Born to be fat
The first time I set eyes on Nancy Wright, she is flat on her back and
cruciate. She is vaguely pretty, her eyes frightened but oddly beguiling.
Even as she lies splayed and sedated on a trolley in Operating Room 17
at Beth Israel Deaconess Medical Centre in Boston, you can sense that
Nancy Wright is possessed of an immutable will.
Fifty years ago, an enormously
fat mutant mouse emerged in a New England research centre. It marked
the start of a long search for a gene that controlled appetite and therefore
weight. In 1994, it was finally located. Now the genetic quest is on
again - this time for a miracle cure for the obesity pandemic that is
rapidly spreading across the world. In the meantime, at least we now
know why some people get fat and others don't. Ellen Ruppel Shell investigates
Saturday January 11, 2003
Nancy once told me that
she'd started out life large and kept on going. She didn't mean it as
a joke. She weighed 10lbs 4oz when she came into this world, and through
childhood ate herself so big that her father thought she had psychological
problems. Nancy herself likens her relationship with food to a doomed
love affair. "Food has always been my best friend and worst enemy,"
she told me. Now, in middle age, this dysfunctional relationship has
made even simple pleasures difficult. It is getting harder for her to
work in her flower garden, harder to play with her five grandchildren.
And she keeps getting sick. She has hypertension, high blood cholesterol
and sleep apnoea (difficulty breathing). She has tried WeightWatchers
and diet pills. They worked, for a while. The pounds melted away, and
Nancy thought she'd found salvation. But then, without knowing why,
she'd fall off the wagon and her old life would rush back.
People tell Nancy she
lacks willpower, but they are wrong. She has plenty. She stayed with
the same thankless social services job for 20 years, and with the same
thankless husband for 19. As a 50th birthday present to herself, she
quit smoking. But food is different. For Nancy, food is more than an
addiction, it is like breathing - a constant, throbbing need.
Dr Edward Mun understands
all this perfectly. He is a surgeon at Beth Israel Deaconess Medical
Centre. What he does is to take perfectly healthy stomachs and replumb
them, fashioning them into pouches the size of robins' eggs. On average,
patients shed about 60% of their excess weight in about 18 months. Nancy
is next in line.
Nancy is 5ft 3ins tall
and, at the time of her operation, weighs 19 stone 8lbs. Mun has not
promised Nancy success, or even survival. Gastric bypass kills one in
100 patients on the operating table. Mun helps the nurses arrange the
layers of sterile drape, leaving exposed a rectangle of stark white
skin roughly the area of a shoebox lid. He paints the rectangle orange
with antiseptic. The flesh ripples thickly, like a crème brûlée. With
a black ballpoint pen, Mun traces down the centre line from the tip
of the breastbone to the navel. A surgical resident traces over that
line again and again with a scalpel until the skin bursts open with
the force of the fat beneath. There is a smell like hamburgers spitting
on a grill. The translucent fat layer glistens yellow under the operating
room lights. Mun and the surgical resident exchange looks, then press
two palms each on either side of the neatly split skin and ease the
fat apart, forming a canyon. There is almost no blood.
Plunging his hand into
the cavity, wrist deep, Mun palpates the taut purple liver and gently
retracts it to examine the junction between the stomach and the oesophagus.
He is now elbow deep, pawing blind for the start of the stomach. Long
seconds pass. No one says a word. Suddenly, Mun finds what he's after.
"I love this organ," he says, pulling the stomach into glorious view.
Nancy Wright knows that
dying on the operating table is a possibility. She knows about the complications
- the exhausting anaemia, the painful gallstones and incisional hernias,
the infections. But Mun has completed 110 gastric bypass procedures
in the past 12 months, and most have gone like clockwork. He reminds
me of this as he manipulates Nancy's guts. Taking aim with his Endo-GIA
II stapler, which cuts as well as rivets, he divides the stomach into
two parts and staples the top portion into a 20-millilitre pouch. An
organ that could once proudly contain a litre of Häagen-Dazs can now
barely hold a shot glass of yogurt. For a few months at least, Nancy's
stomach will no longer have the power to demand a Snickers bar. Mun
has tamed it.
