eLife Episode 47: BatNav, TB and Aspirin
In this eLife Podcast, echolocation in bats, chemical probes for open science, using aspirin to manage TB meningitis, brain topography, and combining science and parenthood...
In this episode
00:32 - How Bats Track Obstacles in 3d
How Bats Track Obstacles in 3d
with Melville Wohlgemuth and Ninad Kothari, Johns Hopkins University
How do our brains keep track of all the things around us? By studying bats flying around a specially adapted laboratory, avoiding obstacles as they went, Johns Hopkins scientists Melville Wohlgemuth and Ninad Kothari explained to Chris Smith how they've ventured where science doesn’t seem to have dared to tread in the past...
Mel - Well, first think about if you're driving on the highway and you are merging from lane to lane, passing cars. You're trying to figure out where you are with respect to those vehicles, and you're trying to move forward so that you don't hit those vehicles, so you have to pay attention to one vehicle move around it change your attention to another vehicle and move around that. And this is a very common thing that we do quite frequently in everyday life, but it actually has not been studied in great detail. Very few studies actually record from the brain of an animal as it moves through space and attends to different objects to avoid them as it's doing their motion. So we found the echolocating bat to be an ideal animal for this particular study because we can train them to fly and navigate around obstacles much like they would in the wild when they're hunting and foraging for insects.
Chris - So, Ninad, how did you actually do this?
Ninad - So the way echolocating bats function they produce very loud, intense high-frequency sounds, which travel into the environment from their mouth; when they hit obstacles, some of these sound energies are reflected back; the bat listens to these echoes that are returning. And this is how the bat can form a three dimensional image of the environment that it is flying in. One very surprising and very interesting thing about echolocation is that it enables bats to estimate extremely accurately - as accurate as one millimetre - the way bats do this is they record when they produce the vocalization, and they record the time when the echo comes back. The time delay gives the bats an accurate measurement of how far an object is.
Chris - But do we know where that - for want of a better phrase - that neurological radar screen is playing out in their nervous system and, when there are blips on that radar screen, how the bat is encoding those blips so it knows where the objects or obstacles are and how they are moved relative to the bat as it flies around the environment? How do you try and probe that?
Ninad - That is where we go into the methods, and so a lot of research in the past has looked at this brain region which is called the superior colliculus. Past research has shown that this midbrain region - the superior colliculus - encodes for two dimensional space; it not only makes a sensory map of the region around the animal, but it also enables the animal to direct its gaze to locations in space. And so that is why we decided, in order to understand how the brain actually represents three dimensional space, to look at this brain region.
Chris - So what did you do, put some electrodes into that region so you could eavesdrop on what the nerve cells there were saying to each other?
Ninad - Exactly. So what we did is train the bats to navigate in a room around obstacles. Now once the bats are trained to navigate in space, we put electrodes in the superior colliculus. We now have a real time view of what the neurons are telling each other and now we are faced with a problem that's how you understand what stimulus, or what echoes, the bats are experiencing as they're flying around.
Chris - Because what you're recording is a bunch of electrical impulses coming off different nerve cells and they're going to change as the bats fly. So presumably you've got this problem: you've got to marry up where the bat is relative to each of the obstacles to then look for some kind of association between the bat in a certain position and the obstacle in a certain position, and it producing a specific and characteristic change in the nerve activity, so you can tie all those things together?
Ninad - Exactly. So in the flight room we have high speed motion capture video cameras, so we put markers on the bat's head, and as the bat flies around we can now get the instantaneous three dimensional position. In addition to this we can also get exactly where in space the bats head is pointed. So once we get the head direction of the bat, we can now record the ultrasonic vocalizations of the bat. So we have an area of 32 ultrasonic microphone channels which are lined all around the room. So wherever the bat flies we can record sonar vocalisations; wherever the bat is in space we can record its position and its heading; and now it is basically going back to a mathematical model, which we call as the Echo model, and now we can start asking questions like how do the neurons in the superior colliculus create a map of three dimensional space in the bat's brain?
Chris - And Mel, do you know the answer to that? How do the neurons in the superior colliculus - based on your recordings - seem to be encoding where the bat is?
