SIXTY years after Edmund Hillary and Tenzing Norgay became the first people to climb Everest, the world’s highest mountain is a busy place. When the weather is good in mid to late May, the upper slopes are crowded with hundreds of climbers. With every step available to view on YouTube, you might think there is nothing left to explore on the roof of the world. You would be wrong.
A team from the at University College London recently spent several weeks on Everest studying hundreds of trekkers, climbers and Sherpas. The findings from their work and that of others is radically changing our understanding of how our bodies adapt to altitude, particularly the low oxygen levels experienced there.
Don’t assume this revolution only affects a few groups of people around the world. Anyone with anaemia, heart failure and a wide variety of other illnesses can experience low oxygen levels. In the UK, at some point in their lives, and a common feature of most of these patients is low oxygen – a state known as hypoxia. Doctors are stuck for ways to deal with the consequences. So could the adaptations of people who have evolved to live in these conditions point to new treatments?
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Since 1953, a great deal of research has deepened our understanding of how humans adapt to life in the high mountains – and what can go wrong. The higher you go, the less oxygen the atmosphere contains. At La Rinconada in Peru, often cited as the highest town on Earth at 5100 metres above sea level, there is only around 50 per cent of the oxygen present at sea level. At the top of Everest, 8848 metres above sea level, it is just 33 per cent (see chart).
The body soon feels the effects. At first, moving around at altitude is immensely effortful – like wading through treacle while breathing through a straw. To compensate for low oxygen levels you breathe faster and deeper, a phenomenon called the hypoxic ventilatory response. Your heart rate and blood pressure increase, which can lead to life-threatening illnesses, notably high-altitude pulmonary and cerebral oedema, as fluid leaks from cells into cavities in your lungs and brain.
But you slowly adapt to the lack of oxygen: your body makes extra red blood cells and haemoglobin – the protein that carries oxygen through the bloodstream to the cells, where it is used in the production of energy. This ups the oxygen your cells receive, allowing your heart rate and blood pressure to fall, and you to breathe more easily and do athletic things like climbing mountains.
At least, that’s the accepted wisdom. But CASE team member , director of the UCL Institute for Human ÎçŇą¸ŁŔű1000ĽŻşĎ and Performance, has begun to question whether increasing haemoglobin is the most effective way to deal with hypoxia – or if it’s just how your body responds. He points out that these are the same reactions that help us deal with blood loss. Perhaps, when the body senses low oxygen in the blood, it kicks off a chain of events that originally evolved to deal with injury. That would certainly make evolutionary sense. After all, injuries would have been a common danger for our forebears, whereas very few of our ancestors would have been climbing mountains.
There are many reasons why increasing haemoglobin isn’t the best way to deal with hypoxia, says Montgomery, not least because it doesn’t significantly improve the uptake of oxygen. That’s because, at high altitude, less gas can dissolve into a liquid. This severely limits the amount of oxygen that can get into the blood, no matter how high its haemoglobin content. “Just increasing the red cell mass doesn’t mean you’re getting more oxygen to your cells,” says Montgomery.
Increasing haemoglobin production also carries many risks. “It turns your blood to porridge,” says Montgomery. “This is not good for you. It knackers your microcirculatory system.” Thicker blood also leaves you more vulnerable to stroke, all of which adds up to a very poor adaptation to high altitude.
Evolved for the high life
This seems to suggest that increased haemoglobin is a side effect of hypoxia, rather than a solution, and more evidence comes from people living on the Tibetan plateau. In recent decades, the migration of Han Chinese onto the plateau has provided a natural experiment to study the adaptational differences between lowlanders and populations that have evolved over thousands of years to live at altitude.
“The migration of Han Chinese to the Tibetan plateau offers a natural experiment to compare lowlanders and populations evolved for life at high altitude”
In the 1990s, Lorna Moore and colleagues at the University of Colorado studied pregnancy and childbirth on the plateau, critical periods from an evolutionary perspective. They found that, like Western tourists on Everest, Han women produce extra haemoglobin during pregnancy, making them vulnerable to the side effects of stickier blood, including stroke and thrombosis. Elevated blood pressure also brings a higher risk of eclampsia.
This is in stark contrast to the physiology of pregnant Tibetans, who do not have elevated levels of haemoglobin – their levels are similar to those of people living at sea level. As a result, Tibetan women have fewer stillbirths and premature babies than the Han Chinese at altitude. Their newborns also have higher birth weights ().
Mysteriously, all Tibetans have a surprisingly low level of oxygen in their blood, yet still seem able to supply their bodies with enough juice to fuel a healthy life. So it would appear that in a population that faces hypoxia on a daily basis, evolution bypassed the risks of thick, soupy blood by finding another way to deal with the suffocating conditions.
Such findings are reinforced by recent work suggesting direct selection on the genes that control haemoglobin in the Tibetans. Rasmus Nielsen at the University of California, Berkeley, and researchers from the Chinese Academy of Sciences in Beijing compared the DNA of 50 Tibetans living in villages at 4300 and 4600 metres high with 40 Han Chinese living in Beijing at just 43 metres above sea level. The biggest difference was in DNA near a gene called EPAS1, which regulates haemoglobin production. This was altered in 87 per cent of the Tibetans but only 9 per cent of the Chinese. Further studies have also found differences in EGLN1, which codes for a protein important in regulating the body’s oxygen levels, and PPARA, which also seems to regulate haemoglobin production ().