Like Nancy, more than
nine million American adults are "morbidly obese", roughly seven stone
or more overweight. Ten million more are almost there, teetering on
the edge. Obesity, the US Surgeon General David Satcher has warned,
is quickly eclipsing tobacco as the number one threat to public health.
Half the adult populations of England, Brazil, Chile, Paraguay, Finland
and Russia are overweight or obese. In China, obesity increased six-fold
in the final decade of the 20th century. On some islands in the South
Pacific as many as three-quarters of adults are dangerously obese. And
adults are not the only victims. In Britain, youth obesity rates have
soared by 70% in a single decade.
Americans spend $33bn
a year - more than the gross national product of most developing countries
- on weight loss products and schemes. We sign lifetime contracts with
health clubs, hire personal trainers, buy diet books and low-fat foods
by the ton. We spend hundreds of millions on weight-loss medications
that can sicken or even kill us, and risk death on the operating table.
And, all the while, we grow fatter.
Pudge is not a new thing.
Consider the Venus of Willendorf, a hand-sized 25,000-year-old sculpture
unearthed early in the 20th century near the Austrian village whose
name she bears. She has erupting breasts, a Falstaffian stomach and
what appear to be no feet. She is lushly, voluptuously obese. About
100 such statues have been unearthed, and they are thought by archaeologists
to be among humankind's earliest artworks. Obesity has its roots in
the Stone Age.
Egyptian pharaohs entombed
themselves in chambers etched with depictions of their own gorgeous
physiques, but studies of their mummified remains betray rolls of belly
fat. (Servants were likely the living models for those hard-body renderings.)
Hippocrates, known as
the father of western medicine, warned his fellow Greeks that "sudden
death is more common in those who are naturally fat than in the lean".
The Cretans disdained the obese, and claimed to possess drugs (likely
either toxic, purgative, or both) that allowed people to eat as much
as they liked without growing fat. Despite their propensity for ritual
gorging, the Romans, too, frowned on obesity. Roman women starved themselves,
sometimes to death, in an effort to please their demanding husbands
and fathers. The Spartans simply exiled their plumper citizens.
Medieval Christian thinkers
ranked gluttony as one of the seven deadly sins. In the 18th century,
numerous doctoral theses and monologues focused on the problem of obesity.
Most famous among these is a discourse on "corpulency" by the Dutch
physician, Malcolm Flemyng. He considered obesity a danger and an evil,
but he did not dismiss the overweight as lazy or sinful. Rather, he
portrayed them as unlucky inheritors of a predisposition that was not
entirely within their power to control.
In the industrialised
age, mechanisation and mass production made life easier, and portliness
was no longer a badge of prosperity. As the working classes grew stout,
any vestiges of sympathy for body fat were overwhelmed by an ardent
campaign to root it out. Underlying this movement was the new "science"
that linked being overweight with ill health.
In the 20th century,
newly hatched notions of psychology brought to light the power of the
unconscious to shape behaviour. The idea took hold - despite a dearth
of hard evidence - that the obese were anxious, unbalanced people who
turned to food as a form of sublimation or escape, possibly from sex.
Obesity became the subject of serious scientific study.
The Jackson Laboratory
in Bar Harbor, Maine, founded in 1929 as a medical research centre,
was and is a sort of mouse ranch, squirming with rodents both ordinary
and fantastic. There are today 2,500 different strains breeding in 47
"mouse rooms" scattered around the campus. While mice do not in any
way resemble humans, they are similar enough genetically to offer a
reasonable model for the study of normal and abnormal human biology,
as well as of human disease.
In the early 1950s, a
mutant suddenly appeared in the lab - a mouse with unusual traits. An
animal caretaker first spotted the creature huddled in a corner of its
cage, grooming itself. It was furrier than most, but what really stood
out was the size of the thing - it was hugely fat. Initially, the researchers
diagnosed the mouse as "pregnant". But there were problems with this
theory. For one thing, the mouse never delivered a baby. And, on closer
inspection, it turned out to be male. The fat mouse ate three times
the chow eaten by a normal mouse, pawing for hours at the bar of the
food dispenser like an embittered gambler banging away at a recalcitrant
slot machine. Between feedings it sat inert. It seemed to have been
placed on this earth for no other purpose than to grow fat. The scientists
christened the new mouse "obese", later abbreviated to "ob", and pronounced
At about the same time,
a British scientist, Gordon Kennedy, conducted a series of elegant experiments
that pointed to something in the fat cells themselves that directly
or indirectly controlled feeding in rodents. He concluded from this
that body weight in rodents is controlled by a sort of fat thermostat
- which he christened a "lipostat" - that senses how much fat there
is on the body, and adjusts eating and energy expenditure accordingly
to maintain a steady state or "set-point".
