Robert Hegele had doubts. Even in 1999, as the research attracted wide media attention and the British Medical Journal declared, "Thrifty gene identified in Manitoba Indians," Dr. Hegele could not be certain - which is telling, since he was the geneticist who had made the discovery.
But back then he still thought further work would bear it out. Part of a small research group, Dr. Hegele had been studying the astonishing prevalence of type 2 diabetes among the Ojibwa-Cree people of Sandy Lake, an isolated reserve in Northern Ontario not far from the Manitoba boundary.
At that time, gene hunting in remote populations was as fashionable as starting a dot-com, and the Sandy Lake project stood out as a model - a rare instance in which a community negotiated compensation for the DNA of its members. In exchange for fresh food, expanded medical services, school programs and a share of any profits, the band council allowed scientists to search for an explanation as to why the diabetes rate was five times the national average - why, in fact, it was the third-highest rate in the world.
The locals knew it as the Sho-goh-wah-pee-nay, the "sugar disease." It afflicted nearly half the adults, could be detected in children as young as 10 and cost many residents their kidneys, sight and limbs. Yet Sandy Lake had recorded no cases of diabetes until the 1960s.
The numbers seemed to have risen alongside its conversion to the unholy trinity of the couch, fast food and the television. When Dr. Hegele, a senior scientist at the University of Western Ontario, first heard the Sandy Lake story, he couldn't help but wonder if this was the work of the elusive thrifty gene.
Since James Van Gundia Neel proposed it almost 50 years ago, the thrifty-gene hypothesis has reigned as the dominant explanation for soaring rates of obesity and diabetes among many aboriginal groups. Native communities where diabetes didn't exist in the first half of the 20th century had, by the end of it, the world's highest prevalence, with Arizona's Pima Indians in first place, followed by the Nauru islanders of Micronesia and the Oji-Cree at Sandy Lake.
Dr. Neel, an influential geneticist at the University of Michigan, felt that genes were partly to blame. He speculated that genetic traits among the world's prehistoric hunter-gatherers enabled them to store calories during times of feast in order to survive in times of famine.
But with "the blessings of civilization," he wrote, these thrifty genes had become hazardous baggage in a sedentary world of all feast and no famine, predisposing carriers to obesity and the diseases it brings.
His idea spread like an epidemic, embraced by everyone from public-health officials and policy-makers to the media and many aboriginal people themselves. Although never billed as more than a hypothesis, it came to be seen as fact - "a scientific axiom," Dr. Hegele says, "dogma almost."
But now, with obesity and diabetes shaping up to be a global pandemic, the theory appears to be dying - raising the prospect that prejudice more than proof gave it such a long life.
A bevy of researchers now questions it. Even true believers such as Dr. Hegele are losing faith; some dismiss it out of hand. Not least because, after four decades in search of thrifty genes, no one can find them.
Even huge genome-wide hunts involving thousands of subjects and boutique projects using the latest technology have come up empty, while the many genetic variants now linked to diabetes and obesity have turned out to be no more prevalent among aboriginal people than anyone else.
Jeffrey Friedman, the renowned Rockefeller University scientist who discovered the appetite-suppressing hormone leptin, has been hunting the thrifty gene since the mid-1990s on the Pacific island of Kosrae. Sixty years ago, its people were lean, living off the land and sea, but after the U.S. started shipping them soft drinks, Spam and processed foods, three-quarters of Kosrae's residents have become overweight, if not obese.
Working with the island's health department, Dr. Friedman has genotyped 3,300 people - most of the population - expecting to find that the few residents to remain thin are descended from a small group of Europeans who arrived in the 19th century. But "we didn't find any genes that could predict who was obese and who wasn't," he says. "So, if you don't even have that as a starting point, there's no where else to go."
John Speakman, a zoologist at Scotland's University of Aberdeen, says there never was anywhere else to go. "The thrifty-gene hypothesis is just a story," he says. "As far as I'm concerned, it's dead and we should discontinue thinking about it. But revolutions in science don't happen overnight."
Given the weight of evidence against the theory, a post-mortem has already begun, raising uncomfortable questions about why, with no real proof, it has been so popular for so long.
Jennifer Poudrier, an associate professor of sociology at the University of Saskatchewan, is one of many scholars to argue that the theory allows society to curl up with the notion that biology shoulders most of the blame for the ill health of native people. She dismisses it as "a colonial lens put on aboriginal history," promoting the myth that indigenous people all have the same genes that make their diabetes "a special problem" beyond the reach of public-health initiatives.
