He's already proved you wrong.
DISCOVER Vol. 21 No. 05 | May 2000

Don’t tell Stephen O’Rahilly
that weight is just a matter of will power. He’s already
proved you wrong. |
Stephen O'Rahilly sits deep in the shadows near the rear of the
restaurant, luxuriating in a moment of hard-earned solitude.
Gripping a pint of lager in one hand, a half-smoked stogie in the
other, he is dressed for the evening as he was for the morning--in a
tie of indifferent weave. The Maharajah is one of the best Indian
restaurants in town, but O'Rahilly does not look pleased. "For
decent food of any kind one really needs to go to London," he
mutters in a mild Irish brogue as he peruses the menu. "In
Cambridge, it's hard to find an edible loaf of bread." Snuffing out
his cigar, he waves over a waiter and orders another beer and enough
curry to feed several maharajahs. O'Rahilly takes his food
seriously, and it shows. A tennis champion in his youth, at 42 he
has the look of a man whose relationship with sports is confined to
that of spectator. "One thing I hated about America was having
people come for dinner, drink one glass of wine, and leave at nine
o'clock, saying that they had to jog in the morning," he says.
Clearly, O’Rahilly is made of sterner stuff. No number
of Saturday night pints and cigars preclude his spending Sunday
mornings at Addenbrooke’s Hospital, a cavernous complex on the
city’s edge with all the charm of a parking garage. There the
physician and researcher makes discoveries that are rocking
long-held beliefs about why people get fat. Using a combination of
old-fashioned clinical observation and modern biochemical analysis,
he has shown that a person’s appetite and their eating behavior can
be linked to specific genes—and that even a tiny defect such as the
absence of a single nucleic acid in a sequence of DNA can lead to
runaway weight gain. The research has not only encouraged new
treatment ideas, but challenged long held notions that being fat, or
not, is a matter of free will.
“I’ve always considered it distinctly unlikely that
there are not genes that effect behavior,” says O’Rahilly, Professor
of Metabolic Medicine at Cambridge University, as he eats a mouthful
of nan, slippery with butter. “This doesn’t mean that every behavior
is genetic: for example, that one has a love affair because one is
genetically determined to do so. But the idea that a fundamental
human behavior like eating is not to some degree genetic, to my
mind, is absurd.” That has been a tough chew for some scientists,
who argue that eating behavior is too complex to reduce to genetics.
“Before O’Rahilly began publishing his findings, a lot of scientists
considered humans exempt from biology,” says Rudolph Leibel, head of
the division of molecular genetics at Columbia University’s College
of Physicians and Surgeons. “Now we can no longer get around the
presence of genes as a regulator of body weight.”
Physicians must also take note of the fact that
O’Rahilly made these major discoveries by simply being a good
old-fashioned doctor who cared about his patients and listened
carefully to them.
Medical sleuthing, O’Rahilly says, works best by
studying patients who seem to defy all sorts of standard diagnoses:
“I study the experiments of nature to illuminate the normal.”
Earlier this morning, for example, he and his scruffy band of
post-doctoral and clinical fellows spent part of their weekly
meeting puzzling over the mystery of a tragic case: an extended
family of Arabian descent afflicted with obesity so severe that it
has killed several members. The family has no apparent genetic
defects, which only seems to galvanize O’Rahilly. “We haven’t found
the problem yet,” he said. “But believe me, we will.”
His ambition is fueled not only by a driving
scientific curiosity but also a bristling social consciousness. “I
had a woman in her twenties in my clinic yesterday who weighed 420
pounds,” he says. “The girl’s life was a ruin, an utter hell. She
never left her house, and she felt like a leper. She’ll undoubtedly
develop obesity-associated diseases like diabetes and arthritis.
Like so many of the people I see, she has and is going to continue
to have a terrible quality of life. Yet in addition to her physical
ailments, she has to endure the jibes of others who treat her
condition as a joke.”
What O’Rahilly finds particularly irksome about public
attitudes, and what he hopes his research will overturn, is our
peculiar habit of blaming the victims of these ills for their
misfortune. “I’m sometimes criticized by so-called liberals who tell
me that I shouldn’t be working to validate these nasty people whose
disgusting behavior has made them so sick,” he goes on. “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.”
“The idea that a fundamental
human behavior like eating is not to
some degree genetic is absurd.”
O’Rahilly’s impatience with moral arrogance runs deep.
He grew up in a working class suburb of Dublin. His mother worked
from age 14. His father, a pharmacist, dismissed his job as “a
glorified clerk selling lipstick to housewives.” In school,
O’Rahilly studied Latin, English literature and little else under
the cheerful tutelage of the good De La Salle Brothers. “Brother
Paddy was the worst biology teacher imaginable,” he says. Still,
O’Rahilly managed to cram in enough on his own to graduate first in
Ireland in chemistry, and enter medical school at the University
College Dublin.
