Fat Genes

A physician and researcher is rocking long-held beliefs about why people get fat, showing that a person’s appetite and their eating behavior can be linked to specific genes.

By Ellen Ruppel Shell and Alastair ThainMay 1, 2000 5:00 AM


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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.”

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.

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.”

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.

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.

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.”

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