Born to Run: Sprinting Science

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.

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.

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.

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.