Born to Run: Sprinting Science

26 February 2019
Presented by Chris Smith, Georgia Mills.

BOY-RUNNING

a child running away from the camera into the sunset

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This week we get off the couch to talk about the science of running. What does it do for our bodies, and our minds? Why did we ever evolve to do it in the first place? Can a man outrun a horse? Plus in the news, a potential kill-switch for tuberculosis, landing on an asteroid, and we tackle the myth of alcohol warming you up...

In this episode

Mycobacterium tuberculosis (TB) bacteria seen under scanning electron microscope (x15000)

00:50 - Triggering tuberculosis to self-destruct

Can a suicide switch that causes TB to die be the next antibiotic?

Triggering tuberculosis to self-destruct
with Andres Floto, Cambridge University

A suicide switch that triggers the bacteria that cause TB - tuberculosis - to kill themselves has been uncovered by scientists in France. The discovery could enable scientists to develop a new class of antibiotic drugs that can trip this switch and cause the bacteria to die. This would also be a big help in combating the problem of antibiotic resistance. Respiratory specialist Andres Floto, from the University of Cambridge, who wasn’t involved in the research itself, took Chris Smith through the findings…

Andres - This group's been interested in understanding how to kill mycobacteria in tuberculosis, which is what causes TB, and what they focused on is a toxin-antitoxin system. This is a strategy that's used by lots of bacteria where they produce a poison, and at the same time produce an antidote. And what that means is that other bacteria that don't have the antidote will die. So what this group have found is that one of the toxin-antitoxin systems can be manipulated, meaning if you block the antitoxin then the bacteria die - and they've proposed that this is an exciting new way to kill tuberculosis.

Chris - So what... We would make some kind of drug molecule that would either activate the toxin or deactivate the antitoxin, so we push the bugs into, basically, committing suicide?

Andres - Absolutely. So the idea is by solving the structure of both the toxin and the antitoxin, understanding how they bind and neutralize each other normally, you can imagine that structure-guided development of a small molecule could block that interaction, allow the toxin to remain active and allow, as you say, the bacteria to commit suicide.

Chris - So this is - when you say ‘structure’ - the three-dimensional structure where the atoms are in three dimensional space, essentially?

Andres -  You're exactly right. It’s a three-dimensional structure and it's done by looking at crystals with x-rays. But once you've got that structure, you can see exactly where each atom is and how to block interactions.

Chris - And how did they uncover this in the first place?

Andres - They sequentially knocked out all of the genes in TB and asked the question: “which genes were essential?”, and it turns out that they’d knocked out one of the antitoxin pairs and by knocking out the antitoxin it allowed the toxin to remain unneutralized and hence the bacteria killed. So once they realized that this toxin-antitoxin system was so potent if you neutralized the antitoxin, they proved that if you induce the expression of the toxin on its own without the antitoxin, you kill the bacteria. They did that in liquid culture and perhaps most impressively in mice.

Chris - And that means that the strategy is sound to try to then activate such a system as a means of persuading these microbes to kill themselves?

Andreas - Right. It's a proof of concept experiment. I think the hard work now is to develop antibiotic-like molecules that can do this in real life.

Chris - Do they know how the toxin persuades the microbe to kill itself? Because that's another interesting part of the story, isn't it? Because if you can not just understand the toxin but also understand what lies downstream of it, you could plug into that downstream system to kill it too?

Andres - Yeah. So TB, like all organisms, relies on metabolism - that's the breakdown of nutrients in order to make energy. And one of the key components of that is this molecule called NAD. And what they found was that this toxin splits NAD and inactivates it and effectively starves the bacteria into death. So you're right, this is a really exciting mechanism of action for the toxin, and again may open up new avenues for new drugs.

Chris - Do we have anything that looks like it could be a candidate to do that? Because that molecule you mentioned, NAD, is it's ubiquitous in life isn't it? Many many systems use that, So by going after it, could we end up with a drug with lots and lots of side effects?

Andres - Yeah. So I think that's absolutely right. I mean, the beauty of the toxin is it seems to be specific for bacteria. They did quite a lot of studies looking at human cells and didn't really find an increase in toxicity in the human cells. Now that's very different from proving that it's safe, but it does kind of suggest that this may be a very neat specific way of killing tuberculosis.

Chris - And will it be specific just for Mycobacterium tuberculosis - what we call ‘human TB’? Because, obviously, if you wind the clock back, there are lots of humans who caught TB from cows - Mycobacterium bovis, its relative. Can it target more than just TB?

Andres - Yeah, no. So, in theory, this should be applicable across all mycobacterial species. There’s about 160 species that infect other animals, or in the environment and occasionally infect vulnerable people. And it may also have effects on other bacteria, so, more distant species of bacteria. So it's potentially very interesting

Chris - Because TB, not to put too fine a point on it, is a massive international scourge and getting worse isn't it?

Andres - It's a huge problem. I mean, the estimates are that about a third of the population have been exposed to TB at some point. There’s something like 10 million or so cases a year of TB, about 2 million deaths... so it's a big problem. There's been huge efforts and a lot of success, actually, in controlling TB. The big problem now is multi-drug resistant TB which is running at about half a million cases a year and is a real headache.

