DR SADAF FAROOQI (Addenbrookes Hospital, Cambridge): In the US where obesity is reaching epidemic proportions deaths from obesity-related diseases rank second only to smoking as a major cause of death.

NARRATOR: You are twice as likely to die from heart disease, at least seven times more prone to diabetes and 40% more inclined to be killed by cancer. The problem is global and it's growing.

DR JOHN CLAPHAM (GlaxoSmithKline Pharmaceuticals): Just in the UK alone they're estimating that a quarter of all adults will be clinically obese by the year 2010.

NARRATOR: Already one in five Britons are obese and one in two are overweight.

JOHN CLAPHAM: It's epidemic proportions and effective treatments are desperately required.

NARRATOR: But more disturbingly still our weight might not be completely within our control. These ladies are united in an unusual cause. They are convinced they are naturally different. For them fat is not only fabulous, it's a foregone conclusion.

TRICIA: By looking at my family and the large number - no pun intended - large number of fat people in my family, it just to me seems inevitable that I would be large.

PADDED LILIES MEMBER: This is my natural look because it's what I've been given from my generations of predecessors.

NARRATOR: In celebration of their size they've formed a water ballet troupe and called themselves the Padded Lilies. They all believe they were born to be fat.

TRICIA: At first, of course, I was normal size but within a year although I was fed normally, nurtured normally, 32lbs. I mean I believe that it was just in my genetic make-up to be that size.

NARRATOR: Could the Padded Lilies be right? Could it be down to genes? Scientists had long suspected that our weight might not just be a result of what we eat and how we exercise. They wondered whether it might also be influenced by our genes. Startling evidence that it was came from a rather unusual double act. Labour Day weekend in New Orleans. Sharon and Debbie are twins, but they are taking their very first holiday together, at the age of 46.

DEBBIE MEHLMAN: Oh look at, is that a chow...

NARRATOR: They were brought up by two completely different families. They didn't even know one another existed. They were separated at birth and were only reunited a year ago.

SHARON POSET: We didn't know that we were identical twins, you know (TALKING TOGETHER) twins...

DEBBIE MEHLMAN: ...so I see her coming out and I'd keep staring at her and she'd be saying don't look at me...

SHARON: Don't look at me.

DEBBIE: Don't look at me.

SHARON: It's, it was like too...

DEBBIE: Too much.

SHARON: ...intense a feeling and then everybody goes ah so it's like looking in the mirror and we're like no dummy, when you look in the mirror...

DEBBIE: That was you.

SHARON: ...that's you.

NARRATOR: The similarities are striking. Over the years there's been little variation in their looks, their heights and their weights. When they finally met there was only 5lbs difference between them. What is astonishing is that they could not have had more opposite upbringings. Sharon lives in Kentucky and was brought up as a Catholic. She didn't worry about her diet, loved meat, particularly pork and fatty foods.

DEBBIE MEHLMAN: Oh look alligator and pork.

NARRATOR: She also did very little exercise.

SHARON POSET: I would do spot exercises for my arms and my waist, but I'm not going to wake up first thing in the morning like she did and go to the exercise gym. That, that's not my priority.

NARRATOR: Debbie eats fish but not meat. She lives in New Jersey and was brought up as a Jew. Unlike her twin sister, she exercises regularly and is very health-conscious.

DEBBIE MEHLMAN: I really watch what I eat and I don't eat dairy products, not just, not with meat, I don't eat them and I don't eat meat, I do eat fish. I know I don't eat poultry.

SHARON POSET: So she's a joy to have over for dinner. (Yes) It's like you know wow (TALKING TOGETHER)

NARRATOR: Even though they've had different upbringings, Sharon and Debbie are carbon copies of each other. It seems they were born to be slim. They are living proof that genes play a crucial role in shaping our weight, but the question is: how? For years scientists thought the answer lay in the genes that control the body's metabolic rate, the rate at which food is broken down and turned into energy. If the body doesn't burn up food fast enough, you put on weight. The idea is that metabolism is to blame for obesity.

TRICIA: I would say that, that probably the reason we're fat is because our metabolism is slow. I mean to suddenly be 32lbs at a year old I don't see any other reason for that than metabolism.

PADDED LILIES MEMBER: Thin people can eat a tremendous amount and still be thin. Fat people can eat next to nothing and still be fat. The amount I'm eating isn't what's making me fat. My metabolism, my genetics, these, this combination of things is what made me fat.