Mel - When we actually have the bat fly in three dimensions, what we find is that these neurons in the superior colliculus fire for unique locations in three dimensional space; so if the bat is at a particular orientation with respect to one of these objects, there are neurons in the superior colliculus that fire when these objects are at a particular horizontal elevation and distance location with respect to the bat?
Chris - So is it tunable? Obviously the bat's not always going to be in your room. So there's going to be a different set of stimuli, in a different set of locations. So all these relative to the bat's present location, these cells, that fire off when the bat is at, say, 2 o'clock and five metres from something there will be a bunch of cells - a population - that will go off like a machine gun when it's in that orientation, in that position?
Mel - That's exactly right. So we talk about it being responsible for keeping track of egocentric space, and like the name suggests ego-centric is centred on yourself. So this particular part of the brain the superior colliculus it's all about the relative location of objects with respect to the animal, and that's why Ninad was saying that we were reconstructing the head aim of the bat, because as you move your head around the position of one object in space is going to change with respect to you. So we always need to know where the bat is with respect to these objects as it flies around in order to reconstruct the three dimensional tuning of these neurons in the superior colliculus. So it doesn't really matter what the object is, it's just whether an object is at a particular distance horizontal and elevation location with respect to the animal.
Chris - Ninad, what does the bat do with that tuned signal from a superior colliculus? How does that in turn translate into better attention for that target on the part of the animal?
Ninad - That's a very good question. So the superior colliculus is a very important part in the attention network. It sends out projections to the frontal cortex and it also sends projections to the motor nuclei, which actually drive behaviour. So now you can consider the superior colliculus computing this three dimensional information. It can send this to the cortex for further planning behaviour; and the sort of continuous feedback between sensory input and the superior colliculus back into the cortex can now help the animal plan its next movement, or the next location where in space it needs to pay attention to...
08:20 - Chemical probes for Open Science
Chemical probes for Open Science
with Susanne Müller-Knapp, Goethe University, Frankfurt
In the domain of cell biology it’s proteins that make the world go around, and if you want to know what a specific protein does, one of the options open to you is to try to turn it off. And there are compounds on the market that purport to do just that. The problem is that these inhibitor molecules are notoriously “dirty” in their actions and can produce off-target effects that can distort the results. Now a number of pharmaceutical companies that do have good quality protein inhibitors, probes and control molecules have got together to share their compounds with the scientific community to try to clean up the published literature. Chris Smith spoke with Susanne - Müller-Knapp, at the Goethe University in Frankfurt, where she is heading up the initiative…
Susanne - These compounds they come from the pharmaceutical industry, and for many years the pharmaceutical industry has been rather closed, and so these high quality compounds they have generated existed but they have not been available. In more recent years these compounds are available through commercial vendors, but not all of them; many of them are just hidden in patents, and if you don't have any chemical synthesis at hand, although this may be a very useful tool compound, the common biologist do not have access to these compounds. Importantly, also what we are providing in this project is a control compound very similar in the chemical structure to the actual compound but lacks the on-target effect of our probe compound. Only with this pair can say with certainty that you're actually hitting your target or the effect you are seeing is owing to inhibition or activation of your target of interest.
Chris - So this is going to be powerful then, because you'll be able to enable scientists to do new science - looking at these targets - but also to clean up our existing data because we can use these non-active versions to see what "dirty" effects we may have accidentally attributed to these proteins in the past?
Susanne - Absolutely, and the literature is full of this contradicting results wrongly assigned to a target protein due to not well-characterized inhibitors. So often an inhibitor is claimed to be specific but has only been tested in a handful of compounds. But we now provide compounds that are very widely profiled - not only against the target, the target family, but also against known pharmacologically-active targets.
Chris - So how did you persuade the pharmaceutical industry to share these compounds with you so you can make them available like this?
Susanne - This was not our idea. It originates from the pharma industry themselves, and that's because pharma industry is reading the same literature as all academics. That means ideas for new targets to develop drugs originate from the literature and studies for sample from Bayer or Amgen has shown that when they try to reproduce published data, very often they fail to do so.
