With the indulgences of Christmas behind us, Steve O'Rahilly sheds some light on shedding a few pounds as he discusses the science of appetite, obesity and weight loss, Len Almond describes the role of exercise in losing weight, John O'Doherty talks about what happens in our brains when we reach for our favourite brands, Jane Visvader and Connie Eaves describe their discovery of the breast stem cell, and Dave and Derek find out what cream and paint have in common in Kitchen Science.
In this episode
Do-you-think-he-saurus... Or Heard Us Even?
Using data from birds, which are close relatives of the dinosaurs, researcher Otto Gleich, from the University of Regensburg, has calculated the range of frequencies a dinosaur would have been able to hear. Amongst birds, hearing range drops with increasing body size and the length of an ear-structure called the basilar papilla. This isn't preserved in fossils, but it is typically two-thirds the size of the well-preserved cochlear duct. By measuring the sizes of the cochlear duct in an archaeopteryx, an allosaurus and a brachiosaur, the researchers estimate that archaeopteryx would have had a hearing range roughly equivalent to modern birds, a 1.5 tonne allosaurus would have heard best at 1.5 kHz and notes no higher than 3KHz, whilst a much larger 75 tonne brachiosaur would have heard best at 700 Hz and been deaf to sounds above 2.4 kHz. A T. rex would have had a hearing range somewhere between the allosaurus and the brachiosaur, and as a human scream has a pitch of over 3 kHz, it's likely that a Tyrannosaur could well have enjoyed you for lunch without having to endure the sound of your protestations. He would, however, have been well able to hear the sound of his stomach rumbling - at about 20 Hz - beforehand!
Stem Cell Scandal
Although science is often seen as perfect, things can go wrong and the Christmas holidays saw the world rocked by a stem cell scandal. Last year, South Korean scientist Woo Suk Hwang announced that he had managed to clone human embryos and make stem cells out of them. But now other stem cell scientists have used genetic fingerprinting techniques to show that Hwang's work was fake. So the prize of cloning the first stem cells is still up for grabs. But it's not all bad news for stem cells. This week, researchers in the US announced that they had managed to make human embryonic stem cells without the use of any animal products. Normally, stem cells need things like cow proteins in order to grow, but such products carry a risk for sparking allergies, or carrying animal viruses. So this is an important breakthrough as it means we can now make stem cells that are much more suitable for transplanting into patients.
Brest Stem cell
with Jane Visvader and Connies Eaves
Chris - Jane Visvader and Connies Eaves have independently discovered the breast stem cell. This is important because if you take that cell and place it elsewhere in the body, it ca make an entirely new breast. That must have have very important cosmetic applications because if you needed to have a new breast after maybe losing one for various disease processes, it could be very handy. But this stem cell may also hold the key to controlling breast cancer. It's becoming increasingly clear that these stem cells play a role in triggering cancers in the first place, but also that chemotherapy which we use to treat cancers doesn't hit those cells very efficiently. They're always loitering there ready to cause the recurrence of the disease. Now we know how to track them down, we may be in a much better position to treat breast cancer properly. First of all, let's talk to Jane Visvader, who is at the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia.
Jane - We've isolated and identified the breast stem cell, and shown that a single cell, when implanted into its correct environment, can in fact give rise to the entire ductal tree that typifies the breast tissue.
Chris - How did you actually track the stem cell down?
Jane - It was years of work by two very talented people in the lab, and by using a whole series of markers that are expressed on the cell surface, went through one by one and eventually found a population among breast tissue that expresses these specific markers. By using these markers, they could actually isolate the cells. They could purify them and then implant them into a mouse model in the fat pad or 'mouse breast' where it normally grows.
Chris - That was Jane Visvader describing how the breast stem cell can give rise to all of the normal tissues in the breast. But the findings also point to one way in which these stem cells could contribute to the formation of abnormal tissues within the breast too; in other words, cancers. Connie Eaves from the Terry Fox Laboratory at the British Columbia Cancer Agency in Vancouver explains.
Connie - One of the most fascinating observations in our paper is that this cell is not what everybody thought would be the case. It is not lying there mostly asleep. It is a very actively dividing cell. But because they are diving all the time, that means that they must be very prone to developing mutations and some of those mutations by chance would be mutations that would give you a cancer. So this may explain why the breast is a tissue where the development of cancer is very prevalent amongst women.
Chris - Now presumably, given that you've identified this cell, you can now look for any markers that distinguish it from other cells or gives it its individuality.
Connie - Yes, well part of this paper is about the identification of certain adhesion molecules that are expressed at very high levels on these cells, more so than any other cells in the breast tissue. That what makes it possible for us to isolate these cells.
