Has been around for billions of years // has been found to control countless functions in the body // has been explored as a treatment target for countless diseases // hasn’t paid off yet.
Endothelin: Still Beyond Reach
Scientists almost always have a soft spot for their own research specialty—a beautiful protein, a rare disease, a gene whose function they uncovered. But endothelin researchers seem particularly bewitched. This ubiquitous human protein, involved in everything from regulating blood pressure to ridding the urine of sodium, has become a scientific superstar during the past 20 years. “There would be no life without endothelin,” says Matthias Barton, a physician and professor at the University of Zurich who has published almost 70 scientific papers on the protein. “It’s on little bit like, Why do we need oxygen?” says Joel Nelson, a physician at the University of Pittsburgh School of Medicine who studies the role of endothelin (ET) in cancer. “It’s the way we’re set up—you can’t survive without it.” Others are similarly effusive, and with three ET-related papers accepted for publication every day over the past two decades, the protein’s importance seems well established.
Endothelin’s primary role is to help blood vessels remain taut and firm, ready to carry blood to every organ. By making small adjustments, contracting or expanding the vessels slightly, it helps keep blood pressure under control. But it doesn’t stop there. In the kidneys, endothelin aids in maintaining a precise balance between sodium and water. It also helps the heart beat rhythmically, modulates the release of hormones and guides the growth of neurons in the brain. It plays a role in the immune and reproductive systems, the liver, the prostate, and muscle, bone, skin and fat tissue—just about every cell makes endothelin.
And endothelin isn’t important only to humans, which are just the latest in a long line of animals to take advantage of the protein. “Endothelin is basically a snake venom toxin,” says Martine Clozel, an ET researcher and chief scientific officer at Actelion Pharmaceuticals in Switzerland. For example, when the Israeli burrowing asp (Atractaspis engaddensis) strikes its prey, it delivers a deadly protein called sarafotoxin, an evolutionary predecessor to endothelin that shares about 75% of its chemical structure. Because the proteins are so similar, sarafotoxin can bind to endothelin receptors on human coronary arteries, causing them to clamp shut, cutting off the supply of blood to the heart muscle and killing within minutes. Sarafotoxin is deadly because our bodies are intimately familiar with the protein it evolved into, and during the millions of years since reptiles became mammals and mammals became human, not much has changed.
“Evolutionarily speaking, this is a very, very old molecule,” says Donald Kohan, an ET researcher at University of Utah Health Sciences Center. In addition to its age, “in all mammals it’s exactly the same protein, which is very rare,” adds Nelson. “It’s a very conserved protein, which means that it is important,” says Clozel.
As vital as endothelin is to our survival, however, it also has a dark side. During disease, endothelin production and utilization can be thrown completely out of whack, as can the receptors that transmit its signal. In such cases, exaggerated versions of its normal functions may do considerable harm, causing inflammation, unfettered cell division or, as sarafotoxin does, a damaging constriction of blood vessels.