Chris - So actually, by sharing and sharing alike amongst the community everyone gets a benefit not just your own company but if you borrow everyone else's data you're benefiting from their insights too?
Susanne - Yes that's correct. It's basically to increase the knowledge and to increase the quality of science.
Chris - Now what's the actual mechanism by which you're doing this. How do people find the compound they need and then obtain the compound so that they can then deploy it at their experiments?
Susanne - We have generated a database, which we try to make very simple, so that you can find your compound; you can find at one glance the important characterisation data; we provide guidance on how to use the compound, because even the best characterized compound will give wrong results if you use it at too high a concentration; and we also have in the database a very simple way how to obtain the data: you basically click that you want to obtain the compound, and we will send the compound, including controls, to you.
Chris - Now how many compounds do you have on your database at the moment, and what mechanism is there to make sure that the library grows? Because, obviously, you've got a starting point: you have a certain number of chemicals - but there are going to be new proteins discovered, new functions discovered, and therefore new inhibitors discovered. So what's your plan for growth?
Susanne - So currently there are about 24 compounds in the database. This is from the first wave of compounds. There is a second meeting now, in June, where the second wave of compounds will be evaluated. So we hope to have about 70 compounds by the end of next year, all profiled and approved by the scientific committee, also, with this article, there is basically an appeal for other people to join the project to provide compounds, and it has already been successful. So I'm currently already negotiating with academic as well as new industry partners who are willing to provide their quality compounds with us.
Chris - How are you going to make sure it's sustainable, because it can't be cheap to be maintaining this archive of chemicals, growing the archive of chemicals, and then when someone wants some of them sending them off all over the world to researchers who want to use them?
Susanne - That is indeed a so far unsolved problem. We have had very generous support of the PDSP. The NIH has supported us. Even companies like Discoverx - Eurofins - have supported us. But we don't have a final solution yet how we will finance this project. So we are constantly talking to funders and I hope they understand that, with this way, we can improve the quality of research...
14:44 - Aspirin for Tuberculous Meningitis
Aspirin for Tuberculous Meningitis
with Guy Thwaites, Oxford University Clinical Research Unit, Vietnam
How one of the most successful and cheapest drugs ever made - aspirin - can make a dent in the morbidity and mortality of one of the manifestations of one of the world’s most common infections, TB, as Chris Smith hears from Oxford University's Guy Thwaites...
Guy - TB tuberculous meningitis is when TB, which is a common and well-known infection throughout the world affects the brain. It's a very serious infection. It kills or disables around half of people who get it. And what we wanted to work out was whether if we added aspirin to the standard treatment of this infection it stopped bad things happening as a consequence.
Chris - First of all tell us what is the treatment for tuberculosis meningitis and what is the rationale for adding aspirin? Why might that change the outcome for people?
Guy - Well there's two ways of treating tuberculous meningitis. The first way is to kill the bacteria that cause the infection, and to do that we give four or five different antibiotics or anti-TB drugs. These drugs are very effective but, when we start killing the bacteria in the brain, it causes the brain to get inflamed and that can cause really bad things to happen that can can harm patients. So the other thing that we have to do is to control that inflammation; and studies that we've done in the past have shown that if we give an anti-inflammatory agent, or steroids as they're called, in addition to the anti-TB drugs, we get more survival from this infection and better outcomes. So what we hypothesised was that we could further improve the outcome of these patients with this very severe infection by giving a very old drug called aspirin as an anti inflammatory agent. Aspirin has two effects. The first is anti-inflammatory - and that might help because if you kill the bacteria you get inflammation - and the second way is to prevent strokes, because of clots in the brain and those are the two reasons why we thought that aspirin might help people with TB meningitis.
Chris - So how did you do this. Is this a clinical trial that you did on patients who were diagnosed with tuberculous meningitis?
Guy - Yes this was a randomised controlled trial. So what we did is that we got adults, with TB meningitis, who were admitted to our hospital in Vietnam. We gave them the standard treatment, and we randomly allocated them to either receiving aspirin or receiving placebo; and the other thing that we did is that we wanted to see whether low dose aspirin was as effective as high dose aspirin,
Chris - And is the reason for looking at different doses of aspirin that, obviously, all drugs come with side effects and aspirin is no exception to that rule?