Chris - That was Connie Eaves describing how breast stem cells might contribute to the formation of breast cancers, and how the unique molecular fingerprint that they express on their surfaces allows them to be singled out from other cells in the breast. But what are the implications of these findings for the ability to treat breast cancers?
Jane - There is growing evidence that many cancers contain a very rare population of stem cells that actually drive tumour formation. They're very difficult to eradicate because they have different properties, so many chemotherapies available now do not target these cells. So in the context of breast cancer, we've characterised the normal breast stem cell, which will share characteristics with this and so our future studies will certainly go in the direction of trying to identify these stem cells that exist in proportions of breast cancers.
- Pavlovian Conditioning in Human Brains
Pavlovian Conditioning in Human Brains
with Prof. John O'Doherty, California Institute of Technology, USA
Chris - Tell us about your amazing study.
John - What we're interested in is how can we learn to predict when good things are going to happen to us. It's very advantageous to be able to predict when either good or bad things are going to happen to us, because then we can prepare ourselves in advance and do the things that we need to do to get as much reward as we can. What we were interested in was the parts of the brain are involved in this learning process. We took a bunch of human volunteers and we put them in an fMRI scanner. What this scanner does is pick up changes in blood oxygenation, which are indirectly connected to neural activity. Therefore, we can actually see the bits of the brain that are being engaged during different types of learning process. What we did was presented the subjects with different flavours of juice, such as blackcurrant, melon and grapefruit juice. The subjects tended to have a preference for the one of the juices. When they were in the scanner, they were getting little squirts of juice. However, just before the squirt they were shown an arbitrary picture. What happened over time is that subjects learned to associate the juice stimuli, which were variably pleasant, with the arbitrary stimuli. What we started to see in the brain was a response that occurred to the juice stimuli which shifted back over time and over learning. Eventually, the subjects' brains were responding to the visual cues.
Chris - So in other words, you were showing them a picture, such as a circle, and then giving them a squirt of grapefruit juice. After a very short time, you showed them a picture of a circle and even without the grapefruit juice, their brains were lighting up.
John - Exactly, so in advance of the grapefruit juice happening, the brain was telling the subject that something good was going to happen to them.
Chris - You said earlier that it was useful to do this to learn how these happen, because for mankind as a whole and any kind of animal, if you can learn to associate cause and effect, then you're better at doing things in future. Now were the size of the signals that you were getting in the brain proportional to how much people liked the juice?
John - Exactly. The more they liked one of the juices, the stronger the signal was for that juice over the others. What that's telling us is that when you see a visual cue or some bit of information that's telling you you're going to get something nice, you can actually access the value that that stimulus has for you.
Chris - So if you know that writing coca Cola in a certain way tells people they're going to get something they like, you can apply that branding to some other product. This would mean that in your brain, there's going to be a transfer of the strength of how much you enjoyed that product before to the other products.
John - Yes, and that's exactly what people who want to market products try to do in advertising. They try to associate arbitrary things like the brand logo with other nice things. For example, in advertising you might show an attractive face or nice environment or scenario. By learning the association between that brand and something you find rewarding, the idea is that the next time you come along and want to make a choice, the information you've learned could bias your decision. You're more likely to choose the thing that's been associated with the thing that's nice.
Chris - What part of the brain did you see all these changes occur in?
John - We're looking at two parts of the brain. One part is called the ventral striatum, and this is deep in the centre of the brain. It's one of the parts of the brain that's important in pleasure. The other part of the brain we saw signals in was in the mid-brain. Again, this is very deep in the brain and this area contains neurons called dopamine neurons. These neurons have been implicated in reward and learning about good things. These neurons project widely around the brain, and they might be broadcasting a signal telling other parts of the brain about how nice something is. This could help the other parts of the brain to learn about that.
Chris - Now you've been able to pinpoint these parts of the brain, what implications does this have for treating human diseases in which, say, people do things too much and are addicted.
John - I think the more we understand about how these parts of the brain work, the more we can understand about how we can start to treat different diseases. These include drug addiction and other sorts of diseases where bits of the brain are not functioning properly and not telling you about how rewarding things should be, like in depression. We think this is a disorder in the ability to process rewards and unpleasant stimuli. The more we can understand how it works, the closer we are to developing treatments for these bits of the brain. This could be by using drugs that target certain parts of the brain or using certain therapies.
- Obesity And The Genetic Basis of Appetite
Obesity And The Genetic Basis of Appetite
with Prof. Steve O'Rahilly, University of Cambridge
Kat - Why is it that you get some people who seem to eat chips and lots of other stuff and they're still skinny as rakes, and I just have to look at chocolate and become a porker?! What's going on?