A picture taken by rover MINERVA-II-1 on the surface of asteroid Ryugu

06:18 - Hayabusa2: Successful touchdown on asteroid

Japanese mission Hayabusa2 begins collecting asteroid samples.

Hayabusa2: Successful touchdown on asteroid
with David Rothery, The Open University

The mystery of how our solar system came to be has puzzled scientists for centuries; how did life develop? And where did our water come from? On 22nd February 2019, a Japanese mission started to tackle those age old questions, as Izzie Clarke reports…

Izzie - In 2014 the Japanese Aerospace Exploration Agency, a.k.a. JAXA, launched Hayabusa 2 spacecraft, the size of a fridge, to explore a nearby asteroid that they hope can tell us about the materials that formed our solar system over four and a half billion years ago. Hayabusa 2 finally caught up with the asteroid Ryugu in June last year travelling in convoy until it was ready to take a closer look.

And now on Friday the 22nd of February the spacecraft began the task of collecting a sample of this rock to bring back to Earth. David Rothery from the Open University explained why this asteroid was so special.

David - Carbonaceous chondrites which is the type represented by this asteroid are meteorites which, when we find them on the earth, they wither away quite quickly because it's quite weak friable material so it's very rare to find really fresh examples. From what we have got we can tell it's very primitive material, it's not been heated or melted, so it's the building blocks from which all the planets have been made. So going to a fresh piece of carbonaceous chondrite material that hasn't been subjected to the Earth's atmosphere is going to give us untainted material from the birth of the solar system that hasn't been processed, so it's a great target for sampling

Izzie - Now what’s actually on board this Hayabusa 2?

David -  It's quite a complicated little spacecraft. There are cameras onboard, we can do a little bit of mineralogy from close range. But the spacecraft has got four Rovers on board, three of which have been deployed so far and they've been down to the surface and they've hooped around a little. They haven’t got any wheels, there’s not enough gravity to get any traction on the surface - they’re hopping around on the surface. The chief aim of the mission though is to bring back some samples and that's what's just been attempted for the first time. The rovers helped identify places that weren't too bouldery and had enough fine dust because the sampling technique is to bring the main spacecraft within touching distance of the surface. So a kind of horn device covers part of the surface and then they fire a pellet into the surface which kicks up some dust if you like, and some dust gets captured in the sample capsule which then is sealed and is brought back to Earth.

Izzie - Essentially, Ryugu is like a giant floating pile of rubble. Because Hayabusa II isn't able to land on its surface, it sort of floats above the asteroid waiting to scoop up any displaced rubble and dust as the pellet is shot into its surface. And if you think that sounds tricky, you'd be absolutely right.

David - The difficulty is that the dust you kick up is quite fine and not a lot of it, and you've got to hope enough of it gets inside your little capsule to be a worthwhile sample. That's a gamble, but any sample brought back to Earth is going to give valuable information because it will be completely fresh pristine material, at least fresh from space. None of these are the kind of material that you'll get from a meteorite that’s fallen to Earth because that's been subject to the Earth's atmosphere on the way in and however long it's been sat on the ground before being collected.

Izzie - The gravity on this object is not very strong so how challenging is that to coordinate a mission?

David - Well yes, it's a one kilometre sized body so the surface gravity varies negligible. If you land on it you're likely to bounce. The tiny rovers that have been deployed, they've done tiny little hops around but they're very leisurely hops so it's a very difficult object to get a hold of, and sampling it is a problem. If you go to the surface to try and grab something, all you're gonna do is push yourself away. Hence the sampling strategy to fire a pellet into it and catch some of the dust kicked off. Low gravity gives you quite a difficult environment to work in.

Izzie - But, all things going well in December 2020, that sample will make its way back to us on Earth. This mission isn't just about finding out how our solar system came to be. It's pushing the forefront of technology and trying to see how humans can take a sample from an object that's 180 million miles away and then bring it back. But how can some rock and dust reveal so much?

David - Well what you can do with samples on the ground is subject them to very precise geochemical analysis and, in particular, you can fingerprint where the sample came from. Different parts of the solar system are characterised by different signatures. And this is important for example to tell us where the Earth's water came from. It used to be supposed, for example, that a lot of the Earth's water was supplied my comets. But you may remember the mission to Comet 67P, the Rosetta mission, that measured the signature of the water in that comet and that doesn't match signature of the water in the Earth's oceans. So assuming that comet is representative, which is quite a big if, it suggests that maybe the Earth's oceans weren't supplied by water delivered by comets. Well maybe the Earth's ocean water was sweated out from hydrous minerals delivered by carbonaceous chondrites hitting the Earth. We'll get an idea of that when we've fingerprinted the material from Ryugu that’s been brought back by Hayabusa 2.