NARRATOR: Glenda is a care nurse. At 21 stone she, too, has been fat all her life, but the physical demands of her job are taking their toll. Her doctor has told her she has to lose weight.

GLENDA BAILEY: I've had enough now, I've had enough. I've had enough of being fat, of people's comments. I just want to be normal. I don't want to be slim, slim, I just want to be nor, you know average.

WOMAN: I haven't spoken to Dan yet, so I will speak to him tonight...

GLENDA BAILEY: When I go to work I think they're going to say you're big, you're fat. Before you've done a morning's work somebody's going to come out with that comment. Right we're going to take you up in the sky now.

WOMAN: Not too high.

GLENDA: Not too high. One, two, three.

WOMAN: There we are darling...

GLENDA BAILEY: I do hurt, I do cry. You see when you're fat people look at you as a fat person, they don't look at you beyond what's inside you. I think the worst is when I married Dave and somebody said to me quite openly why the hell has he married a fat person like you for? Made me feel awful. Then I began to lose my confidence, then I began to wonder why did he marry me, you know, which was stupid. You can't help it.

NARRATOR: Like the Padded Lilies, Glenda also believes that it is not what she eats that makes her fat, but that she has a slow metabolism. She has always wanted to know why she's different, so she visited the Human Nutrition Research Unit in Cambridge where she hoped they'd tell her.

GLENDA BAILEY: I really want them to tell me why my body doesn't burn up calories as it should do. It just make sense.

NARRATOR: To solve the mystery she had to spend the whole night in an airtight chamber where they plan to take some curious measurements.

DR SUSAN JEBB (MRC Human Nutrition Research): If you just pop your bag down on the side and I'll explain to you a little bit (Yes) what we're going to do. Firstly, this room is going to be completely sealed once we shut the door and that allows us to measure the air which is coming in through this ventilation shaft here and then the air which is going out again.

GLENDA BAILEY: Yeah, I definitely think I was born differently. Why is it that I can sit down and eat a meal exactly the same as everybody else, yet I put on weight. I can go on a diet, I can really, really try, but it doesn't do any good. I'm sure that I've got a slow metabolic rate.

NARRATOR: This one night of isolation is all it would take to answer her question once and for all. Overnight the oxygen Glenda breathed in was constantly measured. This enabled them to gauge how many calories her body had burnt. The room was kept at a comfortable temperature so she didn't burn extra energy by shivering and sweating. The measurements were then used to precisely work out Glenda's metabolic rate. In the morning Glenda was given the result, but the answer was a total surprise. Like all large people, Glenda's metabolic rate isn't slow, it's fast.

GLENDA BAILEY: I always imagined my weight was because I'd got a very, a low metabolism and that's why I couldn't lose weight, but basically it's 'cos of the food I've been eating.

SUSAN JEBB: That's right. It's one of the great myths of dieting. The number of people who've been in and said to their doctor: doctor, I've got a slow metabolism is absolutely in the thousands if not millions. We have compared energy expenditure in lean and overweight people. We've looked at siblings, we've looked at parents and children in an attempt to find some evidence of a real difference in energy expenditure between people who remain slim and those who had a tendency to gain weight. What is very clear from all the research is that overweight people actually burn off more energy than slim people. The reason for that is quite simply that bigger people have more cells, they have bigger hearts, bigger lungs, bigger livers. All of these vital organs need energy just to keep ticking over.

NARRATOR: Studies like these have now overthrown the belief that metabolism is the arch enemy, the cause of obesity, but science is now left with a puzzle. If fat people burn up food quickly why do they find it difficult to lose weight? It appears that humans have a problem when presented with lots of food - they eat it. Millions of years ago our ancestors had to fight over scarce food. Today we are confronted with endless choice. Why we find food so difficult to resist fascinates Professor James Hill.

PROF. JAMES HILL (University of Colorado): Eating is one of the most important functions for survival of the human species. Think about it. Here we are with, we're machines that are really designed to get enough food intake. We're designed to get enough even when times are scarce so that we have these drives to eat. This is a great adaptive scenario. You want to eat to survive.

NARRATOR: But this biological drive to eat, hones through evolution over millions of years, is now working against us.

JAMES HILL: Now we're just saturated with good tasting, high energy dense foods, easily available. You can go in a restaurant or anything. Why wouldn't we under those situations really have a high level of food intake and that's the problem is that we're driven to eat and we're given foods that really push all the buttons to eat more.

