Eden Oration 2024

Dr Thomas Eden signed and dated his last will and testament on 24 January 1643.

There are scant weather records for the winter of 1643, but nothing to suggest that this was anything other than a typically dreary January day, when the chill never quite leaves your bones. It is perhaps no surprise, that when Dr Eden’s thoughts turned very generously to us – the future Master, Fellows and Scholars of that poor Society by the River Cam – and considered how he might provide for us, his thoughts turned to fuel. Fuel, in the form of wax candles to provide light and a modest amount of warmth on a cold evening in Chapel, but also the metabolic fuel of Wine and Diet which we will enjoy later this evening.

The release of energy from fuel, whether we burn a wax candle or metabolise the constituent parts of a meal, fundamentally relies on the same simple chemical reaction, whereby reduced carbon in hydrocarbons and carbohydrates is converted to carbon dioxide and water. Those of you who remember the fire triangle from your GCSE chemistry will recall that another essential participant of this reaction is oxygen, specifically diatomic oxygen, O₂, the gas that makes up nearly 21% of the present-day atmosphere on Earth.

Most multicellular organisms rely on a continual supply of oxygen to support metabolic function, and therefore life. Some animals show remarkable physiological adaptations that allow them to tolerate extended periods of hypoxia (low oxygen) or even anoxia (a complete lack of oxygen) – species as diverse as Weddell seals, naked mole rats and the crucian carp. But these really are exceptions. Just as a candle starved of oxygen will extinguish, so too will a human life, and unlike fuel, which we store in great quantities in adipose tissue and other organs, we have only a very limited capacity to store any oxygen at all.

So, whilst I intend to keep you from your supper just a little longer this evening, I am not going to insist that you hold your breath for the duration.

Dr Eden made no provision for oxygen in his will, but this is both unsurprising and, you’ll be pleased to hear, unnecessary. Unsurprising, because the first descriptions of oxygen by Priestley and Lavoisier would not appear for another 130 years. Unnecessary, because being sited essentially at sea level, Trinity Hall profits from a high atmospheric pressure. A poor college we may once have been, but we have always been rich with oxygen.

This veritable abundance of oxygen should not, however, be taken for granted. Hypoxia is a constant lived experience for people at high-altitude, including around 82 million people globally who inhabit locations sited over 2500 m above sea level, and a challenge that is immediately obvious to any of us who choose to visit these regions. As we ascend, the atmospheric pressure falls, and although the air still comprises 21% oxygen, we take in fewer molecules with each breath, challenging the diffusion of oxygen from the lung alveoli, to the blood and through the circulation to the tissues and the mitochondria – subcellular organelles which consume oxygen and metabolic fuel to generate the cellular energy currency, ATP that powers the processes of life. Life at high altitude requires physiological responses; adjustments that increase our heart rate, breathing rate, and the mass of oxygen-carrying red blood cells, whilst at the tissues, metabolic fine-tuning enhances the efficiency of oxygen use.

The effectiveness of these strategies varies from person to person, meaning that some individuals are capable of ascending to the very highest terrestrial altitudes, even without supplementary oxygen, whilst others succumb to severe and debilitating altitude sickness even at much lower elevations. There are genetic components to this variation, as shown by a natural experiment that has taken place in at least three locations globally, where human populations have migrated to high altitude and inhabited these regions for thousands of years and hundreds of generations. On the Tibetan Plateau, the Andean Altiplano and in the Highlands of Ethiopia, humans show physiological adaptations, underpinned by genetic differences that support their capacity to live, work and reproduce at high altitude, but more on this later.

Chronic hypoxia is the defining feature of life at high altitude, but is not unique to this setting. Many common, life-threatening diseases can result in our tissues being deprived of oxygen. Tissue hypoxia occurs with heart failure, lung disease, anaemia and a great many cancers, and is almost universally seen in human critical illness. The COVID-19 pandemic demonstrated the devasting impact of critical illness on a global scale, but even outside a pandemic, one person in 6 in the UK will find themselves on an intensive care unit at some point in their life. Here, mortality rates can be as high as 50-60%, and there is an urgent need to better understand the cellular mechanisms that cause multiple-organ failure. It is, I would argue, valid to question whether a genetic predisposition to tolerate hypoxia at altitude might also predict an individual’s capacity to handle the hypoxic challenge of critical illness. Remarkably though, we all have demonstrated a significant biological capacity to tolerate and survive hypoxia, and even thrive in the face of vanishingly low oxygen tensions.