Smiling laptop

UK Invests hard in Machine Learning and AI
with Scott Hosking, British Antarctic Survey

The UK's leading science funding body, UKRI - UK Research and Innovation - announced a significant investment in artificial intelligence - or A.I. - based research. The purpose of the 200 million pound initiative which will be invested across the country is to help the UK to maintain its status as a world leader in this sector. Cambridge is one of the centres awarded funding where researchers are going to harness A.I. to enable them to sift through massive datasets looking for patterns that the human brain could never spot, in things like climate data and earthquake measurements. Chris Smith spoke to Scott Hosking,  a member of the initiative. Scott is at the British Antarctic Survey and he uses machine learning tools like this to understand climate change...

Scott - This is super exciting; this is an absolute game-changer for Cambridge and also the UK climate community. So our data sets are getting larger and larger year on year, and it's fantastic that we've got some extra help and these algorithms to help us sift through that data.

Chris - What will you spend it on? You’re going to get about six million Pounds worth of funding over, initially, five years with this aren't you? So how would you be managing the project? What are you going to spend the money on?

Scott - So this is a centre for doctoral training, so this is a five year project, which brings in 50 students over the five years, but hopefully will bring in more than that. We have all this industrial funding, so we have Google on board, and Microsoft, and there's over 30 partners in total. So this is big.

Chris - Okay so you're going to be effectively investing in the next generation if you're going for PhD students? These are early career researchers.

Scott - Absolutely. We need these new algorithms we need these new tools and we need to build that expertise first, so we are building the next generation of climate scientists that also have this machine learning artificial intelligence knowhow, which is something my generation didn't have.

Chris - So it's literally investing in the project; it's investing in technology and that sort of research and development, but also a strong investment in people?

Scott - A huge investment in people, exactly. And we'll benefit from that as the general public to improve our future climate predictions. We need these large datasets in order to look at extreme events. For instance, there's no point looking at a one in a thousand year event if you only have a thousand years’ worth of future climate data. So we really need to be running tens-, hundreds of thousands of years into the future and to do that we need fast climate models.

So one thing we're looking at is including AI / machine learning algorithms in the models themselves to speed them up. And also once we have all that data, how are we going to analyse it? As scientists, we really struggle to use traditional tools just to zoom in. If you're interested, for instance, in heatwaves in London, we may just zoom in over Europe but actually we should really be looking at all the data we have and look for those patterns in the data. Maybe there's something in Brazil, or a feature or something we've seen in the Arctic, which is very relevant to our climate, so we can feed all that in.

Chris - So - explaining to people just for a second how this actually works - when we're making predictions about what the climate is going to do in the future, is it fair to say you're essentially getting together enormous numbers of measurements - that might be temperature, it might be pressure measurements, it might be how wind speed is changing and pressures are changing on different parts of the Earth’s surface - I'm just speculating here - but then asking a human at the moment to try to spot patterns in all of that. Whereas, if you ask a computer to relentlessly go through and explore the relationships between all these numbers and all these enormous complexities, it will spot the needle in the haystack that we can't?

Scott - That's right. So the data not only is vast but it's also various. So we have all sorts of information - satellite data, climate model data, all with different variables, different weather variables say temperature humidity pressure etc. and just trying to picture that in anyone's head is just unfathomable. So we need those computer models which can build these really complex large matrices, multi-dimensional systems and search for those relationships, cross-validate things we may not even think is relevant. But actually if it does come out relevant that could be a game changer.

Chris - Now how does the A.I. or the machine learning side of it come into the equation?

Scott - So machine learning, sort of "under the hood", is just statistical algorithms that we've been using for decades. Learning is key here. All we're doing with these algorithms is looking for those relationships and providing an answer or a possible answer to a person. We're not doing AI at the moment because the I, the intelligence, suggests that we're going to do something with that data. Now in for self-driving cars the car needs to be intelligent to know whether to slam the brakes on. Our intelligence comes from the the businesses or the government officials that need to make those decisions. So the machine learning is that layer to provide decision makers with a robust set of tools, a robust set of analysis which they can make their decisions.

Chris - Researchers from many different fields are using these sorts of approaches now though aren't they? For instance in the last two years we've seen researchers take pictures of skin lesions and then ask a computer to learn what a healthy mole versus a potentially cancerous mole looks like. And by the time it's finished learning, it can outperform dermatologists who have been through umpteen years of medical school and board level exams to make sure that they're good doctors. So could this system effectively teach itself what to look for though?

Scott - Absolutely so these algorithms can do -  we can look at satellite images for instance, we could look at how disease spreads in forests, in vegetation, how different crops had their crop yields are suffering say to climate change and so these are things which the naked eye, are human eye, might struggle to pick out those signals, but a machine learning algorithm given enough data can see those signals.

Chris - And what does it then do with that information? Does it sort of flag to you and say “okay I've spotted this relationship, here's one that you need to now work on”?

Scott - Yeah. So we should never use machine learning as a black box and just trust the answer. You do need still maintain your expertise in climate science. Look at that information and say actually does this make sense? And maybe you'll go back to take a more traditional approach and build up a computer model to follow through a new theory.

Chris - I also mentioned earthquake data and things like that because I know that you're looking specifically what the climate has been doing will be doing. But you could take the same knowledge and the same approach, drawing huge amounts of information together to find out how this things and systems work, and apply it to many different things.