Douglas Coleman, a biochemist
at the Jackson laboratories, noting these findings and carrying out
experiments of his own from the early 1960s, came to believe that eating
behaviour in rodents was controlled by a factor in their blood - and
that, in turn, might be controlled by one or more genes. When Coleman
published his findings in the early 1970s, the prevailing scientific
view claimed obesity as a problem of behaviour, not biology. He stuck
staunchly to his theory, and continued to search for the mysterious
satiety factor for the rest of his career.
Three years after his
retirement in 1991 it was found, by a very different sort of scientist.
In July 1980, Jeffrey
Friedman - now head of the Laboratory of Molecular Genetics at Rockefeller
University - arrived at Rockefeller to pursue a research fellowship.
He was assigned to look into the molecular biology of liver regeneration,
but it soon became clear that his real interest was to clone the elusive
ob gene. Friedman, through a colleague, met Rudy Leibel, a scientist
and physician who came to Rockefeller in 1979 and had been searching
for Coleman's satiety factor and the ob gene for several years. Like
Coleman, Leibel thought that something in the fat cell itself was producing
a satiety signal. But what that something was he had not a clue. Leibel
had worked with obese and diabetic patients - in particular, children.
He had also worked on obese mice in the laboratory, and had seen how
they differed fundamentally from ordinary mice. He began to wonder whether
there was something amiss in the physiology of obese humans, too - perhaps
something, such as iron deficiency, that could be remedied.
He was uncomfortably
aware that neither he, nor probably anyone else, knew how to treat obesity.
It was while under this cloud of self-doubt that he happened upon a
lecture by Ethan Allen Sims, a physician at the University of Vermont
College of Medicine who was then exploring the link between obesity
and diabetes. Sims was interested in whether the metabolic differences
observed between fat and thin people were the result or the cause of
their body type. Put simply, he wanted to know whether people are born
fat or made fat. He decided that the best way to sort this out was to
convince a group of slim volunteers to eat themselves fat and to observe
what happened to them when they reduced to their original weight.
Sims was fortunate to
have nearby a ready source of experimental subjects: the inmates at
Vermont state prison, sufficient numbers of whom were willing to gorge
themselves for science. At first the prisoners proved enthusiastic trenchermen,
as much as doubling their usual daily intake of food. But as they fattened,
they became increasingly reluctant to overeat. Most found it extremely
difficult to gain weight, and eventually some started to drop out of
the study. Only 20 made it through the requisite 200 days, achieving
an average weight gain of 20-25lbs. Relieved of the high-calorie, low-exercise
regimen, all but two of the inmates quickly dropped the newly acquired
ballast. The pair of inmates who found it most difficult to lose weight
were those who had experienced the least difficulty gaining weight in
the first place. It was later discovered that both these men had a family
history of obesity.
From this experiment
Sims concluded that the body was remarkably well equipped to balance
energy intake and output, and to reach an energy equilibrium, or "homeostasis",
at which it felt naturally comfortable. What was particularly interesting
was that body weight seemed somehow fixed, and was in most subjects
resistant to change over the short term. The prisoners with obesity
in their backgrounds were, it seemed, genetically inclined to reach
homeostasis at a higher weight than were others; the high-calorie diet
only helped manifest their genetic proclivity.
After hearing Sims's
talk, Leibel became absorbed with the idea of finding the missing link
- the signal that tells the body to eat, or not. He did not question
that psychology played a role in whether or not people chose to behave
in a certain way, but what interested him were the forces that drove
that psychology. Genetics, he felt certain, played an important role
in determining body weight regulation in humans, just as it did in mice.