There, at 17, an age when many teens are bullied by
hormones, he decided to master them. “Science is about revealing
beauty, and I thought that it was somehow beautiful that
chemicals—hormones—could act like messages in the human body,” says
O’Rahilly. “Biomedical science has a pragmatic outcome, of course,
but it’s the beauty part that I’m after. It’s the catch in your
heart, equivalent to the moment you suddenly realize that the
Marriage of Figaro is wonderful. A Mozart aria is perfect because no
one else but Mozart could have done it in the way he did it. And
that’s what one hopes to do in science, do something in a unique way
that is, in some sense, beautiful.”
At Dublin, he was inspired by Professor Ivo Drury, a
medical Johnny Appleseed who had set up diabetes clinics all over
Ireland. “He was an incredibly generous man,” O’Rahilly recalls.
“Utterly admirable. His great pain was that he hadn’t been able to
do more science.” Determined not to suffer a similar disappointment,
O’Rahilly signed at Oxford Univeristy to do research in diabetes
inheritance patterns. Five years later, in 1989, he took a position
at Harvard Medical School where he studied insulin resistance, a
common condition among diabetics that keeps the body from responding
fully to the hormone. He began searching for genetic forces that
might unbalance the body’s exquisitely tuned glucose delivery
system.

THE “FAT” GENE MYSTERY:
Both these mice carry a gene defect that prevents
production of leptin, a hormone that is made in fat cells and
acts in the brain’s hypothalamus to regulate appetite. Without
leptin, mice eat voraciously and balloon in weight (left).
Daily doses of leptin can slim down the huge mice (right). But
is there a human equivalent of this gene? Stephen O’Rahilly
found out. |
At that time the molecular
biology revolution was gearing up, and the polymerase chain
reaction, a tool that makes replicating a sample strand of DNA easy,
had just become available. “PCR was ideal for my sort of genetics,”
O’Rahilly says. “It made it possible for half trained monkeys like
me to do real genetics, because the limiting factor was no longer
technical skill, but the quality of the clinical material being
studied.” His challenge became finding the right genes to decode,
and at that he showed himself to be a master. David Moller, now
senior director of the division of metabolic disorders for Merck
Research in Rahway, New Jersey, worked with O’Rahilly at Harvard in
the late 1980’s. “There are virtually an infinite number of genes
you could look at,” Moller says. “But Steve had a gift for finding
just the right patients, and just the right genes. He was forever
thinking outside the box. He was fearless.”
When he returned to Cambridge two years later,
O’Rahilly began developing a tight network of physicians who send
send him patients with baffling metabolic syndromes. “O’Rahilly is
the only scientist in Europe really looking for unusual patients,”
says endocrinologist Jeffrey Flyer, a former colleague at Harvard.
Ironically, one of O’Rahilly’s most significant patients simply
waltzed into his weekly endocrine clinic. The 42-year-old woman had
struggled throughout her life with health problems doctors blamed on
her weight. O’Rahilly suspected otherwise. “He never prejudges
patients,” says his Addenbrookes colleague, endocrinologist Sadaf
Farooqi. “He listens to them.”
Full text of this article appears in Discover magazine.

Former Surgeon General C. Everett Koop
established the Shape Up America! Web site to broadcast information
about obesity as a U.S. health issue and offer lifestyle-change
advice: www.shapeup.org.
The North American Association for
the Study of Obesity Web site (www.naaso.org) is an
authoritative, scientific on-line resource about obesity.
The
International Association for the Study of Obesity Web site (www.iaso.org)
offers news and links to groups worldwide.
The woman’s story was chilling. She had never
menstruated, but gave birth to quadruplets after extensive hormone
treatments. She suffered frequent bouts of incapacitating shakes,
sweating and dizziness. Recently, driving had become a death-defying
gamble, for she often got drowsy and once fell asleep behind the
wheel. As a child she was so obese she spent 13 months in hospitals
on starvation regimens. “I was given half a tomato and a lettuce
leaf for tea [supper], and was punished for taking a chip [French
fry] from another child’s plate,” she recalls. O’Rahilly asked her
to bring in a childhood photo, and she returned with a picture of
herself at age three hoisted in her father’s straining arms. The
toddler was, says O’Rahilly, “unbelievably huge.” Already 84 pounds,
she was too heavy to walk.
“People who are not obese
believe themselves to be virtuous.
But the truth is, they’re just
lucky.”
O’Rahilly ran a specialized blood test that disclosed
she had very little normal insulin in her blood, but plenty of
proinsulin, a precursor that is normally broken down into insulin by
the enzyme PCl. He discovered that a gene that directs production of
this enzyme was defective in the woman. Furthermore, the woman had
loads of a crucial hormone called leptin, which helps the brain
regulate appetite, but she couldn’t respond to it. The reason, it
turned out, is because PCl wasn’t performing another of its tasks:
converting another precursor hormone, POMC, into TK. O’Rahilly
concluded that the single genetic defect had disrupted the woman’s
blood sugar and made her fat. Obesity wasn’t the cause of her myriad
ailments; it was one symptom of a genetic syndrome.