Scott - We can apply these algorithms all over the world so we can look at ice sheets and melting ice sheets and what that means for the communities in the Himalayas. There are 2 billion people that rely on this water. So these algorithms are an absolute game changer for people.

a blue Computer Generated outline of an embryo

19:56 - Mapping embryonic development

How do predict the earliest stages of human life?

Mapping embryonic development
with Bertie Gottgens, Cambridge University

At conception, a single sperm and egg meet and unite their DNA. And this triggers a developmental programme, controlled by our genes, that causes the fertilised egg - and the cells it turns into - to begin to divide. Next, the ball of cells this produces begins to specialise, with certain groups of those cells ultimately turning into different bits of the body. Sometimes this goes wrong, but because we don't know what genetic programmes are running in which cells, we don't know why or therefore how to fix it. On the flip side, if scientists want to grow replacement body parts in a dish, at the moment we don't know precisely what instructions to feed to the cells to make that happen. But now scientists at Cambridge University have done the painstaking job of reading the genetic instructions that are active in every one of the 100,000 cells that form right at the beginning of the development of a mouse embryo, including at the crucial time when those cells are deciding what to turn into. Bertie Gottgens…

Bertie - What happens is that the embryo grows from a really small number of cells. It's less than 1000 cells. In 48 hours it grows to over 100,000 cells and there is this explosion of diversity. When we begin the cells are unspecified they can turn into any cell in your body whether it's muscle, heart, blood, brain etc., and then within a period of just 48 hours they make decisions of what they want to become.

Chris - Huge, huge challenge though. Embryologist have been grappling with that very issue for about 100 years, so how did you attack it?

Bertie - The opportunity arose through new technology called single cell genomics. And what that means is from a single cell we can make really comprehensive measurements of what goes on in this single cell. Before we had to use millions of cells to do the same types of measurements. Now we can do it on single cells and this technology has really only become available in the last five years.

Chris - Talk me through then what it is you're measuring and how you're measuring it?

Bertie - Each of our cells has about 20,000 genes. These are the bits of our DNA that determine the function of the cells, and what we're measuring is the activity of all of these genes. And the amazing thing is that we can measure the activity of 20,000 genes in each individual cell, and the dataset that we generated has done exactly this in over 100,000 single cells.

Chris - Essentially, it boils down to then you are looking at very early stages of development? Looking at the cells and saying what repertoire of genes are switched on and by how much in these cells and how does that change as these cells grow, proliferate and also, critically, start to turn into things, make decisions about what bits of the future body plan they're going to be?

Bertie - Yes, and this is important for two reasons. What activity profile characterizes a cell directly tells us something about the function of the cell and how this function arises from an unspecified precursor. The second point is it also tells us if we are looking at a situation where there might be a developmental disorder, what's wrong with these cells now compared to normally. Now that we have these very detailed molecular profiles we can ask those questions that before were completely inaccessible to us.

Bertie - The other issue is we want to know how does this particular cell or population of cells know in inverted commas to say become an arm or become an intestine or become a future liver, and what messages are they passing among themselves to fix them to that fate but also tell them not to become something else? So does your system now give us a clue as to what some of those messages and signals and control pathways might be?

Bertie - In essence, not yet, because what our study has provided is a baseline of reference to, in future, ask exactly those questions. Because I think in order to get a solid answer to those questions we do actually have to look at mutations where, let's say, an arm can't be formed and then say what is now different specifically in terms of gene activities? So it is an essential and very vital reference point for us to then move on.

Chris - Now mice are very similar to us but there are also important differences. So to what extent can we take the sort of reference set that you've created and say well that's how a human works?

Bertie - You're absolutely right. And there are differences between mice and human. This period of development, which in the mouse is between six and a half and eight and a half days after fertilisation, translates to between 14 and 20 days after fertilization in human. This stage of human development is inaccessible to us. We can't study this. So we have no choice, at this stage anyway, than to turn to model systems. Mouse is a good model because we have access to a lot of these genetic mutations and they're often really good copies of human developmental mutation. The second important point is where this is then directly useful is if scientists want to grow in the lab organs such as muscle etc., they need to have a reference point of how does the animal make it, and this is what our reference map landscape provides. Let's look how it happens in the animal and then design our in-the-lab protocols based on that.

sparkling wine

25:35 - Myth - alcohol keeps you warm

Is a sip of whiskey to keep you warm a good idea?

Myth - alcohol keeps you warm

Now you may well have come across the idea of taking a slug of whisky on a cold day to keep out the chill. Maybe, you’ve even resorted to it yourself and thought at the time it worked quite well? Unfortunately we’re going to have to burst this boozy bubble, because it’s a myth. And here’s Georgia Mills with why...

Georgia - Oh that mean February chill. Why not have a few sips of whiskey to warm your cockles, and put fire in your blood. Alcohol is the subject of many, many myths.