Everest in utero.

This compelling concept emerged from the work of Sir Joseph Barcroft, the University’s Professor of Physiology in the 1920s and 30s. Barcroft is best remembered for his pioneering studies into the processes through which blood becomes oxygenated. Recognizing the value of high altitude as a natural laboratory, Barcroft initiated a somewhat unlikely but longstanding interest in high altitude physiology which continues in Cambridge to this day. Barcroft led research expeditions to Tenerife Peak, and Monte Rosa in the French Alps. He converted a railway carriage into a functioning laboratory which he transported to Cerro de Pasco – a mining settlement high in the Peruvian Andes, measuring oxygen levels in his own blood, his co-workers’ and that of the locals he met along the way. Satisfyingly, Barcroft was able to settle a debate with his Oxford rival, JBS Haldane, concerning the means by which oxygen crossed the lung to enter the bloodstream. Barcroft was well-known for self-experimentation, and once needed rescuing after spending several days sealed within a plate glass chamber in an effort to establish the limits of human hypoxia tolerance. Later in his career, Barcroft turned his attention to the fetal circulation – postulating that the normal, healthy human fetus in the first trimester of pregnancy is exposed to the same low levels of oxygen as a climber on Everest. This turned out to be a remarkable prediction.

Of course, measurements of placental oxygenation during human pregnancy had not yet been made, and neither had blood gas concentrations at such extreme altitudes. Despite a contemporary fascination with Everest, the mountain had not yet been climbed, and it was a matter of fierce debate as to whether it could be climbed. Alexander Kellas, a Scottish chemist, mountaineer and member of the Alpine Club, went further still, predicting that Everest could not only be summitted but that that it would be possible to do so even without supplementary oxygen. Kellas would not live to see if this were the case, and tragically died of asphyxiation following a heart attack on his way from Sikkim to join the first British Reconnaissance Expedition to Everest in 1921. This expedition included a Himalayan first-timer, the schoolteacher and Magdalene College alumnus, George Mallory. Despite a fractious relationship with the expedition leader, Mallory proved to be an exceptional climber at extreme altitude and assumed the role of de facto lead climber, ascending as far the North Col of Everest at 7000 m and contributing detailed descriptions and sketches of possible routes up the north side of the mountain, including one route he believed would allow for an attempt on the summit. Nevertheless, Mallory offered a less than sanguine assessment of the possibility of success, and the toll that this would inevitably take on any summit party.

Back in London, the Mt Everest Committee met. Encouraged by reports from the mountain a first full attempt via the North Ridge and Face was sanctioned for 1922, and for the first time supplementary oxygen would be used. This did not sit well with some members’ sporting principles.

“Only rotters would use oxygen”. A quote attributed to the Cambridge astronomer AR Hinks, and held to represent the views of many Committee members. In reality, this is something of a mis-quote. Hinks was opposed to the use of oxygen at lower elevations, but was more pragmatic when it came to the final stages of the ascent, recognizing its clear benefits. Nevertheless, a debate concerning oxygen use in the so-called “death zone” of Everest and the notion of what constituted “fair means”, would rage for decades. For the ’22 expedition, a compromise allowed for several summit attempts – the first, by Mallory and others, eschewed supplementary oxygen, whereas subsequent attempts were oxygen-supported – including a third attempt made by Mallory himself, who, at this point battling with crippling exhaustion decided to use oxygen, albeit unsuccessfully.

This year marked the centenary of Mallory’s third expedition in 1924. This would become the most iconic of the early attempts on Everest, giving rise to the mountain’s most enduring mystery. Mallory’s letters are now housed in Magdalene College’s archives, and were recently digitized. In one letter home, dispatched from Base Camp on 27 May, Mallory described a persistent cough and poor conditions on the mountain – “a bad time altogether” as he put it. Nevertheless, the team had cut a course as far as the North Col, and were anticipating an imminent but very testing summit attempt.