And there was growing circumstantial evidence to back the genetic theory,
notably in studies of adopted children. Identical twins tend to have
remarkably similar body mass indexes, far more similar than do siblings
or even fraternal twins. This is true even for identical twins separated
at birth and raised far apart in different adoptive families. The BMI
(body mass index) of adopted children usually correlates nicely with
that of their biological parents, but not with that of their adoptive
parents. This strongly suggests that genetics, not "psychology", play
the larger role in human obesity. Leibel began a painstaking search
for the elusive satiety factor in the adipose tissue of normal mice.
Leibel understood the
physiology of obesity, the cell physiology, and had thought through
the underlying scientific problem. Friedman was at the time mastering
the latest techniques in molecular biology. He had the tools for the
Locating a gene in a
mammalian genome without knowing its protein product is something like
finding the home of a reclusive uncle who lists his address as "Someplace,
USA". A complete human genetic map was more than a decade away when
Leibel and Friedman started their hunt for the ob gene in 1986. The
team at Rockefeller spent six years narrowing the location of the ob
gene to between two markers a few hundred thousand base pairs apart.
Then they narrowed the field to four genes that lay inside the area
where they expected ob to lie. Ultimately, a protein was located that
had all the makings of Coleman's satiety factor: a molecule produced
in the fat, coded for by a gene that was mutant in ob mice. "That moment
was the closest thing to a religious experience I've ever had," says
Friedman of the successful completion of the final test.
His team spent the next
six months learning everything they could about the ob gene and its
mutations, and located its human counterpart, a slightly different version
they called Ob. "Positional Cloning of the Mouse Obese Gene and its
Human Homologue" appeared as a cover story in the journal Nature on
December 1 1994, one day after Friedman had filed for a patent.
The Nobel prize-winning
biologist Roger Guillemin once told Friedman that, in a rational world,
the obese gene would be renamed lepto, from the Greek word for "thin".
It might be considered a gene for thinness, in the sense that mice grow
fat without a properly working copy. Friedman picked up on Guillemin's
suggestion and christened the ob gene product "leptin". The great hope,
of course, was that leptin would work as an appetite inhibitor in humans.
The first step was to test it in mice.
Injected with the newly
synthesised leptin, ob mice slimmed down dramatically, and normal mice,
pumped with an excess of leptin, lost every gram of their body fat.
Leptin, then, was the long-sought satiety factor. It was an overnight
sensation. Rockefeller's switchboard ignited with callers frantic to
participate in human trials of the hormone. Food writer Jeffrey Steingarten
spoke for weight watchers the world over when he told a scientist he'd
be willing to inject the stuff "into my eyeball" if necessary.
After months of arduous
negotiations, drug giant Amgen of Thousand Oaks, California, bought
the rights to leptin for an astonishing up-front $20m payment, reportedly
the largest ever for a university-held patent.
But for three years scientists
searched in vain for a leptin deficit in humans. Leptin deficiency,
it seemed, was not a factor in human obesity; in fact, probably quite
the opposite was true. Leptin is manufactured in fat cells, so it seemed
logical that obese people would have, if anything, an overabundance
of the hormone. And tests showed that many of them did.
There were rare exceptions.
Stephen O'Rahilly, professor of metabolic medicine at Cambridge University,
was the first to show that Coleman's big idea could apply to humans.
Among the strangest cases he had encountered was a pair of cousins,
bright and engaging children whose parents had years earlier immigrated
to London from the Punjab, in Pakistan. The father and mother of each
child were themselves first cousins. The older child, an eight-year-old
girl, weighed nearly 190lbs (13 stone). Despite liposuction and surgery,
she could no longer walk and was transported by her parents in a wheelchair.
The younger child, a two-year-old boy, weighed a staggering 65lbs (4
The parents reported
that at the age of four months the cousins became possessed by a voracious
hunger. Like starving explorers and concentration camp survivors, the
Punjabi cousins were obsessed with thoughts of food. They ate more than
their siblings, more than their parents, more than anyone could believe.