NARRATOR: Scientists had long been intrigued by the theory that we all have a biological compulsion to eat, but it didn't answer the question of why some people are fat and others aren't. Genes were involved somehow, but not through metabolism. They were on the edge of the first major breakthrough the field had seen in years, but in the absence of hard proof they could go no further. Then along came a big, fat clue. From the day it was born this mouse had never stopped eating.

PROF. JEFFREY FRIEDMAN (Rockefeller University): In the Jackson laboratory in Maine they breed millions of mice a year and every now and then a mouse appears that they call a variant and they can establish, using breeding experiments, that a particular variant is so because of a defect in a single gene and so whereas a normal mouse looks like this, one day in the 1950s a mouse appeared that looked like this and you'll notice that mouse is rather obese.

NARRATOR: It was tantalising evidence that the mouse's appetite was genetically hard wired. Friedman and his team spent the next 10 years comparing the fat mouse with its thin relatives to find out how a gene could make it hungry. Then he discovered something missing in the blood of the obese mouse that was present in the thin mouse - it was a hormone. They called it leptin. They gave the fat mouse this missing hormone. Years of research hinged on whether it would stop eating.

JEFFREY FRIEDMAN: The results of the injections were pretty profound. The mice lost 30% of their weight after two weeks and 40% of their weight after, after four weeks.

NARRATOR: A revolution in the science of obesity had begun. The mouse was fat because it wouldn't stop eating. Without leptin it couldn't curb its appetite. The discovery that a chemical made fat mice thin had massive popular appeal. The question was whether it would work on humans. Researchers suspected that the hormone leptin was a messenger molecule. It travelled through the blood and up to the brain. There, they guessed, it turned the appetite off. Could leptin be the long awaited miracle cure for obesity? The answer was in the bottom of a freezer - two blood samples which were to make medical history. They'd been lying there undisturbed for nine months. Until the discovery of leptin, the head of the laboratory hadn't even been researching the causes of obesity.

PROF. STEPHEN O'RAHILLY (Addenbrookes Hospital, Cambridge): I didn't know how to take the field forward. I really just ignored it as a scientific problem. I'd barely read the literature, I was, wasn't terribly interested, so I think fields move forward when something makes it possible, a paradigm shift and I think the discovery of leptin was such a paradigm shift in, in thinking about obesity.

NARRATOR: O'Rahilly hired a new research fellow in the lab. He asked her to look for leptin in people.

SADAF FAROOQI: I went to Professor O'Rahilly and asked him whose leptin he'd like me to measure, and he had in mind that there were a couple of patients he'd been thinking about for some time but, and always wondered about their leptin levels so I went and we dug out this sample from the bottom of the freezer somewhere. These particular children he'd always been interested in because there was something quite unusual about them. There were two children in a family and they were very, very obese from an early age and all the conventional tests in these children had shown them to be normal and yet something didn't fit. There was clearly something else going on.

NARRATOR: It was the first time she'd ever done the test. If Farooqi found there was no leptin in the samples it meant that this could be the cause of the two children's obesity. It would be the first proof that leptin played a vital role in controlling appetite, not just in mice but also in humans. In the morning she went to tell her boss what she had found: there was no leptin in the first blood sample.

SADAF FAROOQI: Well I went up to see him and I showed him the results and I said well I think I can measure leptin now. That seems to be working, but it's very strange, this particular patient's blood sample doesn't look like there's any leptin and yet isn't she very obese, and he said oh my God, do you know what this means?

NARRATOR: One child's obesity was so extreme it had caused her knee joints to collapse. There was no doubt they were both constantly consumed with hunger. Without leptin they simply couldn't turn their appetites off. Farooqi administered both children with the missing hormone. The results were astounding. Both of them lost a stone in weight, but the very existence of these children had a more fundamental significance.

STEPHEN O'RAHILLY: There were a number of interesting implications, the first being that leptin was just as important for human beings as it was for mice and secondly, that as really the first genetic defect in humans found cause obesity we really had the first evidence that you could become very obese as a human being through no conscious fault of your own, but simply through a defect in your genes.

SADAF FAROOQI: We were really very excited about it. It was incredible moments. We'd found for the first time a gene causing human obesity and in a way we couldn't believe our luck.