“It is 50 to 1 against us but we’ll have a whack yet & do ourselves proud.” With that, Mallory signed off on what was to be his final letter home. On June 2, Mallory and his climbing partner “Sandy” Irvine, left their high camp at 8200 m, using Irvine’s modified oxygen apparatus, and were spotted by Noel Odell, another expedition member, moving upwards high on the summit ridge. Neither man would be seen again. It remains unknown as to whether either reached the summit, but Mallory’s body would be found in 1999. His wallet, including paper documents, was remarkably well preserved, but missing was a photograph of his wife, Ruth, which he had intended to leave on the summit. There was also no sign of the camera he and Irvine had taken, which may yet hold evidence of a successful summit. The discovery of Sandy Irvine’s disembodied foot on the Rongbuk Glacier in October just this year, has reignited hope that his body, and the camera, may yet be found.

Further expeditions took place on the Tibetan side of Everest throughout the 1930s. A hiatus during the war years and immediate post-war period ended when Nepal opened its borders in 1950, and with it the possibility of ascent via the Western Cwm, Lhotse Face and South Col – the all-too-popular route used (and over-used) by most climbers today. This sparked a brief international rivalry. In 1952, a Swiss-led team including lead climbers Raymond Lambert and Tenzing Norgay made it within 150 m of the summit. With the French securing permission for a climb in 1954, and the Swiss due to return in ‘55, an urgency surrounded the British-led expedition of 1953. Eric Shipton was to be replaced by John Hunt as expedition leader, and Tenzing was recruited from the Swiss team to join the climbing party.

Nevertheless frustrated by a perceived lack of drive in the preparations, the expedition doctor, Mike Ward, recruited a physiologist, Griffith Pugh, leader of the Laboratory of Field Physiology at the Medical Research Council’s unit in Hampstead. Pugh scrutinised every aspect of high-altitude mountaineering and thoroughly modernized the approach. Acclimatisation protocols were overhauled. Footwear and clothing were now properly fitted, with tents and climbing gear fashioned from more modern, wind and weatherproof fabrics. Fluid intake, a particular obsession of Pugh’s, was examined through meticulous field measurements, with climbers instructed to consume 6 or 7 pints of fluid a day, and to keep rigorous records of this. Edmund Hillary would later remark that he had never felt so well-hydrated on a mountain, noting that he even had to pause a few hundred yards before the summit to relieve himself.

Pugh’s radical approaches were not easily accepted by all; but he had a influential champion in the form of Cambridge physiologist, Sir Bryan Matthews, who ensured that his recommendations were taken seriously by the stuffed shirts on the Mt Everest Committee.

Of course, oxygen did not escape Pugh’s attention. Noting that the Swiss were fitter and more experienced climbers than the British, Pugh realised that only the very best apparatus available would ensure success. Two systems were in contention. The classic, open circuit system was deemed more reliable but wasteful of oxygen, as any not absorbed across the lungs would be exhaled and lost to the atmosphere. A closed-circuit system, based on 100% O₂, in which exhaled carbon dioxide was scavenged and unabsorbed oxygen recirculated was both lighter and less wasteful, but its reliability was a concern. The soda lime used to capture CO₂ added resistance to breathing, and the valves were prone to freezing.

In the event, both systems were taken to the mountain. A first summit attempt made by Charles Evans and Tom Bourdillon on 26 May used the closed-circuit apparatus. The pair made the first ascent of Everest’s South Summit at 8750 m, before difficulties with the breathing apparatus forced them back. Using the open circuit system, Hillary and Tenzing reached the Summit on 29 May, just in time for the news to make it back to Britain for the morning of coronation day. “Coronation Everest” ran the headlines, ushering in a new Elizabethan era. The expedition party were hailed as heroes. Hillary and John Hunt arrived back in Kathmandu to find they had been knighted. Tenzing would receive the George Medal from the newly-crowned Queen, and the Order of the Star of Nepal.

In contrast, Pugh’s contributions remained overlooked for many years, barely warranting mention in Hunt’s official account of the expedition. In comparison with the physical act of climbing, scientific endeavour was likely regarded as rather unheroic and at odds with the notion of derring-do. Personally, I retain a great deal of admiration for this unfussy Welsh physiologist, who single-mindedly got the job done.

Pugh’s work at high-altitude would continue, and in 1960, alongside Hillary, Ward, John West and Jim Milledge, Pugh over-wintered at 5800 m on Everest in a prefabricated cabin, which gave the Silver Hut Expedition its name. Whilst Hillary set off on a hunt for the Yeti, the scientific party made vital measurements of heart and lung function during prolonged altitude exposure describing the effects of deconditioning. Nevertheless, Pugh concluded that, in line with Kellas’ earlier prediction, an oxygen-less ascent of Everest would indeed be physiologically possible.

