Trillion Dollar Disease

A few years ago, Stephen O’Rahilly, a professor of metabolic medicine at Cambridge and consultant of last resort for the dangerously overweight, had two cousins from the Punjab referred to him for treatment. One was an eight-year-old girl who weighed almost 190 pounds and was too heavy to walk. The other was a two-year-old boy. He tipped the scales at 65 pounds. The parents described the children’s ravenous appetites, which no amount of food could sate, how they foraged in rubbish bins for discarded chips, and stole fish fingers from the freezer to chew without waiting for them to thaw. O’Rahilly’s team saw for themselves how the youngsters gorged: the boy would put away 2500 calories at a single meal, and still be up for more.

The scientists discovered that the children had a genetic mutation which meant they lacked a protein called leptin. Leptin had been discovered a few years earlier by scientists in the US working with an insatiable mutant mouse strain called ob. The huge, ever hungry ob mice had also lacked leptin; given it, they rapidly slimmed down. If the obese cousins were given synthetic human leptin, perhaps their desperate desire to eat would fade away, too. It took months to get permission from clinical regulators, but when the children started receiving injections of the substance, the effect was astonishing. They no longer felt that they were starving. The girl got out of her wheelchair and walked again. Was this it? Was leptin the elixir that would make us all lean? It turned out that it was, indeed, able to help a few massively obese individuals around the world – 12, so far, according to Ellen Ruppel Shell – but the rest of the fat world will have to wait longer for its get-thin pills. The truth is, they may never come, but anyone who starts to read this book could be forgiven for thinking we’re almost there.

Shell, who writes, and teaches the writing of, science journalism in the US, has mixed remarkable stories such as that of the Punjabi cousins, with smart reportage and reasonably accessible accounts of the competitive world of obesity research. In the end, however, the disparity between what the book promises and what it delivers is considerable. Shell purports to stand apart from the purveyors of fad diets and failed slimming pills, yet her work involves just as brash a marketing exercise as theirs.

She is selling two ideas. One is that obesity is building into a grand international tragedy. Everyone from the morbidly obese to those with flabby arms and a slight waistband overhang is lumped together in one great mass of ‘casualties’ and ‘victims’. She describes obesity researchers as ‘heroes’. That Frank Shuttlesmith from Des Moines, 48 years old and with generations of comfortable forebears stretching out behind him, is a noble victim of a fearful global epidemic because he’s thick around the middle, doesn’t care to walk and enjoys extra cheese on his burgers, is an attractive proposition.

The other idea she is selling is that society has been unfair to the overweight and the obese; that science tells us people are fat because they are genetically programmed to eat more. Shell presents enough intriguing evidence to suggest that this is partly true. Still, she overdoes it. The opening of the book hints that the overweight are completely at the mercy of an inner eating machine they are powerless to switch off, but that science is about to find the switch. A telling passage which seems to belong more to the inspirational world of self-help and dieting manuals than to a book concerned with scientific data informs us that ‘at the heart of the story are the people whose lives are bound by their struggle with weight. It is their stories – the eminently human ones – that are the common thread, and it is their lives that this book is meant to change.’ Maybe. But I wonder how delighted these people are going to be to reach the end of the book, only to find the author expounding on ways to get people to eat less fast food and walk more. All that hope, and it comes down to fresh fruit and vegetables, and exercise. Again. Damn!

The number of people who are dangerously obese is large and growing, and not just in the rich world. So is the number who have the lesser problem of being technically ‘overweight’. Grouping together those who are in imminent danger of multiple organ failure because they are so heavy with those who are stout is misleading. Being a few pounds overweight may increase the risk of heart disease and other nasties, but everyone has to die of something. The experience which unites all the overweight, from the massively obese to the faintly porky, may be not health problems but a loss of dignity, whether it involves the quest for food, the search for a way to become thin or submitting to the lies of the marketeers who plug both.

In the US, people spend $33 billion a year on weight-loss products. Marketing and research by food and pharmaceutical companies – a distinction which is beginning to blur with the introduction of ‘nutraceuticals’ – is aimed at making us buy and eat more food, and buy and take expensive anti-fat drugs, all at the same time. One genetics researcher interviewed by Shell refers to obesity as ‘the trillion dollar disease’.

Behind the parade of diets and workout regimes there have been more direct interventions. In the postwar West, doctors have tried binding patients’ gullets as Japanese fishermen do cormorants’; inserting and inflating balloons in people’s stomachs; tying cords around their waists; and wiring up their jaws (patients were advised to keep a set of wire-cutters with them at all times in case of emergencies, such as vomiting). In the 1960s and 1970s, a hundred thousand Americans had intestinal bypasses, which meant that food simply slipped through them. Many suffered side effects, including infections and liver failure. Some died.

