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Ben Cravatt

In Search of New Treatments for Chronic Pain, Nervous System Disorders, and Other Pressing 21st Century Diseases

Scripps Research Professor Ben Cravatt, who serves as Chair of the Department of Chemical Physiology and a member of the Dorris Neuroscience Center, has made an impressive number of key scientific advances with the goal of identifying novel therapeutic targets for the treatment of human disease.

To achieve this goal, Ben develops and applies new technologies that bridge the fields of chemistry and biology, ascribing to the philosophy that the most significant biomedical problems require creative multidisciplinary approaches for their solution.

Researchers only have a good handle on the functioning of 30 to 40 percent of the human proteome, or the proteins we produce.  The rest remains largely uncharacterized, and solving this problem has been a focus of Ben’s.  He and his team focus especially on enzymes, which facilitate every chemical reaction in the body, with results that have significantly advanced understanding of basic biology, and uncovered a massive array of targets for drug discovery, across many diseases.

Ben has built a long-standing and successful collaboration with the pharmaceutical company Pfizer to develop potent and selective inhibitors for the fatty acid amide hydrolase (FAAH) enzyme as a possible chronic pain treatment.  Ben’s preclinical studies have shown that genetic or pharmacological blockade of FAAH produces a range of beneficial effects, including the reduction of pain, inflammation, depression, and anxiety.  Several  of these inhibitors have gone into human clinical trials.

“Uniting the basic research expertise of Scripps Research with the drug development process of a company like Pfizer has made for an extremely potent combination that promises to accelerate the generation of new therapeutics for the most pressing 21st century diseases,” said Ben.

Much of Ben’s work was initially made possible through the funding of philanthropists Sam and Aline Skaggs, who have a deep interest in drugs for treating pain.

“Without the support of the Skaggs family at the formative stages of our research, the path to FAAH discovery and drug development would not have been possible,” said Ben.  “They pushed it forward.”

Proteomics offers the possibility of identifying proteins associated with specific diseases.  These proteins can potentially be used as markers for detection or prevention, or as targets for the design of new drugs.  For example, Ben and his colleagues have looked at dozens of samples of human tumors from breast cancer patients, and have successfully analyzed them with proteomics.  The scientists were able to detect human proteins that may be associated with breast cancer – including some never before associated with the disease.

“We have found some known and novel markers of breast cancer pathogenesis,” said Ben.  “This method could potentially be applied to other human diseases to discover new markers currently evading detection by other methods.”

“Understanding the proteome, the structure and function of each protein and the complexities of protein-protein interactions will be critical for developing the most effective diagnostic techniques at early stages to stop disease in its tracks, and treat disease in the future,” said Ben.  “Proteomics is fundamental to translating genetic information into knowledge that will allow us to predict and manage diseases such as cancer, diabetes, and neurodegenerative disorders.”

In a recent project, Ben and his colleagues identified a class of compounds that could be a boon to basic research and drug discovery by powerfully and selectively blocking the activity of a large and diverse group of enzymes known as “serine hydrolases.”  Previously discovered serine hydrolase-blocking compounds have turned into drugs to treat obesity, diabetes, and Alzheimer’s disease, and are currently in testing as treatments for pain, anxiety, and depression.

“There are more than 200 serine hydrolases in human cells, but for most we’ve lacked chemical inhibitors of their activity, so we’ve had only a limited ability to study them in the lab or to block them to treat medical conditions,” said Ben.  This new research allows us to grandly expand our list of these inhibitors.”

In another research project with MIT, Ben and his colleagues discovered an extremely potent class of potential anti-cancer and anti-neurodegenerative disorder compounds through a National Institutes of Health-sponsored program to find potential medicines and other biologically useful molecules.  Ben hopes the findings will one day lead to new therapies for cancer and Alzheimer’s disease patients.

Last year, Ben and his colleagues discovered an enzyme that normally helps break down stored fats goes into overdrive in some cancer cells, making them more malignant.  The enzyme, called monoacylglycerol lipase (MAGL), may provide a target for treating more malignant forms of cancer or for preventing cancer progression.

Ben’s lab is a young and energetic place, and wears its enthusiasm on its sleeve.  Asked what distinguishes his lab from most, Ben said, “We’re fairly technically fearless.  Our people run the gamut in a variety of integrated disciplines.  We all learn a lot from each other because we’re doing so many different things to solve extremely complex problems.  It was this level of scientific diversity that brought me to Scripps Research in the first place.”

Much of the versatility in Ben’s research has come as a result of attending Scripps Research’s graduate program.  A native of Los Angeles, Ben came to Scripps Research in the early 1990s after completing his undergraduate degree at Stanford University.

“That’s one of the few decisions in my life that I have absolutely no regrets about,” said Ben.  “At that point, there was no other place that was promoting a chemistry-biology interface.  Scripps Research was practicing something that was totally unique at that time.  When I visited for the first time, I was struck by two things.  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 the most energetic and creative I’d met.  We all had the feeling Scripps Research was a special place.

Ben’s class – 1996 – was one of the first to graduate from the Institute, and he immediately joined the faculty.  A biologist by training, he was always attracted to the chemistry lab.  As an undergraduate, he was lucky enough to find a friendly chemistry professor, who invited him to work in the lab, and who didn’t care whether he had any formal training or not.  He found the same kind of freedom at Scripps Research.

“Scripps Research is very collaborative and interactive – it allows you to do great research,” said Ben.  “Science is first here – it is different than at a standard university.  Here, there are minimal administrative burdens – you can do science that advances human health 24 hours a day.”

Ben has now come full circle and finds himself training tomorrow’s scientists.  “I like to watch young scientists build their careers,” said Ben.  “Many of the scientists who have worked in our lab have gone on to other top-notch institutions, such as Harvard, the University of California at Berkeley, and University of Michigan.  As they leave, new talent comes in.  Our lab is always fresh and dynamic, and never stale”

Ben’s impressive array of awards includes a Pfizer Fellowship for Creativity in Chemistry and Chemical Biology, a Technology Review Top 100 Young Innovators Award for research that will shape how we live and work in the future, a EUREKA Award from the National Institutes of Health for exceptionally innovative research projects, and an American Chemistry Society Eli Lilly Award in Biological Chemistry for work of unusual merit, independence of thought, and originality by a young scientist.

“The thing I love about science is that there are very few professions where you can do something new every day, and have the ability to make potential groundbreaking discoveries that have such an impact on devastating diseases” said Ben.  “I love what I’m doing.  This isn’t labor for me.  Scientific research is fun.”

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“Scripps Research is very collaborative and interactive – it allows you to do great research,” says Ben Cravatt, chair of the Department of Chemical Physiology.