This feat was finally achieved by Peter Habeler and Reinhold Messner in 1978. Messner described the final trudge up the summit ridge, “I am nothing more than a single, gasping lung, floating over the mists and summit”, poetically underlining the importance of hyperventilation at altitude. Messner would go on to ascend all 14 of the world’s 8000 m mountains without oxygen, returning to Everest in 1980 to make an oxygen-less solo ascent during the monsoon, establishing a new route up the North Face in the process. Widely held to be the greatest mountaineer of all-time, it was natural to place Messner’s undoubtedly remarkable physiology under the microscope. In the mid-1980s, his lung volumes, aerobic capacity, and anaerobic threshold were all examined and found, in most aspects to be… well, strikingly normal. The investigators questioned whether Messner’s achievements simply owed more to his obsessive nature, than his biology.

In reality, by today’s standards, these studies were rather limited, pre-dating our modern, molecular understanding of oxygen-sensing. The mechanisms whereby the cells of our bodies detect and respond to hypoxia became apparent through meticulous work through the 1990s, that culminated in the award of the 2019 Nobel Prize in Physiology or Medicine to Sir Peter Ratcliffe, Gregg Semenza and Bill Kaelin. In the post-human genome era, there was a renewed need for field research to understand the limits and mechanisms of human hypoxia tolerance.

In 2007, our group, led by Mike Grocott, conducted the Caudwell Xtreme Everest expedition – the largest study to date of integrative human physiology at high-altitude. Over 200 members of the public joined us, following an identical trek into Everest Base Camp. Across this large cohort, we sought to understand the factors that determine who does well and who does rather less well in the context of sustained hypoxia – ultimately hoping to translate these concepts into an understanding of how humans can survive critical illness. Meanwhile, a smaller climbing party carried out tests further up the mountain, making the highest measurements to date of exercise capacity using cycle ergometers on the South Col, and aiming to measure arterial blood gases on the summit.

In the event, arterial blood was sampled from 4 members of our climbing team on the Balcony of Everest at 8400 m. The sealed tubes were handed over to the lead climbing Sherpa, Pasang Tenzing, who descended around 2000 m in a little over 20 minutes to reach the blood gas machine. Oxygen tension in one participant came in at just under 20 mmHg – that’s less than one fifth of that in your blood right now, and still the lowest such measurement made in a healthy adult human. This climber was not only conscious and lucid, but was dexterously sampling blood from other members of the team – truly resetting our understanding of the limits of human hypoxia tolerance.

Of note, this oxygen tension of 20 mmHg was also strikingly close to measurements of human placental oxygenation made just a few years earlier – supporting Barcroft’s remarkable Everest in Utero hypothesis.

Work led by my research group during the 2007 expedition concentrated on metabolic processes that were altered in climbers during prolonged high-altitude exposure. Measuring heart and muscle energetics using NMR spectroscopy, and analysing biopsies taken from the thigh muscle, we showed a stark suppression of mitochondrial oxygen demand and in particular fatty acid oxidation – pointing towards improved efficiency of oxygen use. We later reported similar changes in the muscle of critically ill patients back at sea level, with a more rapid suppression of fat metabolism occurring in those patients who would go on to survive critical illness in comparison with non-survivors. Metabolic adjustments were thus revealed to be a vital response to hypoxia, not only on the mountain but also in the ICU.

Shortly after we returned from Everest, the first reports emerged of genetic signals of adaptation in established human highlander populations in Tibet and the Andes. In Tibet, the strongest signals localized to genes with an established role in cellular oxygen sensing, but to my amazement and delight, one study by Tatum Simonson and her colleagues, based in San Diego, highlighted a strong signal of selection in a gene, PPARA. This gene is a master regulator of fat metabolism in heart, muscle and liver. A decade earlier, this gene been a major focus of my PhD work into the links between diabetes and heart failure, and it featured strongly in our ideas surrounding metabolic regulation in hypoxia

In 2013, we returned to Nepal for the Xtreme Everest 2 expedition. This expedition did not feature a summit attempt, but instead the centrepiece of our work included technically-challenging, real-time measurements of mitochondrial oxygen consumption in muscle biopsies taken from lowlander and Sherpa volunteers, following the same ascent to Base Camp. Work that, to a large degree, happened thanks to the efforts of a PhD student in my lab and former Trinity Hall JCR President, James Horscroft.

