William and Mary Alumni Magazine | Winter 2007/2008, Vol. 73, No. 2
Illustration by Ryan Snook
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After many years of groundbreaking research on how the human body manufactures and stores adipose tissue, leading cell biologist and researcher Bruce Spiegelman '74 has come up with a provocative insight: Fat is actually our friend!
It was the kind of sudden breakthrough that a scientist never forgets.
Thirteen years ago, Bruce M. Spiegelman '74 hurried across the Harvard University lab to join his excited graduate student, Peter Tontonoz, who was peering into the viewing lens of a state-of-the-art inverted phase contrast microscope.
A moment later, the grad student stepped aside and Spiegelman was gazing into the depths of an illuminated Petri dish, where a solution of mouse cells taken from ordinary skin tissue swarmed and seethed beneath a flood of brilliant light.
As Spiegelman slowly brought the cells into focus, he caught his breath. Were his eyes deceiving him? No ... there could be no mistake. The cells had grown much larger during the past few hours; they had swelled into gleaming bubbles that were now faintly tinged with gold.
In a flash, the cell biologist realized that he was looking into a Petri dish full of fat.
After 10 years of relentless effort, Spiegelman had finally succeeded in pinpointing the gene that "turns on" the protein-based messaging system required to create fat.
For Spiegelman and his then-graduate assistant (these days a professor of pathology and laboratory medicine at the Howard Hughes Medical Institute of University of California, Los Angeles), it was an unforgettable event -- one of those rarely encountered moments in science when a major breakthrough suddenly becomes obvious. "As soon as I looked at the cells, I could see they were full of [lipid] droplets," says Spiegelman today, recalling the excitement of that summer afternoon.
"All at once, it was clear that we'd been able to make fat cells by inserting material from a gene, known as PPARgamma, into ordinary, undifferentiated cells. In other words, we had just uncovered the process by which the body tells a cell: 'Go ahead and become a fat cell, so that you can store excess energy for later use as needed.'"
Why was the discovery of the "golden bubbles" in the Petri dish so significant? It's simple, says Spiegelman: "Once you crack the [genetic] code and figure out the biochemical steps in human fat storage, you can begin to use that knowledge for all kinds of research related to metabolism -- including research on obesity, diabetes, insulin resistance -- you name it."
For Spiegelman, the discovery soon led to a key insight that has come to dominate his research on obesity in recent years: the rather startling notion that ordinary human fat, far from being a health-threatening culprit, actually performs several vitally positive functions.
"Although it may seem a bit surprising at first," notes Spiegelman, "our research shows clearly that adipose tissue [fat] actually does us a great service -- by storing excess energy in ways that are usually healthy and harmless. Without fat cells, the excess calories we take in would end up in vital organs such as the liver and the kidneys, where they would cause great damage and perhaps even prove fatal over time.
"There's also some very interesting new evidence out there that the PPARgamma 'fat gene' may play a beneficial role in the body's reaction to prostate cancer in men, by 'turning off' the growth of prostate tumors early in the disease. It may sound strange to hear this -- especially in a society where ever-increasing obesity constitutes a major public health threat -- but in terms of its metabolic role as a reservoir of excess energy, fat is actually our friend."
Time To Stop Blaming Fat Cells?
After spending the past two decades on the frontier between genetics and cell physiology, Spiegelman probably knows more about how the human body converts excess calories into flab than anybody else in America.
In recent years, he's also become a staunch fan of the ordinary fat cell -- while frequently pointing out that this hard-working component of the human metabolic system has been getting a bum rap lately, as the so-called "obesity epidemic" increasingly shows up on the nation's front pages and TV screens.
Superbly credentialed (a Phi Beta Kappa degree from William and Mary, a Ph.D. in biochemistry from Princeton and postdoctoral research in cell biology at MIT), the 54-year-old Spiegelman now ranks as an international authority on the physiology of fat production and maintenance in the increasingly chubby Homo sapiens.
Although he's the first to acknowledge the growing health threat from soaring obesity rates in the U.S. -- and to pinpoint the clear-cut links between chronic obesity and such fat-related ailments as diabetes, hypertension and heart disease -- Spiegelman also likes to point out that blaming fat itself for the problems is beside the point.
"Far from being a health culprit, fat cells actually play a very positive role in regulating energy balance in the human metabolism," says the veteran scientist. "What a lot of people don't seem to understand is that the real villain in obesity is the lack of energy balance -- and not merely the adipose tissue on hips or thighs.
