Climbers call it the “death zone”. at an altitude of 8,000m, there is just a third of the amount of oxygen in the air as at sea level. no matter how much you breathe or how well you acclimatise, your body cannot get enough oxygen to keep you alive. with your lungs filling with fluid and your brain swelling, if you don’t descend swiftly it will not be long before you slip into a coma and die.
Yet on the morning of 23 may 2007, four mountaineers stopped on their way down from the summit of Everest. at 8,400m they removed their mittens and unzipped their layers of insulating clothing to take blood samples from each other. the group were part of the Caudwell Xtreme Everest expedition, which saw more than 200 healthy volunteers undergo a variety of tests at makeshift, high-altitude labs including their exercise capacity, blood oxygen levels, brain performance and metabolism.
The oxygen deficiency that affects climbers is also seen in intensive care patients. the medics leading Xtreme Everest hoped to gain insights into the problem by studying how expedition members reacted to high altitude. Their efforts form part of a long tradition of researchers seeking to understand how to treat the sick by studying healthy volunteers in extreme environments. “Studying physiology at the limits of human tolerance allows us to look at the body under conditions of stress, which in many ways are mimicked during a variety of different illnesses,” says Professor Mike Grocott, co-founder of the Centre for Altitude, Space and Extreme Environment Medicine (CASE), at University College London and leader of the 2007 expedition.
More than four years on, the data gathered from Xtreme Everest is still generating new insights. one of the latest findings, published last month, concerns how treatments that encourage increased nitric oxide production could promote better recovery in critically ill patients. the gas is produced by almost all cells in the body, and has important roles in blood pressure regulation, learning, memory, and protection from infectious diseases. Previous work has shown that residents of the Tibetan plateau produce elevated levels of it.
Professor Martin Feelisch at the University of Warwick carried out measurements that showed increased nitric oxide production and activity in Xtreme Everest participants, alongside changes in blood flow in small blood vessels. further work is ongoing to determine the causal relationship. “In the years ahead, this research may herald a change in emergency treatment and intensive care,” says Feelisch. “It suggests there is an alternative way of alleviating the consequences of low oxygen levels by creating a more sustained tolerance to those low levels through treatments that boost nitric oxide production.”
Others are seeking to learn from those high-altitude dwellers. A key question is why they are unaffected by altitude sickness. Last year, researchers took a significant step towards an answer when they discovered that Tibetans have evolved genetically to cope with their environment.
The scientists compared the DNA of Tibetan villagers living at about 4,500m above sea level with that of people from lowland China and Japan. they identified 10 genes in which variants thought to facilitate high-altitude living were more common among the Tibetans.
Two of the variants were in genes that play a role in reducing levels of haemoglobin, the protein that transports oxygen around the body. It might appear that more haemoglobin would help deliver more oxygen to parts of the body; however it makes the blood more viscous and impedes tissue oxygenation. the variants found in Tibetans help them to maintain the right levels of red blood cells and haemoglobin for optimal oxygen delivery.
A Tibetan hangs prayer flags to celebrate new year. Tibetans are adapted to high-altitude living. Photograph: Dermot Tatlow/PANOS/Panos Pictures
Back down at altitudes where the vast majority of humans live, problems in the lungs, heart, arteries and veins or in red blood cells can lead to hypoxia – the deprivation of oxygen to the millions of cells in our bodies that need it to function. This is one of the main causes of many of the most common and deadly illness and injuries. Ischemic strokes, for example, are caused by blood clots that block the passage of blood and oxygen to the brain. Heart or kidney disease can result in pulmonary oedema, in which fluid fills the tiny air pockets of the lungs called alveoli, which again stops the normal transport of oxygen around the body.
The study of how high-altitude adaptations provide protection from hypoxia is offering clues in the hunt for treatments. “The idea is to learn from these beneficial adaptations,” says Professor Josef Prchal, a haematologist at the University of Utah and a senior author of the high-altitude genetics study published in the journal Science. “If we can find the genes that protect Tibetans from hypoxia and its effects, then we should be able to design drugs to copy their actions.” Prchal says his group has recently discovered the first known Tibetan-specific gene variant. the finding, if confirmed, could be central to Tibetans’ enhanced hypoxia defences, and clinically of great importance.
Differences in haemoglobin levels are only part of the jigsaw. Diabetes expert Professor Donald McClain, also of the University of Utah, has recently found that locals with genetic adaptations to altitude metabolise food differently, with a greater preference for glucose over fats in comparison to other populations, presumably because fat requires more oxygen to metabolise. Tibetans who move to lower altitudes appear to be at increased risk of diabetes. McClain is investigating how high-fat diets cause a greater buildup of harmful byproducts of fat oxidation for those adapted for high-altitude living, and hopes the work could provide targets for new treatments for obesity and diabetes.
Hyperbaric oxygen therapy (HBOT) is the medical administration of 100% oxygen at higher than atmospheric pressures. the treatment, which dates back to the 1660s, was popular across Europe in the 19th century but saw a downturn as medicine became more evidence-based. Its use to treat decompression sickness suffered by divers and tunnel workers took off again during the 20th century. Since then, HBOT’s effectiveness in treating a number of other conditions has been demonstrated.
