Picture yourself on a mountaintop. The piercing cold temperature. The unbarred views. The thin air.
Dr Hugh Montgomery presented the mountaintop to us as a natural laboratory space. As Director of UCL Institute for Human Health and Performance, and Professor of Intensive Care Medicine, Hugh is interested in how the human body responds to exercise. And the mountaintop presents an extreme environment for a particularly elite class of exercisers, the mountaineers. Not only is mountain climbing a gruelling challenge for the body's muscles, but climbers must also tolerate low levels of oxygen in the air. The higher they climb, the lower the oxygen levels fall. But by studying the physical changes that mountain climbers undergo on a climb, and scrutinising the underlying genetic causes, Hugh's research group have produced some startling lessons for critical care of hospital patients.
Hugh, smiling and fresh-faced, took to the stand at Bristol M-Shed to discuss his research. He is the kind of researcher who deserves his own HBO television show. This hypothetical show would incorporate genuine scientific research, as well as offering plenty of scope for macho posturing and man vs. death escapades on the mountaintop. Indeed, the man's achievements and hobbies would make any fiction unnecessary. A diver, a record-breaking underwater piano player, an 'occasional' ultra-runner, a mountaineer, author, screenwriter, and a pioneering cardiovascular geneticist. I could easily add more, but I am already lost in awe.
"Studying acute physiology can tell you really important things about yourself, and patients," said Hugh. He began by outlining the key scientific tools that we needed to understand. Angiotensin is an important hormone for your blood system, and the renin-angiotensin system (RAS) controls the blood pressure of the body. It is a network of different hormones, including angiotensin, which tweak the size of blood vessels and the amount of water kept in the blood. A key controlling element is angiotensin-converting-enzyme (ACE). A high level of ACE in your RAS raises your blood pressure.
"That's where it stopped when I was in medical school," said Hugh. "But it turns out, like most things I was taught at medical school, that wasn't half the story. Because these systems are everywhere - in plants, in locusts, in fish, in jellyfish- all things that have been there for millions of years. And jellyfish don't even have blood pressure!"
So RAS and ACE must affect more than blood pressure. In fact, they are found in a huge range of human bodily tissues, from your brain to your eyeballs to your skin. It is now understood that ACE also influences cell growth, inflammation, and metabolism in body tissues, even if the finer details of how it does this are still being uncovered.
In the 1980s, it was observed that increased amounts of ACE in rats leads them to develop bigger hearts. Knockout the ACE gene, and hearts can't grow in size.
In humans, the old romantic maxim is untrue. Having a big heart is not a good thing - unless your heart has become big due to regular exercise. Otherwise, a large heart is associated with a higher likelihood of heart attack. So whatever causes the increase in size also damages the heart tissues.
Based on the studies of ACE and heart size in animals, Hugh needed to see if the link between ACE levels and heart size applied in humans. His group had found two different ACE gene variants - the I allele, and the D allele. People with the I allele produced lower amounts of ACE. People with the D allele produced more ACE. And because everyone has two copies of each gene, any human could have II, ID, or DD. But based on rules of inheritance, in a group of people 25% will have II, 50% will have ID, and the final 25% will have DD.
So if Hugh could take a group of humans, measure the differences in their heart size, and then correlate the heart size to the different genes, he would be able to prove ACE was affecting heart size in humans.
But how could this be done, and more so, done ethically? There could be many confounding factors affecting heart size. Hugh found the perfect experimental subjects in the form of military recruits. Military recruits all undergo the same strict regime of training and diet. Exercise naturally causes heart growth. So at the end of 8 weeks of training, Hugh would be able to measure differences in heart size, and link this to the I or D alleles.
After 8 weeks of training, the recruits with II alleles - producing the lowest levels of ACE - showed heart growth of approximately 2%. In DD recruits, who produced the highest levels of ACE, the heart growth was 6%.
Hugh sketched out the scientific reason that ACE caused heart growth. In the RAS system, ACE breaks down kinins, proteins which are involved in blood vessel dilation. High ACE equals low levels of kinin, which means greater growth in heart size. As in most science, the chain of cause and effect was becoming a little long, but we were still with him.
So the military recruits proved the link between ACE and heart size. And there was more. Through a muscle fatigue test- a fancy way of saying, how long could each recruit hold a weight at arm's length without buckling - it was proved that II recruits have the best response to exercise. ID recruits respond moderately to exercise, showing only small improvement in muscle fatigue after training. DD, statistically speaking, showed no better improvement by end of their training.
Now, back to the mountains. Mountain climbers with II are more likely to reach the peaks than DDs. Similar trends can be seen in other oxygen-hungry sports, like marathon running, where runners are much more likely to have II alleles. Hugh revealed another interesting tidbit. Although gruelling endurance challenges like the Tour de France are dogged by doping scandals, where athletes use erythropoietin hormone to increase red blood cell loads, the ability to accumulate more oxygen on a mountaintop is not actually helpful to your body. To put it more simply- if you put a Tibetan and a Westerner on a mountaintop, the Tibetan's body will generate less haemoglobin. The genetic selection for successful living at high altitudes appears to be in keeping haemoglobin lower.
Hugh explained that I or D alleles affect how efficiently mitochondria use oxygen. Mitochondria are the power plants of the cell, generating ATP energy from oxygen. Low ACE levels make mitochondria better at generating ATP from oxygen, even low levels of oxygen. D alleles are more like "leaky batteries" - they lead to a higher level of ACE in the body, which raises oxygen demand.