The Sherpas are a population of Tibetan descent, and elite climbing Sherpas have long been renowned for their prowess as climbers on the highest Himalayan peaks. Paradoxically, Tibetans and Sherpas, have lower levels of the oxygen-carrying protein haemoglobin in their blood than either lowlanders or other highlander populations. This means that at any given altitude a Sherpa will be carrying less oxygen in the blood than you or I, but this adaptation decreases blood viscosity, improving flow. We reasoned, however, that this would necessitate changes in metabolism to optimize oxygen use.

The Sherpa volunteers in our study were drawn from the relatively low-lying Kathmandu area, and despite having highlander ancestry had no recent exposure to higher altitudes. Owing to their ancestry, however, they possessed gene variants that had undergone selection for life at altitude, and we found that their mitochondria showed enhanced efficiency and lower fat oxidation compared with lowlanders – clear signals of adaptation that allow the Sherpas to defend muscle energetics at altitude and stave off the oxidative stress that we as lowlanders experience. At the very least, I find this is a suitably convincing excuse to use when lagging behind my trekking group or demanding yet another rest break on the long slog up Namche Hill.

Our most recent work continues to draw inspiration from Barcroft and others. Working with Lorna Moore and Colleen Julian at the University of Colorado, and Lilian Toledo-Jaldin in La Paz, Bolivia, we are extending the notion of Everest in Utero to consider Everest in Utero on Everest. Pregnancy at altitude is an extreme hypoxic challenge. Birthweight falls by around 100 g for every 1000 m of elevation, and at higher altitudes pregnancy complications such as preeclampsia are rife. Strikingly, birthweight is relatively protected in Tibetans, Sherpas and Andean populations. Our work has shown that placental mitochondria are protected in Andean pregnancies, in conjunction with a large rise in blood flow to the uterus. Working with Tatum and her group, we have been able to pick out genetic signals that associate with these metabolic phenotypes, including new signals surrounding fat metabolism. Ultimately, we hope that a better understanding of how maternal and infant health are protected in the pregnancies of highlanders will shed new light on mechanisms that could protect pregnancies beset by common complications here at sea level.

High-altitude regions are rightly held to be some of the most extreme environments on Earth, but I would argue that they are far from remote. Rather, mountains are valuable natural laboratories in which we can address questions of fundamental importance to our understanding of physiology, healthy human development and common disorders of pregnancy, as well as some of the most serious and debilitating diseases facing humans here at sea level.

To close, I will return briefly to George Mallory. It seems customary that no discussion of Mallory’s legacy omits what might in fact be his most enduring contribution to popular culture. A phrase, capturing a sentiment, that has been adapted and co-opted by explorers, sportspeople, scientists and politicians, almost from the moment it was first uttered on a fundraising trip to New York City ahead of the 1924 expedition. Mallory, collared by a reporter, was asked why he wanted to climb Everest, enigmatically remarking: “Because it is there”. Was this a finely-honed, well-rehearsed response, or simply a spontaneous utterance to curtly dismiss an irritating journalist standing between Mallory and a much-needed drink at a nearby bar. We may never know, but on this, the centenary year of his ill-fated final attempt on Everest, it seems a fitting note on which to conclude this oration and suggest that we move through to the Master’s Lodge where we can enjoy Trinity Hall’s finest oxygen – the perfect accompaniment to Dr Eden’s generous gift of Wine and Diet.

It is customary on the occasion of Dr Eden’s Feast to celebrate new arrivals to the Fellowship and remember those who have left us. This year we welcome Doctorandus Justin Davies, Dr Becky Dell, Professor Campbell McLachlan, Dr Deme Kasimis, Professor Henrietta Bowden-Jones, Dr Sofia Lövestam, Dr Vidya Venkatesh, Dr Victoria South and Dr Edd Mair. We also welcome our new Honorary Fellows: Ms Fiona Cousins, Dr Waheed Arian and Professor Jo Dunkley. This year, we have said goodbye to Dr Nelson Lam, Dr Alana Mailes, Dr Tristen Naylor, Dr Gwen Wyatt-Moon, Dr David Cowan, Dr Hannah Bower, and Dr Ben Tutolo. We also mourn two of our Honorary Fellows who died this year, Prof Sir Roy Calne and Professor Sandy Goehr.

Professor Andrew Murray is Professor of Metabolic Physiology.

His research is concerned with the effect of factors such as disease, diet and exercise on mitochondrial function and physiological performance.