Variable and Full of Perturbation

Transcription

utting basic scientists and more applied scientists together. And of course you have that in your new facility at 170 Tottenham Court Road. You exhibit those three features very fully and I think that augurs well for the success of this enterprise, but there are two or three other determinants that I'd like to add. First amongst those is stakeholder engagement. We have many stakeholders and interested parties here this evening. Second is that underestimated quality, I suspect both in sport and certainly in academic endeavour, which is resilience, and I know you've had to work hard to end up where you are. But third, and perhaps most important of all, is leadership. Leadership exhibited through you, Fares, through you, Monty Mythen and through you, Hugh Montgomery and others that have made this progress a reality. So, delighted to be here to record our commitment at UCL level to these enterprises and I'm sure you have a very exciting evening ahead. Thank you. [Applause] >>[Fares] Thank you very much. We'll start the lectures with Professor Hugh Montgomery who really needs no introduction. Hugh has had a stellar academic career, he's a Professor of Intensive Care Medicine, he's an active clinician, a very active researcher in the sport and exercise field and he's made a massive contribution in the genetics of performance and he's going to share with us some thoughts on some of his current research: Hugh. >>[Montgomery] Thanks very much Fares. I'll see if that's me or if that's Mike's. Oh, don't want to use Mike's talk. Fares, thanks very much, and Sir John, thank you for your kind words. This is ten minutes and I can't gallop through the whole of genetics in physical performance in ten minutes, but I can give it a damn good try. As human beings what defines you as human is your genome, and you have somewhere in the region of 16,000-20,000 genes depending on how you want to define a gene, comprising a diploid genome, around 6 billion base pairs. That's what makes you human, but of course we are all different from one another, we're not genomic clones; we don't all look and behave the same. And part of that difference is down to genetics. These are perhaps slightly spurious but certainly in terms of exome sequencing if you look at the similarities between humans and lower primates we share around 96% of that genome. You can all sorts of games - we share around 60% of our genome with a fruit fly and around 54% with a banana. [Laughter.] And you can usually tell the difference between your colleagues and fruit. [Laughter.] Sometimes it's harder than others. But if that defines difference between species, the differences between us as humans is really a great deal smaller, and within this room, if you look at your next door neighbour, unless you're related to them, there'll be less than 1% of your genome that differentiates you from your next door neighbour in this room. Is it just the genes? Well, quite evidently not. It's both nature and nurture. It's the interaction of the complex environment from in utero to what you expose yourself to in life with your genomic propensity that determines the way you are. And you can see that even simply in this. These are, believe it or not, identical twins. They have an identical genome, but in utero, one of them has been starved of circulation and the other has had a much more luxuriant circulation, and the resulting phenotype is very different. And it turns out that somewhere in the region of 30 upwards percent of the variation across any phenotype in this room, whether it's your propensity to smoke cigarettes or how many, whether you drink alcohol and how much, let alone height and so forth, at least 30% of that variation will be genetic in origin, and that certainly applies to many performance phenotypes, whether it ranges from lean muscle mass, your ability just to stand with both feet on the floor and jump high, or even your reaction time, a generous proportion of each of the variants is down to the genes that you carry. And upon that genetic propensity to be able to do something, there's also a strong genetic implement even on your wish to take part. So whilst that's not denigrating the effects of environment and politics in encouraging people to exercise, those of us that choose to take stairs rather than lifts, those of us that choose to take a walk after a meal, the people you know that might drive round and round the block waiting for a parking space outside a shop, or are prepared to park up the road 200m away, a lot of these behaviours are known to be strongly genetically influenced, and indeed there have now been three studies confirming that at least two of these genes which are hypothalamic and seem to be involved in what you might broadly call 'energy balance', energy homeostasis. So some people are genetically predisposed to wish to take more exercise and some are predisposed to be more capable of doing that. The candidate we've worked on forever, and for those of you that work with me, you can switch off now, because you'll know this data. This is a gene, the angiotensin-converting enzyme gene. It has a great deal of polymorphic variation, there's been found 110 variants in the gene. This is the most informative. It's the presence or absence of [unintelligible] DNA and if you had the extra bit in, you have low ACE levels and because the alleles are equally frequent, a quarter of you in this room have low ACE activity with two I vents, half of you have a nadir in the middle and the range, 25% are like me with two D versions and high ACE activity. And we showed, as early ago as 1994, that these genes strongly influenced heart growth in response to exercise. This work in military recruitment, we've done this study now three times to be sure we were right, there's very substantial difference in growth of the left ventricle, the high ACE genotype, a quarter of the population, growing their heart about threefold more than those of you in the audience who are low ACE genotypes, if one does the same physical training. We know that it affects skeletal muscle efficiency, so if you measure this, if you measure delta efficiency, and this was work actually first authored by Alan Williams, who's in this audience, delta efficiency in external work compared to internal work, roughly 25% efficiency prior to military recruit training but the percentage change in that with training, very substantially more with the IIs, and we DDs at the end are statistically a little worse than what we were before we even joined