"It makes people feel deflated and defeated," says Prof. Poudrier, a Métis who counsels native women on body image. "It detracts from a focus on the social context."
That context, she notes, includes conditions on Saskatchewan reserves where fast food, such as Kentucky Fried Chicken and pop, sell for a small fraction of the cost of milk and ingredients for a salad. Yet "diabetes is not seen as a social issue, but a biomedical one."
Jeff Reading, director of the Centre for Aboriginal Health Research at the University of Victoria, calls the theory "potentially damaging" because "it discounts the social circumstances of poverty - it suggests that you'd be okay if you didn't have faulty genes.
"But saying your genes are bad is not that helpful; it's just an excuse not to do anything about it."
He says indigenous groups in New Zealand, northern Finland and Canada have very different genetic histories, yet all suffer from similar social and health problems. "It's not about race. It's more about colonization."
Fresh veg just turnips and spuds
Sandy Lake was a ramshackle collection of government-issue, two-bedroom cottages when Stewart Harris arrived in 1990, some so dilapidated that "you wouldn't park your car" in them. Unemployment hovered at 80 per cent, running water was a novelty and potatoes and turnips were the only produce available.
Posted to the reserve as the region's medical director, Dr. Harris was the first to call attention to its rampant diabetes. He and Bernard Zinman, an expert at Mount Sinai Hospital in Toronto, formed a partnership with the community to set up nutrition and exercise programs as they tried to gauge the scope of the problem.
Once they had the shocking numbers in hand, they contacted Dr. Hegele, suspecting that genes, not just environmental forces, played a role. Four years later, they pinpointed the first diabetes-risk gene ever identified in an aboriginal population.
In their 1999 report, the researchers wrote that the variant seemed to fit Dr. Neel's theory of a thrifty gene - especially given the Oji-Cree once lived as hunters and survived hungry winters.
"But even then," Dr. Hegele says, "we knew the variant couldn't be the sole factor underlying diabetes. It wasn't even present in the majority of diabetic Oji-Cree." Only two of five band members carried it. Neither did it have any bearing on diabetes in populations outside Sandy Lake. "In those early days, I speculated that perhaps we would find additional variants that would fill the gap," Dr. Hegele says.
But they didn't. In fact, he says, "newer genetic data suggest it's incorrect to pin the blame for type 2 diabetes on a single gene in any population. Environmental or lifestyle factors are the key ingredients." Susceptibility appears to involve "a diverse network of dozens or hundreds of genes, each of which plays a very small part," he says - "genetic factors that can be found across all human populations."
Dr. Hegele, now director of cardiovascular research at UWO's Robarts Research Institute, says he once had "an unquestioning acceptance" of Dr. Neel's theory, and liked the way it invoked Charles Darwin and the pressures of evolution and adaptation. More recently, "the whole thrifty-gene idea seems to me not to capture the subtlety and complexity… of type 2 diabetes in first nations communities."
A chronic condition, type 2 diabetes occurs when the body makes too little of the insulin it needs to metabolize glucose, its fuel source, or is unable to use the insulin properly. Obesity is a leading risk factor. Dr. Zinman says it was reasonable to search for the role that genes may have played.
And former chief Harry Meekis, who helped to negotiate the research agreement, said at the time, "We didn't want to be known as the people with the third-highest rate of diabetes - we wanted to be the community that did something about it."
International press coverage of the finding at Sandy Lake helped to cement the thrifty-gene theory in the public consciousness - and spark a backlash from academics such as Prof. Poudrier. She was completing her PhD at Queen's University when she read of the discovery, and it drew her deep into the underpinnings of the famous Neel theory.
"There was a lot of cultural panache around the notion of genes at the time," she says, "and it was born in the thick of the eugenics movement."
Indeed, in his landmark paper, published in the American Journal of Human Genetics in 1962 (just nine years after the double-helix structure of DNA had been discovered), Dr. Neel suggests running blood-insulin tests on "primitive hunters and gatherers." He also includes a section entitled "Some Eugenic Considerations" in which he says that, if correct, his theory poses an ethical dilemma because "modern medicine makes it possible for diabetics to propagate," allowing the disease to spread. But intervening to eradicate the gene could backfire, he added, if famine ever returned on a major scale and it was required again.
Indirect evidence to support the theory was bountiful after Dr. Neel proposed it - a mouse with a mutated gene that led to obesity and diabetes, research surveys showing famines could kill off more than a quarter of a population and, most compelling, the sudden spike of obesity and diabetes in aboriginal communities where none had existed before.