Guy - That's right. So one of the common side effects of aspirin, which many people will know because it's a very commonly taken drug, is that it can cause stomach upsets and more seriously it can cause bleeding from the stomach. And so we were a little nervous that if we added very high doses of aspirin particularly we'd get more bleeding from the stomach. So this was one of the primary outcomes from the trial. We really wanted to make sure that it was safe for patients to receive this drug in addition to the other drugs that they were receiving.
Chris - So what were the outcome measures of this study? You've taken the patients you've randomised them to aspirin at high dose aspirin at low dose or placebo. What are you looking for over the follow up period?
Guy - So this is what we would describe as a Phase 2 study. So this is a study that explores whether it's safe to give a particular drug or treatment and whether it's likely to be effective. But it gives doctors an idea and it gives researchers an idea whether or not this is going to be a safe and effective treatment. So we had two measures that we were interested in. The first one was whether or not it caused increased bleeding from the stomach. And the second one was whether it reduced the number of brain infarcts - or dead areas of the brain - as a consequence of the infection, and survival from the infection itself in the first 60 days of treatment.
Chris - What was the result. That's the key thing. What did you find?
Guy - Well the result was that it's appeared to be safe. There was a very small - probably just occurring by chance - increase in the number of small minor stomach bleeds; but what it did do, it seemed, particularly in those people who definitely had TB meningitis - in that we were able to grow the bug from the brain fluid - in that group it seemed to reduce the number of brain infarcts, and it seemed to increase survival.
Chris - Do you still think on the basis of the measurements you've now made that the aspirin is working the way that you thought it might?
Guy - Well one of the things that we did is that we measured the substances in the brain fluid that might go up or down when you give aspirin. And what we found was very very interesting, because we found that the substances that might reduce the body's ability to clot blood, that substance was very very low and those people who had high dose aspirin, suggesting that that was one of the mechanisms by which aspirin was having its effect. The other really interesting thing - and this is a completely new mechanism really for how aspirin might help people with TB and TB meningitis - is that it increases the amount of substances that help inflammation resolve. People have known for a long time that aspirin has an effect on inflammation and it reduces inflammation, but it's only been very recently that they've discovered these new molecules that help the body resolve inflammation, and we think that it's probably this way that aspirin had its really quite dramatic effects particularly at a high dose and this is really fascinating, because no one's ever shown this before in any form of TB but certainly not in TB meningitis.
20:22 - Shaping individuality
with Janine Bijsterbosch, University of Oxford
Over 100 years ago, neuroscientists showed that the surface of brain is carved up into different territories that each subserve specialised neurological functions. There are motor areas, pre-motor areas, visual areas, and somatosensory areas. Subsequently, brain imaging confirmed these findings and enabled scientists to build “connectivity maps” that highlight the relative strengths of the connections linking between different areas and this we ascribed to things like behaviour and IQ. But, like all these things, a new study shows that the devil’s in the detail and the concept might now need a rethink. Chris Smith hears how...
Janine - I am Janine Bijsterbosch, and I work at the University of Oxford. In the past years there's been a lot of interest in mapping out the strength of the connectivity between different regions in the brain, and this is typically done using an MRI scan where we measure a movie of the brain activity in different brain regions while subjects are just lying there and doing nothing in particular. And several studies have shown that this pattern of connectivity differs from one person to another person in a way that is meaningfully related to behaviour. And for this study we wanted to ask whether it is really these patterns of these connectivity strengths that are linked to behaviour, or whether there are other aspects of the MRI data that may be even more important.
Chris - And how did you approach that. What did you do?
Janine - What we did was to make use of a method that allows us to decompose or essentially summarise the data from one person's scan into a number of different features. So specifically we can estimate three different measures. The first one is the pattern of connectivity strength between the different brain regions, like I mentioned before; the second summary measure is the strength of the MRI signal: so the size of the signal in different brain regions. And the last measure describes the spatial layout of the brain regions. So essentially the exact shape and the location of where a region is in the brain.
