Breathing on the Edge.

Going to great heights hurts, and scientists are learning why

In 1923, George Mallory famously proclaimed that he would climb to the summit of Mount Everest, the highest place on Earth, "because it's there." At 29,035 feet, more than 5 miles above sea level, that summit harbors some of the most inhospitable conditions on this planet.

Still, each year, more and more Mallory types scale summits nearly that high, into air so thin that few can make it without oxygen tanks. In addition, climbers aren't the only ones experiencing high altitudes. More people than ever are playing, living, and working at altitudes high enough to alter their physiology. In the western United States alone, more than 30 million people will live in or visit altitudes above 5,000 feet this year.

That's providing incentives for new studies of how people respond to high altitudes physically, biochemically, and genetically, according to researchers discussing the topic in San Francisco at the February annual meeting of the American Association for the Advancement of Science.

Such studies, these researchers say, might reveal how people have been able to cope with the low-oxygen conditions of such places as the Andean and Tibetan plateaus for thousands of years. The studies could also enhance the well-being and productivity of people who climb mountains, drive to the slopes for a ski holiday, or work at high-altitude telescopes and mines. These same studies could help physicians understand and treat certain diseases that strike at lower altitudes, as well.

One of the biggest challenges for people who travel to high altitudes is a condition known as hypoxia, in which the body doesn't get enough oxygen to run efficiently.

Pretty much anywhere in the atmosphere, high or low, about 21 percent of the molecules are oxygen. However, at a mountain summit, the barometric pressure is so low that there are fewer total air molecules available than at lower elevations. Therefore, fewer oxygen molecules fill each lungfull. In some people, this lack of oxygen can cause altitude sickness, which can include headaches, fatigue, unsteadiness, nausea, shortness of breath, and, in extreme cases, seizures and coma.

Scientists have long known about some of the ways that people acclimate to hypoxic conditions as they spend more time at high altitudes. Breathing increases, as does the production of red blood cells, which shuttle the precious oxygen molecules throughout the body.

However, many details of the biochemical pathways for various physiological responses to low oxygen are still unknown, as are potential genetic cues turning them on and off, says Thomas F. Hornbein of the University of Washington School of Medicine in Seattle. Also, there appear to be many oxygen sensors throughout the body, says Hornbein, but researchers don't yet know how they all work. "There's really a multiring circus" in the body, he says.

Hornbein has experienced low oxygen's effects firsthand. In 1963, when he was descending from a successful climb of Mount Everest, he accidentally knocked his oxygen cylinder's regulator against some ice. As oxygen hissed out, he reached back and turned the cylinder off, figuring that since he was going downhill he'd be OK. "Then very quickly, my vision began to get dark," he says. "It was like the a sun was setting before it really Was."

Hornbein turned the cylinder back on and made it back down the mountain without harm, but the incident created in him a fascination with what happens to a brain as it ascends and descends great heights. "Thinking about this event afterwards ... made me realize how close we were to the limits of tolerance to hypoxia and that the brain [may be] the most sensitive or vulnerable organ," he says.

Over the years, many studies have shown that climbers to extremely high altitudes have more difficulty with memorization, spelling, multiplication, addition, pronunciation, and following simple instructions after they return to sea level than before they climb, says Hornbein. The climbers also lose motor skills and can't tap their fingers as quickly.

Even a year after the 1981 American Medical Research Expedition to Everest had ascended the mountain, 13 of the 16 climbers Hornbein tested still couldn't tap their fingers as fast as they had before they'd been exposed to the low-oxygen environment. Even elite climbers show cognitive impairments for 2 to 10 months following a high climb, says Hornbein.

The impact of hypoxia is long lasting and sometimes severe, says Frank L. Powell, a physiologist at the University of California, San Diego and director of the White Mountain Research Station headquartered near Bishop, Calif., where he and his colleagues study people's physiological responses to high altitude. Even at just 12,000 feet, he notes, blood-oxygen concentrations dip so low that, if they showed up in a person at sea level, "your HMO or Medicare insurance would pay for you to have supplemental oxygen."