And still they wanted more. O'Rahilly knew immediately that this behaviour
was beyond gluttony - even greedy children don't eat frozen fish fingers
and paw through garbage bins. But exhaustive testing by specialists
had found nothing - there was no brain lesion or thyroid tumour, no
obvious genetic aberration.
O'Rahilly didn't really
expect to find leptin deficiency in the Punjabi cousins, but ran the
tests, anyway. The results were remarkable - the children's blood showed
not a trace of leptin. The intermarriage of cousins had allowed an exceedingly
rare mutation to surface. Like the ob mice, the cousins were constitutionally
unable to produce leptin. O'Rahilly and his team had found the first
human carriers of the obese gene mutation: these children were fat and
getting fatter because their bodies were telling their brains they were
Finally, leptin treatment
was ready and approved. They began slowly, with a low dose injected
once daily in the girl. The effect was sudden and, to the girl's parents,
miraculous. For the first time in her life, she was willing to push
away from the table. She began eating no more than her brothers and
sisters, and sometimes less. She stopped begging for food, and slept
through the night, rather than haunting the kitchen. In a year, the
girl had lost 35lbs (2 stone) and was walking without assistance. The
younger cousin, who began leptin treatments two years later at age four,
showed similar improvement.
Since O'Rahilly and his
team announced their discovery in 1997, about a dozen people worldwide
have been found with the leptin mutation [ie, an absence of leptin].
Just as with ob mice, it seems humans with the Ob mutation are infertile.
A Harvard scientist, Jeffrey Flier, had shown that a decline in leptin
is a warning signal to the body that something is amiss, and that the
response - a heightening of appetite, a reduction of fertility - is
protective. The primary role of leptin, then, is not to keep us from
getting fat - as Friedman had first surmised - but to keep us from getting
too thin, by setting in motion the starvation response. "For one or
two months people considered leptin the Great White Hope," Flier says.
"But we now know that leptin is not very good at preventing people from
eating too much."
Friedman, who holds a
multimillion-dollar stake in the success of the drug, is now looking
to see whether leptin might play an important role in maintaining weight
loss. Jeff Flier is among scores of scientists researching the pathways
connecting leptin to fertility and appetite: "It's well within reason
that we will know enough about the pathways that affect body weight
to control obesity in 10 years," he says.
Since the discovery of
leptin, obesity has become one of the hottest fields in science, drawing
in the hottest young scientists. Who, after all, can blame them? The
worried weighty constitute the largest - and wealthiest - drug market
to obesity once implied a slow metabolism. But we now know that the
overweight generally have a faster than average metabolic rate, and
expend not less but more energy than do normal-weight people. Scientists
now believe that a genetic inclination toward obesity manifests itself
in a constitution more finely tuned to environmental triggers. Primary
among these triggers is easy access to high-fat food, coupled with a
sedentary lifestyle. Most, or perhaps even all, of us are susceptible
to overeating and to becoming overweight. Our genes tip the balance
for each of us at a different point. Some of us succumb easily, others
conducts the business once performed by our bodies. A parade of labour-saving
gizmos - the television remote control, the electric garage door opener,
cordless phones, power steering, food processors - add up to an environment
where fewer of us every year are expending the energy necessary to maintain
a grip on our appetite. Andrew Prentice, of the London School of Hygiene
and Tropical Medicine, says that using a cordless phone - because it
relieves us from finding a stationary phone - robs us of the equivalent
of a 10km walk each year. Using a television remote rather than getting
up to change channels, he reckons, can add up to as much as an extra
pound a year.
Appetite control is asymmetrical:
our bodies are better designed to respond to hunger than to satiety.
When we are inactive, controlling appetite is not instinctive; it is
something we have to impose on ourselves. The less we exert ourselves,
the more difficult this becomes.
In addition, humans show
considerable individ ual variation in response to overeating. Generally,
scientists agree that metabolic rate is a very poor predictor of obesity,
but what is almost certainly a potent factor is "non-exercise activity
thermogenesis", or Neat. Neat is what most of us think of as nervous
energy - the fidgeting, restless pacing, maintenance of posture and
other subliminal activities of daily life. For reasons not yet understood,
some people sharply increase these unconscious exertions in response
to overeating. James Levine, an endocrinologist at the Mayo Clinic in
Minnesota, conducted a study in which 16 volunteers (including Levine
himself) were overfed 1,000 calories a day for two months. On average,
the volunteers gained 10lbs. But, as is often the case, the average
was not particularly revealing. One subject gained only 2lbs, while
another gained 16lbs. Levine sorted through a range of factors and concluded
that differences in Neat levels accounted for a tenfold difference in
fat storage among the volunteers.