Although O’Rahilly considers this his most original
work, a study he published a month earlier got a lot more attention
from the media. In it, he reported conclusive proof that there is a
human equivalent of the so-called fat gene in mice. Scientists had
been searching in vain for such a gene since 1994 when Rockefeller
University scientist Jeffery Friedman found that lab mice with a
specific genetic mutation fail to produce leptin and as a result
have uncontrollable appetites, and become huge. Researchers
theorized that something similar might be going on in obese humans,
but when they began taking blood samples, they found that obese
people show very high levels of leptin.
O’Rahilly’s discovery came when he took on the strange
case of a pair of first cousins, bright and engaging children whose
parents had married their own first cousins. Although consanguineous
marriage can lead to birth defects, it is common in the family’s
native Punjab, a fertile, wheat growing region of Pakistan shared
with northwest India. Shehla Mohammed, an Oxford University
physician and clinical geneticst who referred the case, wrote
that the children
seemed to have suffered no ill effects of inbreeding and were
generally healthy aside from their tragic obesity. The
eight-year-old girl weighed almost 190 pounds, and despite
liposuction and surgery, could no longer walk. The two-year old boy
weighed 65 pounds and seemed doomed to a similar fate.

“Biomedical science has a pragmatic
outcome, but it’s also about revealing beauty,” says
O’Rahilly. “I thought that it was somehow beautiful that
chemicals—hormones—could act like messages in the human
body.” |
The youngsters had undergone
chromosomal analysis, brain scans, and thyroid checks, all of which
were normal. Still, they had a voracious hunger which first appeared
when each was about four months old. On a strong hunch, O’Rahilly
asked Farooqi to analyze the cousins’ blood for leptin. She found
none. To check that this wasn’t due to a test error, O’Rahilly
ordered a second run. Farooqi drove to London, took more blood
samples, packed them in a bucket of ice, and sped back to Cambridge.
She reran the test that night, and the next morning broke the news
to O’Rahilly: the children’s blood again showed no trace of leptin.
O’Rahilly knew that the absence of leptin did not prove the children
harbored a human version of the mouse fat gene, it merely posed the
possibility. Returning to the lab, he examined DNA in tissue samples
taken from the children. His suspicionswas confirmed: the children
had an identical defect—a missing single nucleic acid, called
guanine—in the gene coding for leptin. Like the obese mice, the
children were constitutionally unable to produce the
appetite-regulating hormone.
But he wasn’t finished. Ever the clinician, he wanted
to find out if he could cure or at least improve the health of the
cousins. So he contacted Amgen, a California-based drug company that
had developed a synthetic version of leptin. The hormone was being
tried in adults, but had never been given to children. O’Rahilly
spent seven months designing and clearing a child-friendly protocol.
In that time the older child gained another 18 pounds. But after two
weeks of daily leptin injections, her weight began a steady descent.
“It was one of the most remarkable things I’d ever seen in
medicine,” Farooqi says. Within a year the girl lost 35 pounds,
dropping from TK to TK pounds, and the next year, after her dose was
increased slightly, she dropped ten more. Her young cousin, who
began leptin treatment at age four, has shown similar improvement.
“Finding leptin deficiency in fat kids was not a major intellectual
leap,” O’Rahilly says. “More important was giving it to the kids and
showing that it worked. This has proven that leptin is not a
vestigial throwback, like the appendix, sitting around the genome
doing nothing. It means that leptin performs an important function
in humans.”
These days O’Rahilly stays plenty busy scrutinizing
the DNA of 330 children who became severely obese before the age of
ten, searching for other genetic glitches. Recently he found that
eight of the youngsters have a defect in a gene that codes for a
receptor protein called melanocortin-4, known to regulate eating in
mice. Ultimately, his aim is to find new treatments that will cure
these devastating ailments. Meanwhile, his work is helping dispel
the myths that obesity is simply a consequence of sloth or gluttony.
O’Rahilly is sensitive to charges that what he
uncovers about the genetic underpinnings of disease and behavior
will be used to control or cull those with imperfect DNA. He was
stunned recently when the Duke of Edinburgh, in for a formal visit,
asked: “Why anyone would want to keep these people with mutations
alive?”
“Farooqi told him he was a complete barbarian,”
O’Rahilly recalls. “But the question becomes: Is it a good or bad
society that gets rid of DNA with an attached disorder? I’ve been
accused of being a biological determinist. Well, in fact, I am. I
think biological determinism has a degree of human decency and
kindness about it that is completely absent from the
environmentalist view espoused by Puritans who want to make everyone
behave in a particular way. Obesity is morally neutral, and I have
no problem seeing it as a biological problem. Obesity is
fundamentally boring, and I’d love to make it more boring, by
helping the people who are really fat get rid of some of that
baggage and get on with the interesting things in life, like making
beautiful things and having families. Whatever one’s ideology, isn’t
the point to help people get on with their lives? As a scientist, as
a clinician, I certainly think so. And as a human being, I certainly
hope so.”