NARRATOR: The two children had offered the first intriguing glimpse into the genetic controls on appetite. The science of obesity was close to its next big breakthrough, but the excitement was short-lived. After years of hunting, the Cambridge team only ever found three other leptin deficient cases. The gene defect was exceptionally rare, so although their discovery had proved that genes can cause obesity maybe these defects occur so infrequently that they're not really that important. It was time to look for clues elsewhere. Researchers speculated that leptin is not the only hormone involved in switching off hunger. The science gets interesting when it reaches the brain. Here, they theorised, leptin triggers the release of a cascade of other chemicals. These pass along the neurons and eventually turn off the appetite. They called this chain reaction the appetite pathway. It implied that leptin was just the beginning of the story.

STEPHEN O'RAHILLY: What happened then is the attention of several groups round the world was focused on severely obese children in the hope that perhaps if they didn't have leptin deficiency, if we looked further along the pathway of where leptin was working we might find defects there too.

NARRATOR: And so it seemed to prove. A child with all the tell-tale signs came to light in Germany. At two years of age Alina was already so heavy her legs were starting to bow underneath her weight. She was always hungry. By four she had become obese and she continued to put on weight. Her mother suspected something was wrong.

ALINA'S MOTHER: When we laid the table at home and tried to eat normally she would eat faster and faster with a tendency to stuff the food in because she always wanted more.

NARRATOR: Alina's hunger seemed beyond control. There was little her mother could do to stop her eating.

ALINA'S MOTHER: When I go out with Alina and people stare at her or make stupid remarks it makes me very sad because she's my daughter, who I love totally. She's had a difficult time and will in the future. This hurts me deeply because I love her very much.

NARRATOR: Alina had all the symptoms of a defect in her appetite pathway, but when scientists examined her they found she had plenty of leptin. Further tests revealed the sad truth. Alina did have a defect. It was in the next chemical in the pathway and without it she was for ever hungry. Alina's misfortune was a clue to a far wider picture, but more evidence was needed. Back in Cambridge the hunt began anew. Calls went out for blood samples from obsess children like Alina. The next big breakthrough was on its way. to head the search they called in a man with unusual credentials.

DR GILES YEO (Addenbrookes Hospital,Cambridge): I'm a gene hunter. It's my job to look for mutations in genes. I had already looked at about 30 or so patients not, not finding, not finding anything and it was late afternoon and I was working on the next batch of patients. All of a sudden I, I stopped 'cos I thought I saw, I saw something. Now is this real?

SADAF FAROOQI: So the first thing he did was give me a call and told me that we might be onto something here. There may be a defect in this gene.

GILES YEO: And so she came and we, we both had a look at it and she goes well, it looks real, is it real? She goes, and I said well, we have to repeat it in order to be 100% sure.

NARRATOR: So Giles immediately reran his DNA sequencing gel. If there was a defect it would be the next big discovery after leptin.

GILES YEO: I actually stood there pretty much the entire time waiting for the, for the data to come through and Sadaf was there with me and so we wait, we wait and wait and then the thing comes through and voila, there it is.

NARRATOR: They'd found a flaw in a gene for another chemical in the appetite pathway called melanocortin. As with leptin, the defect caused obesity.

GILES YEO: Everyone dreams of, of, of knowing when, when, when they, when they find something that looks like the, the genuine article and we were extremely excited.

NARRATOR: But the search then continued, with surprising results.

SADAF FAROOQI: Almost every few months we were finding another child with a defect in this gene and very soon the numbers began to grow and we realised that we'd found many children with defects in this gene and this really was quite different from leptin deficiency.

NARRATOR: It turned out to be far bigger than they ever could have imagined. After six months they'd found more obese children with the melanocortin defect than they'd ever found with leptin. By 12 months this number had tripled. Eventually they realised that this single gene defect on its own accounted for a staggering 5% of the children they'd looked at.

GILES YEO: I guess that makes defects in the melanocortin receptor gene the commonest single gene cause of obesity.

NARRATOR: It was the evidence scientists needed to completely overturn the way we view obesity. Incontrovertible proof that genes have a widespread and important effect on appetite. Obesity is not necessarily a failure of character, but can be an inescapable biological inheritance and this genetic drive to eat affects everyone. In all of us each of the chemicals in the appetite pathway will be controlled by a variety of different genes. Tiny variations in any one of these genes could make the difference between having a large or a small appetite.

STEPHEN O'RAHILLY: It's quite obvious to me that there must be individuals who are born with a more intense or a less intense appetite than others and put in the right situation or the wrong situation with abundant access to food those individuals born with greater appetite drive are much more likely to become obese.

