Trimethylamine oxide is called osmolite. So it protects cells of animals from high osmotic pressure and deep sea animals from hydrostatic pressure in deep waters.
Chris - Is there potentially then a role for it in human health? Because there are certain tissues in our body which do from time to time or periodically moment to moment experience extremely high pressures. And relevant to the cardiovascular system, I'm thinking every time my heart beats, especially if I'm running around, it's going to develop extremely high pressure in the muscle cells. So could this have a role in protecting the muscle cells then from those high pressures?
Marcin - Well, actually this was our hypothesis, but our experiments show that actually it's not the correct pathway and the beneficial effect of trimethylamine oxide seem to be associated with osmotic pressure. And in our case, this was like a rat model of heart failure. They accumulate too much water and too much salt. So giving trimethylamine oxide, we increased excretion with urine of salt and water. So actually trimethylamine oxide works as a diuretic.
Chris - Talk us through the experiments you actually did then to prove that that was the case in your rats.
Marcin - We performed two experiments in rats with hypertension, and in two models of heart failure. And in both experiments, we treated rats with trimethylamine oxide for one year. The rats were given this trimethylamine oxide with drinking water. We tried to give them a dose that would be similar to the dose of trimethylamine oxide that would be consumed if you were just eating seafood all the time.
Chris - And then you're following up the rats to see if there is an obvious morbidity and mortality outcome difference in the animals that eat the normal rat chow versus the animals supplemented with what would be rat seafood?
Marcin - Yeah, and it was really striking for us. Rats that were receiving trimethylamine oxide all survived, whereas in a control group, only 66% survived. Also other parameters, such as blood pressure, were lower in animals on trimethylamine oxide.
Chris - How did you link the outcome - this dramatic reduction in mortality that's a third down that's very considerable - how did you link that to it being the trimethylamine oxide, the TMAO? And what mechanism do ascribe to it to cause that dramatic reduction in mortality?
Marcin - In both of these experiments we observed increased urine output. And we were wondering whether this might be related with the final outcome. So we designed another experiment in which we looked at the effect of trimethylamine oxide on urination. And we found that rats that were treated with trimethylamine oxide acutely with higher doses had significantly increased urine output, significantly increased excretion of water and excretion of sodium, which was very similar to what we observe after administering drugs that are called diuretics.
Chris - What did this do to the heart itself? Because we know that if you look at heart tissue in people with heart failure, there are various changes that happen over a period of time, which is alleviated by taking drugs like diuretics to reduce the amount of load on the heart, but there are other changes that happen - the heart remodels itself to compensate, doesn't it, so do your rats also respond in the same way to the TMAO when you give it?
Marcin - Yeah. These rats had lower fibrosis. So in general, when you have a failing heart, the cardiomyocytes, the muscle tissue is substituted by other tissue - by fibroblasts. And in our rats that were treated with trimethylamine oxide, we had lower fibrosis and we also had better parameters, haemodynamic parameters of the heart.
Chris - Do you think that this could translate to humans then? Obviously it suggests that the reason people who have a very seafood rich diet, and I'm thinking people in Japan, people who are Inuit, people who have a correspondingly low level of heart disease might be our natural experiments already happening. But do you think that this could be a therapy for humans?
Marcin - I hope it could be a supplement for a diet that does not have it. We could start with doses that will be just similar to doses that are taken by people who eat a lot of seafood.
24:42 - Getting your professorship
Getting your professorship
Amanda Haage, University of North Dakota
So you’ve got your PhD; you’ve done a post-doc or two, and you’ve pumped out papers and pimped your CV so it’s a resume to die for. Now you want that tenured post in your dream institution. So how do you get it? And are you making yourself as marketable as possible? As Chris Smith heard, Amanda Haage and her colleagues wondered exactly the same thing, but were frustrated by the apparent lack of transparency and mentorship in science, so they set up a survey to find out whether they were the only ones, and what really needs to change...
Amanda - We're going through and there's all these communities and Twitter and all these advice pieces out there of how you get that job. But there's no numbers. That's what we wanted - to make the numbers. So we made a survey from the people that are actually trying to be professors. We got them to put their numbers into the survey and then looked at the correlations and comparisons between different people.
Chris - And what does the survey show? What did it reveal?
