By David N. Leff

During TV commercials, the tube is a veritable chamber of medical horrors, from baldness and dandruff at the top of the body, through arthritis and erectile dysfunction to athlete's foot at the bottom.

Halfway along this trajectory of disorders comes heartburn, for which there's a huge market in antacids. Physicians know this all-too-common affliction as GERD, standing for "gastroesophageal reflux disease." It strikes when the caustic contents of the stomach regurgitate up the esophagus into the throat, and sometimes back down the airway passages. At its worst, chronic GERD can cause esophageal inflammation, ulcers, and massive hemorrhages.

"GERD is currently being treated," observed molecular pharmacologist Andrew Howard, "by the so-called proton-pump inhibitors, such as omeprazole and orlansoprazole. In that disorder what's being treated is overproduction of acid in the stomach - heartburn. But it's been thought for a while that the defect involved in GERD has to do with the lower esophageal sphincter muscle, which abuts the stomach. Relaxation of that muscle is the reason acid reflux happens, and causes heartburn."

Howard is a senior research fellow in the department of metabolic disorders at the Merck Research Laboratories, in Rahway, N.J. GERD is one of his group's drug-discovery targets.

"If we were able to stimulate the contraction of that lower esophageal sphincter muscle, maybe we would be able to reverse the defect in GERD," he said. "And it wouldn't have anything to do with acid secretion per se, but working on the sphincter muscle. In industrialized nations, GERD is a huge problem. For prescription-marketed drugs the dollar figure is in excess of $1.5 billion per year. [It's] much more when you count in over-the-counter medications."

But GERD isn't his whole story. "There's also another gastrointestinal disorder called dyspepsia," Howard noted, "which relates more to fullness or bloating and gas after a meal. That's another possibility for a compound that would stimulate gut motility. And there's gastroparesis - late emptying of the stomach - which affects many people who are diabetic, as well as post-surgical conditions."

Howard and his co-workers at Merck have just announced a metabolic discovery with the long-range potential of treating such digestive disorders at their root causes, rather than their distressing symptoms. He is senior author of a paper in today's Science, dated June 25, 1999, that reports this finding. Its title: "Receptor for motilin identified in the human gastrointestinal [GI] system."

"Motilin," Howard told BioWorld Today, "is a 22-amino acid peptide hormone that's expressed throughout the mammalian GI tract, including humans. It's been around for quite some time, having been isolated by a Canadian group in 1972 or 73. A lot of work on motilin was done since, mainly showing its importance in GI function and motility. But it remained a peptide in search of its parent."

He and his team had mounted a concerted effort to identify ligands for orphan G-protein-coupled receptors. "We set up broad-based screens for such orphan receptors," Howard recalled, "including one orphan that turned out to be the motilin receptor."

That finding, as reported in Science, he observed, "makes it possible to better understand motilin physiology, as well as to design drugs that may be important for a variety of gastrointestinal disorders.

"That would probably be the most direct application," he said. "Besides, as we noted in the paper, it's been known for some time that erythromycin, the antibiotic, has effects on the GI tract that are somewhat unpleasant, such as cramping, nausea, vomiting and diarrhea. In fact, erythromycin does have a therapeutic use besides its antibacterial effect. Physicians give it intravenously to get the digestive system going after surgery.

Antibiotic Double-Dips As Gut-Gooser

"It's been known for a while that erythromycin might exert its effects through the motilin receptor, but it hadn't been proven, for lack of that receptor," Howard said. "Now, we've been able to tie that loose end up by showing that the antibiotic in fact does bind and activate the cloned motilin receptor. So now we can provide a basis for why erythromycin is doing what it's doing."

The motilin gene is expressed predominantly in the antrum of the stomach, where that organ opens into the small intestine. Its peptide also occurs at various intestinal locations, primarily the duodenum. Motilin presumably gets released by a certain population of cells in that area.

"Recently," Howard said, "people have shown that the gene is also expressed in various regions of the brain, especially in the cerebellum. It's not yet clear what its function is there. But it has elevated people's interest in obesity, food intake, things like that. Motilin is like a lot of neuropeptides. Sometimes, these get identified in the gut first and then show up in the brain. Certainly, the converse is true as well."

The motilin gene contains multiple exons and two or three introns. The Merck co-authors compared its genetic endowment with that of the living-fossil puffer fish.

"The puffer is a very old fish, in evolutionary terms," Howard said. "It's been known that the total DNA in a puffer fish is less complex than that in the mammalian genome, including humans. What's also known is that the reason puffers have less complexity than humans is because at the DNA level it has fewer introns - non-coding sequences - than do mammals. Even so, it looks as if most of the exons - coding sequences - for genes between puffer fish and humans are conserved; their sequences are similar.

Motilin's Gene Sequence Turns Up In Living Fossil

"In effect," the Merck scientist said, "the puffer has a more economical genome than do mammals. Mammalian genes have tremendous amounts of repeat sequences that don't code for anything. We decided to look in the puffer fish to make the evolutionary comparisons between humans and that ancient fish's receptor-ligand system. We've isolated a clone in the puffer that we think may represent the ancestral motilin receptor in that species.

"If proven, it would tell us that this system has been conserved for at least 400 million years - about the time when the human and fish species diverged," Howard said. "During those years, as evolution has gone on, many things have been deleted as unessential, but the fact that this system has been conserved suggests how important it is in evolution."