the army, if we did. And that translates, as you might expect, into differences in human physical performance. So this was simple work--on the Y axis there's this time at which one can do a simple performance, this was heels, bums, backs to the wall, fifteen kilo barb along the thighs, every time the metronome goes ping, lift it up every time the metronome goes ping, it goes down. But when you can't keep up, then you're out. And the number of seconds are counted. The first bar is prior to training, and you'll see that everyone, independent of genotype, goes on for around 100 seconds. But six weeks of training, which is the middle bar, the IIs have roared away with an extra minute of exercise time, and by the end of the training, they've doubled their exercise time and we DDs, statistically, are no better at the end of training than we were to start with. These are data that we published with Richard Budgett who was here earlier today, from the British Olympic Association, looking at distance run, and if one looks at the allele frequency, which I've said is roughly 50-50 or .5, you'll see that the allele frequency rises in elite runners as the distance they run increases. So the I allele seems to be associated with propensity to elite performance or fatie-resistant or endurance-dependent performance. And if that happens at C level, it sure as hell happens in mountaineers. These are 1906 UK controls, which are the same as you, roughly 25% II, 25% DD. But look at the mountaineers. This great cramming over towards the prevalence of the II genotype and an excess of the I allele. And that translates into simple, almost Darwinian findings. Giorgios Tsianos, one of our PhD students sat in the Gouter hut on Mont Blanc and people headed for the summit, he took some DNA before they left, and when they came back he said: did you get to the top or did you? And you see that all the IIs get to the top, and somewhere around 12% of the DDs don't. And you can see the same effect in short term ascents of Kilimanjaro, for instance, where the strongest determinant is not whether you've got grit and determination, it's just whether you've got the right genes. So the 'I' allele is associated with endurance performance, but if you think about it, there's a deficiency of the I-allele's in the sprinters, if you look at the D-allele frequency you see the opposite. There's an excess of the D-allele and that's because the D-allele is associated with advantage in strength performance and sprint. So you not only see this in sprinters, you see it in swimmers, because swimming even at 400 metres is largely a power and sprint-related sport, so again the controls: rouhgly 25/50/25, and again, this crunch towards the D-allele amongst swimmers, and I think we'll flick through, I might have the Russians there where you see the same effect in the Russians for short and long distance swimming. Now just to close out then, this is all pruriently very interesting, and it's been very productive and has probably kept me employed at UCL [laughter], but there are other reasons for taking interest other than just being able to pay one's mortgage. And that's because many of us are clinicians, and the people that I try and look after, and Mike Grocott, who speaks after me, looks after and Monty Mythen, are critically ill. These patients have respiratory distress syndrome, where their lungs eventually flood with fluid, they become profoundly short of oxygen and they're in for the world's longest ultra-distance race upon which their lives depend. And patients quite often die from this, around a quarter of them will die. And when they survive, when we didn't expect them to, they have long interrogations about, well after we've gone and drunk a lot and congratulated ourselves on what fantastic clinicians we are, we then have a postmortem about what we did right. And when a young person dies that really shouldn't have done, and we're feeling terrible, we have a long post mortem about what we did wrong. And in fact, if you look at these data, there's a fivefold difference in mortality across just these genotypes which, sad to say, as long as I'm not grossly incompetent, trumps pretty much anything I could do. And it opens up the potential for therapeutic intervention. Low ACE activity people do better, and that's something that Mike and I are exploring at the moment, is delivering ACE inhibition safely to such patients. We know it also applies to meningococcal disease, the sort of disease you read about in the papers in the winter, where children die. A study we did with Liverpool looking at children coming in, some of them were left on the ward because they looked pretty much alright, some of them make it to PICU (Paediatric Intensive Care Unit) and some of them then die. And you'll see the percentage of DD genotype in each of those groups -- again there's a very strong association with poor outcome and death. So that's where I'm going to finish. This sort of work is important. It's not just important to elite athletes, it's not just important to helping define gold medal winners, perhaps select them or train them differently, this sort of work has absolute direct relevance to small children, premature babies, or to you or I when we become ill or our parents. And that's the reason why I think we should be focusing on the sports and exercise agenda -- it has direct relevance outside the olympics. And just to finish then, on terms of is it nature or nurture, which is how we started, just to say that great athletes are both born and made. Thanks very much. [Applause] >>[Fares Haddad] That's outstanding. We'll have some time for questions at the end. I'd like to introduce Professor Mike Grocott, who's already been briefly alluded to a moment ago. Mike is a professor of intensive care medicine, he's also the founder and a leader of the Extreme Everest Expedition and leading another expedition next year. Mike's made a massive translation and research contribution in that arena, which is very relevant to sport and to intensive care. And he's going to talk to us about Everest learning from extreme environments. Mike. >>[Mike] Thank you very much, Fares, for the very kind introduction. The other Mike and I were just sitting there feeling slightly rueful as some kind of sacrificial sandwich between Sir Clive and Hugh, who are both magnificent performers, and ourselves. But we'll do our best. Hopefully some slides will come up in a moment. So Kevin Fong and I, almost exactly 12 years ago, stood in this room and started the UCL Centre for Altitude, Space and