Chris - And where did you get the data from?
Janine - So this was data from the human connectome project - so we used data from just over 800 individuals.
Chris - Men, women, young, old?
Janine - Men, women, all relatively young. So this is a young healthy population.
Chris - Okay so basically you take a large corpus of data that's already been generated and you're analyzing it in this new way where you can fix one of the things and ask how that varies when compared with the averages of the other two. And you work your way through those three features?
Janine - Yes that's right. So once we have those three different features that I described, we can fix two out of the three of them to the group average, so that they don't vary from one person to the next, and only allow one of the three features to vary across people, and that then allows us to ask the question of which of these three features of brain data varies the most across individuals and is most strongly linked to behaviour?
Chris - Because previously we would have said thats the connectivity but now you can actually analyse it in this new way, what did you find?
Janine - So we found that in fact it was not the connectivity patterns that were the most strongly linked to behaviour but instead it was the spatial organisation of the brain regions. So this means that the exact shape and the location of the regions in the brain is very strongly linked to behavioural factors such as intelligence and life satisfaction and drug use.
Chris - That's incredible isn't it. Why should that make such a difference. One would think that it doesn't matter where they are or necessarily how big they are but if they're really richly connected that was the prevailing thinking that should make all the difference, so why this totally 180 degree turn around?
Janine - Yes well that is one of the big questions that now follows up from our research and we're currently doing work to try and understand this better. There's a few different reasons why it could be; it could be something to do with the underlying anatomy of how the brain is organised between these different individuals. Or it could be something to do with how we represent how these regions interact with each other. So, for example, it might be that there are particularly overlapping regions that contribute to multiple networks in the brain that might explain these findings but this is an area that we're currently delving into further.
Chris - So what are the overall implications then? Do we have to sort of tear up our book of knowledge on how connectivity and behaviour go hand in hand and begin again, looking at it through the lens that you've created here?
Janine - Yes well I I think these findings are important for a number of different reasons and the first one is, like you suggest, that the methods that we currently use to estimate these connectivity patterns are actually quite strongly driven by the spatial layout of these brain regions. And this is quite important because typically we interpret these changes in the strength of connectivity measured with MRI in terms of the amount of communication that that exists between the different brain regions. However of course if those connectivity patterns are to some degree driven by the spatial layout, then that interpretation is incorrect so I think one of the implications of our results is that it really highlights the importance of separating out these different features from the MRI data more precisely in our analysis so that we can draw appropriate conclusions based on different measures.
Chris - And if we consider, just in finishing, people who are not neurotypical - people with Asperger's for example - where classically neuroscientists have said "look there's a connectivity difference in the brains of these individuals compared to what we would regard as normal," if you were to apply your techniques to those individuals what do you think you'd see?
Janine - Yes that's a really interesting question and a lot of studies are looking into whether we can use connectivity measures as predictors for quite a wide range of different psychiatric and neurological disorders. And our findings show that in healthy people the strongest link is actually between these spatial layout information and behaviour and so I think that's a really good opportunity to study whether this spatial information can also be used as a meaningful indicator in patient groups.
26:38 - Science plus parenthood
Science plus parenthood
with Susanne Franssen, Sanger Institute, and Daniel Fabian, University of Cambridge
What it’s like to be a scientific parent? In April 2018, eLife published a series of insights into the lives of researchers juggling the demands of lab work and a young family. Chris Smith went to meet Dan, Susanne and Clara...
Chris - Hello it's Chris here. <sounds of door opening...>
Susanne - My name is Susanne Franssen and I work as a postdoc at the Sanger Institute.
Dan - And my name is Daniel Fabian and I also work as a postdoc, at the University of Cambridge.
Susanne - - And we are at our flat where all three of us live. This is me. I'm the mum. And then we have the dad and our little daughter, Clara, who is almost one and half years old.
Chris - And dad, Daniel, what do you do?
Dan - So I'm studying evolutionary biology. And specifically how which genes are involved in determining the immune response to viruses and other parasites.