It's anyone's guess as to why that could be, but the beer jacket belief is one of the more dangerous ones out there. Alcohol, far from warming you up makes you much more vulnerable to cold. In moderate amounts, alcohol is a vasodilator, a word designed so that no inebriated person could ever say it. It means that the blood vessels in your skin widen, which causes more blood to travel from your core to your outer surfaces. The blood brings heat with it and your skin is full of nerves and very sensitive to temperature change. So while your core temperature has actually got lower, from that warm blood leaving your brain is told you're feeling hotter. This alongside heat generated from the liver trying to break down those tequila shots can be a real treat for the odd reveler who forgot to take their coat to a party as they can skip merrily home unaware of the cold and presumably pass out in a bush somewhere.

Unfortunately being aware of the cold is a pretty solid survival tool. We have physiological and behavioral contingency plans in place to prevent us from getting too cold. If it's chilly your body should redirect the blood to your core, as this means you lose less heat. Just like a pie will cool down quicker on the window than by the oven, blood near your skin loses heat much more quickly. So by redirecting blood to the surface, all those wines have unhelpfully reversed the process that's meant to keep us from getting too cold. Booze can also prevent us from shivering properly and the fact that you feel so hot can even trick your body into sweating. Thus cooling you down even more. All this combines to mean we're feeling a lot hotter but we're actually much colder. This can and has caused death from hypothermia in some cases.

So does this mean we should save those cocktails for a hot summer's day to cool ourselves down. Well maybe not, alcohol just isn't our friend. According to one study in rats, scientists found the alcohol simply stopped the hot or cold rodents from maintaining their healthy temperature. This means that after a pint or two, in cold weather you get colder and in hot weather you get hotter. Sometimes you just can't win.

a group of runners on a track

The physiology of running
with Christof Schwiening, Cambridge University, Jenn Gaskell, University of Nottingham

When any of us run, either to the bus stop or across an entire mountain range, our body goes through several changes. We've all felt them. But what are they? And why do they happen? A physiologist and keen runner Christof Schwiening from Cambridge University took Georgia Mills through what happens when you start at a gentle jog, after a word from Jenn Gaskell, Professor and Ultra Marathon runner, who discussed her love, of a good run...

Jenn- I always loved running around as a kid and I really liked being in the mountains and just ended up running lots of mountain races and increasing the distance every year. My favorite race is towards Tor des Géants in Italy. That's 340 kilometres long with three times the height of Everest, goes through some really beautiful mountains in the Italian Alps.

Georgia - Three hundred and forty! How long does that take?

Jenn - My best time is 115 hours, but I think I can do under 100 hours next time.

Georgia - When do you sleep?

Jenn - So they do have checkpoints down in the valleys and you pass some mountain refuges where you're allowed to stay for an hour or two. And sometimes just at the side of the trail in the sun if it's nice weather. I think in total I had about six hours the first time I did it.

Georgia - What made you want to go sort of beyond a marathon?

Jenn - I just really enjoyed the long adventures because you see so much and you see it at unique times of the day. So you might not go out for a hike in the Italian Alps at 3:00 a.m. in a storm, but if you're out running already you'll see this amazing lightning and things. And you cover quite a lot of ground, so one of the races I've done as well is the Ultra-Trail du Mont Blanc, where you run the 11 day hiking route around Mont Blanc where you can run it in one or two days. So you really see quite a lot of things doing this ultra running.

Georgia - And is the Mont Blanc trail the hardest ultra marathon there is or if you got an eye on a new challenge?

Jenn -  So there is a 450 kilometre version of Tor des Géants this year called Tor des Glacier, and that's got even more accent, probably four times the height of Everest. And next year I'll be running a 900 kilometre race across the Himalayas, but I think by then it becomes a bit easier because you actually do have to sleep every night.

Georgia - Now Jen has reached the extremes of long distance running but when any of us run, either to the bus stop or across an entire mountain range, our body goes through several changes. We've all felt them. But what are they? And why do they happen? A physiologist and keen runner Christof Schwiening from Cambridge University took me through what happens when you start at a gentle jog.

Christof - What we see are a set of changes that gradually develop over time and most of the time you won't be aware of what those changes are. They'll be occurring at the cellular level, the level of the microcirculation around the muscles. So when you first start this very gentle running your, muscles will be contracting more often. As a result, they'll be squeezing the blood vessels within them, and most importantly the veins, pushing blood gradually back towards the heart. So we call that an increase in venous return. So there'll be changes within your circulatory system, the control of your heart rate. Also as those muscles gradually become more active, they start to run down some of the early initial energy sources that you've got within the muscle and they'll gradually begin to build up metabolites which will lead to a dilatation of the blood vessels. Dilatation means simply the blood vessel swelling in size allowing more blood flow through the muscles. Even your breathing rate that will gradually start to increase and you won't even notice that the rate has begun to increase. Obviously the temperature will start to rise first of all in the active muscles it will creep up, by a tenth of a degree C gradually, maybe every minute or so, and you won't notice that your core body temperature will also gradually start to rise as well. Now as you start to run progressively faster, those changes begin to build up and the whole of your physiology begins to fight all of these changes to try and maintain the various parameters within your body within a range that is acceptable and compatible for life. So for instance as the blood flow increases through your muscles your heart will gradually have to work harder, will have to pump more blood to keep your blood pressure up and to keep your brain perfused with blood and that increase in rate will begin to put a stress upon the circulatory system. The consumption of oxygen and the buildup of CO2 will start to change the blood gases. And actually it's the buildup of CO2 which begins to be the first thing that you really notice. And that's because that CO2 enters the brain, a specific part of the brain, where it changes the pH. And that drives up your breathing frequency, so your respiration rate increases, and you actually breathe more deeply as well. So those changes then start to become obvious and gradually larger as you run you start to get hotter. And as you start to get hotter you begin to sweat and that becomes something that you will notice as well, you might even notice the slight pickling on the skin as the blood flow increases to the skin as well.In the end if you keep on running there is almost no system within the body that doesn't start to change.