Extreme Environment Medicine, and since then it's thrived along with Hugh, Monty Mythen, Martin, Kay Mitchell and Danny Levitt, along with many others. We've managed to teach a BSc course, we've had MSc students, postgraduate students and a number of research themes in different extreme environments. But today I'm going to focus on altitude in particular and particularly the Caudwell Xtreme Everest study which we conducted in 2007. And I'm going to talk to you a little bit about why we went to Everest and have a brief jog through some of the important results. So why go to Everest? The two principal reasons were that, from our perspective we feel that it's a useful model for critical illness. And Hugh set me up very nicely with the links between ACE genotype and performance, and specifically performance at altitude and ACE genotype in ARDS, but there are other parallels, and hypoxia (and hypoxia is what you have at altitude as the air thins and there's less oxygen), hypoxia along with inflammation are probably two cardinal pathophysiological processes -- they are two things that cause harm in critically ill patients. The second reason we went there is that we felt there was some unfinished business in terms of altitude research, and that the classical oxygen flux model of how humans adapt to high altitude really didn't explain what we see in terms of the dramatic differences in performance between individuals. So, critical illness, we could study patients, but one of the problems with patients is that they're such a wildly mixed group that it's very difficult to separate any single factor from the soup of things that are going on. So we took the alternative approach of looking at healthy volunteers where the single change was their exposure to altitude and specifically their exposure to hypoxia. The problem that I alluded to in the altitude explanations is something that's probably very counterintuitive from a sports perspective, and that's the fact that oxygen convection does not equal performance. So you'd expect -- and what the books imply -- is that people who are most able to adapt and improve their convection of oxygen down towards the tissues that would do the best, but it's simply untrue. Probably the best example is these two individuals, the first to summit Everest without supplemental oxygen. They've been very extensively studied, this is VO^2 max data -- they are two of the subjects highlighted by the red box, and the green box are sedentary Swiss couch potatoes. So very unremarkable physiologically, but extraordinary in their ability to perform at altitude. This is some of our data from 2007, a paper which was notable for the highest management of oxygen in terms of altitude close to the summit of Everest, but provides a useful reminder that in well-adapted individuals at altitude, their oxygen content, the amount of oxygen being carried around in the blood, is actually pretty much the same as it is at sea level. So there's plenty of oxygen going around. So, elite climbers, there's no obvious explanation why - from simple physiology - why they succeed, and actually all of us, when we've had time to adapt, have enough oxygen, so it's not simply about classic oxygen delivery. So what we set out to do was test one particular hypothesis which led to several others, which was that none of the changes that we saw at altitude would be explained by changes in oxygen content or oxygen delivery. And therefore we have needed some alternative mechanisms and particularly wanted to focus on the function of microcirculation, the very small blood vessels that are responsible for getting oxygen and other nutrients from the larger blood vessels down to the tissues, the possibility that there was an improvement in efficiency, so you almost get more miles per gallon, more ATP per unit of oxygen metabolised, and there's plenty of basic science work which suggests that there's possible, or that there were alternative mitochondrial adaptations. And as I've mentioned this was underpinning a translation agenda, and this was I guess the model that we used -- so we measure physiological variables at altitude, both at rest and under the perturbation of exercise to volitional maximum, and then combining that with plasma biomarker data and genetic data and Hughes alluded to some of that, we're looking for a signature of those who are adapting well and those who are adapting badly, and that in turn can lead to either candidate by-markers for prognostication, restratification or even more intriguingly, to candidate mechanisms which we can then empirically test in a variety of other models. So, we have a very pleasant working environment [laughter]. We took more than two hundred healthy volunteers for a three week trek to Everest base camp. And of the 60 investigators, 24 of them followed them the same trek a little bit more slowly and 15 of those ascended higher on the mountain, some of them right up to the summit. This is a figure describing the ascent profiles. So the trekkers going a little bit quicker, and some of the differences that that created were very intriguing, the climb was a little bit slower and then some initial testing followed by, in some cases, an ascent to the summit. So this was the ultimate destination, and you can see in the foreground our two laboratory tents, and in the background, the medical and logistics tent. And this is what it looked like inside. And we could do almost anything in there that we could do at sea level. I think the only exception was the functional MRI. It's difficult to get a magnet up there. Otherwise 240-volt AC electricity, any technology that you care to mention in a sea-level laboratory. So I'm now going to take you on a rapid jog through the highlights of the data, really focusing on the key elements of hypoxic adaptation. So the first thing is to emphasise the point I made that, and this is the change in oxygen consumption vs change in oxygen content, there's absolutely no relationship. It's completely counterintuitive to an exercise audience, it's what we kind of knew before we went although the data was relatively thin, this is data and in this particular slide 148 subjects, but it's consistent across all the comparisons that we'd looked at. So there must be something else explaining the substantial increases, the substantial variability that you see between people, from the mesmas who can reach the summit of Everest without supplemental oxygen to the individuals who will struggle to get to Everest base camp 4,000 metres lower. One of our primary -- our key