NARRATOR: The news that our hunger might be beyond our control was greeted with very mixed feelings by the Padded Lilies.

TRICIA: I think it takes away the shame that I got from years of dieting, years of dieting years of thinking I hadn't exercised enough, that I was somehow lazy. I think it takes away that.

REBECCA: I think it just confirms to me what inherently I knew is that I was different and it makes sense to me, makes sense that, that I have a predisposition for hunger.

PADDED LILIES MEMBER: As a child I was very aware of being more hungry than the other kids. Not of feeling hungry all the time necessarily, but of sitting down to eat with other kids and they would be done and I would want more food.

PADDED LILIES MEMBER: You're the first person who comes up to me and says oh you're one of those people with the fat gene and that's why you're eating that hot-dog, that person is going to get sat on.

NARRATOR: But this rethink in the way we understand obesity is enabling science to take the next much needed step. This top secret research facility is where the war against obesity is being waged. Here millions of pounds are being poured into the hunt for a magic bullet, a drug to treat the disease. John Clapham is at the front line of this research.

JOHN CLAPHAM: To find a treatment, an effective treatment, for obesity is of paramount importance.

NARRATOR: And the mission is to find a pill to kill hunger, a pill that works by manipulating our desire to eat. To do this they need to map out all the chemical signals in the appetite pathway.

JOHN CLAPHAM: 'Cos every one of those is a potential new drug target and the more drug targets we've got to work on the chances for success are much greater and we have every hope in the future of getting a new drug.

NARRATOR: As suspected, leptin and melanocortin are turning out to be just the tip of the iceberg.

SADAF FAROOQI: We now know about a number of other chemicals in the brain that act to regulate appetite. We know there are some that act to decrease appetite.

JOHN CLAPHAM: Such as the melanocortins, bombesin, the neuromedins.

SADAF FAROOQI: POM C, the melanocortin receptor, there's been CART.

JOHN CLAPHAM: There are those that decrease appetite such as the orexins, galanin

SADAF FAROOQI: Neuropeptide Y.

JOHN CLAPHAM: There are a number of peptides released from the gut that affect appetite such as glucagons-like peptide 1, enterostatin, cholecystokinin and on and on and on. We're expecting more discoveries all the time.

NARRATOR: But even with all these drug targets they still have a long way to go.

JOHN CLAPHAM: In terms of drug treatment for obesity we're lagging 20 years behind other avenues of research. We're at the beginning of a long road now and we're still, even if a treatment were to be identified tomorrow, then we're looking at 10/12 years before any treatment is actually available.

NARRATOR: With no pill to conquer hunger on the horizon, dieters are left to battle it out the hard way. Glenda decided to embark on an unusual weight loss programme.

GLENDA BAILEY: Yes.

DR NICHOLAS FINER (Luton and Dunstable Hospital): And you can have unlimited calorie-free drinks.

GLENDA: Oh lovely, yes.

NICHOLAS: Now the purpose of this period on the diet is really to demonstrate and to show that you can lose weight and to really be the first step into what is going to be the longer programme.

It's about 1,000 calories a day, so it's not very low in calories, but what it is doing is providing her with the protein that she needs, it's providing her with the vitamins she'll be taking with everything she needs except excessive calories. Well I'd like to measure your waist circumference 'cos that's quite important these days so if you come and stand yourself up and perhaps if you just lift that up there. I'll slip this round here.

The great thing is it allows her to move into a position where she doesn't have to make choices about food about how to cook and it works.

NARRATOR: Since her wedding day Glenda has tried many different diets with little success. This time, to keep up her motivation, she decided to keep a video diary.

DAVE BAILEY: Go out and get some superglue. She's... I think she's got it.

NARRATOR: The diet began with an unlikely challenge: a miserly three pints of milk a day.

GLENDA BAILEY: When I looked at these three pints of milk the first day I thought my God, he must be joking. How ever am I going to survive working on three pints of milk, but, as you can see, we started drinking it bit by bit, in coffee, plain milk and we've done it and it's not too bad now. If I stick to it I'm going to lose weight and this is what I want to do more than anything, is to lose weight and for people to pass me in the street and say I didn't recognise you, which is a wonderful feeling, but no, I haven't been even tempted at all. I mean I've painted my fingernails, I've done my face, I've done things to keep me occupied, to stop thinking of food. I must have the cleanest drawers in Bedford upstairs, I keep tidying my bedroom drawers out and everything, just to keep me stopping of eating. How can I explain it? My cheekbones are now appearing. I don't seem to... I've lost all me fat round here and up here and it seems to be a lot better. My double chin here I'm hoping will disappear.