Steve - Like everything in science, you have to work out whether your premises are correct or not. I have to say that the evidence you just said then is actually very poor. When you take people who are predisposed to obesity and put them under controlled settings and monitor what they eat, in general, obese people eat more than thin people. Although we all think we have friends and colleagues who can eat like pigs and not put on weight, when you put them under experimental conditions, it's very hard to prove that that actually happens, or at least happens on a regular basis. There's no doubt that people with some conditions, such as when your thyroid is over-active and your metabolism is extremely stimulated, will eat lots and still lose weight. However under normal circumstances, the cause of obesity is eating that little bit too much for your metabolic rate. That's not a blame issue. It's an issue that some people really are driven to eat rather more than others. We've looked into that over the last ten years or more, looking at children for example that are particularly prone to obesity at an early age. We've found that many of them have genetic defects causing then to fail to notice fullness, so they continue to eat even when others have stopped. Our particular interest is in the genetic basis of appetite. Going back to your initial question, what you've suggested as a common scenario isn't actually that common. That's one of the great things about science; sometimes things that seem common sense turn out not to be true.
Chris - What do we now understand about how appetite is controlled in the nervous system and in the stomach.
Steve - Firstly, we're beginning to know that it is controlled to some extent, but for many years people were of the opinion that we're at the mercy of our exogenous environment. It's only in the past few years that we've discovered that there are signals sent out to the brain that at least provides the brain with information about how many nutrients are being stored. In the absence of those signals, your brain is ravenously hungry. One of those signals is called leptin, and if you don't have that, you are ravenously hungry all the time.
Chris - Where does it come from?
Steve - It comes from fat cells, so the cells you use to store excess energy. We have these so that in times of starvation, we can use it. Very cleverly, these cells produce this peptide hormone called leptin which travels to the brain and keeps the brain informed about how much stored energy we have on board.
Chris - So how do the fat cells know how much leptin to produce? Presumably if the brain can see a certain amount of leptin, it knows there must a certain amount of fat on the body. It must then know how hungry it should feel. Is that how it works?
Steve - It sort of works like that but it has a slightly different mechanism and isn't quite as simple as we'd like it to be. If it was very precise, we'd all be the same weight and would all be able to readily control our weight. Leptin works best at the very very low end, in other words, when you are very thin. The leptin levels become very low and your brain tells you that you are starving and must go and find food. It dominates your life and also switches off reproduction, which you can see when girls with anorexia nervosa stop having periods. At that very low end, leptin works. The problem is that when leptin levels get higher, the brain gets bored and stops taking any notice.
Chris - So does this mean that if you get a bit too big, you get too high levels of this protein and the brain goes deaf to the signal?
Steve - Yes, so-called leptin resistance comes in.
Chris - So if you take an animal and you inject it artificially, does it think it's full up and not eat even though it's eaten nothing?
Steve - Absolutely. You can give it to a rat and it remains a perfectly fit and well rat but without any body fat. It's also been given to humans, and in normal human beings, they lose fat.
Chris - What about in fat people?
Steve - Due to leptin resistance in fat people, injecting leptin is less effective. It probably isn't ineffective, but we can't get enough of it in because the body is so leptin resistant. A lot of research now is going into why people are leptin resistant and what's downstream of leptin in the brain. This is where lots of the exciting current research is.
Kat - How close are we to finding the wonder pill that people can take, or is that not really the answer?
Steve - I don't think that there will be one wonder pill, but I'm not as anti-pill as many people are with respect to obesity. If we go back 50 years and look at high blood pressure, everyone thought it was down to stress and lifestyle and that it wasn't really a disease. People were a bit uncomfortable about giving people a pill for something to do with stress. Now we treat high blood pressure extremely well and stroke rates in this country have come down and people are living longer due to good hypertensive therapy. We sometimes have to use two, three or four drugs to cure people but doctors prescribe them and we pay for them as a nation. In twenty or thirty year's time, we'll probably have the same attitude towards obesity, and we'll see that people with obesity are at serious risk and we'll see nothing wrong with helping them with therapies to go along with lifestyle, exercise and diet.
Chris - What is the potential cost to the UK at the moment of the roughly one person in five who's obese?
Steve - I'm not a health economist but it's billions in terms of lost work days and secondary illnesses associated with obesity such as diabetes. It's an enormous cost.
Len - It's about 8.3 billion per year.
- The Benefit of Exercise
The Benefit of Exercise
with Prof. Len Almond, Loughborough University
Chris - Now let's talk about one way in which we can lose weight very effectively, and that's exercise. What is the contribution of exercise and to what extent can it really make a difference?
Len - Steve has mentioned energy balance, and that's an important concept to get over. What's also important in energy balance is the idea that people do more sitting than they actually realise. The average person does at least 90 per cent sitting throughout a whole day. We also tend to sleep far more at weekends. One of the reasons people tend to put on more weight at middle age is that from 35 years onwards, you start to decline in terms of functional capacity. What you also do is tend to do less activity at weekends, sleep and sit more, and this can add up to 17 kilograms over the amount of time Steve was talking about. So it's a very simple equation.
