Charles River symposium highlights the diversity of ideas in ion channel drug discovery

About seven years ago, Harvard neurobiologist Bruce Bean and his former colleague, Rod MacKinnon, developed extreme forearm cramps during a kayaking trip on the Atlantic. Thinking the depleted electrolytes might have triggered the problem, the duo made sure to stock up on Gatorade before their next outing, but the energy drink didn’t help. In fact, the suffering was worse.

Thus began a research project that serendipitously pulled together their common research interests in ion channels to solve a problem common among athletes, even not-so-elite ones. The two developed a beverage made from cinnamon, ginger and chili pepper extracts that can be taken right before or during a workout to relieve cramping. The beverage works by activating certain transient receptor potential (TRP) channels that mediate a variety of sensations, including pain. They have also started a biotech company—Flex Pharma—that develops innovative and proprietary treatments for exercise-induced muscle cramps and nocturnal leg cramps.

Bean, who oversees a lab focused on the biophysics of sodium, calcium and potassium ion signaling in relation to pain processing, related details of this unique adventure during a symposia last week, Ion Channels in Drug Discovery, held at the Norton Wood’s Conference Center in Cambridge, MA. Bean was the keynoter who kicked off the event and focused mostly on pain research. The nine other speakers covered a range of other topics that foretell a potentially bright future for ion channel inhibitors, particularly in the field of cancer and cystic fibrosis.

In CF, for instance, researchers are using organoid cultures—mini organs with a stable genotype and phenotype—from rectal biopsies that express the dysfunction of the gene for the ion channel cystic fibrosis transmembrane conductor receptor or CFTR that gives rise to this fatal disease. Other talks focused on targeting potassium channels in cancer drug development and the emergence of cardio-oncology in safety assessment.

The muscle cramping research was an “unexpected illustration” of the role of ion channels. Both Bean and MacKinnon, a molecular neurobiologist at Rockefeller University who won a Nobel Prize for research in potassium ion channels, were initially curious about finding a remedy that might inhibit cramping. There were not animal models being used to study this, but Bean and MacKinnon did find a study describing how if you stimulate any muscle repetitively at a certain frequently you can induce cramps. So they conducted the experiment on themselves—specifically on their big toes and briefly their calf muscles—and recorded the results using electromyography, a tool that measures electrical activity produced by skeletal muscles.

In the process of their “homegrown” study they became aware of a published study describing a folk remedy—pickle juice—being given to bikers in Texas that seemed to relieve cramps in minutes. One thing pickle juice does is activate TRP channels, and Bean and MacKinnon were soon in the hunt for natural products that could accomplish the same.

Their blend of ginger, cinnamon and chili pepper extracts, diluted in water and corn syrup, doesn’t taste half-bad, says Bean. And systematic studies in 32 studies look favorable. Bean said they are now hoping to develop an oral version of the beverage. They are also hunting around for agents even more effective at inhibiting cramping.”

Bean said they still don’t understand the precise mechanism. The current hypothesis, he says, is that ion receptors in the tongue or oral/pharyngeal system send signals into the brain stem. “We think this is like a chemical stimulation of the nerve and we’re now doing a pharmacology study in animal models to try and test this hypothesis,” says Bean.