NARRATOR: But for Glenda her success is only the beginning.

NICHOLAS FINER: I really do not have difficulties in helping people lose weight. What I have difficulties and what I struggle with is helping people maintain the weight that they have lost. That is the real crux of the matter. It's hard to lose weight, but it's even harder for people like this to keep their weight off long-term.

NARRATOR: The Padded Lilies have long since given up the struggle. They had been dieting ever since childhood. Nothing had ever worked, although they all remember unpleasant and extreme attempts to lose weight.

PADDED LILIES MEMBER: At the age of 8 I was given Speed to help me control my weight. In fact the whole family was taking it off and on, which made for a real interesting family dynamic.

NARRATOR: By the time Timna was 13 she was so fat her teeth were wired together to make her stop eating.

TIMNA: My mother thought it was a great idea and I thought it was a great idea. That's the really damaging part is not that it was done to me, but that I said yes, I'm so awful and so horrible I need to do that to myself.

NARRATOR: Rebecca was only 14 when she was trained to reject food. She was wired up and given electric shocks.

REBECCA: You'd sit in front of a mirror where you couldn't see who was doing the shocks and every time you'd go to take a bite you'd get shocked and I thought, you know I thought it a personal thing because I didn't lose weight on this. I mean like, you know, rats could lose weight on this, but I couldn't and I mean I just did it for another 20 years trying all sorts of things, you know, starving, the, the liquid diets, the, I did the Phen-Phen and it came to a point where I thought I don't want to live this way.

NARRATOR: The need to find a humane drug treatment has never been more desperate. In the absence of a wonder drug that tackles appetite scientists are scouring the field for other potential leads. This approach may have led to the next extraordinary breakthrough. John Clapham decided to revisit a completely unexpected area: metabolism. Scientists had discarded metabolism as a cause of obesity, but Clapham was intrigued by what might happen if you could turn it to our advantage, what if you could speed it up? His first clue came from history.

In World War 1 while the Allies were fighting the Germans in the trenches, back in French munitions factories the scene was being set for the discovery of possibly the most effective obesity drug the world has ever known. It started when workers were having curious reactions to a certain explosive they were handling called DNP. They were breaking out in fevers and strangely losing weight.

JOHN CLAPHAM: Well if I took DNP I would feel a big increase in my body temperature. I would probably feel a widespread heat throughout my body I would guess.

NARRATOR: Scientists eventually revealed the mystery behind these soaring temperatures. They learned that DNP actually speeds up metabolism, so that food isn't laid down as fat but burnt off as heat. Unwittingly they had stumbled across an extraordinary diet drug.

JOHN CLAPHAM: In its day DNP was very, very effective at weight loss. I think weight loss of up to 3lbs a week were reported, but very shortly after that the, the downside of DNP started to emerge.

NARRATOR: The side-effects were bizarre and extreme. Some dieters actually cooked to death. DNP is deadly because it speeds up the metabolism of every cell in the body. With millions of cells burning off food your temperature quickly rockets out of control. For a treatment to be safe it would have to work in selected cells. Clapham knew the human body contains proteins that behave similarly to DNP. Crucially, they only work in a few specific cells. His challenge was to see if by manipulating these proteins he could burn off fat without fatal meltdown. He decided to genetically engineer a mouse, a mouse with genes for these special proteins. When Clapham inspected his mouse for the first time he was not prepared for what he was about to see.

JOHN CLAPHAM: As soon as I looked into the cage it really knocked you out. We could see straightaway the difference between the animals carrying the gene and those that were not carrying the gene and wow, it was it.

NARRATOR: His genetic creation looked far skinnier than its natural-born sister. Scanning them confirmed his hopes.

JOHN CLAPHAM: What surprised us was the degree of fat loss. It was, it was 50%. I mean that is a huge fat loss and an amazing fat loss. We would have been happy with, with half that. The idea that there's an evolutionary based biological drive to eat

NARRATOR: But the surprises didn't end. It turned out that the skinny mouse was eating as much as 50% more than its plump sister. Clapham had cracked the problem. He had sped up the mouse's metabolism so it could over-eat without putting on weight, and it was safe. It was a world first, but to take the science from mouse to man is a big step.