Kat - Some people like going to the gym, but some people just hate the gym. What's the best kind of exercise to take?
Len - By far the best and simplest thing is walking. We need to be walking at least 30 minutes every single day. Now that represents just two per cent of your day, whereas you will sit for over 90 per cent. I have some patients who sit for five hours every evening.
Chris - Can we put some figures on it? How many calories do you burn watching the telly.
Len - That's very difficult to say. If you want to lose two pounds in weight, you need to lose 700 kilocalories in a week. So we're talking about 500 kilocalories in terms of food each day and 500 in terms of exercise. Now it's quite easy to lose 500 kilocalories interms of food because you could just have an apple instead of an apple pie. But it's more difficult in terms of exercise. You need to get about 30 minutes of exercise in per day but you also need to reduce your sitting behaviour. That's an important factor.
Kat - There are some statistics here about the calories you burn doing different types of exercise. If you're an average 10 stone person, you can burn 370 calories cycling for an hour, 580 calories running for an hour, 330 calories downhill skiing, 266 calories weight training, about 400 doing aerobics, 140 doing yoga, 460 swimming, and having sex for an hour burns 360 calories!
Chris - I think it depends how active your sex life is though!
Kat - Yes, that's an hour not three minutes Chris.
Chris - Don't speak for your own standards Kat!
Does laughing gas really make you laugh?
Yes, it kind of does. Laughing gas is nitrous oxide, and it acts as an anaesthetic-type agent. It makes your brain feel a bit woozy in the same way that alcohol does. As a result, if you take some laughing gas, you fell a little bit drunk and a little bit cheerful. If you have enough of it, you start to feel a little bit sleepy, but it's very good at pain killing. If you're having an operation, it's sometimes used with other anaesthetics to kill pain and make you more comfortable. There is a sub-set of people in the population that have a particular form of a gene that is involved in making new blood cells. If they have this sub-set and have laughing gas, then it can affect their bone marrow in the long term. It can make your bone marrow work less well. Luckily, it's only temporary, but I don't think that I'll be inhaling lots of laughing gas.
- Why does clotted blood change colour over time?
Why does clotted blood change colour over time?
Initially, the blood is red due to the oxygen in the haemoglobin. As it sits around, it loses its oxygen and turns a purple colour. After that, the body starts to metabolise the blood products into more red and green pigments. You can tell the approximate timing of bleeding by the combination of those pigments. Haemoglobin is made of four rings joined together, a bit like a clover leaf. When you first bleed, you get that stuff in your bleed. Very quickly after that, cells move in and start attacking that molecule and break it open into a long chain of these rings. That's a molecule called bilirubin, and another related molecule called biliverdin. Biliverdin is a green colour and bilirubin is a browny-yellow colour. Too much bilirubin is what makes your skin go yellow when you get jaundice. All these things happen just in the site of your bruise or bleed, and that's why your bruise changes colour from a red to a browny-green to yellow.
- Why do I stay thin regardless of what I eat?
Why do I stay thin regardless of what I eat?
They all boil down to the same question, which is what underlies the differences between human beings between their body weight trajectories throughout life. In other words, why do some people remain thin while other people become fat. Obesity is terribly simple. There are just two sides to the equation and that's energy in, that is how much you eat, and energy out, how much you expend. So really we all know the answer, and that's that one side is greater that the other. The paradox is that it's very difficult to accurately measure energy in and energy out in any one individual throughout their life. You only need a tiny disturbance on a day-to-day basis, such as a half finger of twix too much every day for thirty years, and that can add up to 20 kilograms of weight. Our ability as scientists to measure each individual is difficult, especially when we try to take into account what people perceive as stuffing themselves. Ken's idea of stuffing himself might be nothing in comparison to my idea of stuffing myself, and I'm a big guy! Our research suggests that genetics is an underestimated factor. Body weights tend to run in families very strongly, and those genetic differences may affect the same parts of the brain that we talked about when we were saying about leptin hitting the brain. Our research is indicating quite strongly that it's variation in those parts of the brain might control both what you want to eat and in some cases, what you want to expend. If we can understand those, then perhaps we can manipulate them.
- If you take a lot of exercise but eat a poor diet, is this still bad for your heart?
If you take a lot of exercise but eat a poor diet, is this still bad for your heart?
The answer to that is in fact quite difficult. It all depends on exactly how much activity that person is doing. A person doing a lot of exercise needs a lot more energy to keep them going. The advantage of exercise is that it does help to break down the fat, but I would say as a common sense notion that if you're eating more fat and having more cholesterol, it's not good for. So I would say to reduce fat.
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