Taking that thought further, Powell notes that high-altitude research could benefit patients with illnesses such as chronic obstructive pulmonary disease, which afflicts more than 2 million Americans. Also, learning more about the genetic basis of high-altitude acclimatization could help researchers solve medical mysteries, such as why some people naturally respond to similar lung diseases by breathing harder and turning pink, while others breathe less hard and turn blue.

To answer such questions, researchers have searched for biological distinctions in the isolated Andean and Tibetan highlanders. Physical anthropologist Cynthia M. Beall of Case Western Reserve University in Cleveland has spent years testing the highlanders, trying to discover what makes them so successful at living where they do.

The questions she's seeking to answer include, Has natural selection acted on the two groups? Have the Andean people and Tibetans evolved similar mechanisms for coping with low oxygen? How do their responses resemble those of lowlanders? Does a genetic basis exist for any of these responses?

By analyzing reams of medical-test data from several scientists' studies of the Tibetan and Andean highlanders, Beall has found similarities and differences between the two native groups in how they cope with low oxygen.

Beall made comparisons among the highlanders and altitude-acclimated lowlanders. These are people who lived at sea level but then moved to locations 10,000 feet or higher at least a year before the testing. In this way, Beall hoped to investigate how natural selection might have acted on the highlanders to favor individuals with better biological coping mechanisms for high altitudes.

One of the biological traits she compared was the hemoglobin concentrations in the different groups' blood. The more hemoglobin molecules in a given amount of blood, the more oxygen that blood can carry. As expected, Beall found that the acclimatized lowlanders had higher hemoglobin concentrations the higher they lived. She noted a similar response in the Andean highlanders.

However, Tibetan highlanders were different. Hemoglobin concentrations of people living in villages up to 13,000 feet didn't increase with altitude. Tibetans living above 13,000 feet, however, had higher hemoglobin concentrations the higher their villages were located.

Beall also compared g the percentage of hemoglobin in each person's blood that carries oxygen--a value known by physiologists as oxygen saturation. Acclimated lowlanders' had less and less oxygen saturation the higher up they lived. Tibetan highlanders' blood behaved similarly to the acclimated lowlanders', exhibiting less oxygen saturation the higher a person's home, Beall says.

Strangely, however, oxygen-saturation levels in Andean highlanders halfway across the world were different. Some had better saturation at higher elevations; others had worse. Beall says it isn't clear why.

Finally, Beall investigated differences in breathing between highlanders and acclimated lowlanders. Typically, a person living at sea level who vacations in the mountains for a few weeks breathes harder and harder over a period of 8 days and then maintains the heaviest breathing until returning home.

That's why Beall was surprised to find that the regular breathing, or resting ventilation, of acclimatized lowlanders she studied in their high-altitude homes was about the same as that of people at sea level. The same was true for Andean highlanders. Again, the Tibetans didn't match. They had a 50 percent higher resting ventilation at 13,000 feet than did people at sea level. "Tibetans seemed to have diverged from the ancestral response in terms of ventilation," notes Beall.

Beall says that researchers need better genetic data to determine whether natural selection has acted on these populations. Until recently, researchers haven't studied blood, breathing, and other high-altitude responses for which they know the controlling genes and biochemical pathways, Beall points out.

She, for one, has begun to do so. In a presentation this week at the annual meeting of the American Association of Physical Anthropologists in Kansas City, Mo., Beall reported results of testing high-altitude residents for a physiological response for which the relevant genes are known.

At sea level, a person with a condition causing decreased blood flow to the lungs will produce less of the blood vessel dilator nitric oxide--a response to hypoxia that's controlled by known genes. Blood vessels in hypoxic areas of the lungs thus constrict and redistribute blood to areas with more oxygen. The reaction isn't as useful at high altitudes, where hypoxia isn't localized merely to damaged tissues, Beall points out.