hypothesis that before we went we said that we're this is going to be the case, we were completely wrong. There was absolutely no change in efficiency, and I won't go into the nuances of measurement here but essentially if you measure it in steady state you can look at oxygen-ATP relationships in the cell -- no change at all. But economy, which is the same thing measured on a ramp, changes substantially, and to cut a long story short that can only be explained by changes in oxygen kinetics, the speed at which oxygen is transitting through the body, from the mouth down towards the cells. Why might that be? Well, Dan Martin's studies very elegantly showed -- and I'm just going to flip back so you get that first video -- very elegantly showed that the microcirculation, for some reason the first one is not flagging up -- is, this is sea level, this is 6,400 metres. The microcirculation at altitude is dramatically dysfunctional. There's a very slow flow, and we'd expected to see a much more rapid flow. Why might that be? Well, initially we were unsure. It's completely unrelated to hematocrit, which is an obvious candidate explanatory mechanism, but it turned out when we started to look at nitric oxide, nitrogen oxygen metabolism, not only were they dramatically deranged, but those derangements, and you can see here that nitrate and blood flow in small blood vessels, in very small and medium to small sized blood vessels, the nitrogen oxide changes are related to and we can't know for sure whether that's causal, the changes in blood flow. And those who have the higher levels of nitrogen oxide, seem to be doing better at altitude. We also took muscle biopsies, and we showed what many have shown before: that there's loss of mitochondria at altitude, so these muscle biopsies are taken at altitude, the loss of mitochondria at altitude compared to at sea level, but what we showed that was novel is that there are changes in mitichondrian proteins so you can see here changes in complex one and complex four and some of the mitochondrial biogenesis factors clearly pointing to cellular energetic adaptation, and that was confirmed by the MRI data that we have from before and after. So shortly before people left and immediately returned, and this is in collaboration with Kieran Clark at Oxford, clear decrements in this case phosphate and ATP rates and operations in cellular energetics, we saw similar things in skeletal muscle, but that's not what I'm showing you here. This is one of the intriguing findings that did surprise us a little. This is trekkers vs climbers before we go, and their intracellular cytosolic inorganic phosphate are different. And there was several variables for which that was true. So before we exposed them to altitude, our trekkers and our basecamp staff and our climbers stratified for a number of variables. And this has raised the intriguing possibility, either very simply they've selected themselves -- they've gone to altitude, they've got on well so they keep going back, so they're a self-selected group. Or, it's a consequence of that repeated exposure to altitude. So they're imprinted and we clearly in epigenetics have a potential mechanism whereby that might occur. So to summarise the science, as we knew before the oxygen consumption changes are not explained by oxygen delivery, efficiency doesn't change but the kinetics do and that's probably explained by the microcirculation, the very smallest blood vessels, that in turn may be explained by nitrogen oxide metabolism, there's clear, significant changes in cellular and mitochondrial regulation, and we've got baseline differences that are suggestive of epigenetics. So, where does that take us clinically? Well, a whole host of different avenues. We've started looking at this idea of permissive hypoxemia -- can we lower the oxygen level that we're giving to some of our patients because we can work out in advance that they're likely to tolerate it, and monitor them for any harm that might cause, we're looking at nitrogen oxide as a therapy for cellular hypoxia in sepsis. Hugh's doing a lot of work on skeletal muscle harm and recovery in critical illness, closely related to this. We're looking at skeletal muscle harm and recovery which Monty's already alluded to following chemotherapy. We're obviously very intrigued by the epigenetic basis of susceptibility to critical illness in the same way that we think we're seeing at altitude, and then there's some intriguing ideas about how the pulmonary venous blood flow may actually be acting as a driver for organ dysfunction. Where do we go from here? Well, Xtreme Everest has become a multicentre international collaboration, involving also now University of Southampton and Duke University in North Carolina in the United States. And we have three separate strands of research, the clinical translational work which I've alluded to already, field environment studies with Dan Martin leading Xtreme Everest 2 next year, focusing on sherpa adaptation and twins and the epigentic changes that you can identify in a large twin population, and then in addition we're doing some small focused chamber and tent studies and in particular in collaboration with our chamber team in Duke. So, I can't close without acknowledging the very generous funders without whom this would not have been possible, and of course the investigators, trekkers and sherpas. And I'll leave you with a nice picture of UCL on top of the world. [Applause.] >>[Fares] Outstanding work, Mike. We'll move on to the other Mike now. Dr Mike Loosemore is a leader in sport and exercise medicine, he's a consultant here at UCH and with the English Institute of Sport, he has had a number of leadership roles in sport and exercise medicine over the years but he's currently the lead for exercise medicine in the UK, and he's going to share with us the role of exercise: 'Moving forward: Exercise as medicine.' Thanks. >>[Dr Mike Loosemore] Okay, well I was told I had eight minutes to change your lives, so let's give it my best shot. My talk involves some of the genetic work that Hugh's been talking about and also some of the adaptive work that Mike was talking about. So, genetics, evolution. Well, we're familiar with this stage and I think everybody's now familiar with this stage here. We all spend most of our days, I hope I'm not just speaking for myself, crouched over a computer. So, is this how we should be? Well, probably not. We know that we are designed to be endurance hunters. There's only two mammals that actually have endurance, and that's humans and horses. And