JOHN CLAPHAM: Well it's very early days to say how effective this is going to be. We need to show in humans we get the same effect and that, perfectly honestly, is a long way off. The best treatment for obesity at the moment, and this should never change, is diet and exercise and that's really what's required at the moment.

NARRATOR: But there are some lucky people who don't seem to need to diet or exercise.

JEFF VAN KIRK: I eat a lot of unhealthy food - Burger King, McDonalds, pizza, love pizza. I will eat and eat and eat and not do any exercise and I don't have to. I would rather sit on the couch, be a couch potato. I believe the most exercise I do is maybe changing a tape in the VCR, getting up to find the clicker, to sit on the couch.

NARRATOR: And yet Jeff rarely puts on weight.

DR JIM LEVINE (Mayo Clinic, Minnesota): Why is it that some people appear to eat whatever they like and never gain a pound, whereas others just look at food and instantly gain weight?

NARRATOR: Levine was determined to solve this mystery, so he recruited Jeff and 15 other game guinea-pigs. For weeks he collected precise measurements while subjecting them to a strict slob regime of masses of food and no exercise. After two months of over-indulgence Jeff had only put on 2lbs.

JEFF VAN KIRK: The only part that you could see that I gained weight was right here in my face, in my cheekbones and in my neck and my pants got a little bit tighter, but nothing to worry about.

JIM LEVINE: And what was incredible was that other people in the study gained 8lbs in body fat showing a huge variation in fat gain between different people.

NARRATOR: Levine started to work through his data. He knew it wasn't appetite, as they had all eaten the same amount of food. It knew it wasn't exercise. None of them had been taking it. When he looked at their basic metabolism they were virtually the same. He just couldn't find an explanation.

JIM LEVINE: And at that point I actually mailed a friend and said you know I've done years of work and we've found nothing, but then we started looking at the data that came from the non-exercise daily activity data and then we'd struck gold.

NARRATOR: Non exercise daily activity is everything Jeff did that wasn't exercise and this was the answer. Jeff couldn't put on weight because he couldn't keep still.

JEFF VAN KIRK: I'm always fidgeting, moving my feet, constantly, constantly tapping my feet. I touch my hands a lot, play with my thumbs a lot, I can't keep my hands off my face. Rub my hair a lot. Pretty much anything I'm doing I'm, I'm moving. I just constantly move. I can't help it. I just move, move, move, move, but it's not exercise.

JIM LEVINE: Jeff gained almost no fat because it increased his general activity level completely subconsciously. Every time he noshes more he starts to amble more, he starts to toe tap more, he even starts to fidget more.

NARRATOR: Levine eventually worked out how much food Jeff burnt off through all his fidgeting. it was a shockingly large amount - half his total calorie burn. Jeff was proof of just how important it is simply to move.

Scientists now know that a bit of get up and go, particularly by walking more, has a surprisingly large influence. Over a period of time it can make the difference between being fat and being thin, but for those with a large amount of weight to lose the answer isn't that easy. In the absence of a wonder drug there is only one way to fight fat and unfortunately it's the hard way.

Glenda has bought a new bike to get more exercise. By the end of her diet she weighed 11 stone less than she did on her wedding day and she's determined to keep it up until she loses her double-chin.

GLENDA BAILEY: You take this off and you've got a new me. I've got cheekbones now. I never had cheek-bones before. My eyes always seemed so tiny, but because the fat has gone my eyes are... My bust, well I actually haven't got anything there now, I used to be quite big busted, I used to be a 52. I'm now a 42. That's 10 inches gone off. I felt so ashamed of being so big, but then one day something just clicked and I knew I'd got to do it. I feel as though I'm a new person. There's this person's escaped that's normal now.

DAVE BAILEY: So I said to her like you know all that weight that you've lost you think how that, that could have been a third person in bed, we could have had three people in bed with us you know because she's lost well, how much is it now girl?

GLENDA BAILEY: 11 stone over.

DAVE: 11 stone, that's a big person innit.

NARRATOR: Glenda's achievement is only the beginning of a never ending struggle. A few months later she was gaining weight. For some people the road to permanent weight loss is as simple as upping the pace of life, but for others it will always be long and hard. A series of breakthroughs have led to a revolution in the way we view obesity. it can no longer be seen simply as a failure of character. In some the genetic drive to eat is all consuming, but now more than ever before scientists are closer to developing a drug that will triumph in our fight against fat.