Two Generations of TSRI Graduates

By Jason Socrates Bardi

When Assistant Professor Ben Cravatt places the hood over the head of Matthew Patricelli and hands Patricelli his diploma at this year’s graduation ceremony, three milestones will be passed.

For Patricelli, the ceremony is the culmination of the work he started nearly five years ago when he came to The Scripps Research Institute (TSRI) from McGill University.

For Cravatt, this moment will be a special one because Patricelli is his first student.

And for the institute, the event is a first as well, because Cravatt is the first alumnus of TSRI’s graduate program to guide another student to completion of the program.

Cravatt came to TSRI in the early 1990s after completing his undergraduate degree at Stanford University. When Patricelli came to TSRI in 1996, Cravatt was finishing his Ph.D. under the guidance of Professor Dale Boger, Vice President for Academic Affairs and Dean of Graduate Studies Norton Gilula, and President Richard Lerner. Patricelli’s research arose out of the last phase of Cravatt’s dissertation.

“As a graduate student, I was working on identifying proteins associated with the fatty acid amide oleamide,” says Cravatt. Oleamide is a neurologically active molecule that appears in the cerebrospinal fluid of tired mammals.

The last part of Cravatt’s thesis was characterizing how oleamide works. "But that was hard work without genes," says Cravatt. "I wanted to find enzymes associated with oleamide and get their associated genes and manipulate the system that way. That’s how we got fatty acid amide hydrolase (FAAH)."

FAAH is a 587-amino acid membrane-bound enzyme that breaks down small molecules like oleamide. It belongs to a large group of serine hydrolases, a class of enzymes containing active site serine residues that catalyze the hydrolysis of specific substrate molecules. These enzymes arose very early in evolution and are ubiquitous in nature—found even in the earliest single-celled organisms.

When Patricelli started working with Cravatt, he was simply characterizing FAAH as a small project, but the study quickly turned into full-fledged thesis research.

"When I started working on the project, Ben was still a grad student but just for a few months," says Patricelli. "I got here in August, he defended in October, and then we started the lab in January [1997]."

Significantly, Patricelli found that FAAH has an unusual mechanism. Almost all mammalian serine hydrolases cleave their substrates through a reaction involving a Ser– His–Asp active site catalytic triad, but FAAH uses a Lys–Ser catalytic dyad.

Patricelli’s dissertation, titled Biochemical and Physiological Investigations of Fatty Acid Amide Hydrolase, incorporates everything from his early expression and purification of FAAH to its mutagenesis and the results of comparative kinetic and in vivo studies.

"He reminds me of myself in many ways," says Cravatt. "He’s very excited about science, and he likes to think of the intricacies of what he’s doing and develop hypotheses, but at the same time he’s not so attached to his hypotheses that if his data tell him otherwise, he isn't willing to dump the original hypotheses and start anew."

"I'm definitely very proud of him and will miss him greatly," he adds.



Assistant Professor Ben Cravatt helps his student, Matthew Patricelli, with his robe.