humans have got better endurance than horses. And there's certainly evidence from neolithic times of big animals having butchering marks on them, so what you do is you wait until the heat of the day, you start chasing your big animal, and you keep chasing it, and you keep chasing it, and you keep chasing and it drops down dead with heatstroke and you cut its throat and you eat it. It's very easy. That's really what we're designed to do. We're not designed to sit here and listen to me, or to sit at a computer, we're meat to be out chasing animals down. So we know there's a big problem with obesity and it's a big problem in America, but if you look at the Amish community in the States, if you know the Amish community in Lancaster, Pennsylvania, where they shun mechanical aids. They looked at men and none of them were obese. None of them. They looked at women and 9% were obese only. Against 30% of the normal population. If you look about recommended levels of activity, you can see that even the young are not reaching the recommended levels of activity, and that falls off as you get older. Compared to 1980, we now travel 25% less under our own steam, watch twice as much television, don't play extracurricular sport, don't have physically active employment. Everybody now works on a computer. There is a range of labour saving devices, which means we don't do physical activity or exercise. [Laughter.] As I said, in the States this is a bigger problem than we have over here. And what we need to do is work to improve that. We know that if you look at the risk of death and activity, that if you increase your activity, your risk of death reduces. If you decrease your activity, your risk of death gets worse. This is my favourite slide, which is why some of you would have seen it twice now. This is non-vigorous activity and mortality, this is non-vigorous physical activity and mortality. So if you're doing nothing and you increase your activity by 2.5 hours a week--not a day, a week--you can reduce your mortality by 19%. 19%! Now I don't know how many people are paying a pension but you know, I'd be out there doing a bit more exercise, and am. Increase it by seven hours a week and you reduce your mortality by 7% and that's not running marathons, that's just increasing your activity. That's taking the stairs instead of the escalator. That's walking down the stairs instead of taking the lift. Makes a big difference. If you look at attributable factors for all death, we know about obesity, lots of stuff on obesity, lots of stuff on smoking, government legislation, hypertension, high cholesterol, diabetes, but the biggest effect on death is low cardiorespiratory fitness. This is the big problem we've got. And then again if you look at death vs BMI, so BMI 27-30 and greater than 30, if you're fit, you still have a lower chance of dying. Even if you're fat, if you're fit you still have a lower chance of dying early. So, we're all worrying about, well, maybe I'm speaking for myself -- I'm worrying about getting older. This is the geriatric curve. Oh, that hasn't worked. That's the end of the geriatric curve. That should all be red. This is, the area here, is deficient survival. This is where somebody's having to come in and wipe your backside for you. This area at the end of this curve is where we don't want to be. And that's if you've got a high risk lifestyle, you're inactive, you're smoking. This is where you want to be. You want to be fit and then dying. [Laughter.] That's where you want to be. So "the goal is to die young, but as late as possible." [Laughter.] So what are the benefits of physical activity? Well, it reduces heart disease by 40%, lowers risk of stroke by 27%, reduces diabetes by 50%, reduces blood pressure by almost 50%, reduces mortality and breast cancer and recurrent breast cancer by 50%! So if you've had breast cancer, if you exercise, you can reduce the recurrence of that breast cancer by 50%. That's about the same as tamoxifen. You can reduce the risk of developing Alzheimer's disease by a third. And we know that the big problems and the amount of money that has to be put into Alzheimer's disease. And as effective at reducing depression as SSRIs. So, I haven't got long so I'm going to try and do some big hits. So this is exercise vs angioplasty. Angioplasty, very good, very techy, very expensive. And this is a vent-free survival on patients who had angioplasty against patients who had exercised in stable angina. And the patients who exercised, who had stable angina, did better than the patients who had angioplasty, after a year. They just exercised. They didn't have the machine that went bleep or anything. Now if you look at the cost, I mean this is 20 minutes a day on a cycle ergometer, this is with a personal trainer. But it's still considerably cheaper than having the operation. That is the same for peripheral vascular disease as well. Look at hip fractures in post-menopausal women. Again, this is the nurse's health study. 61,000 women; this is not a small study. This is straight line graph. The more you exercise, the less chance you have of fracturing your hip. And as most of the orthopaedic surgeons here know, fracturing your hip when you're elderly usually leads directly to the morgue. Well, not in everybody's case but--. 55% drop. And this is dementia. Exercising less than three times a week, exercising more than three times a week, you're almost halving your risk of dementia. 40% risk. So, renal disease. The studies that show if you exercise when you're being dialysed. So if you're being dialysed, you're sitting in a renal dialysis unit watching tele watching tele for a couple of hours a day three times a week. If you sit in your renal unit and ride a bike or use a handbike, you can improve the figures on the dialysis by 25%. Now, renal dialysis costs two billion pounds a year. If you can save 25% of that, that's a 500 million pound saving. Cancer, we talked about cancer, it reduces the rate of cancer. Reduces the rate of colon cancer by 60%. Reduces the recurrence talked about. Improves outcomes of chemotherapy and radiotherapy. So if you exercise during your chemotherapy, there's a good chance that the chemotherapy will one, be more effective and two, there won't be as many side-effects from the chemotherapy. And that's something we hope to explore with the McMillan Sensor at UCLH. Mental illness: physical activity is useful in major mental illness. I'm talking about schizophrenia, bipolar disorders. And also the problem with mental illness is that if you have mental illness