January 20, 2010

Beyond Calories

In confronting the obesity epidemic, scientist Thomas Hughes urges researchers to consider medical causes of weight gain

By Marjorie Howard

Oprah Winfrey’s battle with her weight is well known to TV audiences who have watched the talk show host shed lots of pounds several times, only to gain them back. Her struggle, going back more than 20 years, is evidence that for some people, the dieting wars may not end in victory, says Thomas E. Hughes, N87, A10P.

When there is stress during fetal development, “it leads to obesity,” says Thomas Hughes. Photo: John Soares

If Winfrey, who has a personal trainer, a personal chef, coaches and unlimited resources, can’t battle the bulge, what does it mean for the rest of us? “She’s intelligent and not lacking in discipline—look at what she’s done with her career,” Hughes says. “So if controlling body weight was nothing more than discipline, wouldn’t someone like her be able to solve this?”

We are quick to blame obese people for their problems, he says. But just maybe it’s not entirely their fault.

Hughes is well versed in the calories-in-equals-calories-out prescription for weight control. He spent 20 years at the pharmaceutical company Novartis, where he researched diabetes prevention and treatment, and is now the chief executive officer of Zafgen, a Cambridge-based company working to develop a drug to treat obesity.

He has heard about the traditional theories to explain weight gain—from processed food to video game overload—yet he’s still not convinced we’ve tracked down every lead in the search for why, as a society, we have gotten so fat so quickly. What if there are other factors at play that can’t be controlled by lifestyle changes?

3 Million and Gaining

The obesity epidemic, he reasons, started in the 1980s. Back then, some 130,000 Americans weighed more than 300 pounds. By 2004, the number had climbed to 3 million.

“I don’t know what is available now that wasn’t available then,” says Hughes, a Friedman School overseer. There are certainly people who simply eat too much and don’t exercise. But there may be other reasons—medical reasons—for obesity that have not been fully studied.

Consider, for example, adenovirus 36, the only human virus linked to obesity. This adenovirus “appears to be unique in that it can change the way the stem cells that make fat tissue in our body function,” Hughes says. If adenovirus 36 infects fat cells, he says, it lays down “fat much more aggressively and becomes super fat cells.” And, he adds, if you measure the antibodies to the virus in a person’s blood, you’ll find a dramatic over-proportion of obese people infected with this virus.

Another potential cause of obesity, he says, is the stress that occurs to the fetus during development. “You can reproduce this in animals over and over again: When there is stress, it leads to obesity, and there is developing data that say this may be happening in people, too.”

A third possibility is intestinal bacteria, a finding Hughes calls “fascinating.” The studies that have been done so far suggest if you take bacteria from the guts of obese animals and feed them to lean animals, they become obese. Perhaps, he says, people developing obesity have bacteria that are more efficient at extracting calories, or thin people may have the opposite problem: bacteria that are poor at using energy.

If the scientific community acknowledged that obesity may have numerous causes, then, Hughes says, researchers might discover even better leads and “insert them more directly into the current discussions around the problem.”

Perhaps obesity is to the 21st century what peptic ulcers were to the middle of the 20th century: something once blamed on the sufferer and only later found to have other causes. People with ulcers were once labeled Type A, hard-driving workaholics who wouldn’t have ulcers if they could only learn to relax. Yet in 1994, it was widely recognized that a bacteria, Helicobacter pylori, was the real cause of most stomach ulcers.

There is no doubt, Hughes is quick to say, that a societal “perfect storm” has created just the right conditions for obesity. Food is cheaper and more abundant than ever, with supermarkets and fast-food restaurants offering plenty of processed, calorie-laden foods. We also live in a social and cultural environment where people are less likely to exercise. “Things are easier to get to; there are fewer sidewalks, less recess at school. A convenience lifestyle has evolved,” he says.

And while all that makes sense in understanding how obesity has reached epidemic proportions in America, something still bothers Hughes: “Why is it that even within individual families, where you have people living together who are genetically similar, some people will become obese and some will not?”

While at Novartis, Hughes worked with scientists from the Broad Institute in Cambridge to study the underlying genetic causes of diabetes. “We hoped going into this we would hit home runs, that genes would pop out at us that would explain the extent of the problem,” he says. Instead they found a fairly large number of genetic associations to diabetes and obesity but nothing that explained it to an appreciable extent.

“So what we thought would be a rich vein of ore, the mother lode of information that would teach us about how to treat diabetes and obesity, came back with an unimpressive list of things that pointed more to additional mysteries,” Hughes says. “This impressive lack of concrete findings about new obesity genes has not permeated public opinion.”

Hughes came to Zafgen after giving a lot of thought to the best way to treat and prevent diabetes. It became clear, he says, that obesity is “one of the biggest underlying drivers” for the disease. “In this modern age, the most addressable, preventable or treatable cause of diabetes is obesity—yet in the environment I was in, in the pharmaceutical industry, we weren’t able to address the problem in a way I found satisfactory.”

A Thin Drug?

Zafgen is developing an obesity treatment specifically for people with “hungry adipose.” People with this overactive fat tissue (it’s evident in some individuals and not in others) are more likely to store calories that otherwise could be used by the body for energy. Zafgen’s compound, based on observations made by its co-founder, Maria Rupnick, unlocks the defect of hungry adipose, allowing fat to leave the tissue and be used by the body. In obese mice, the compound suppresses food intake and causes rapid and sustained fat loss, returning their body size and makeup to that of normal, lean mice. Clinical trials in humans will begin this year.

While new therapies like this offer some hope to obese people, Hughes says these approaches only treat the problem without addressing the underlying cause or causes. Maybe, he says, a vaccine will be developed for the adenovirus or there will be better diagnostic tools to assess whether people have a predisposition for obesity “that is not simply related to how much television they watch. Obese people are told ‘you’re a bad person; what’s wrong with you?’ You would never say something like that to someone who has schizophrenia or hypertension or cancer or HIV.”

If Hughes is right and some people were to learn their bodies are the enemy in their battles with weight loss, at least they will have the ability to cope with it, he says. “You can accept it and become obese. You can fight it and maybe it will be a lifelong struggle, like Oprah’s.” And maybe, more research will lead to a cure.

This story first appeared in the Fall 2009 issue of Tufts Nutrition magazine.

Marjorie Howard can be reached at marjorie.howard@tufts.edu.

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