Jeffrey M. Friedman was born in Orlando, Florida, United States, in 1954, but was brought up in the suburbs of New York City. His father was a radiologist and his mother a teacher. He finished polytechnic studies in 1971 and went on to complete an MD at Union University in 1977.
During his medical studies he got his first taste of research, and soon took up a recommendation from one of his teachers to enter the basic research lab at The Rockefeller University, where he started out studying the effects of endorphins on the development of narcotic addiction under Dr. Mary-Jane Kreek. After receiving his PhD in 1986, he stayed on at Rockefeller in a professorial post, while continuing his investigation into the nature of the ob/ob gene present in obese mice. This research project culminated in 1994 with his discovery and characterization of the leptin hormone.
In the late 1970s, Jeffrey Friedman had just completed a doctorate in medicine. He had a year free before starting his specialist training in gastroenterology, and one of his professors suggested he try his hand at research. Friedman joined an expert group studying the chemistry of addiction. And he soon found himself so “entirely captivated” by the idea that a few loose molecules could govern human conduct and emotions that he is still researching in the same field: this time on the biological control of an impulse as basic yet complex as the drive to eat. His discovery of the leptin hormone, which regulates appetite, and the work of Douglas Coleman, the chemist who predicted its existence, have now been distinguished with the BBVA Foundation Frontiers of Knowledge Award in Biomedicine.
The discovery of leptin is a major breakthrough at a time when obesity is increasingly rife throughout the developed world. Not only that, it is a problem with no clear solution, since weight-loss regimes are ineffective in the medium and long run for the majority of dieters. Coleman and Friedman’s findings, in the view of the jury, have not only opened up a new era of research into the biological roots of obesity, but have also brought about a paradigm shift in social attitudes by showing that obesity is not due to “inappropriate behavior, but is the consequence of imbalance in a hormone-driven process.”
“Overweight people don’t lack the willpower to get thin, their genes are actually altered,” says Friedman; “the cause of obesity is not gluttony, it’s genetics.” The corollary is evident enough: “We must stop stigmatizing the obese. In their efforts to lose weight they are fighting against their biology. But they also are fighting against a society that wrongly believes that obesity is a personal failing.” In other words, a change of approach that comes with medical consequences but also a large dose of hope. “By accepting the biological foundations of obesity we can start concentrating on health instead of weight,” the new laureate continues, and improving health calls for “moderate weight loss only.” From this new perspective, “victory” becomes more attainable.
Obesity research began with a mouse born in the Jackson Laboratory, Maine (United States), in 1949. Three times fatter than normal, the animal ate voraciously and developed diabetes, to the puzzlement of researchers. It soon became plain, from classic genetic crosses, that the cause lay in a single gene. But the techniques of the time were too limited to find it, which left the team laboring along with no real progress.
In 1965, Coleman (Ontario, Canada; 1931) arrived at the Jackson Laboratory – where he is now emeritus professor – for what he thought would be a short stay and with no fixed research objective. He was assigned to work on a second strain of obese mice, running comparative studies with the first. After a series of ingenious experiments connecting up the circulatory systems of obese and normal mouse pairs, he concluded that there must be a circulating satiety factor in the blood with the power to suppress appetite. And he also discovered that this hormone acted on the brain.
Despite the conclusiveness of these findings, many of Coleman’s colleagues, he recalls now, “maintained the dogma that obesity is entirely behavioral, not physiological.” Others, however, embarked on a search for the elusive hormone, and “the hunt became a race,” in which Coleman too was an eager participant.
But the race turned out to be long-distance. The next chapter had to wait until 1986, when Friedman set up his own lab at Rockefeller University, New York – where he is now full professor – and resolved to seek out the satiety factor gene. Nowadays it would take him just a few weeks, but the era of genomics was still a distant dream. “Back then we didn’t have the technology to isolate genes,” Friedman explains, “so I knew it was going to be a hard task, and decided to call Coleman to get more background.”
Coleman remembers that call, and also the satisfaction he felt eight years later, when his hypothesis was borne out. Because in 1994 Friedman reached the finish line. He describes some of his feelings during what was a very intense period: “Each phone call I got, my first thought was that someone had beaten me to it.” And when the breakthrough came: “It was absolutely exhilarating. I couldn’t sleep at night for months just thinking about how unbelievably elegant and beautiful nature’s solution to the calorie-counting problem is.”
Leptin – from the Greek leptos, thin – operates just as Coleman predicted. It is a hormone produced by fat cells that circulates in the bloodstream and acts on appetite control centers in the brain. The more fat you have, the more leptin your body makes and the less hungry you feel, which stops obese people from gaining more weight. And vice versa. If you lose body fat, you produce less leptin and your appetite increases. This important mechanism, as Friedman explains, has an evolutionary purpose: “It would be very dangerous to have no fat, because you would risk dying of starvation, but it would also be dangerous to be too fat, because you would be at the mercy of predators. So the system tries to maintain an optimal level.”
The robustness and precision of the system, capable under normal circumstances of keeping body weight stable over decades, is a source of wonderment to Friedman and Coleman, but it is also what makes dieting so hard. “The feeling of hunger that the obese must resist after they have lost a significant amount of weight is probably no less powerful than the drive to drink when one is thirsty,” Friedman has written. Studies show that the psychological and physiological profile of an obese person following a strict diet is comparable to that of someone suffering starvation.
We now know that leptin is not the only gene associated with obesity, but its identification is a first step towards a better understanding of the factors controlling appetite and, both laureates concur, towards the development of future drug therapies.