and you're sitting around having mental illness, you don't exercise, and you smoke, and you don't die of your illness, you die of coronary artery disease. And as we know, physical activity is as effective as Prozac in mild depression. Going back to genetics. The GLUT-4 protein and the GLUT-4 gene is responsible for getting glucose into the cells of the body. It's a very important protein, particularly in Type-2 diabetes. Physical activity switches on that gene. So, genetically, we know that -- I told you, we're exercise monkeys, that's what we are-- and when you exercise, you turn on these genes, which improves your diabetes. No drugs required. There's another gene, PGC-1alpha which is known as a 'master regulator' gene. It controls various things, including blood pressure and cellular cholesterol and the development of diabetes. Again, this is another gene which is switched on by physical activity and exercise. So, exercise -- one drug, one disease cured. And we know diabetes you take several drugs. And if you've got diabetes you've probably got hypertension, and if you've got hypertension, you're gonna get your cholesterol lowering drug because everybody does, don't they? And then if you're taking that, or if you've got arthritis, you may have to take a non-steroidal, and if you're taking a non-steroidal, you're probably going to have to take a BPI, so etc etc etc. One drug, one disease, one operation. I'm afraid, Fares, one disease cured. [Laughter.] Exercise, you can exercise and you can do all of those things at the same time. You an affect all those diseases. So, physical inactivity is a major risk factor. It exists in every populations. The World Health Organisation, in 2005, did a survey: 2% of the health resources across the world are spent on prevention. 98% are spent trying to cure the diseases that have not been prevented. Mad. [Laughter.] Okay. So exercise is under-utilised, and we've talked about trying to improve the education of doctors and all health care professionals. Physical activity is the major public health problem of our time, and you all have the answer. You have to be more active. Thank you very much. [Applause.] >>[Fares] Mike, that's outstanding. Three great talks. Last, but not least, to Clive Woodward. Really needs no introduction. Outstanding rugby player, one of the perks of sport is you get to meet your heroes, and one of the greats when I was growing up and learning the game then master coach delivered the ultimate prize in terms of rugby and performance in 2003. And he's taken a few moments out from guarding the GB team to the Olympics as Director of Performance to come and speak to us this evening. Sir Clive Woodward. [Applause.] >>[Clive] There you go. Thank you Fares, and good evening ladies and gentleman, can I just pause for a toast to Fares. Congratulations, a big, big day for you today and I know it's been a tough road, but a really significant day for sport in the opening of this Institute of Sport and Exercise Health, so congratulations. Really well done, I know it's not been easy but it was well worthwhile. So, like my fellow speakers, I've got eight minutes. And obviously we'll be answering some questions after. I just want to really to throw out a few ideas about sport and this concept of creating champions and elite athletes. I want to share with you this model that I use, which really is something that I've not learnt, I've not studied, I've just generally learned through experiences-- I played at one point as a coach--so what are the ingredients that go into making this champion athlete, is there something special that you actually need? And I'm going to quickly just describe four people, and as I go through this, this is how I kind of work when I'm speaking to athletes and coaches and people from the sports science world and exercise and health world. So, this is the model I use to describe this champion, and I'm going to describe four people pretty quickly, and I'll obviously take questions afterwards. The first person we describe is someone called 'talented'. And if we use the people in this room as an example, everyone in this room has to be talented. You wouldn't be sitting here in this university unless you've got a talent to do your subject. Sport is no different. I stand not in front of the sports science world but I stand in front of athletes and the athletes I get to meet are talented. And the key thing to talent is the criteria I use -- the ability to do your job, and the ability to play sport, and what I use on the right hand, you've got the skill to improve. But what I put out in a competitive world and in terms of sport is that we're sitting here with these talented athletes, let's say within a rugby team, and I'm sitting here with this incredible talented group of players, but the people we're competing with, let's say they're next door, unfortunately next door they've also got a very talented group of athletes. They've got the New Zealand All Blacks, you've got the South Africans in that room, you've got the Australians, the Welsh, the Scots and the Irish, so everyone's got talent. And talent comes in various areas which we're not going to go through, but in terms of understanding, you've got this talent. What I want to just quickly go through is what I see on top of talent, which I really look for, and this is something when I first started coaching and playing I didn't really think about, I just thought about talent and various things. I'm going to describe three of the people I think you need on top of talent. Be very, very clear, you can't put someone in this room and make them an England rugby player, or put them into your world unless you've got talent to do the job, but if you're in a competitive environment, it's what else you need on top of your talent to actually leverage this to really become a champion or an Olympic gold medalist. And these are things I really look for. And when I'm speaking to athletes and coaches, that's my favourite line. Talent alone is not enough. Talent gets you into rooms like this, gets you into sports team, it certainly doesn't get you into winning gold medals or the rugby world cup. You need something on top of talent to actually get the job done. The three things I look for is first of all this concept I just called 'teachability'. And quite simply, teachability is your ability to learn or take on knowledge. And in my language, you go from being someone called talented, you go above the red line and you become what I call the 'student'. So teachability, quite simply, in my coaching language