The current surgical fashion is gastric bypass surgery, a drastic operation in which a surgeon removes a patient’s stomach, uses a powerful stapler to close up most of it, leaving only a two-tablespoon pouch available for food, and puts it back. In 2000, forty thousand Americans had the operation. Last year, it was more than sixty thousand. Every hundredth patient dies on the operating table, and unpleasant side effects kill and bring much suffering to others. It works – on average, bypassees lose 60 per cent of their weight over 18 months – but then it can stop working. US guidelines say that only those whose weight causes severe health problems should be considered for surgery. In practice, this means anyone with a Body Mass Index of 40 or more. BMI is your weight in kilogrammes divided by the square of your height in metres – a BMI of more than 25 is considered overweight, 35 or more is obese. Millions of Americans qualify: in Mississippi, a quarter of the population is obese.

Shell saw the operation performed on a woman who weighs 20 stone and is 5'3" tall. The patient’s daughter and two of her colleagues had already had the operation and shed wheelbarrows of fat between them. The surgeon, Edward Mun, who has operated on people weighing as much as 700 pounds, has to plunge his arm in up to his elbow to fish for the woman’s stomach, a moment Shell recounts in fascinated detail: ‘The flesh ripples thickly, like a crème brûlée . . . the skin bursts open with the force of the fat beneath . . . the smell . . . is savoury, like hamburgers spitting on a grill. The translucent fat layer glistens yellow.’

With juvenile obesity on the rise, surgeons propose carrying out gastric bypasses on 12-year-old children. Mun admits to Shell that the operation is barbaric, but ‘it’s all we’ve got.’ It is not necessarily enough. The patient Shell follows loses a miraculous 125 pounds in the months following the operation. Then she discovers how to eat more by melting biscuits in her mouth before swallowing them, and the weight begins to return. The 90 pounds her daughter lost came back, too. I wonder how long it will be before surgeons begin offering to remove entire stomachs. As some cancer patients discover, it is possible to live without one.

Between the gastric bypass and the difficult discipline of diet and exercise, lies the murky territory of anti-fat medication. Shell is good on the often incestuous relationship between the pharma-food corporations and obesity researchers. She points out that many of the most prominent obesity researchers in the US are consultants to, or receive research grants from, the various industries which help Westerners get fat and promise to help them get thin.

In the 1990s, a combination of two drugs, fenfluramine and phentermine – fen-phen – was shown to have a mild short-term effect in helping overweight people lose a few pounds. The drugs had been approved separately but not in combination by the Food and Drug Administration, and on the back of massive media hype, the weight-loss industry began selling them like popcorn. In 1995, the FDA turned down an application by a subsidiary of American Home Products to market a more powerful form of fenfluramine, Redux. They were concerned by reports that a hundred people in Europe – where Redux was produced – had developed a rare, incurable and fatal respiratory disease after taking it. AHP and their allies lobbied for a second hearing and, despite fresh evidence that the drug was dangerous and not particularly effective, the FDA approved it in 1996. A year and 18 million prescriptions later, it transpired that as many as 30 per cent of the people who took Redux had suffered some damaging side effect. The FDA withdrew it from the market, but not before hundreds of people had become seriously, and in some cases terminally, ill. In 2001, AHP set aside $12 billion to settle lawsuits brought on account of the drug.

Meridia, which has been approved for use in the NHS under the brand name Reductil, has been the subject of a $50 million marketing campaign in the US, aimed at doctors and their weight-conscious middle-aged female patients. It was discovered by accident at laboratories then belonging to Boots in Nottingham, and subsequently bought by BASF. The drug, generically known as sibutramine, was supposed to be an anti-depressant, but patients who took it stayed depressed and lost weight. There are still doubts about its effectiveness and its safety. In some patients, it raises blood pressure, which weight loss is supposed to lower. In March last year, Italian regulators took it off the market after two women died and dozens of other patients reported high blood pressure, accelerated heartbeat, anxiety and gastrointestinal problems.

Shell reveals the ugliness of the weight-pill peddler’s trade. Wyeth-Ayerst, for example, which distributed Redux, paid two distinguished obesity researchers, Albert Stunkard and F. Xavier Pi-Sunyer, to pose as authors of favourable papers they neither wrote nor researched. Another eminent obesity specialist, George Bray, fumes that only 2 per cent of the 36 million Americans with a BMI of more than 30 take obesity drugs – ‘a disappointing failure at the marketing end’.

And yet Shell’s scepticism, even cynicism about the actions and motives of those involved in obesity research sits uncomfortably with her eager portrayal of the progress that scientists are making in understanding the biological basis of fatness. It’s true that this is a difficult time for science writers: it is hard to reconcile the excitement of discovery in the new genetic wonderland with the sordid and premature commercialisation of those discoveries. Shell does not meet the challenge. It sometimes seems as if The Hungry Gene was produced by two different writers: the first is determined to explain how far we have come in understanding the science of obesity, with all the academic rivalries, triumphs and false dawns along the way; the second assembles a saga of commercial greed, regulatory failure and systemic betrayal of the citizen.