Georgia -But what causes those horrible feelings when you push yourself further than you can really go?

Christof - If you're exercising very intensely and you don't have the adaptations at the level of the muscle to support the exercise intensity that you're doing, you can end up not burning fat and carbohydrates efficiently using oxygen, but actually relying on anaerobic metabolism. And the result of that is that you lose a lot of that energy from the muscle, it literally disappears out into the circulatory system as lactate, and you get alongside that an acidosis. So you can end up with the muscle becoming acidic, the result of that is that the muscle then becomes very inefficient and you also can get alongside that the painful feelings that some people refer to as a burn. The demand on the heart can end up being too high such that your blood pressure begins to fall and you begin to feel woozy or light headed. There are a whole set of problems that you can run up against. Another one is the gradual overheating. So as you're exercising your muscles are getting very hot. Now if your sweat glands are not adapted or they haven't started sweating early enough, then your temperature is going to rise higher than is compatible with normal processing in the brain. So the first thing that you find is it becomes much harder to think straight, as you get progressively hotter and indeed your motivation to continuing exercising decreases quite dramatically.

Georgia - All that being said I had to go on Christof's lab based treadmill measuring my heart rate and skin temperature to get a quantifiable measurement of quite how unfit I was. My heart rate was too high being too small and inefficient to get enough oxygen to the muscles, and I heated up like a lamp. Clearly an inefficient use of energy, so Christof gave me a challenge. Go on a 2k run, twice every single day, for a month to see what happens.

Christof - So what I'm hoping we're going to see is that one of the adaptations will be the training of your sweat glands that will have the effect of keeping your body a little bit cooler preventing the temperature rise. I'm expecting to see that your heart rate will be lower. The reason for that is you will have undergone a little bit of plasma volume expansion. You will have literally produced more blood. That more blood means that with each heartbeat you'll be pumping around a little bit more blood and therefore a little bit more oxygen as well. Now we're going to require you to get a bigger heart and unfortunately that's not gonna be a transplant. We can either stretch your heart a little bit...

Georgia - Sounds very painful!

Christof - Well you do that all the time. So when blood comes back to your heart, that stretches the heart a little bit so that stretching is going to become a little bit greater.

Woman running in the sunset

Why do we run
with Daniel Lieberman, Harvard

With running having such a drastic impact on our bodies both short and long term, is it something we're particularly well suited to do? Georgia Mills spoke with Daniel Lieberman is a professor at Harvard University of human evolutionary biology. He looks at when, why and how humans first got on the fast-track...

Daniel - Well humans have probably been running...always right? You know, our ancestors had to run away from leopards and predators or when they fight each other. But we started probably to do long distance running, a very peculiar form of running, sometime between about two and three million years ago.

Georgia - Why do you say long distance is a peculiar form of running?

Daniel - Well very few animals run long distances. So chimpanzees for example, or other monkeys and apes, will run occasionally, but usually they sprint briefly for 100 meters or so and then they collapse. They get hot and bothered and they don't really go very far, just to get away from each other when they're fighting or to get away from a predator that chases them briefly into a tree. But humans are special. Humans are one of a few groups of animals that will run very long distances, like five or ten or fifteen kilometers on a regular basis. Not many animals do that.

Georgia - And why did we start doing that.

Daniel - Well it's impossible to know for sure without a time machine. But the only explanation that anybody's really been able to come up with is that we ran in order to get meat. You know, carnivores have to run. Most carnivores do that by chasing rapidly their prey, they sprint, so think of a cheetah chasing a gazelle. But we can't do that. Humans are slow. Because we're bipeds we can produce force with only two legs as opposed to four legs. So we're about half as slow as most animals our body size.

And so humans do something completely different. We chase animals over long distances and tire them out. We actually cause them to develop heatstroke. Here's how it works. Most animals when they run, they use four legs and they cool by panting and it's not that effective a way of cooling your body. We cool by sweating, so we secrete water all over our bodies and that enables us to dump heat very effectively. And that gives us a huge advantage over four-legged animals because four-legged animals can pant when they're trotting but when four-legged animals run fast, when they gallop, they can no longer pant. And the reason for that is that galloping is a sort of seesaw gait in which the guts of the animal slam into the diaphragm with every step. So galloping animals, if you take a dog for a run you can find this out very quickly, if you make your dog run fast your dog will have to gallop. The dog will not be able to pant while it's galloping. Don't do this for too long on a hot day or you’ll kill your dog. But we can,  because we don't gallop, we don't have that problem.