Aberdeen's Prof. Speakman feels it's easy to understand why the hypothesis has been so highly regarded. "Because it's a great idea: 'In times of famine, it's the lean ones who are gonna die.' It's a simple idea; it all makes sense."
Except that it's wrong, he adds. There is no proof that fatter people survive famines better than thinner ones. In fact, says Prof. Speakman, a specialist in how animals use energy, throughout evolution, "most populations would never see a famine. There's one every 100 years or so, but in those times, people only lived 25 or 30 years."
Anthropologists have long argued the theory wrongly assumes that all hunter-gatherers suffered regular famines, when crop failures made starvation more common among early farmers, suggesting Europeans should face a greater risk of being obese and diabetic. Farming arose about 12,000 years ago - which, in evolution, is like the day before yesterday - and not enough time, says Prof. Speakman, for alleged thrifty genes to have spread as widely as they seemed to have.
That such arguments have been missed, or dismissed, by biomedical researchers comes as no surprise to him. "People who are medically trained are not well trained in evolutionary biology," he says.
No extra calories to be stored
Biological anthropologist Emöke Szathmàry, a former president of the University of Manitoba, says the popularity of the thrifty-gene hypothesis "has always amazed me." She studied the Dogrib people of the Northwest Territories in the 1980s, and found it hard to believe they had evolved a gene that stored extra calories from carbohydrates when their traditional diet was mostly protein - fish, moose and caribou. Given the sub-Arctic's two-month growing season, their bodies would have required every bit of glucose when and if they got it.
But raising such critical questions made her "a voice in the wilderness," she says. "Anthropology papers are not necessary reading for those who read the medical literature."
To her, the thrifty gene reflects, to some extent, "the old 15th-century view that, if you see one American Indian, you've seen them all. ... What I didn't understand is why public-health agencies glommed onto it - that was nuts."
Dr. Szathmàry suspects that because it was regarded as "settled science," the theory may have compromised efforts to investigate other causes of the diabetes epidemic.
Dr. Reading agrees. "Lots of research grants have been funded hunting for the thrifty gene." Yet, despite eight years spent compiling ethics guidelines for conducting research in aboriginal communities and three requests for a long-term study of native children, nothing has been approved.
"It's a curious omission," he says, "since here's a population, with the poorest health, that could benefit most from it."
At least the alarm was raised
Twice before he died in 2000, Dr. Neel refined his thrifty-gene hypothesis as evidence grew to challenge it. But in the end, he still saw it as viable, as many researchers still do. Dr. Harris, who first sounded the alarm at Sandy Lake, is one who keeps the faith - "even though we don't have the genes."
Mount Sinai's Dr. Zinman says it has "been a disappointment" that the genetic story is not simple. "At the end of the day, it's wrong to say there is a thrifty gene, but maybe there will be a thrifty genotype" - a collection of genetic traits that contribute to type 2 diabetes.
He disagrees that this "stigmatizes" anyone, as the thrifty gene would have been a positive, protective trait if it existed. "You have to be careful not to confuse the science with the politics."
For now, it's clear that "the environment trumps your genetic susceptibility and in certain environments the risk is greater."
Dr. Harris, now a professor of family medicine and epidemiology at Western's Schulich School of Medicine and Dentistry, is calling for even more community and clinical-care programs to help solve the problem. His latest studies of Canada's aboriginal people paint a bleak picture - with more and younger children being diagnosed with diabetes and 18 times more end-stage kidney failure than the general population.
Mr. Meekis, the former deputy chief, was diagnosed with diabetes two years ago, but reports that he hopes Sandy lake will be a success story. The community programs the research helped to launch continue. A covered arena has sprung up, along with two new schools with athletic facilities, and the kids, Dr. Harris says, play broomball and hockey, and go to a diabetes camp where they learn about nutrition.
Fresh produce is still flown in, but few residents can afford it, and fast-food outlets have moved into the region. Is progress being made? Dr. Harris hoped to conduct another study last year to learn if two decades of effort have paid off, but could get no funding. He plans to try again this year.
Either way, he says, the Sandy Lake story "played a key role in prompting the government to pay attention to the problem." He is certain it spurred Ottawa's multimillion-dollar national campaign to educate native people about the disease.
This summer marks the 20th anniversary of the researchers' collaboration with Sandy Lake, which plans to mark the occasion with "a celebratory feast."
Carolyn Abraham is The Globe and Mail's medical reporter.