Albert Lasker
Basic Medical Research Award

Award Presentation by Michael Brown

This year's Lasker Basic Science Award honors two scientists who challenged our notion of free will. Let me explain. The thin among you take pride in your will power. Through rigid self-control you pass up rich deserts and you never touch a French fried potato or a pepperoni pizza. Only the slothful succumb. Today's honorees taught us that you shouldn't be so smug. Your will power alone doesn't protect you from gluttony. It needs help from your leptin.

Let me illustrate. Each of you received a booklet describing today's ceremonies. Please turn to page 15. At the top you see a three year old baby who weighs 92 pounds. Imagine hefting a 92 pound baby around the zoo. The baby is fat because he never stops eating. His body cannot produce a hormone called leptin. His two genetic templates for leptin are both defective. Leptin is a hormone that circulates in the blood and enters the brain where it makes us stop eating. If our bodies lack leptin we are condemned to eat ourselves to death, will power or no.

Now look at the picture on the bottom. This is the same boy at age 7. His parents have injected him daily with leptin. His appetite is tamed and he has joined the ranks of the strong- willed. Not because of his will, but because of his leptin. The lesson is clear. If any of you were deficient in leptin you would weigh 400 pounds. Right now you would be begging for a second helping of desert. So much for free will.

How did we find out about leptin? The story begins in 1950 on the cliffs above the sea in Maine. Here we find the world's largest mouse genetics laboratory — the Jackson laboratory, named for one Roscoe B. Jackson, a defunct executive of the defunct Hudson motor company. Mice are ideal subjects for geneticists. They reproduce every three months. Unlike other mammals, they survive many generations of brother-sister matings. This produces inbred mice that inherit the same genes from both parents. Parents and offspring are all identical twins. In 1950 a Jackson geneticist observed a line of mutant mice that was massively obese. He called them ob, short for obesity. Normal mice weigh 30 grams. Ob mice weigh three times as much because they overeat.

The ob mice were a curiosity until the 1960's when Douglas Coleman, a scientist at Jackson, decided to figure out the defect. Coleman did a bold experiment. He stitched a normal mouse to an ob mouse so that their blood circulations were joined. Remarkably, the ob mouse stopped eating and lost its excessive weight. Coleman made the correct interpretation. The normal mouse has a circulating hormone that prevents overeating. The ob mouse lacks this hormone. When the two mice are joined, the hormone from the normal mouse crosses into the ob mouse and stops the eating.

Coleman also studied another line of obese mice called db that are just as fat as ob mice. However, when the db mouse was stitched to a normal mouse the db mouse did not lose weight. Instead, the normal mouse stopped eating and wasted away. Coleman then performed the crucial experiment. He stitched the ob mouse to the db mouse. The ob mouse lost weight, while the db mouse remained obese. Coleman made the correct deduction. The ob mouse cannot produce the hormone that limits appetite. The db mouse produces the hormone, but it cannot respond to it. The db mouse must have a defect in the receptor that senses the hormone.

In the late 1980's the scene shifts south to the Rockefeller University, another scientific oasis on the seashore. The sea is the East River, and the cliffs are apartment buildings. Here a young physician scientist, Jeff Friedman, decides to bet his career on finding the defective gene in ob mice. A few defective genes had already been found in mice. The technique seems simple: you mate hundreds of ob mice with thin mice, identify the offspring that are obese, and then identify the single ob gene that all of the fat offspring inherit. In reality, the task was extremely complex. For one thing, the ob gene is recessive. Obesity doesn't occur unless the mice inherit the ob gene from both parents. You can't tell which offspring have the gene until you mate the offspring together so that some inherit two copies of the ob gene. Another problem is that ob mice do not reproduce well. Friedman had to transplant ovaries from ob mice into normal mice. The eggs came from the ob mice, but the reproductive capacity came from the recipient females. In these early studies, Friedman was aided by Rudy Leibel, another young physician-scientist at Rockefeller.

It took 8 years to find the ob gene. During these years, Friedman had little to show for his effort. His work was supported by the Howard Hughes Medical Institute. I was on their review panel when Friedman's work came up for periodic renewal. Each year, all Friedman could say was that he was getting closer. Each mating allowed him to creep closer to the gene. HHMI deserves enormous credit for supporting Friedman during this long silent period. I'm not sure it would happen today.

Friedman used every genetic trick in the book, and some that weren't. In 1994 he made a final monumental push, and found the gene. Coleman was right. The ob gene produces a hormone that circulates in blood, enters the brain and commands us to stop eating. Friedman named the hormone leptin from the Greek word leptos which means thin. The huge surprise was where leptin is produced. Our brilliant brains are controlled by a hormone produced in our dumbest cells — the lowly fat cell. Fat tissues are composed of billions of fat cells, each one stuffed with fat and little else. Fat cells were considered to be simple storage tanks. The idea that they could produce a hormone was revolutionary. That this hormone would dictate our behavior literally boggled the mind. Who says Mother Nature doesn't have a sense of humor?

Once leptin was discovered it was straightforward to prove that Coleman's other deduction was correct. Friedman and others soon identified the receptor for leptin, and sure enough, the db mice have a defect in that receptor. Friedman also found that leptin receptors are clustered in a tiny region of the brain called the hypothalamus. There, leptin triggers a chain reaction among a network of cells that secrete messengers called neuropeptides. Like musicians in an orchestra, the neuropeptide symphony harmonizes our food intake and our metabolism. Leptin is the orchestra conductor.

Leptin behaves like the fuel gauge in our cars. When our gas tanks are empty the gauge swings to the left and this changes our behavior — we fill up the tank. When the gauge moves to the right we turn off the pump. Likewise, when our fat cell tanks are depleted, our leptin falls, and this changes our behavior — we eat. When our fat cells are filled, leptin rises, it binds to its receptor in the brain, the neuropeptide symphony begins, and we stop eating.

There is still a burning question. Genetic leptin deficiency is rare. If most of us produce leptin, why are so many so fat? The answer was a huge disappointment to Friedman, and to people like me who were hoping for a crutch to support their self-control. When people force-feed themselves, their fat cells expand, and their leptin rises. Their brains adapt to the high leptins, which the orchestra now considers normal. When fat people stop eating, their leptin falls, and they become hungry even though they still have lots of fat on board. Injecting them with extra leptin does no good. They still need to fill up their fat cells. Obese people are like a car with an extra gas tank. When the level falls in one tank, the fuel gauge falls. This causes us to fill up the tank even though there is plenty of fuel in the other tank. Leptin does leave some room for will power. We can try to resist the hunger call of our falling leptin. It's just that the falling leptin makes it so much harder. No wonder so many find it so tough to lose weight.

The leptin discovery tells us that will power alone cannot prevent addiction to food. We need leptin to help fight that addiction. Is there a different leptin that helps us to fight alcohol addiction? Narcotic addiction? Nicotine addiction? Sex addiction? Are some of us deficient in these other leptins? Do some people find it impossible to fight these addictions, just as the leptin deficient child cannot fight his food addiction? Coleman and Friedman's discovery of leptin took the smugness out of our belief in free will. I suspect that new leptins will soon challenge our smugness even more.

For the discovery of leptin, a milestone in behavioral neuroscience, the Lasker Foundation presents the 2010 Lasker Basic Science Award to Douglas Coleman and Jeffrey Friedman.