So if you can make an animal gallop for a long period of time in the heat you can actually cause that animal to overheat and it will collapse. So hunters sometimes take advantage of this. What they'll do is they'll find an animal, and they'll find the biggest animal they can because big animals just like big humans overheat faster than small animals, and then they'll chase it. And of course the animal will run faster than the human can but the human will track it and then chase it again. And if the hunter can get to the animal and chase it again before the animal has cooled down, then the animal's body temperature will go up and up and up and up and eventually, usually after about a half marathon’s distance of running, the animal will completely collapse and then the hunter doesn't even need any weapons or technology, can just walk up and kill it with a rock or something like that without much danger.

Georgia - You put your money where your mouth is, is that right, in this theory?

Daniel - Oh yeah. So a few years ago, just to kind of try this out, I entered a race that's been run every year for the last, I don't know, 25 years or so, in a town called Prescott, Arizona. It's called Man Against Horse. And every year a bunch of humans race horses over a mountain. It's a marathon length race and even though I'm not a particularly great runner, I'm just a middle aged professor, there were I think fifty-something horses and I beat all but thirteen of them. And again, I am not a great runner, I'm not an elite runner. And the reason is the horses get too hot, but the humans can keep going.

Georgia - Considering then that this long distance running was basically how we got our food, what ways did our bodies change, how did we adapt to this lifestyle?

Daniel - Our bodies are changed literally from head to toe. I mean we have features all over our bodies that help us be incredible long distance runners and they include having short toes. So we have short toes to prevent ourselves from breaking them when we run. We have arches in our feet which act like springs, which store and release mechanical energy. We have long Achilles tendons, much, much longer than those of say chimpanzees and gorillas. And again those ac as giant springs to help us run efficiently. The largest muscle in our body is the gluteus maximus, that very beautiful muscle indeed but also very important for running and to prevent us from falling over and not important for walking. We have waists that are able to twist independently, we have special mechanisms in our necks to help keep our head stable, we're furless and have sweat glands all over our bodies. In our ears we have organs of balance that are specially tuned to handle the frequencies and demands of running. I mean literally we have changes from the tops to the bottoms of our body that make us really good at running...

Brain schematic

43:10 - Our brains on running

What happens to our minds when we run?

Our brains on running
with Henriette van Praag, Florida University

What effect does running have on the brain, how good is it for us? Georgia Mills spoke to Henriette van Praag, an Associate Professor of Biomedical Sciences at the Brain Institute at Florida University...

Henriette - Well running has extensive effects on the brain. In humans overall the effects are very beneficial. What we see is that there's benefits for our ability to think, manage time, pay attention, plan. We also see benefits for our ability to remember events, places, people and how they are linked together.

In addition to that we see actual changes in brain structure with exercise. So there is an increase in what we call the grey matter, the part of the brain that contains the neurons, and also white matter which consists of the external pathways that connect cells to each other. And we see also an increase in particular, in the size of the brain area that's very important for learning and memory, called the hippocampus. Incidentally this is the same brain area that is often affected in neurodegenerative conditions such as Alzheimer's disease.

And what happens with exercise is that there is an increase in the volume of the hippocampus and we also see up-regulation of blood flow in that area and in other areas of the brain. And then if we talk about things such as mood or anxiety is that with exercise there's a reduction in anxiety. There's improvement in sleep quality, reduction in stress hormone levels. So these are the kind of the things we know in humans.

Georgia - Why do we think you get these benefits in the brain?

Henriette - With exercise there are neurochemical changes in the brain. So there are changes in neurotransmitters and some of these neurotransmitters are called monoamines and they include dopamine, serotonin norepinephrine, and that family of neurotransmitters is strongly implicated. Exercise up-regulates the level of monoamines. In addition exercise will also up-regulate a protein called Brain-derived Neurotrophic Factor or BDNF.

This is a very important growth factor in the brain which is important for survival, growth of neurons. It influences their complexity, it also influences the ability of neurons to communicate with each other. So it's been shown that if levels of BDNF are low there can be increased anxiety and there can also be learning and memory problems. But other things we can see in terms of measures of anxieties, for example stress hormone levels, such as cortisol in the bloodstream, those also go down with exercise over time and may lead to a reduction in anxiety and depression.

Georgia - But Henriette and her team had an idea. Perhaps not all of these changes were originating inside the brain

Henriette - Not just the brain is running, your whole body is running, you are recruiting you know your heart, bloodstream and of course skeletal muscle. So one of the things that we are very interested in is what is released out of skeletal muscle that might influence brain function.

Georgia - Henriette and isolated muscle cells and treated them with compounds to activate energy pathways, basically engineering exercise in a dish. They took the metabolic soup that came out of the cells, found the compound of interest inside and then added it to brain cells to see what the effect was.

Henriette - You can see an increase in endurance if you give these kind of compounds and you can also see improvement in memory function, suggesting that this kind of pathway of activation may be one of the sources of the effects of exercise on the brain.