Converging paths
Genetic adaptations to lower oxygen can also be found in another high-altitude population: the Amhara, who have lived for around 70,000 years in Ethiopia’s Simien mountains at altitudes of up to 3800 metres. Intriguingly, Cynthia Beall at Case Western Reserve University in Cleveland, Ohio, has found that, like the Tibetans, the Amhara have normal haemoglobin levels but ,” she says. “On one level – the biological response – they are the same. On another level – the changes in the gene pool – they are different.”
That two populations independently evolved different ways to limit haemoglobin production in response to low oxygen levels certainly lends weight to the idea that the textbook descriptions of hypoxia need a rethink. Nevertheless, it’s important to note that not all high-altitude populations have evolved the changes seen in the Tibetans and Amhara. People in the Andes, for instance, have high haemoglobin just like the Han Chinese and Western climbers. Tellingly, however, they are also more likely than Tibetans to suffer from problems such as .
More work is needed to understand exactly how all these populations cope with low oxygen – and how such knowledge might be used in a medical setting. Many illnesses affecting the respiratory and cardiovascular systems result in reduced oxygen supply to the body’s organs, leading to hypoxia. At the moment, it is very difficult to find out how the body reacts to this process in the hospital ward – or how to respond to increase the chances of survival. As Montgomery points out, “to tease out the pathways, you have to take people and make them hypoxic for long enough to work out how they are adapting” – hardly an ethical experiment to try in the lab or on patients.
In the past, most efforts in intensive care have centred on improving the supply of oxygen. But the fact that Tibetans can live with permanently low levels of blood oxygen, without any ill effects, might suggest other ways to deal with the problem.
One possible answer stems from the discovery that Tibetans have unusually high levels of nitric oxide in their blood. This dilates vessels, allowing larger volumes of blood to move through the body in the same amount of time. Together with their deeper and faster breathing patterns, this could explain how Tibetans move enough oxygen to their tissues. If so, CASE researchers hope they can to improve the delivery of oxygen in hospital patients.
Another idea being explored by the CASE team is that the secret to coping with altitude lies in using the limited oxygen more efficiently, through an altered metabolism. On the CASE team’s first Everest expedition in 2007, Denny Levett took muscle samples from 17 climbers at base camp and sent them to . The samples revealed that during the early days at base camp, muscle cells mothballed some of their mitochondria, presumably so that if conditions became less hypoxic they could get them working again. However, after several weeks, cells had lost 20 per cent of their mitochondria (). “This striking finding might suggest that when oxygen supply is limited, the muscle chooses to sacrifice some of its energy-requiring functions in favour of maintaining others,” says Murray.
These changes may form part of the process of acclimatisation experienced by trekkers and climbers going to altitude. But do they also reflect what happens in people who have evolved to cope with low oxygen? This year, Murray’s team conducted similar experiments to compare lowlanders’ muscles with those of Sherpas before and after acclimatisation. The results are not yet in, but he predicts that Sherpas have evolved protection against a drop in cell function, which could explain their superior performance at altitude.
Might it be possible to induce similar metabolic changes in hospital patients? “The therapeutic direction this is taking us in is to try to help the body reduce oxygen consumption, rather than driving delivery as was previously the case,” says Montgomery.
Understanding this mechanism will also shed light on the factors that limit a patient’s long-term recovery. Both lowlanders trekking up Everest and hospital patients often show rapid weight loss following hypoxia. A loss of appetite makes sense if your metabolism slows down to reduce oxygen consumption, but these changes can take a long time to reverse once conditions have returned to normal, supporting the idea that hypoxia turns the body into a lean-burn engine. “Eighty per cent of people of working age can’t go back to work a year after leaving an intensive care unit. They’ve got nothing left,” says Montgomery.
Weight loss is a particular problem for people with respiratory illnesses like chronic obstructive pulmonary disease. Since Sherpas don’t seem to pay the same metabolic price as lowlanders in the face of hypoxia, understanding these differences may help us manage these symptoms, says Murray.
These are potentially the first of many lines of enquiry, as the CASE team get to work on the findings from their latest trip. What’s clear is that we are only just beginning to understand the human body’s ability to evolve and adapt to extreme existence. That is why, 60 years after it was first climbed, the high drama of our struggle on Everest continues to offer new horizons.
A fishy solution
The history of adaptation to hypoxia is a lot older than our species. Since oxygen appeared in the atmosphere 2.45 billion years ago, there have been several anoxic events, especially in the oceans. Life had to find ways of dealing with lowered oxygen – and some of the species are still alive today.
When the thermometer drops and their ponds freeze over, crucian carp (Carassius carassius) survive the anoxic conditions partly by slowing their metabolism but mostly using a clever metabolic trick: anaerobic respiration. The fish turn reserves of glycogen built up over summer into glucose and ethanol, releasing energy in the process. Crucian carp have been shown to survive anoxic conditions for up to 140 days using this method.
Crucian carp brains have a large store of glycogen, which has alarmed dissectionists unprepared for the fish’s ability to survive being disconnected from its heart for several hours.
Producing ethanol as a by-product of hypoxia might appeal to some climbers. The UK barrister and mountaineer Terry Mooney once observed that since climbing at altitude was like going to work with a hangover, then the best training for Everest should involve spending as much time in the pub as possible.