and those of you who've worked with me will know, these are words I use, you're either a sponge or a rock. And quite simply, you've either got a sponge between your ears or you've got a rock between your ears. And you'd be amazing at the people who get to the top in sport, they're knowledge of what they do is often equal or greater than that of the actual coach. And that's the greatest accolade you can pay the coach of a team or the coach of the athlete. Because when you think about, when you're doing sport, how much of your sporting time is actually spent with your coach stood next to you? Almost every single sport I can think of there's very, very little, so the key as a coach is to make sure that when you're athlete is practicing, the athlete is practicing the right things. There's absolutely no point practicing unless you're doing the right things. So the more you put this knowledge into the player, the better they're going to practice, the more they're going to practice properly, because there's this great saying about 'practice makes perfect'. Well, actually that's not very true. For me, it's knowledgable practice or perfect practice that makes perfect. You gotta actually know what you're doing. And when you take this down a level to those of you who have got kids or those of you who are involved with children -- and I really get on my soapbox about this subject -- I don't think we teach sport very well, and this is not just an issue in the UK, I think it's worldwide. In my job now I'm able to go into Olympic sports all around the world and I don't see anything different in the way we teach sport. And to me, the way we teach sport, at least 25% of sports teaching should be in a classroom or a lecture room like this, where you're actually teaching sport, rugby, cricket, football, boxing, whatever your sport is -- it's not different to teaching maths, history, english, medicine. There's no difference; you've got to study it. And yes, we're lucky in sport, we spend a lot of time out there doing it on the field and in the pools and all these places, but unless you've got an academic side, a learning side -- you see in sport, we don't do that -- but the real top athletes, their knowledge of what they do is quite amazing. You look at someone like Chris Hoy, three gold medals in Beijing, we hope he'll deliver next month -- when you sit down with Chris, he's a very talented athlete, but his knowledge of what he does is unbelievable, and the way he pushes his coaching teams is unbelievable. That's why he's the best in the world. So this concept about teachability is amazing, and what frustrates me a lot when I go round sports. You kind of sit there, and most sports teams when you walk in, there's not a pen in sight, there's not a bit of paper in sight, no one's taking notes. I've never been to any lecture, any top businessman or anybody top in your field, there's people in there taking notes. Sport doesn't think they need to do this, it's complete nonsense. So one of the things I would do with the rugby team, I completely changed this whole culture, and I think we got the job done, because we had these very talented athletes but we spent a lot of time in classrooms, a lot of time in lecture theatres learning, studying, writing things down, then presenting back to us. Almost like doing exams. So in terms of being an elite sportsman, your knowledge of what you do has to be right up there with your coach, arguably greater than that of the coach. And I repeat, that's the biggest accolade you can pay the coach, if you find an athlete who has incredible knowledge about everything he does. And of course, in your world, in terms of the physiology and sports science and all that sort of stuff, it's absolutely key. You can't just stand back, and when I train the athletes I say, you should be working with your sports scientists, with your physiologists to really understand why you're doing stuff, not just doing it because they say do it. Look at strength condition, nutrition, all these areas of sport, this is all part of the learning process that they've got to do. And if you got this real champion person they will normally take the barriers far higher than you can actually imagine because you're just a coach. They know what limits they can take it to. So this teachability, being a sponge not a rock, is absolutely massive. There's nothing wrong with being a rock. If you are being a rock, to me, you've just got to go below the red line and understand this fingers crossed approach. The real champion people go above the line and become real experts, actually capturing this knowledge and keeping it for themselves. The third thing I look for, on top of being a talented person, is that this person can play under pressure. We speak about this a lot and it's one of my favourite sayings in sport, I call this person a warrior, so if you've got talent, you've got the ability to take on knowledge, if you've got the ability to play under pressure you become what I call a warrior. And the key thing, and it's a very English term, this term called T-CUP. T-CUP stands for 'thinking correctly under pressure.' And the key word is correctly. Those of you in this room, those involved under Fares operations, that's what you do. But when you're under pressure in operations, it's how can you think correctly when all of these things are happening. When things aren't going to plan, that's when the real champion people in your world will also be thinking correctly - under pressure. But we really work on this, because when you think of a sportsman or an athlete, when you think of these athletes in a few weeks time, the pressure will be huge. And it's the people who can think correctly and not get fazed by what's going on who will actually get the job done. And I firmly believe that pressure is good, I think pressure's fantastic, because you've got to understand that you're under pressure, but also that person next to you is under pressure. And it's quite simple -- you've got to make sure that you've got strategies in place, and that you coach this, and it is coachable. I'll be very, very clear -- you're not born with this gene to play under pressure, you can coach this, you can teach people how to actually do this. And I'll give you just one example of what I'm big on when I'm coaching, when I was coaching, and I hadn't noticed anyone else working this way before. If we go back to the England rugby team again, I'd have up on the wall three key things in any meeting room. We had a lot of meetings, I'll be very clear, I think meetings are