"So what genetics is telling us, is that when oxygen availability is low, we should try to increase the efficiency in which we use the oxygen," commented Hugh. He recalled that the convention treatments for ICU patients in hospital is to try, forcibly, to put oxygen into their bodies. But modern treatment needs to change, as studies have shown forcible oxygen transfusions can increase mortality. Based on lessons from mountaineers, new modes of treatment are being introduced into hospitals to allow oxygen levels to reach lower levels than conventional treatment had allowed. A normal person has an oxygen tension of 12 kPA. On a ward, lower levels of 8 kPa is now being allowed. A level of 6 kPA is still considered very worrisome. However one experienced mountaineer has been able to reach 2 kPA. This is conventionally considered terminal... but for him, it was not. His body was attuned to that low level of oxygen.
Many animals adjust their body systems to withstand low oxygen environments. These include a few fish with coincidentally interesting names - the epaulettes shark, the oscar fish, and the Crucian carp - who shut off unnecessary body functions when oxygen levels decline. With a wry grin, Hugh admitted that when he explained his research to his 6-year old son, he was told his research was "very obvious". When a car is low on fuel, you don't leave all its systems running, you tune down to the bare essentials. Why had it taken his father 20 years to work out that the human body does the same?
But the most startling and sobering impact of ACE was yet to come. Hugh showed us the relationship between the ACE gene variants and medical conditions, especially in the ICU. In premature babies with under-developed lungs, high ACE levels are associated with respiratory distress. In patients who undergo bypass surgery, II patients with low ACE show better survival rates. In meningitis patients, having the DD alleles is associated with the most severe examples of sudden meningococcal sepsis. It was sobering to realise that survival, especially in the face of respiratory complications, could be so clearly linked to the ACE gene.
"In this audience, if we all came down with Adult Respiratory Distress Syndrome and ended up in Bristol ICU, the IIs could have a 90% chance of surviving. Whereas DDs have an over 55% chance of dying. That puts my job in perspective. We like to congratulate ourselves as how good we are when someone lives - but a lot of that living and dying, is down to our genes."
Hugh moved onto another lesson of mountaineering - starvation. Hypoxia, meaning low levels of oxygen, causes weight loss. Mountaineers lose both fat and muscle in the hypoxic conditions of the mountain. ICU patients, whose body tissues are low in oxygen, also show weight loss. A key clue is that muscle is lost, along with fat, even in highly active and well-fed mountaineers. A group of Hugh's mountaineers who scaled Everest lost 9 kg each, on average. Hugh explained that the 90% of the body's energy goes into producing protein, to rebuild and renew the body. It used to be thought that in low oxygen conditions, the body's regulation was simply thrown into disarray, causing inevitable weight loss. But now it is shown that the body actually orchestrates sophisticated survival plans. It tries to conserve oxygen by shutting down demanding systems. Essentially, the body willingly creates a 'starvation' mode.
In starvation, a process known as ketosis occurs where fat is broken down for energy, producing chemicals known as ketones. This is the fundamental concept of the Atkins diet. Ketosis is also carried out by hibernating animals. It appears likely that ketones have some kind of beneficial effect. And this is true. Ketones are an anticonvulsant, which is why the severity of epileptic fits can be reduced by putting patients on diets. Ketones protect the brain from hypoxia and low levels of glucose. Even sperm are more motile in ketones, and the heart increases its workload.
In short, starvation can actually be beneficial. A synthetic ketone is being trialled in adults with heart failure in Belgium, and there are more studies which will test ketone compounds with patients and premature babies. And studies have shown that force-feeding of ICU patients in hospital can lead to muscle wasting, a new method of intermittent, low feeding may prove much more helpful. Perhaps a more modern and effective treatment needs to accept starvation as one of the body's natural defence mechanisms. There's some truth in granny's advice - 'feed a cold, starve a fever'.
Ketones, ACE, genes, and fitness. I wondered what would my genotype be. Did I respond to exercise well, like an II, or fall in between, as an ID? I have only ever ventured up a bouldering slope, but I have dreams of climbing Kilimanjaro. How much extra preparation would I need?
"Should I take ACE inhibitors to improve my chances of reaching the summit of Everest?" asked an audience member, a self-diagnosed DD.
"Yes... but we haven't done the study yet." The study is in the planning stage, but they still don't know how ACE inhibitors will react with the body in hypoxic conditions. This is too big a risk to take on a mountaintop.
And throughout his talk, Hugh pointed out that D alleles were not to be perceived as inferior. This is the first gene that was discovered which was directly related to fitness. It has some striking lessons for hospital care. But it is not a case of genetic determinism, stating who is likely to be the best at keeping fit, or surviving overall. The D allele confers its own benefits. People with DD appear to be more resilient to haemorrhage. And they are likely to be stronger, better at swimming and sprinting. They tend to show greater muscle mass in old age which significantly reduces the problems of frailty and falls.
I thought of my father, silver-haired and 70-something, still stomping round, still operating heavy machinery, still involved in the mysterious and never-ending movings of heavy objects around his property. For that matter, I also thought of my mother, thin, frail, and disabled, but who has been doggedly picking up an entire bulldozed bungalow, brick by brick, and assembling them into an array of neat stacked cubes in her garden (don't ask). I might never know my genotype for I or D and I might find it hard to predict, but it probably didn't matter anyway for my fitness. What matters is the mind - willpower, determination. For his part, Hugh was vehemently opposed to casual genotyping for these alleles. The research needed to carry on, and it would be too easy for, say, medical insurance companies to jump the gun and draw broad - and expensive - conclusions.
After all, for all his incredible-sounding athleticism, Hugh himself is a DD.
You can listen to a recording of Hugh's talk here ...
And the following questions here ...
Hugh Montgomery also talks about his discovery of the first gene for fitness to Jim Al-Khalili, on the BBC's The Life Scientific
This blog is OLD... I'm working it over...