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Focusing on the Long Term: A Profile of Dale Boger

By Mark Schrope

In 1992, there was a single jagged peak on an instrument readout that would dramatically shape decades of research for Dale Boger and his colleagues at The Scripps Research Institute. Studies of the compound represented, which is critical in controlling the mysterious realm of sleep, would lead to potential new treatments not only for sleep disorders, but also for pain relief.

More importantly, the research would help reveal an untapped class of enzymes that, while still largely unexplored, offers potential routes to treatments aimed at just about all known afflictions. In December, Boger and Ben Cravatt, a Scripps Research chemical biologist, launched a new company to commercialize the drugs they create at Scripps Research to manipulate these enzymes.

Such efforts are just one facet of an overall program aimed at studying and exploiting the chemistry of compounds with substantial medical potential. Boger’s team has long distinguished itself as capable of building some of the most complex molecules ever synthesized in the laboratory, and then going on to make tactical chemical improvements that may well save lives in the long run.

Boger, who grew up in Kansas, was always fond of chemistry, in no small part because it came easily to him. His first memory of getting truly excited about the field was as an undergraduate at the University of Kansas, during a lecture about a vitamin critical to the proper functioning of a certain enzyme. “Not only could I understand the lecture, but I found it fascinating how chemistry influenced the process and how chemical principles could be used to understand events in biology,” he says, “and that’s what I always wanted to do.”

As his academic training progressed, eventually taking him to Harvard for graduate school, he discovered a great love for building molecules. “There was a feeling of accomplishment associated with that that I just loved.”

Sweet Dreams

Decades later, he’s still at it, and still doing much to achieve that sense of accomplishment. The critical peak back in 1992 was an electronic rendering of a compound called oleamide. Steve Hendrikson, then a neuroscientist at Scripps Research, had been working with cats to identify compounds that help to control the poorly understood process of sleep. “That’s how it all started,” says Boger, who had moved to Scripps Research in 1990.

Hendrikson detected the peak and it was Cravatt who isolated the chemical it represented. Boger and Cravatt would later go on to identify the compound and decipher its chemical structure. Years of collaborative research followed with Richard Lerner, who is Lita Annenberg Hazen Professor of Immunochemistry and Scripps Research’s former president, and Cravatt, who is now chair of the Scripps Research Department of Chemical Physiology but at that time was just starting out as a graduate student at Scripps Research.

This work led to the discovery that oleamide builds up in cerebrospinal fluid not only in cats, but also in humans as they grow tired. The more oleamide that accumulates, the sleepier you get. When you do sleep, the oleamide breaks down and the cycle begins again.

Boger and his colleagues wondered if there might be a way to control oleamide levels as a sleep aid. His lab began working to figure out oleamide’s structure, and in parallel the researchers were studying just what controlled oleamide breakdown.

The answer was an enzyme originally called oleamide hydrolase but now known as fatty acid amide hydrolase (FAAH). Beyond offering an interesting glimpse into the chemistry of sleep, the discovery also offered great medical potential—much more than the researchers could have realized at the time.

Gaining Control

If FAAH’s activity could be at least partially blocked, Boger and his colleagues reasoned, then this would prevent oleamide breakdown, raising levels and helping to induce sleep. This led to a long quest for compounds that would have just such an effect.

Interestingly, as this work was proceeding, another group was studying something similar to the oleamide cycle in how we feel pain. After an injury, the body releases anandamide, a natural pain killer. In time, the body breaks anandamide down and researchers were looking to slow that process to kill pain.

A team at the State University of New York in Stony Brook found an enzyme they called anandamide hydrolase controlling the process. But, as the teams published their work, it became clear that the two enzymes were in fact the same one. FAAH controls both chemical cycles. This meant that all of Boger and his colleagues’ work could potentially apply to pain management as well as sleep control.

“For the first several years, up to about 2002, most people thought this work was kind of flaky,” says Boger, “It wasn’t clear whether the approach would work or not. It took a long time to assemble all the knowledge we have today in order to make ourselves feel comfortable with the idea.”

Ultimately, Boger and others at Scripps Research would identify and produce a range of FAAH inhibitors that continue to show great promise in regulating pain and sleep, and that Boger and Cravatt’s new company, Abide, will be pushing toward clinical trials.