Susanne - I'm also doing evolutionary biology and in particular I'm looking at the genomes of parasites that are in the tropics.
Chris - So the pair of you are quite interested in infectious diseases and immunity and stuff? Because most people only discover what their immune systems are really for when they have kids.
Dan - Yes I can totally confirm this, in particular because kids don't have very good immunity. They get ill all the time and particularly when they start going in to the nursery.
Chris - So she's sort of nursery age. How are you sort of feathering in maintaining an active research life while also trying to fit around your first child?
Susanne - In the morning, we get ready, we have to get her ready. She's going to the nursery that is on site of the genome campus where I work. We go there, I leave her there, then I have some hours of research until the nursery closes. And then I pick her up and then we have to make her happy first.
Chris - Is it compatible with the way that you were working as an early career scientist before Clara came along?
Dan - I think it is quite different now, as you can imagine. We don't have as much time as before. For instance, I used to work almost every weekend. If I would be doing this, I would not have any chance to play with my daughter, or raise her, or help at home.
Chris - Have you changed how you work though? Do you find that you do less, but what you do do, you do better because you're more focused on what you do? Or do you think there has been a cost?
Dan - Yes. So I'm I think I've become more efficient since Clara was born, particularly, I know I have now much more limited time so I'm trying to really focus and try to get as much done as possible in the time that I have.
Susanne - For me, certainly. Especially because I have to bring her there and I have to pick her up because she works next to me, which is good. But of course it also means that really my time is limited to the time that she's there. For me, generally it also helps that my work is computer based so I can also do things from home. But especially in the beginning when she is small that is not so easy, because also in the evenings she's demanding and she doesn't want to go to bed as early. That can be different for different kids but you have to fit it into the time that you have.
Chris - Do you think that science is particularly unforgiving for parenthood? Or do you think it wouldn't matter what career both of you were in, you'd still face all these challenges, it wouldn't matter?
Susanne - For science, generally I think you have more flexible time when you start and when you end. And you yourself have to be more the one who's looking after that you're doing enough work, and that you progress in your project. But of course you also need to have a good career track, because usually especially when you're at an early career stage, you have to have a good track record to be able to get the next job in the next ladder where it becomes more and more challenging, basically. Also to some extent, it depends quite a lot on the working environment, which can differ between groups. And at my current work environment, that is quite good because my boss also has kids and he understands that sometimes it doesn't go exactly as planned, and that also helps.
Chris - Does your experience give you any insight into why we have this big problem, which is that we're really good at recruiting women into science at the PhD level; there are loads of people who do PhD's who are female, and then you look a bit further down the track and they're all gone. And many people say it's once you get to the time when you think about having kids that's when they all evaporate and vanish. Do you have any insights into why that happens?
Susanne - For us, for example it was initially that she was being breast fed so of course it was me. It's still the women to a larger extent that are looking for the children and have some of the disadvantages. But yeah I can clearly see that this is hard. And also there's an issue when it's hard in the beginning to bring really young children to the nursery and then you also often have the feeling "is it good for my kid?" especially when they're staying full days and are still quite small.
Chris - So you feel there's a sort of tension there? You know that you should be in the lab working but at the same time you don't want her in the nursery all day.
Dan - Well yeah it's it's a tradeoff between your career and how well you raise your kid. I think of course if you're not doing enough work then it's going to be bad for your kid, also in the long run they might need a bit more attention than when they are a bit older.
Chris - Well she looks pretty happy at the moment, do you think you're succeeding?
Susanne - Yeah. I think recently it's been going quite well, and also when they grow up you start to notice that they're having fun there. And you kind of at some point get the feeling staying all day at home with you would be maybe boring.
Chris - So what would be your advice or guidance to other people who find themselves in the same sort of position as you? Are there any "gotchas" or pitfalls or any things that you say "no don't be scared of that. That's something we were worried about but actually you don't need to be."
Dan - it's difficult, it always depends on the situation that you're in. For us we tried to plan having a kid, but then Clara came as a surprise. So I think one advice is that first of all if you can plan it, then you probably should plan it. But if you fail to plan it then you have no choice but to make the best out of everything, right?