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couple decades ago, that might have seemed like an obscure choice, but by the late 1990s, the young biochemist was out ahead of his peers when it came to understanding, and appreciating, the power of lipids.

For years, lipids were treated like the Rodney Dangerfield of compounds. Nobody thought that much about them, or gave them much respect when they did; one article described lipids as playing "a relatively conservative role in cell activity." Despite their diversity -- and ubiquity -- lipids were thought of as vessels to store metabolic fuel -- in other words, little molecular satchels of fat.

Then, in the 1990s, new studies emerged showing that certain lipids were actually important biological regulators and mediators, acting in virtually all biological processes including immune response, transmission of neuronal information and inflammation, among others. As a family of critical chemical messengers, these lipids helped deliver signals into the cell that affected a number of vital physiological functions. For Cravatt, an assistant professor and Searle Scholar at The Skaggs Institute for Chemical Biology and the Department of Cell Biology at TSRI, the fatty acid amides were the most interesting and the most mysterious.

"Fatty acid amides are found in neural tissue and fluids, but no one knows exactly where they come from or how they're made," Cravatt says. "They possess a remarkable and potent pharmacology -- they can induce sleep, change body temperature, spur angiogenesis, even reduce sensitivity to pain."

While the scientific community seemed to know what fatty acid amides could do in vitro, Cravatt wanted to understand their function in vivo -- inside the body -- where it was clear they were capable of doing astounding things. This was all part of Cravatt's basic scientific oeuvre -- trying to understand complex physiology and behavior at the chemical and molecular level. Small molecules, as Cravatt describes them, are central to the cross talk between different physiologic processes like sleep, providing a kind of molecular phone system for intersystem communication. But many of these molecular messages remain unknown, and even when their molecular origins are known, how they function is still mostly a mystery.

While there were a number of fatty acid amides, Cravatt has focused much of his research on oleamide, which he first identified in 1995. Oleamide has been shown to accumulate in the cerebrospinal fluid of tired animals and may be the molecular indicator of an animal's need for rest. Indeed, rats injected with oleamide do fall asleep.

OLEAMIDE IN ITS NATURAL HABITAT

Cravatt, who describes his research with the confident enthusiasm of an expert climber about to tackle a really great mountain, draws a distinction between what he and the members of his lab are doing with oleamide, and the work of pharmacologists -- people who study the effects of drug compounds. Traditional pharmacology can tell you, for instance, what oleamide does because of its chemical properties, but not what the normal levels regulate (or do not regulate) in the body. Cravatt wants to study oleamide in its natural habitat.

"Our goal is to find enzymes that modulate compounds like fatty acid amides, so we can find out what happens when you terminate their ability to break down in vivo," he says. "We were the first laboratory to discover that there was a molecular breakdown mechanism common to all fatty acid amides -- fatty acid amide hydrolase (FAAH)."

FAAH degrades these amides' signaling ability, turning them back into fatty acids, those little satchels of fat. Without FAAH, the amides might simply go on signaling. In the case of oleamide, that signaling might keep you asleep -- forever. Without gatekeepers like FAAH, things would start to fall apart in a big hurry.

"A good example is acetylcholinesterase, the catalyst for terminating cholingeric nerve impulses," Cravatt says. "If you inhibit the action of acetylcholinesterase, the system doesn't stop firing and you die of respiratory paralysis. The system would overload. It's a natural process, the signals have their time and then the body rids itself of the signal."

For Cravatt, the discovery of the inhibiting qualities of FAAH raised a whole set of complex questions. How exactly does FAAH inhibit oleamide in the body? At what endogenous levels does it kick in? If the endogenous levels of oleamide are sufficient to induce sleep, and you inhibit FAAH, how long will the effect last? Will the endogenous levels keep rising? What would happen to an organism if you did that?

WHILE THE QUESTIONS ARE COMPLEX, THE ANSWERS REVOLVE AROUND A SINGULAR POINT

"Once you know the body's system," Cravatt says, "you can tinker with ways that will make the process more efficient. For example, with mood altering drugs like Prozac, you don't necessarily overload the body with exogenous serotonin, you inhibit the compound's uptake, so there is more of the endogenous compound present in the system."

So, if you had an organism with no natural FAAH, one with no protection against the eternal signaling capabilities of fatty acid amides like oleamide, you might actually be able to answer the questions once and for all.

Cravatt's lab has developed a breed of genetically altered mice that produce no FAAH of their own, about a dozen of them so far. With the mutant mice on board, Cravatt can begin testing to see if they sleep longer or are less sensitive to pain in response to changing amide levels. It's slightly reminiscent of Flowers For Algernon, the story of a mouse (and later a man) made smarter by molecular manipulation.

"I wouldn't call our mice science fiction," Cravatt says. "The scientific community has already generated genetically altered mice that are impervious to pain. They feed them chili peppers, the hottest kind around, and the mice don't feel a thing. Our challenge right now is to manipulate the endogenous system to test the relationship between oleamide and sleep systems, and then validate that FAAH is involved in controlling oleamide's action."

On the behavioral level, Cravatt will test the mice to see whether they sleep more or have less sensitivity to mild increases in pain. On the molecular level, Cravatt's lab will be the first to actually manipulate the entire fatty acid amide communications system. A third task will be to map the chemical structure of FAAH, which belongs to a huge group of enzymes found in everything from flies to yeast, but for which there is still no workable blueprint. His research philosophy is not to try to define the questions based on the techniques he has available to him in the laboratory but vice versa.

"I have no prejudice against or for fatty acid amides," Cravatt says. "We start with a complicated question first, and then go looking for the molecules responsible. This is an entirely new field, but one with a strong foundation of pharmacology to support it. As a scientist, you want to gather the most rigorous evidence possible. By their very existence, our mice will end up validating years of pharmacology research in some areas, and destroying years of research in others. On balance, they represent a huge step forward."

What distinguishes Cravatt's studies from most labs, he says, is that the people in it run the gamut from synthetic chemistry to mammalian genetics: "We'll have one person studying mouse behavior, another person doing synthetic chemistry. We all learn a lot from each other because we're all doing so many different things." It was this high level of scientific diversity that brought him to The Scripps Research Institute in the first place. A Los Angeles native,

"When I visited Scripps for the first time, I was struck by two things," Cravatt says. "It had the most integrated chemistry and biology program I'd seen by far, and those students who would be my future classmates were the brightest and most creative I'd met. Most of the people who visited the Institute with me ended up attending. We all had the feeling it was a special place."

SOMETHING NEW EVERYDAY

Cravatt admits to spending most of his time with his colleagues in the lab. It's a young and energetic place, and wears its enthusiasm on its sleeve. On the Cravatt lab Web site are pictures from some of their more memorable outings -- the famous Los Angeles sushi bar with the dancing sushi chefs where he goes on special occasions. And the white-water rafting expedition, a side trip while attending the Oregon wedding of one of his graduate students.

When not in the lab, Cravatt spends some of his off hours running. But probably not that many. "The thing I love about science is that there are very few professions where you can do something new everyday," Cravatt says. "I love what I'm doing, I love doing experiments, I love working at the bench. This isn't labor for me. Work is fun. I fight the clock everyday just to keep doing it."