Investigator Profile: Warren Zapol, MD and Nitric Oxide

A profile of Warren Zapol, MD, the Emeritus Anesthetist-in-Chief and Reginald Jenney Professor of Anesthesia at Harvard Medical School

In the 25 years since discovering a life-saving therapy consisting of breathing low levels of the gas nitric oxide—which is still the only selective inhaled pulmonary vasodilator—Massachusetts General Hospital (MGH) anesthesiologist Warren M. Zapol, MD, and his MGH team has given clinicians a treatment to simply save the lives of vast numbers of hypoxic newborns (“blue babies”)and prevent or reverse pulmonary hypertension in hundreds of thousands of adults during surgery. The MGH team included Claes Frostell MD, fellow in anesthesia, Jesse Roberts MD, a neonatologist and anesthesiologist, and John Wain MD, a thoracic surgeon. But those impacts pale in comparison to his vision for the future, says Dr. Zapol, the Emeritus Anesthetist-in-Chief and Reginald Jenney Professor of Anesthesia at Harvard Medical School, and Director of the MGH Anesthesia Center for Critical Care Research. In the coming years, he hopes to provide even the most isolated clinics in the poorest regions of the world with the means to produce nitric oxide using just a battery. Years ago, Dr. Zapol's original discovery was inspired by his friendship with Louis Ignarro, PhD, a pharmacology researcher at the University of California, Los Angeles. Ignarro received the 1998 Nobel Prize in Medicine for his discovery in the mid-1980s that the human body produces nitric oxide to regulate blood pressure. In 1990, Dr. Zapol revealed that nitric oxide, a pollutant gas long considered poisonous prior to Ignarro's findings, could save lives. “We were able to show that if you breathe tiny doses of nitric oxide—a known poisonous gas that comes out of the exhaust pipes of cars and trucks and forms nitrogen dioxide, which when dissolved in water produces acid rain and kills fish—that the blood vessels in the lung would dilate, but not the vessels in the body. It's all about the dose and local action. That's the key to the invention,” says Dr. Zapol. Dr. Zapol's work resulted in a patent that spawned an enormous market and thriving companies. Ikaria, the company that produces inhaled nitric oxide in the USA, recently sold for $1.6 billion to Madison Dearborn Partners. “It's one of the great MGH successes, it really is, of the translation of a laboratory finding,” notes Dr. Zapol, recalling his original work in sheep models of pulmonary hypertension. “A half million Americans have breathed this gas for up to 5 days. It saves blue babies and they go on to live normal lives. It's the most satisfying thing I've ever done.” There's only one problem: Nitric oxide is expensive, costing an estimated $12,000 per infant. “It's now a required treatment for blue babies,” he says, “but pediatricians and respiratory therapists hate the price, because it's the most expensive drug in the newborn nursery.” Unfortunately, Dr. Zapol says, the world has a lot of blue babies that can't afford $12,000 each. But he has a solution. “To make it easily available, all you need is electricity or a battery,” Dr. Zapol says. “One of my dreams is to manufacture from air by plasma fusion, in a spark. I make a spark and combine the nitrogen and oxygen in air, therefore creating the active moiety of nitric oxide cheaply and anywhere.” Patients would breathe the nitric oxide though a facemask or a ventilator. Dr. Zapol's group submitted a provisional patent last year. “It's a way to make nitric oxide economically without requiring gas cylinders or a delivery system for tanks or drugs. We'd like to replace the cylinder with our beautiful pure NO gas made from air.” While the device waits for FDA approval, Dr. Zapol looks to the past for signs of hope that future generations, perhaps in nations less fortunate than ours, will benefit from his discovery. “Nitric oxide has contributed to saving a lot of babies,” Dr. Zapol says, “I have letters here from kids. Every time I give my nitric oxide talk, someone comes up to me and says, ‘You saved my baby.'”