At normal atmospheric pressure, oxygen is mainly transported around the body via the oxygen-biding properties of haemoglobin in red blood cells, with very little carried by the blood plasma. at higher pressures, plasma is able to transport more oxygen. the treatment fights infections by creating a hostile environment for bacteria that thrive and cause infection in the absence of oxygen. there is also evidence to suggest HBOT increases the activity of bone marrow stem cells.
Certainly it has been shown to be effective in the treatment of carbon monoxide toxicity, bone and bladder damage caused by radiation, poorly healing wounds, gas gangrene and severe anaemia. Benefits have been suggested for more than 100 conditions including autism, senile dementia and impotence. However, many such claims have rested on small, uncontrolled studies, which may have been susceptible to placebo effects.
Meanwhile, sport science seeks to improve sporting performance through the application of scientific principles, often through improved training regimes. while the focus is primarily on helping elite athletes, insights into how the human body reacts to exercise in different environments can also inform clinical medicine.
Exercise has long been known to reduce the likelihood of heart disease. However, studies found its effect on the traditional risk factors – raised cholesterol, blood pressure and blood sugar levels – accounted for only about half of those associated for heart disease risk reduction.
It was long thought the role of the endothelium, the thin layer of cells that lines the inside of blood vessels, was to stop blood from leaking out. It is now known, however, that healthy functioning of this lining allows it to produce hormones, including nitric oxide, which relax muscles, allowing blood vessels to dilate and increase the flow of blood, along with oxygen and nutrients. Sports scientists have found that exercise strengthens the endothelium, reducing heart disease. Researchers at Liverpool John Moores University have shown how exercise strengthens endothelial function through the repetitive shear stresses caused by increased blood flow.
Space stories
Significant early strides were made in understanding the role of gravity in human physiology during three Skylab missions in the 1970s. Astronauts showed signs of calcium loss, bone density loss, muscle atrophy, as well as cardiovascular, blood flow, metabolic and immune system changes. the initial fears that they were prematurely ageing were laid to rest when they returned to Earth and made rapid recoveries. Yet these parallels have allowed astronauts to be used as models to study potential treatments for various conditions.
the study of how affects the body gives us clues about the physiology of old age. Photograph: NASA/Getty Images North America
“Medical advances have contributed to the extension of life, yet technological inventions encourage an increasingly sedentary lifestyle,” wrote Victor Schneider of Nasa’s human research program in the journal Gerontology in 2009. “Gravitational physiology may lead to useful insights to help delay or prevent the physical incapacitation that seems inevitable with living longer.”
German anatomist and surgeon Julius Wolff first came up with the idea that the bones of humans and other animals change according to the loads under which they are placed in the 19th century. This can be clearly seen in sportsmen or women who use one arm or hand more for their sport and have larger limbs or digits on that side. Astronauts who spend long periods in space return to Earth with weakened bones as a result of the lack of the force of gravity. when old bone cells develop micro-fractures, cells called osteoclasts break them down. the body then issues instructions for new bone cells to be generated by cells called osteoblasts.
In the microgravity environment of space, this process is one of the many body systems that becomes unbalanced. Bone density declines by about 1.5% per month in astronauts while they are in space – a much quicker rate than in osteoporosis patients. Professor Toshio Matusumoto of the University of Tokushima in Japan, has given osteoporosis drugs called bisphosphonates to astronauts to see whether this prevents bone loss. He hopes the accelerated nature of the changes that occur in space will shed light on how the body triggers bone cell growth, and potentially help provide new treatments.
“A lot of the things that happen to astronauts also happen to the elderly,” says Dr Kevin Fong, a leading space medicine expert and physiology lecturer at UCL. “They may not be the same processes, but studying astronauts who have returned from missions has contributed to our understanding of the physiology of old age.”
Another area in which space medicine has provided lessons for the Earth-bound is in the understanding of the role of the inner ear in balance and co-ordination. A series of symptoms has been identified in astronauts on their return to Earth including clumsiness, vertigo and blurred vision, as well as concentration and walking difficulties. This has helped researchers work out how chronic ear disease, diving accidents and viral illnesses can cause “labyrinthine dysfunction” in which patients suffer vertigo, motion sickness and related symptoms.
Fong says that the practical, scientific rationale for expensive expeditions, whether up mountains or in space, is sometimes exaggerated and the basic desire of participants to go to interesting places underplayed in public. Yet, he says, the desire to explore extreme environments and scientific curiosity are intertwined and so funding such expeditions often pays both basic knowledge and practical application dividends.
“The relationship between exploration, science, technology and health is more complicated than many people realise,” says Fong. “They can often be codependent. People go to extremes primarily because humans are naturally driven to explore. Along the way they can make unexpected and remarkable discoveries. in financially difficult times, when it comes to funding science there can be a tendency to try to back winners. But we would lose discoveries of genuinely fundamental importance if researchers were not free to engage in curiosity-driven exploration and science.”
Plans are already under way for an Xtreme Everest expedition in 2013. Measurements of biological changes in sherpas ascending to high altitude will be compared to those from participants on the previous trip. Another focus will be whether the variability in how well people adapt to the low oxygen environment can be explained by epigenetics – heritable changes in gene expression caused by an individual’s environment. How fruitful those lines of enquiry prove to be remains to be seen. However the chances are the boundaries of human knowledge about how our bodies work will be pushed further forward, and that can only be good news for those with sickness and disease.