In his office at Massachusetts General Hospital, Warren Zapol ’62, who directs the hospital’s Anesthesia Center for Critical Care Research, keeps a small tank of nitric oxide with the warning “poison—call a physician” flanked by skull-and-crossbones symbols. When he purchased this tank 25 years ago, nitric oxide was known primarily as a component of car exhaust and cigarette smoke. But researchers had also discovered that the body itself uses it to dilate blood vessels, and Zapol wondered if inhaled nitric oxide might help people who can’t get enough oxygen because they have high blood pressure in the vessels leading to the lungs—a problem that in newborns is known as blue baby syndrome. Treating these infants traditionally involved risky procedures.
Doctors had experimented with ways of relaxing these vessels using compounds that reduce blood pressure in general. But that, too, can be dangerous. Zapol hypothesized that inhaled nitric oxide might work better since it would be destroyed by red blood cells, so it would not circulate throughout the body. To test this idea, he and his colleagues at Mass General gave a sheep a drug to induce pulmonary hypertension. Then they opened all the windows in the lab, put on gas masks, and administered nitric oxide by way of a tracheostomy. They found that the blood pressure in its lungs quickly fell, without a corresponding drop elsewhere. Then they tested the gas on newborn lambs and got the same results. Babies would be next.
In 1990, the team administered nitric oxide to its first human newborn: a boy who was “quite blue” from lack of oxygen, according to Jesse Roberts, a neonatologist who worked with Zapol at the time. The group was confident it was safe because of the work on newborn animals, Roberts says. And after all, as Zapol says, “all medicines are poisons. You just want to cut the dose way, way, way down.” Still, when they treated the baby, “we covered the skulls and crossbones on the tank with a piece of paper,” says Zapol. Remarkably, the boy’s pulmonary blood flow increased within a minute; he went from blue to pink. “It was so rapid we got chills,” says Roberts. In 2000, nitric oxide was approved by the Food and Drug Administration for use in babies with pulmonary hypertension. Today, it is given to around 30,000 patients per year, both babies and adults.
Previously, “blue babies” were typically placed on artificial lungs—a technology that Zapol himself helped develop early on. The treatment, which involves a surgical procedure and can cause bleeding in the brain, generally took five days to two weeks, Zapol estimates. Nitric oxide, by contrast, is usually needed for only four to five days, by which time around 80 percent of babies respond. Only if the treatment doesn’t work do doctors resort to the artificial lungs. Zapol likes to joke, “My first project only gets done if you do my second project first.”
Zapol, who was chief anesthesiologist at MGH from 1994 to 2008 and has been a Harvard faculty member since 1972, has long been interested in the complexities of breathing and pulmonary circulation—not only in mice, sheep, and babies but in mammals in the wild. Shortly after he finished his residency in anesthesia at MGH, in the early 1970s, he was told about the Weddell seal of Antarctica, which can hold its breath for over an hour. At first he dismissed that claim as “bullshit,” he recalls. But when he learned that the seal does indeed make extended, deep dives under the ice, he applied for a grant to study it, thinking it might yield some insight into human physiology. “As an anesthesiologist, if you could get your patients to hold their breath for an hour and a half, it would be really nice,” he says.
On a series of expeditions that began in the mid-1970s, Zapol and his colleagues went to what he calls “the most beautiful lab in the world”—the National Science Foundation’s McMurdo Station, which is built on the volcanic rock of Antarctica’s Ross Island. They convinced the Navy to drill a hole in the ice 15 miles offshore, where they would release the seals they’d captured in colonies on sea ice near the island. (Since there were no other breathing holes nearby, the team reasoned, the seals would return to the same place at the end of the dive, making it possible to collect data.) One of Zapol’s colleagues at MGH had designed a portable microcomputer that could withstand extreme pressure and freezing temperatures while collecting information on the seals’ heart rate, oxygen levels, and other variables. They coaxed the first seal into a sledge and transported it across the ice using a snowcat, whose powerful track treads came in handy pulling an animal that can be 10 feet long and weigh as much as 1,200 pounds. They attached a microcomputer to a rubber sheet, which they glued to the seal’s back before guiding the animal into the hole.