Georgia - Right so something that sort of leaks out of our muscles while we exercise makes its way into the brain and we think could be potentially causing some of those benefits?

Henriette - Yes, or at least setting a cascade of events in motion that links to all this plethora of effects that I just described.

Georgia - Does this mean that we could, if we know that factor, could we sort of bottle up exercise and put it in a pill, for maybe those of us who on able to go?

Henriette - Oh no, no, no, no. That would be extremely dangerous! Good try but unfortunately those kind of factors are very tied to our physiology and if you have too much it could be detrimental, too little it’s also not good. That said, it's not completely out of the realm of possible that if we learned more about these factors and know how to potentially modify them, let's say chop off a little bit of the sequences that are potentially involved in detrimental effects, that we could harness them. But then I would probably think only say in cases where you know somebody is incapacitated, cannot walk well, and help to kind of transition back to an active lifestyle. But it would definitely not replace the complete package of the benefits of exercise on our brains, on memory function and on mood.

Person running, jogging and stretching

48:48 - Long term impact of a run

What benefits does running have long term?

Long term impact of a run
with Christof Schwiening, Cambridge University, Jenn Gaskell, University of Nottingham

What benefits does running have if you stick with it? Why do so many give up? Georgia found out from Christof Schwiening from Cambridge University, before hearing again from Jenn Gaskell, about the joys of a runner's high...

Christof - So when you first start off running there are a whole load of changes that the level of the neurons in your perception of what running is about it's before the fatigue kicks in. So you start to feel very good, you get if you like after the very first run maybe a little bit of a runner's high, it's never happened to me but I hear it can happen, and then gradually the fatigue starts to build up. Whilst you run you do a little bit of damage to the muscles and that gradually accumulates. Then hopefully after a period of about two to three weeks things start to get better. Unfortunately, I think you got the flu just at the critical point and you stop running in fact you had a little bit of bed rest I think which is the worst possible thing you can do for run training. The real big change is they take a period of many weeks to occur. So a couple of months and then things start to get really a lot better. But the plasma volume expansion that you can get, that gradual thinning of the blood as you pull in more water from the extra cells space, that can happen very quickly indeed. So we were sort of hoping that that would happen after your last minute bout of running that you did over the weekend. Unfortunately it doesn't look like we were able to detect that maybe it wasn't quite intense enough. I don't know.

Georgia - I mean I said I do ten k a day and I did about four. That's probably why. And this Christof says is another useful lesson if you're training for a marathon or similar, last minute panic training does very very little. So if you can push past the two week mark and keep at it what is the long term impact on your health?

Christof - There are very very many long term benefits of running. Obviously the first thing is you're burning a little bit more energy which is generally a good thing to do because we live in an environment where energy is very easy to come by, so being a little bit more active is good. You tend to start off by lowering blood pressure, that tends to fall as well as you run. And then longer term of course you’re helping to build a more healthy heart, one with a greater blood supply and generally a more elastic circulatory system and that's all very good. So the long term effects of running and indeed the effects of loading the bones, so bone density tends to increase, everything tends to get a little bit better when you do a bit more exercise. To get a healthy life into old age, I think exercise is absolutely critical.

Georgia - So there you have it. It's good for our body, it's good for our brains and as Dan Lieberman said it's why we have such big beautiful bums. So we should really make use of them. I've definitely had enough to give it another go. So I asked Christof as a runner himself, for any tips to keep motivated.

Christof - Okay so the first bit of advice is don't get injured. There's nothing worse than getting injured, every runner has a story about injury and my story at the moment is very real to me. So one is take it sensibly, and exercise very sensibly, build it into a lifestyle as well. There's no point in making running something special that you have to make a special time for during the day, and running isn't something that you have to be particularly prepared or set up to do. You can add running into many of your daily activities. I do something that's known as a run commute. Building it into those times where you need to do some form of transportation. And I would also say take the intensity of your running down. Sure, add in some high intensity if you enjoy it. But there's a very nice social aspect to running a little bit more slowly, of taking a little bit of time. So doing that kind of social running is a very powerful way of enabling yourself to continue with the exercise through life. Don't get obsessed with it and also don't assume that the limits that you see now, are the real limits that exist. Everybody is capable of being a runner.

Georgia - And to add a couple from me find a running buddy who doesn't run faster than you, don't useless fat spaniel who will slow you down, and definitely definitely don't get the flu. Good luck. And if you run enough you might just experience the wonderful feeling known as runner's high. Back to Jen.

Jen - You might have just had the worst low of your life. You might have had absolutely no energy at all and then you eat a little bit, you drink a little bit and 20 minutes later you'll be running along through the storm, you'll be running up hills and you'll feel like if Usain Bolt turned up and wanted a 100 metre race against you, you’d definitely beat him. And everything is just fantastic. Like the views you just love everything, you love all your friends around you, you just absolutely love doing what you're doing and you never want to stop. So you just keep running.

Comments

Great episode, as a runner and as a teacher of biology, I will definitely be throwing some of this into my lessons!

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