Nonetheless, lowlanders make less nitric oxide in their lungs as they ascend to high altitudes. Figuring that the lungs of always-hypoxic, high-altitude natives would produce even less nitric oxide, Beall went to the Andes and Tibet last summer and tested for nitric oxide in the exhaled breath of hundreds of healthy, nonsmoking natives.

"And I found exactly the opposite," says Beall. The Andean people were exhaling 50 percent more nitric oxide than healthy people at sea level were, while the Tibetans exhaled more than twice as much, she reported.

Now, Beall says her preliminary results from tests on sea-level volunteers suggest that the lungs' release of high amounts of nitric oxide may aid the uptake of oxygen by blood. The bodies of highlanders may have evolved this strategy to cope with oxygen-thin air, she suggests. Says Beall, "The exciting part is, we know the relevant genes."

A better understanding of the genetic basis of highlanders' responses to hypoxia might one day help doctors aid both lowlanders and highlanders, says Beall. For example, this sort of information might allow a doctor to counsel a person who's predisposed to severe altitude sickness to choose a beach vacation over a ski outing.

Some highlanders, such as those who inexplicably lose their natural coping mechanisms for high altitudes, stand to benefit from such research, as well.

In another genetic approach to high-altitude biology, Powell and his colleagues at the White Mountain Research Station will soon start investigating DNA differences between high- and low-altitude mice. The team will study a common lab mouse native to both low and high altitudes in California. They'll also examine an Old World mouse found in low and high altitudes of the Andes. Since this mouse arrived in the 16th century with the conquistadors, researchers know how long it's had to adapt to its altitudes.

Such genetic studies could eventually lead to better understanding of hypoxia and its effects on people at low and high altitudes. Meanwhile, some researchers are pioneering strategies for helping people cope with high altitudes right now.

One of these is to find new ways to enrich people's living and working environments with higher concentrations of oxygen. Some 140 million people around the world work and live at altitudes above 8,000 feet, says physiologist John B. West of the University of California, San Diego. Many workers, such as miners, commute from sea level to work at these high elevations. Some people work as high as almost 20,000 feet, he says.

West, who led the 1981 American Medical Research Expedition to Everest, has been studying the effects of enriching the working environments of people at high altitudes. His research team has done most of this work at the White Mountain Research Station. Early results show that enriching air with an extra 3 percent oxygen--up to 24 percent oxygen--improves mental performance, sleep quality, general well being, and symptoms of acute mountain sickness.

In one of the first working examples of this approach, researchers from the California Institute of Technology in Pasadena, Calif., work and sleep at 16,000 feet at the Cosmic Background Imager observatory in northern Chile. Inside their four-room facility is an enriched atmosphere that's 27 percent oxygen.

For every 1 percent that oxygen concentration is enriched, it's like a 1,000foot drop in altitude, says West, so the scientists have been working in the equivalent of a 10,000-foot atmosphere.

The radioastronomers have performed better since the oxygen-enriched environment was established soon after the facility opened about 18 months ago, says West. Other telescope facilities intend to follow suit, he says. Anthony Readhead, who runs the observatory, wrote West that "there is no question that the oxygen enriched environment helps enormously.... After about 10 days we started using oxygen, and the difference was immediately noticeable."

The telescope facility now has a rule that everyone working on the telescope or using power tools must be breathing enriched oxygen, noted Readhead.

People have used oxygen enrichment as far back as the 1920s, when mountaineers carried canisters of the gas with them in attempts to scale Mount Everest. Until recently, however, no one had done a systematic study of the benefits of fully enriching the rooms in which people live, work, and sleep at high altitudes.

Modern advances of medicine and technology probably won't ever make the highest altitudes exactly hospitable. Mountain survival involves more than enduring low oxygen: Consider the raging storm that claimed the lives of eight Everest climbers in May 1996.

But life at high places could become more bearable as researchers like Beall, West, Powell, and Hornbein learn more about coping with thin air such science could benefit the millions of people who experience high altitude as a way of life, a vacation, or just part of the job. Meanwhile, of course, the researchers' work might also help people who, like Mallory, push the boundaries of human biology simply because the challenge "is there.