"For the most part, our fatty tissue does a good job of storing the extra calories we take in, whenever that balance gets out of whack. If you look at it medically, fat is actually what we call an 'endocrine organ,' and it's vitally connected to every other organ of the body. Fat creates many different hormones, for example, that are essential for regulating all sorts of different activities throughout the body.
"In many ways, fat is our friend. And I think the actual key to losing weight -- as well as keeping it off -- is to simply make sure that the calories you take in while you're eating don't exceed the calories you burn during the rest of the day and night."
Remembering The "Fabulous Dr. Schiavelli"
Ask Bruce Spiegelman how he became one of America's most influential fat gurus, and he'll tell you that he took his first steps on the long road to a Harvard professorship in cell biology while in Williamsburg.
"In many ways, I feel that I got my start as a biochemist at William and Mary in the early 1970s," he says with a nostalgic chuckle, "back when I signed up for the course that all of the biology and chemistry majors dreaded. That course was organic chemistry, and it was certainly very challenging.
"But fortunately for me, the professor turned out to be a gentleman named Mel [Dr. Melvyn D., later Provost] Schiavelli, and he was a fabulous teacher. I don't know what it was, exactly -- but he had a natural talent for teaching, and he really brought the subject alive. Anyway, something clicked for me during that course," recalls Spiegelman. "I think organic chemistry is a very geometric, very logical kind of subject ... and I just found that I could grasp it pretty easily."
Spiegelman believed he was doing fairly well in the course, but then he got a major surprise. "When the day of the final exam rolled around, about 200 of us showed up to take it," he remembers. "But before we even got started, Professor Schiavelli came up to me and said: 'You can leave. You don't have to take the exam.' And I said: 'What do you mean?'
"He said: 'The student with the best [grade] average doesn't have to take the exam. You can leave.' And I was absolutely floored. Until that moment, I'd considered myself to be a decent student, a 'B' student, really. But all at once, thanks to Schiavelli, I thought: 'Maybe I can do this stuff!'
"I think that course really changed my life -- and I wound up becoming a biochemist as a result."
His Advice: Exercise More, Eat Less
After departing William and Mary, Spiegelman went on to become a tenacious cancer researcher whose pioneering work in the genetics of tumor-growth would win him several national awards -- including election to the prestigious National Academy of Sciences in 2002.
He says it was only while working on a series of staggeringly complicated problems related to cell differentiation in tumors that he happened to become interested in the lowly fat cell as an object of study.
"I didn't really decide to go into the world of diabetes and obesity consciously," he says. "What happened was that I was using fat cells as a model, and I kind of got drawn into the study of metabolism and metabolic control. And then that interest really took off, and I began to work very hard at exploring the processes that take place during the differentiation of fat cells."
Since 1991, when he became a full professor at Harvard and the director of a wide-ranging biochemistry research program at its affiliated Dana-Farber Cancer Institute, Spiegelman has focused most of his attention on problems related in one way or another to the physiology of fat-manufacture. He's also taught hundreds of graduate students the intricacies of cell biology at the molecular level.
Says Peter Tontonoz, the UCLA scientist who helped Spiegelman create fat cells in a Petri dish back in 1994: "Bruce is one of those rare people that can visualize the big picture when only a few pieces are in place. Fat cell biology is now one of the hottest areas of medical research, and he's led the field in this area for many years.
"He had the vision to see the biological importance and medical relevance of adipose tissue before most everyone else. His enthusiasm for science is inspiring ... and I've tried to emulate him in building my own research group."
A singles player on several highly ranked William and Mary teams as an undergraduate, Spiegelman is still an avid tennis player. He lives in a leafy Boston-area neighborhood with spouse Susan Loffredo, a Ph.D. in French literature who currently serves as a career counselor at nearby Northeastern University.
And how does the fat expert respond when friends and colleagues ask him for advice on the best way to drop the extra pounds so many of us are lugging around today?
"Well, the first thing I often point out is that we're mighty dependent on cars these days," he says with a light-hearted smile. "And of course, it's also true that food today is highly palatable and readily available. And when you put those two things together, it's kind of inevitable that the energy balance of the population is going to start getting out of whack.
"What we need right now, I think, is a combination of expanded public health initiatives and increased medical research. We also need to do a much better job of getting the word out that we're already paying a high price for our obesity, as a society ... and that it's probably going to get even higher in the years immediately up ahead.
"The key for all of us is to better understand the concept of energy balance -- and to figure out how we can do a better job of exercising our bodies and brains each day, while eating a whole lot less!"
Freelance journalist Tom Nugent, who attended William and Mary for a semester in 1961, is the author of Death at Buffalo Creek and writes often for the Washington Post and Chicago Tribune.