The burden of Shell’s argument in the early part of the book seems to be that our traditional understanding of obesity as a failure of individual willpower is being proved wrong in the laboratory: that genes play a more significant role, perhaps the dominant one, in determining who overeats and who does not. She quotes scientists such as O’Rahilly, who are angry at society’s reluctance to acknowledge the part inheritance plays in overeating. ‘I’m sometimes criticised by so-called liberals, who tell me that I shouldn’t be working to validate these nasty people whose disgusting behaviour has made them so sick,’ he says. ‘People who are not victims of these disorders have claimed the moral high ground; they believe themselves to be virtuous. But the truth is, they’re just lucky.’

Genetics-based obesity research has three broad components. There is the race to map the hunger ‘pathway’, the cascade of chemical messages from our metabolism to our brain which add up to the fateful want-food signal, a race consuming hundreds of millions of dollars, immense stretches of human and computer time, and tens of thousands of mutant mice.

There is the study of ethnic groups which seem particularly susceptible to catastrophic weight gain when exposed to the Western lifestyle. Shell visits Kosrae, effectively a US military colony in Micronesia, where almost 85 per cent of those between the ages of 45 and 64 are obese. None of the shops sells fresh fruit or fish and the islanders use imported artificial coconut flavouring instead of the real coconuts, which nobody bothers to collect. They gorge themselves on imported turkey tails and drive everywhere. Some older Kosraeans will no longer drink unsweetened water. Most hospital in-patients are being treated for diet-related diabetes. Nine out of ten surgical operations, many of them amputations, are linked to diabetes.

Scientists believe that, before Westerners arrived, the Kosraeans were exposed to savage famines caused by typhoons, in which up to 90 per cent of the population died. Such extreme events can cause rapid evolutionary change: those who survive famine, so the theory goes, are likely to be those able to store fat most effectively in times of plenty. Notionally, they have a ‘thrifty gene’, or, as one researcher puts it, a ‘greedy gene’: they are able to store up more fat than their fellows in the good years, to live off their corpulence when the going gets hard. But if the plenty never goes away these thrifty/greedy genotypes will continue to stuff themselves in thrall to an impulse over which they have no control.

The third direction of obesity research is into the mysterious, and still disputed, realm of foetal programming; the theory that the food a person is exposed to in the womb affects their propensity to obesity in later life. Evidence for this came in the 1970s, from studies of adults whose mothers had been pregnant during the Nazi-organised famine in the Netherlands in 1944. The children of mothers exposed to famine in the first six months of pregnancy were 80 per cent more likely to be obese when they grew up. It seemed as if a mechanism had been acquired that primed a child for scarcity from birth; when that child was born into a land of plenty, it grew up perilously fat.

All this research points to one broad conclusion that it is hard to argue with: millions of years of evolution, through the extreme swings in food availability which occur in the wild, have bequeathed us a metabolism designed to cope with alternate scarcity and abundance, an abundance, however, which can be harvested only by a great expenditure of energy. In the sedentary, mechanised, fast-food world of the 21st century, there is no such scarcity, and no such expenditure of energy. Beyond that, the conclusions are open to dispute. Far from showing science closing in on a medical solution, as the opening of her book suggests she will, Shell reveals only that every step the scientists take brings new mysteries to light and emphasises how entangled are the natural systems which keep us alive.

The story of the discovery of the leptin gene is instructive. A pharmaceutical company paid millions of dollars for the rights to the patented gene. Yet leptin turned out to be far from the natural fatstopper it was first believed to be. Researchers originally thought it was the message the body transmitted to the brain to indicate that it was sated. The higher the leptin levels, the more sure the individual was that he or she had had enough to eat. As it turns out, the brain watches not for rising leptin levels as a sign of fullness, but for lowering leptin levels as a red alert for starvation – hence the Punjabi cousins’ leptinless gorging. Evolution has laid down multiple systems for protecting us against hunger; it has not given us much to protect against plenty.

The appetite pathway, along which the chemical couriers travel with their ‘I am hungry’ messages, is not a single clear track through the tangled forest of genes and proteins, but a winding, forking route that intersects, in ways our minds may not be capable of grasping, with a myriad other pathways carrying equally vital information. Scientists can dig a pit somewhere along the pathway to stop a hunger courier reaching its destination; but what if the courier is carrying more than one message? The tale of the depressed patients in the sibutramine trial who took a pill to make them feel less sad and ended up still depressed but thinner shows both scientists’ lack of knowledge and the way in which mind and body are entwined. Shell barely nods at the relationship between eating and mood, or questions society’s intolerance towards fat people. That being overweight (as opposed to obese) is a burden is never questioned. Having hinted at a scientific revolution, and reassured the obese that it is not their fault, Shell leaves them in the end with nothing to do but listen to her angry calls for subsidised fresh fruit and vegetables in ‘publicly supported food service venues’.

It is easy for obesity researchers and the socially concerned to be more interested in fat people’s bodies than their souls. For the merely overweight, at least, the worse thing may not be the fatty food they eat or the slimming remedies they turn to, but the swallowing of the lies involved in their promotion. Shell makes an interesting point about very fat people: in order to carry that enormous extra weight around with them, they have much more powerful muscles than less fat people do. It isn’t that inside every fat man there is a thin man trying to get out; every fat man is actually a thin man carrying another thin man with him wherever he goes. The obese are stronger than the non-obese think.