good, I read books about meetings and that you shouldn't have meetings but I think meetings are good as long as there is a clear timescale, a clear agenda, you know what you're trying to do, but in this meeting room, it's a classroom, there's education. The players would come in, and we're in the business of trying to win on Saturday, but on the wall I'd always have three things. I'd have a big clock, a big scoreboard and a big whiteboard with 30 players on it, 15 per side. In any meeting like this, I would just stop the meeting and ask someone like Fares and go 'here: clock, one minute to go, scoreboard: South Africa 12, England 10", and then I'd set the situation up and then I'd ask that player, Fares as an example, to go to the board and immediately tell me what he would do in that situation. If he can't immediately tell me that's what he would do, there's a minute to go in the game, we're two points down, that's the situation, if he can't immediately tell me what to do, he's not a warrior. He's just a student of the game. And what warriors do, they think of every single possible thing that could happen, and when it happens, if you've thought it through, especially if you've documented and studied it, when it happens you've got a very high chance of getting through it and making the right decision or the correct decision. T-CUP. If you've not even thought about it before and you're there in the moment and things are all kicking off, which happens in sport and in your world, if you've got to think about it and then you've got to assume you can use your experience, the chances are very high that you'll make a wrong decision. So this T-CUP - thinking correctly under pressure -- is massive for me and we do lots of scenario after scenario after scenario, both individually and as a team. Because individually you've got to know how to operate, and as a team you've got to know how to operate. And these are the things you need on top of talent. So it's your ability to play and perform under pressure, and last thing, last one, how I define a champion, or champion athlete, is this: people have this incredible word and one of my favourite words in sport is people with the right attitude. Now attitude is something I don't think you're necessarily born with, it's certainly developed as you grow up, through your experiences, when you go to school and what actually happens in your life, but again, I think you can coach attitude. And what I do -- and I'm not going to go through this because I've only got eight minutes and I got a lot to go -- I have 10 definitions of attitude. So what I do, I define what attitude means to me in a sporting world, and I make these very detailed definitions. And quite simply, the people who are working with me, the athletes and coaches, we all work off that template. You can do very sophisticated psychometric tests to measure these ten attributes of attitude. But you don't actually need to do that because you can just do a bar graph and you measure how you measure up against attitude. An example is punctuality. I'm absolutely massive on punctuality. You know, how can you possibly trust or work with somebody -- it says more about an individual than anything I can think of. So punctuality is huge. We put huge store in punctuality, because you just can't be late. And that reflects how we play the game and the whole thing. You know, you need to have a very clear definition of what that means. So you can measure someone's attitude. Attitudes are measurable. As I said, you can do quite sophisticated tests on this but you actually don't need to do that. So you can measure those areas. To me it's quite straight-forward. You've got to have this incredible talent. You can't take people off the street. But on top of that, you've got to have that talent -- just to summarise -- you've got to have that. But everyone's got talent, to a different degree. If you're working at the elite sport level, there's lots of talent all round the world, and so on top of that, what sets people apart to me is quite straight forward. It's your ability to learn and take on knowledge and really push the boat out. I would get on a plane tomorrow and fly to the far side of the world if it meant that I had the slightest pretender's chance of becoming a better chance -- I would do that. Once you lose that passion, your passion or hunger or thirst for knowledge, the chances are you'll just go below the red line and come second. And professional sport is not about coming second. And then the next thing is thinking, thinking every possible scenario, T-CUP, pressure, and documenting this study and showing it to the people. So when these things happen you can actually make the right decision. The TCUP thing is interesting because it must be massive in your world. I've got three great kids, but if they were sitting here now they would all fold their arms and crossed their legs and say, oh here he goes again, he's off on his TCUP moment. Because that's simply, that's how we brought the kids up. They're out there, they're normal kids, they're doing all sorts of stuff that probably they shouldn't be doing, they're going to get in situations that we hope they won't but probably will, and quite simply, that's how you teach them, it's how they can think correctly in that situation and handle what actually happens to them. It's no different at all. It's a very simple practical way of working but it works. And now they're older, you get all sorts of messages and phone messages saying have a look at this, not a very good TCUP moment for this person, so they get it now. But at the time they would go oh here he goes again. And just lastly, there's no substitute for hard work. That's the key thing. So that's just briefly, I thought I'd touch on them. I could literally spend a day on each of those subjects in terms of lecturing and break out groups and real academia on the side. But it kind of works. When you see someone win, they've not just done it because they've got this natural, God-given talent. I just don't believe that that's what happens. It's amazing what people do, especially people here who are naturally gifted. You think of Usain Bolt, you think of all sorts of Messi in football. If you go behind the scenes, you'll be staggered at how they work, how much knowledge they've got. They may come across that way in public but behind the scenes, if you're lucky enough to see what they really do, you'll find that model stacks up. So thank you very much. Well done again to Fares. It's been a real pleasure to be here. >>[Applause]