By controlling natural cycles, these potential drugs offer major benefits over currently available treatments.  Most sleep aids, for instance, are central nervous system (CNS) depressants that essentially knock a patient out. “You lose all the benefits of what is called physiological sleep,” says Boger, such as the way a day’s memories are processed. And a knocked out patient loses other benefits, such as being able to wake in response to something like a loud noise. Oleamide manipulation simply leads to normal sleep.

Controlling pain and sleep alone are exciting applications of Boger’s career efforts, he says, but those are really just the earliest applications of a much larger discovery. Work at Scripps Research, combined with a growing understanding of the human proteome—the vast array of proteins encoded in DNA—has revealed that FAAH is one of a huge class of more than 250 enzymes known as serine hydrolases.

Only a handful of these have been the focus of any targeted drug discovery efforts, and for more than half of these enzymes, researchers don’t even know what they do. Among those at least partially understood are enzymes tied to everything from cancer progression to metabolic diseases. “There’s probably a serine hydrolase involved in almost every sort of physiological process,” says Boger, “It’s more or less an untapped class.”

And with the techniques developed by Boger, Cravatt, and others, tapping that class has become a much more realistic goal. While it took 15 years to find suitable FAAH inhibitors, scientists can now accomplish the same goals with other enzymes in a tenth of that time. “We’re still not finished with all that’s there,” says Boger. “There are still things to learn.”

Antibiotic Feats

Boger has found ways to produce countless potential cancer and other kinds of drugs in the laboratory, but another major component of Boger’s work that has spanned multiple decades is research tied to the antibiotic vancomycin. First discovered in 1956, this successful drug is still widely used to treat patients on dialysis and those allergic to certain other antibiotics. But its most important application is in zapping resistant strains of Staph bacteria including MRSA (methicillin-resistant Staphylococcus aureus).

Researchers hadn’t even identified vancomycin’s full chemical structure until 1982. “Isn’t that amazing,” says Boger, who’s career was just getting started then. “I looked at that molecule and said, ‘That’s exactly the sort of project I’d like to work on.’” 

Boger became one of the first to ever synthesize the compound in the lab—in 1999, a chemical feat akin to building the Empire State Building. His team went on to synthesize several other compounds in the same group and to develop slightly altered forms of vancomycin, or analogs, in a quest to create versions with significant benefits over the original.

As with much of his research, a key aspect of this work was to study the structure systematically to learn how each of its chemical components and branches functions, information that can be invaluable when looking for alterations that might bring about enhancements.

With even the most popular antibiotics such as penicillin, some bacteria developed resistance within a couple of years of initial clinical use. But one of the key reasons Boger has remained intrigued with vancomycin is that it took decades before resistant strains emerged.

That longevity comes from how the drug kills bacteria. Vancomycin binds to components that bacteria use to build their cell walls, preventing the interlinking that provides stability. Without stable cell walls, bacterial cells can’t survive. It’s a complex process that bacteria can’t circumvent with a single advantageous mutation as they can with many antibiotics.

Outsmarting Bacteria

When bacteria resistant to vancomycin did finally emerge recently, they pulled this off only through a process known as gene transfer. A few harmful bacterial strains were able to incorporate genes from the bacterium that actually produces vancomycin with a built-in defense against it.

Remarkably, Boger’s team has been able to overcome the resistance by replacing a single atom on vancomycin. “It’s unbelievable,” says Boger. “You almost never have a problem where the answer is so crystal clear.”

That one oxygen atom may well mean the difference between life and death for countless future patients. But while changing a single atom may sound simple, creating the altered version actually took about four years. “There is a great feeling of accomplishment when you invest that much time and effort in something then have it work so well,” says Boger.

His team is working now to incorporate alterations discovered by other research teams that may allow them to make a new drug that’s even more potent. Besides adding such a turbocharge, they’re also working modifications that, while not needed for lab tests, would most likely be required for the drug to work in the human body. Then they’ll develop a way to produce the new compound economically. “Now that we’ve overcome that resistance. I think this is an antibiotic that may have a rich and long life still ahead of it,” says Boger.

And if past history is any indicator, Boger has the scientific fidelity to finish this and his other skyscraper tasks, however long they take.

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Professor Dale Boger’s research is aimed at studying and exploiting the chemistry of compounds with substantial medical potential.