Over nine Antarctic research expeditions, Zapol and his colleagues collected a wealth of data on what happens to the seals as they plunge beneath the ice. Other researchers had observed that the seals’ heart rate slows dramatically during dives. But they disagreed on whether this response, called a diving reflex, was an artifact of lab conditions, in which the seals had less control. Zapol’s group demonstrated that the animals do exhibit a diving reflex in the wild; their heart rate decreases to conserve oxygen, falling even lower on longer trips down. (Under artificial conditions, in which they didn’t know how long the dive would be, they seemed to protect themselves fully every time, says Zapol.) They found that seals stay underwater by storing oxygen-carrying red blood cells in their spleen and releasing them as needed. On one expedition, Zapol’s team took ultrasound images of the animals’ spleens before and after a long dive, calculating the precise decrease in the organ’s volume as the blood cells were released. They also studied the physiology of pregnant seals and their fetuses—as Zapol puts it, “a submarine within a submarine.” In a sense, all Weddell seals “become fetal” when they dive, he adds, because they collapse their lungs and, like fetuses, don’t rely on them to obtain oxygen. (Both seal and human fetuses receive oxygen through the umbilical cord.) The researchers found that the seals’ ability to collapse their lungs also helped them avoid decompression sickness, or the bends.
Ultimately, Zapol and his team did not find a link between the seals’ physiology and the challenges faced by humans who lack sufficient oxygenation. Still, the expeditions contributed to researchers’ understanding of the seals themselves. Joining Zapol on his 1992 expedition was a “life-changing experience,” says William Hurford, now chair of anesthesiology at the University of Cincinnati College of Medicine. “The wonderful part was the pureness of the research … the meditativeness … You only had one thing to do and it never got dark.” It seems amazing, he adds, that these expeditions occurred at all. Zapol called experts from around the world, including busy clinicians working in a range of fields, to say, “Hey, why not come down to Antarctica for a couple of months and chase some seals around?” he recalls. “I mean, that’s ludicrous from the outset, but he was able to do it.” In 2006, an Antarctic glacier was named after Zapol in recognition of his contributions.
Over the years, Zapol’s curiosity also led him to Japan and Korea, where he and his colleagues studied female abalone divers who descend as far as 25 meters without air tanks or scuba equipment. Presidents George Bush and Barack Obama appointed him to the U.S. Arctic Research Commission, through which he has championed work on the mental health of indigenous peoples in the Arctic. He has received 13 U.S. patents related to his research on nitric oxide; others are pending. And royalties from earlier work are funding additional studies on the gas. Those royalties also made it possible for Zapol and his wife, Nikki, to set up a $3 million charitable remainder trust to fund a professorship in MIT’s new Institute for Medical Engineering and Science (IMES) last year. (The Zapols have been married for 45 years and have two children; their son, David ’95, met his wife on one of the Antarctic expeditions.) “His success has really been at the interface of basic science and clinical research, and I think he chose IMES as a way to foster that,” says IMES associate director Emery Brown, a fellow anesthesiologist at MGH and a professor of computational neuroscience and health sciences and technology at MIT. (Brown also happens to hold a professorship in anesthesia at Harvard Medical School that’s named for Zapol.)
Today Zapol, who is now 72, is combining his work on nitric oxide with a long-standing interest in a disease he knows firsthand. Just after graduating from MIT, he contracted malaria while leading an expedition through southwest Asia, exploring and documenting areas that had rarely been visited by outsiders. That experience, he says, kindled his interest in medicine. Now he is leading a pilot study in Uganda to test the use of nitric oxide in children with a severe complication called cerebral malaria, in which diseased blood cells clog vessels to the brain. The condition can cause brain damage, coma, or even death. Previous studies in mice have suggested that nitric oxide might have benefits as an adjunct therapy, so Zapol and his African colleagues are conducting a trial with roughly 90 children. If the results are promising, they will move on to larger clinical trials at multiple sites across the continent.
Zapol is also working on a cheaper way to generate nitric oxide at the bedside, using a small inhaler with a spark plug to pull the gas directly from air. This would be especially valuable in the developing world, where transporting and delivering large gas cylinders could prove difficult. “I’m a physician at heart,” he says. “Though I spend a lot of time studying seals and sheep and other animals, my primary interest is people.”
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