Childhood obesity in
the US jumped from 5% in 1964 to 14% in 1999. In Australia, one out
of every five children is overweight. Obesity-linked "adult onset" diabetes
mellitus is for the first time being reported in children and adolescents
in the UK and many other countries. In 1985 Steven Gortmaker, a psychologist
at Harvard Medical School, and William Dietz, a paediatrician who now
heads the nutrition and physical activity division of the Centres for
Disease Control and Prevention, collaborated on a landmark study of
obesity and television viewing. They found a clear association between
the number of hours of television a child watched and the risk of that
child becoming obese or overweight. In 12- to 17-year-olds, the prevalence
of obesity increased by 2% for every hour of weekly television time.
A more recent study found that, while 8% of children watching one hour
or less of television a day were obese, 18% of children watching four
or more hours were obese. The more television children watch, the more
they eat. (By comparison, even reading is a workout, at least in studies
that have been done with obese children, perhaps because it engages
their minds a bit more emphatically.) Television viewing prompts children
to consume more food while they consume less energy, an ideal recipe
When children dictate
family food choices, as is increasingly the case in the US, entire households
are immersed in a miasma of one-dimensional sweet taste that reinforces
juvenile preferences. Marketing soft, sweet and salty foods is good
business, and children are the most vulnerable targets. Childhood obesity
rates are highest in countries where advertising on children's television
programmes is least regulated - in Australia, the US and England. Sweden
and Norway maintain a virtual ban on advertising to children, and have
consistently low levels of childhood obesity. Ireland, Belgium, Italy
and Denmark pose restrictions on children's advertising, and are pressing
the other states of the European Union to do the same. The US and other
countries can afford to do no less. Public nutrition campaigns should
go beyond vague recommendations to exercise and eat a balanced diet:
the link between inactivity, junk food consumption and obesity should
be made explicit. The food industry will lobby against these efforts,
of course, claiming that they constitute "legislation of food choices".
Nancy Wright wasn't expecting
miracles when she had her stomach stapled. For a while, though, she
thought she'd been handed one: she lost 125lbs (nine stone) in 18 months.
She bought new clothes, got a new job, and started to feel pretty good
about herself. Then she hit upon the trick of melting crackers slowly
on her tongue, and found she could suck down quite a few without upsetting
her newly abbreviated stomach. Ten pounds have already crept back, and
she is wondering where this will end. She has cause for concern: her
daughter lost 90lbs (6 stone) after gastric bypass surgery, and over
the past year has gained every one back. Obesity resists easy remedy
for good reason - the human body evolved biochemical redundancies to
protect at all costs the instinct to nourish itself.
So many of us eat convenience
foods more often than we intend, many scientists contend, because we
have become habituated to them. And there is strong evidence to suggest
that calorie-dense food such as fast food can entrain a neurological
feedback mechanism that contributes to overeating. "As we develop a
full understanding of the neuro-regulation of appetite, I think the
addictive nature of foods will come clear," Charles Billington, an obesity
expert at the Minneapolis VA Medical Centre, told me. "And I think we
will learn that these addictions can develop at various stages in life.
And I think we will learn that they are very, very powerful."
Like Big Tobacco, Big
Food is a cunning manipulator of public opinion. Without intervention,
virtually all Americans will be overweight by 2030, and half will be
obese. Other industrialised nations are not far behind. We can no longer
afford to be embarrassed, or to avert our eyes from the forces underlying
this tragic pandemic. Science has taught us that the obesity pandemic
is less a matter of individual preferences than of societal pressures,
and of the power of the institutions that impose them. We can and should
© Ellen Ruppel Shell,
This is an edited extract from The Hungry
Gene: The Science Of Fat And The Future Of Thin, by Ellen Ruppel Shell,
published by Atlantic Books at £17.99.