Amanda - So the survey shows that essentially there's no super clear path to becoming a professor. Those numbers, all the little metrics from training help to a certain degree, but nothing is like a super good predictor of what it takes to be a professor. So there's no one clear path. There's a lot of different factors. One of the biggest ones that we saw was the number of applications you put in, has a strong correlate for how many interviews you get, which is then how many job offers you get: applying to more places helps.
Chris - How many people actually filled in the survey? And do you think that what you found is representative of the pool of people? i.e. It includes people who are successful, but also people who are not successful. Because, I put it to you, that if you end up with everyone who's disgruntled filling in, you're going to get a distorted picture. Or if you get everyone who's Einstein filling it in, you're going to get a distorted picture,
Amanda - Right! We got over 300 responses and it does have a bit of a survivorship bias to it in that our pool of those 300 people, about 60% of them ended up getting a job offer to be a professor, and that's pretty high. And that makes sense. Because it was born out of this peer mentoring group where everybody kind of knew they wanted to be a professor. So all those people they're already looking at this career and they're already kind of driving down this path. But I will say, even though we do have this bias, there was not a single positive comment about the process itself. Even though these are the people that are getting jobs.
Chris - And did any themes keep on emerging as repeatedly being said as 'this is a downside, this is a downside. this is a problem'. I.e. things that we could tractably say well, there's our intervention point.
Amanda - Yeah. We've had this conversation a lot. One of the things that was repeatedly reported was this lack of mentorship and a lack of feedback. There's, you know, trainees, they're working underneath someone that's supposed to help them become this professor. The people that are making the hiring decisions, aren't really telling people what they need to become that professor.
Chris - Is the survey, not just a bit one sided in the sense that, okay, you've got the opinion of people who have, or haven't made it, the people who are on the rough end of the interview process. Wouldn't a more valid approach be to go to the people who sit on these panels and ask them for examples where they've definitely got it right, and definitely got it wrong, because then you can see whether or not they really are asking the right sorts of questions. Because we've all hired people that we regret, I mean, it happens.
Amanda - Yeah. And I think that's a really interesting point. It's something we tried to get at a little bit. We did do a survey of hiring committees. And it's true, like the things that the applicants think is important and those metrics and those numbers of what the applicants have, didn't exactly match up with what the search committees say they value. And so that disconnect is a really interesting and a really important spot for improvement.
Chris - It's something though of a buyer's market, isn't it? And the market knows it.
Amanda - Yup. It's definitely trending in that direction. One of the things we say early in our introduction is that we're continually producing more and more people with PhDs and all of these people are coming out of this training, but the number of faculty positions has not really increased. So it's just kind of driving this hyper-competitive environment. We can just keep pushing the envelope of what we can ask. And we're seeing that with like papers that are published, that's been well-documented that the number of papers people are publishing at the point where they're applying to be a professor's like increased astronomically over the last 20 years,
Chris - Because on the one hand, science is the beneficiary. If you've got loads and loads of good people applying for jobs, you can have the pick of the bunch and you're going to get good people. So that's wonderful. But then on the other hand, my concern is if the system is driving people to think in the sort of way that the system is making people think i.e. I've got to have loads of publications, then people aren't necessarily thinking like a scientist. They're thinking strategically like a career person. And that isn't necessarily the same thing. And I think back to, I read John Sulston who got the Nobel prize for sequencing the human genome and the wonderful work he did with C. elegans, I read his book. At one very poignant point and he says he'd been in post for about 10 years before someone said, well, you know, really, we ought to write a paper about some of this work, John. You wouldn't see that happening today, and this is someone who went on to get a Nobel prize.
Amanda - Yeah, it's really interesting how much it's changed the landscape with this like hyper-competitiveness. And I don't disagree that we're maybe doing a disservice to science by making the super hyper competitive, hyper stressful environment. Because the other aspect that you see, a lot of people commented when we're talking about their feelings about the process, is anxiety. And I struggled with it when I was applying too is that we are taking these people that are super, super smart and just exhausting them and making them super stressed out just to get over this hump of trying to continue to have a career in science.
Chris - Well, I'm glad you brought that up because my next question to you was going to be when you're in the position of being on these panels now, you're going to be in a position to change things. So do you not think that because a lot of people have now come through this, been stressed to hell, okay, they've paid a high price, but now they're in a position to fix it and they will?
Amanda - Yeah, I really hope so. I plan to. Hopefully we get this generation of scientists, which I'm hoping is my generation, we all care about the culture change and then we all bring it forward with us as we go.