News: April 2015

Innovator Profile: Innovation's Building Blocks

A profile of Charles Serhan, PhD, DSc, a mastermind behind the inflammation pro-resolving therapies known as resolvins and the specialized pro-resolving mediators (SPM).

Charles Serhan, PhD, DSc, a mastermind behind the inflammation pro-resolving therapies known as resolvins and the specialized pro-resolving mediators (SPM), is no stranger to the celebrity side of science. Coming of age in the laboratories of Nobel laureates, Lasker recipients, and the most prominent names in modern immunology, Charles Serhan has watched innovation unfold in real time – and he's learned a few things about its origins. “The pomp, the reward, is fantastic. But that's not what innovation is about,” says Prof. Serhan, Director of the Center for Experimental Therapeutics and Reperfusion Injury at Brigham and Women's Hospital; The Simon Gelman Professor of Anaesthesia at Harvard Medical School; and a professor of oral medicine, infection and immunity at the Harvard School of Dental Medicine. “It's about the importance of history; the intellectual origins. Many people don't realize it, but scientific innovation is about understanding where we've been and where the mistakes have been made. That's critical,” he says. “Then, backing up and finding the right path.” As a postdoctoral fellow in the laboratory of Nobel Laureate Bengt Samuelsson in the 1980s, Serhan helped discover a new family of lipid mediators with a mysterious role in inflammation. The group named them lipoxins. More than a decade later, Serhan's laboratory at the Brigham characterized lipoxins as cellular signals that actively turn off the body's inflammatory response. Unlike existing drugs that block the inflammatory response and may eventually trigger chronic inflammatory diseases, Serhan's team revealed in the 1990s that low-dose aspirin enhances the body's own mechanisms for curbing inflammation by prolonging the action of mediators like the lipoxins. “It's the first time I can think of where a drug was triggering an endogenous pathway and twisting the products in these pathways so that they were longer-acting,” Serhan says. His team ran with the idea. “We've worked out the biology of these structures, which are pretty cool on their own, and now we're building designer molecules that are more druggable, longer lasting, and can do the job better.” Together with BWH researchers Drs. Bruce Levy, Nan Chiang, Matthew Spite and Jesmond Dalli, Serhan has created synthetic analogs of lipoxin and eight other inflammation-resolving mediators, including the molecular families they named the resolvins, protectins, and maresins. They ultimately hope to target diseases such as ocular inflammation, periodontal disease, asthma, and Alzheimer's disease. The group has so far created several patent portfolios, some of which are already licensed to drug companies to pursue applications ranging from medicated stents that deliver pro-resolving molecules to therapies that can regulate inflammation and pain after cataract surgery. Other new patents are seeking partners for licensing and development. “Since the concept of pro-resolving mediators was truly revolutionary, there were challenges getting industry uptake. Now that drugs based on Dr. Serhan's work are reaching the clinic, we expect a transformation in inflammatory disease markets as far ranging as dry eye, periodontitis, irritable bowel disease, or even cystic fibrosis,” says Jonathan Behr, PhD, Partners Innovation Market Sector Leader. Recent findings suggest an even more powerful prospect: certain pro-resolvins may stimulate tissue regeneration, opening the door to myriad possibilities for therapeutic development. “We're showing that as you actively close an acute inflammatory response and get some resolution, that resolution then signals the next steps: tissue regeneration,” says Serhan. Serhan and Dalli are systematically isolating and solving the molecular structures of additional pro-resolving mediators, creating templates for designer drug development. “We want to be able to help a knee injury repair, for example, go twice as fast,” Serhan says. “We can do that now with worms, believe it or not. We have pro-resolvin peptidio-conjugates that stimulate tissue regeneration in a model. If you cut a worm in half, they'll grow back a head or a tail in about 6 to 7 days that can be shortened with these new molecules.” Though Serhan's recent successes have been lauded as pioneering and innovative, he's careful to note the timeless nature of his work. “Our innovation stems from a classic approach – we defined molecules in the body that are biologically active and built structures around them to improve them and use them as drugs,” he says. “What's old is new sometimes.”