High medicine! Humans at altitude

Many of the world’s population are lowlanders. We certainly don’t live in the mountains. So what happens to our lowlander bodies at high altitude, and how could understanding the science involved help us treat critically ill patients in hospital? Cambridge University physiologist Andrew Murray works on exactly this, and he spoke to Katie Haylor...

Andrew - I brought along a collection of Tibetan prayer flags, so squares of cloth in a really defined order - blue representing the sky, white representing air, red representing fire, green is water and yellow is the earth. You find them all over Nepal and that's why brought them along, it reminds me of many fun times and exciting times we've had doing science in Nepal, all the way from Kathmandu right up to the high passes of the Himalayas and even flying on the summit of Everest.

Katie - So before we hear about your adventures, what happens to the human body as you ascend?

Andrew - Well, there's a real distinct time-dependent response as we go to the mountains. When you land, when you step off and airplane at about 2000 metres your body instantly responds: you start breathing harder to try and bring more oxygen in, that's the challenge of course, it's trying to deal with the low oxygen at altitude, so you're trying to bring more oxygen into your lungs. Your heart starts beating faster to deliver more blood around, therefore oxygen around the body to the tissues, such as the muscles, that need it. And then given enough time, you might see more changes, so after a couple of weeks your body will be making more red blood cells to carry more oxygen.

Katie - Your work involves having healthy people trek up Everest and then you do science with them so, first of all, what is it like?

Andrew - It takes your breath away, quite literally. The views are absolutely stunning, the scenery, the wildlife. But more and more you notice yourself getting breathless, not being able to push yourself to quite the same extent as you do at sea level. I mean, around 2000 metres, which is the altitude where the airport is in the Everest region, if you fly in there you do feel it pretty instantly.

Katie - Wow. So you haven't even started climbing and your out of breath?

Andrew - Yes, absolutely. And then there's a nice steep flight of steps just coming away from the airport to really let you know that you're in the mountains.

Katie - Once you're actually up there, what science are you doing?

Andrew - What we've done in the past is set up labs at lots of different altitudes and they’ll trek on a regimented ascent so nobody is going any faster than anybody else. And then we'll do things like put them on exercise bikes, we’ll measure how much oxygen they are using and from that we can calculate their efficiency. And, of course, we wouldn't be medical scientists if we weren't poking and prodding them with needles and taking blood, lots of samples to study back in our lab.

We had our first big expedition in 2007 where we took over 200 lowlanders trekking to base camp. You see some people who do really rather well who will acclimatise and can function very well at altitude, and others who do rather less well and we're trying to understand why that is. And with large numbers we are hoping we could get a handle on the genetics that might underlie that.

Katie - What are the general applications of doing this kind of research on healthy people at high altitudes?

Andrew - That's always been the goal of our group is to understand then why it is that some people do well with less oxygen at altitude and some do less well. And is it the same factors at play that determine whether a patient in the intensive care unit who is struggling with a lack of oxygen, whether they will pull through and survive or whether they will succumb to their illness?

The story about altitude acclimatisation when we first started doing this was largely: okay, it's all about trying to get more oxygen through the system, to the tissues to fuel the metabolisms. So it's all about the heart rate, and the breathing rate and the red blood cells. And actually what we found is it's certainly not the full story. It's much more about how your tissues use the oxygen when it gets there, it's how your metabolism is finely tuned to deal with low levels of oxygen. We find that the same thing may very well be useful to a patient. If they were in hospital and their heart is not working properly, they've got low levels of oxygen in their blood, that oxygen getting to the tissues, it makes a lot of sense that that tissue would use the oxygen more efficiently. So what we're looking at in some of these critically ill patients is how their tissues are changing the metabolism to deal with low levels of oxygen.

Katie - So what have you learnt then so far paralleling these two situations?

Andrew - Looking at the patients, I've been working with colleagues from Extreme Everest who are based at the Royal Free Hospital in London and we actually see many of the same patterns of change both at altitude and in the clinics. The muscle starts to decrease its capacity to use fat as a fuel. We think of fat as being an unhealthy thing, actually it's the most important fuel in the body. We store most of our fuel as fat, so you've got have a good reason to shutdown your ability to use fat. And the problem with fat is that it's quite oxygen hungry: to get energy in the form of ATP out of our fat, it requires quite a lot of oxygen to do that. So we've seen evidence in both settings that the tissues are switching away from fat towards more oxygen efficient fuels, perhaps glucose for instance.

Katie - Is it incredibly far-fetched to say you could maybe capture a mechanism or something and distill it into a drug that you then give to people who are critically ill? What are you hoping to achieve?

Andrew - That would be the ideal outcome, of course, is that you could help a patient who, perhaps, who wasn't dealing with the low levels of oxygen, to fine-tune their metabolism to deal with that. But, interestingly, I think this work has already made a big impact in the clinic in that, previously, the obvious response to dealing with a patient with low oxygen was to ventilate them, to give them pure oxygen to breathe to try to bring those oxygen levels back up. And interestingly, the recent research has shown that that isn't helpful, in fact it may even be harming the patients, oxygen in high concentrations is actually toxic to the body. So instead we are going for a bit of a middle ground and the clinicians I work with talk about something called permissive hypoxaemia. Hypoxaemia is low levels of oxygen in the blood. So we're allowing the patients to deal with this low level of oxygen, to adjust to it. Maybe they’re shutting down their body's oxygen requirements and there's probably a Goldilocks zone, a sweet spot at which they want to be. We are not going to take all the oxygen away, but finding out what the right amount is is probably the most obvious and easy application.

Katie - Now you've actually ditched your snow boots for a lab coat, what are you working on now?

Andrew - Really in the last few weeks we've started to study looking at high altitude placentas, so these are placentas from women living in either Colorado or in the Andes, so we're looking in La Paz in Bolivia. And our collaborators have been collecting these placentas, they've been preserving them, freezing them and then flying them over to our lab in Cambridge where we've been looking at the metabolism of the placenta. And particularly the mitochondria, these molecular powerhouses and how they are using the oxygen to make cellular energy to support the growth of the developing foetus.

As pregnancies take place at higher and higher altitudes, the birthweight of the baby tends to fall so, on average, for every thousand metres you ascend the baby’s birth weight is about 100 grams lighter. Now this isn't quite true for some high altitude natives, so if you look at the women in Tibet and Nepal, or you look at the women in the Andes who have giving birth, their babies are still lighter, but only by about 80 grams. So they're relatively protected against the low levels of oxygen crucially, but why that is we don't really know and there's a number of possible explanations. It could be to do with the blood supply, it could make it easier for the oxygen to get across the placenta to the foetus. It could be metabolism, they could be using the oxygen more efficiently. Or it could be things like antioxidant molecules that protect them against the free radicals, these reactive oxygen species that could be damaging in high quantities and which are produced in low oxygen.

Katie - So is there anything then that can be applied to people who are having a troublesome pregnancy?

Andrew - Well, that's the ultimate application. So if we can understand why it is that these women can give birth to relatively healthy babies, even at high altitudes, we can apply some of these findings to troublesome pregnancies back here at sea level, where conditions like preeclampsia or intrauterine growth restriction might also alter oxygen supply to the foetus.

Katie - So we're going to have to invite you back to find out what's going on.

Andrew - Yeah. Hopefully we'll have answers in a few months time.